Adapted Cell + Stress Inju Inju ry ry Normal cell Reversibly injured cell Irreversibly Injured cell Dead cell +Stress Apoptosis Apoptosis Necrosis Necrosis - Stress - Stress Overview Overview
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AdaptedCell
+ Stress
InjuryInjury
Normal cell
Reversibly injured cell
Irreversibly Injured cell
Dead cell
+Stress
ApoptosisApoptosis
NecrosisNecrosis
- Stress
- Stress
OverviewOverview
Cell Adaptation Injury and DeathCell Adaptation Injury and Death
Adaptation In response to stimuli the cell Adaptation In response to stimuli the cell develops a new altered state but remains develops a new altered state but remains functional (able to maintain homeostasis)functional (able to maintain homeostasis)
HyperplasiaHyperplasia - uarr cell - uarr cell HypertrophyHypertrophy - uarr cell mass - uarr cell mass AtrophyAtrophy - darr cell mass - darr cell mass Metaplasia Metaplasia ndash change from one adult ndash change from one adult
form to anotherform to another
Morphology of cell injuryMorphology of cell injury
Swelling (via increased water Swelling (via increased water content)content)
Fatty change (steatosis TG)Fatty change (steatosis TG) Necrosis (dead cells)Necrosis (dead cells) Intracellular deposits (lipid CHO Intracellular deposits (lipid CHO
protein)protein) Loss of cellular fine structure Loss of cellular fine structure
(microvilli)(microvilli) Karyolysis (DNA degradation)Karyolysis (DNA degradation) Pyknosis (nuclear shrinkage)Pyknosis (nuclear shrinkage) Karyorrhexis (nuclear Karyorrhexis (nuclear
fragmentation)fragmentation)
Subcellular response to Subcellular response to injuryinjury
1Lysosomes (heterophagy autophagy)
2Smooth ER (induction)
3Mitochondria ( number size and shape)
4Cytoskeleton ( phagocytosis locomotion)
5Nucleus (karyolysis karyorrhexis pyknosis)
6Membranes (cellular and subcellullar)
Causes of Cell InjuryCauses of Cell Injury
11 O2 deprivationO2 deprivation which impairs aerobic which impairs aerobic respiration amp the ability to produce ATP This respiration amp the ability to produce ATP This is a common cause of cell deathis a common cause of cell death
a Hypoxia- lack of O2 results in a Hypoxia- lack of O2 results in decreased aerobic respirationdecreased aerobic respirationb Ischemia- lack of O2 amp metabolic b Ischemia- lack of O2 amp metabolic substratessubstrates
22 Physical agentsPhysical agents- mechanical trauma - mechanical trauma temperature changes shock radiation etctemperature changes shock radiation etc
33 Chemical agents amp drugsChemical agents amp drugs - acids bases - acids bases toxins therapeutic drugs pollutants ldquosocial toxins therapeutic drugs pollutants ldquosocial stimulantsrdquo etcstimulantsrdquo etc
Causes of Cell InjuryCauses of Cell Injury
44 Infectious agentsInfectious agents
5 5 Immunologic reactionsImmunologic reactions
a Xeno-immune reactiona Xeno-immune reaction
b Autoimmune reactionb Autoimmune reaction
c ldquoNormalldquo immune responsec ldquoNormalldquo immune response
6 6 Genetic derangementsGenetic derangements
7 7 Nutritional imbalancesNutritional imbalances
a Deficienciesa Deficiencies
b Excessesb Excesses
Mechanisms of cell injuryMechanisms of cell injury
3 Principles3 Principles11 The cellular response to injury depends on the The cellular response to injury depends on the
type duration and severity of the injurytype duration and severity of the injury2 2 The consequences of the injury depend on the The consequences of the injury depend on the
type state and adaptability of the celltype state and adaptability of the cell33 Cell injury results from an abnormality in one or Cell injury results from an abnormality in one or
more essential cellular componentsmore essential cellular componentsbull Aerobic respiration (mitochondrial oxidation amp ATP Aerobic respiration (mitochondrial oxidation amp ATP
production)production)bull Membrane integrity (cell amp organelle membranes)Membrane integrity (cell amp organelle membranes)bull Protein synthesisProtein synthesisbull Cytoskeletal structureCytoskeletal structurebull The genetic apparatusThe genetic apparatus
Causes of Cell InjuryCauses of Cell Injury
Oxygen DeprivationOxygen Deprivation Physical AgentsPhysical Agents Chemical Agents and DrugsChemical Agents and Drugs Infectious AgentsInfectious Agents Immunologic ReactionsImmunologic Reactions Genetic DerangementsGenetic Derangements Nutritional ImbalancesNutritional Imbalances
Physical AgentsPhysical Agents
Mechanical traumaMechanical trauma Extremes of temperature ndash Extremes of temperature ndash burnsburns
deep colddeep cold RadiationRadiation Electric shockElectric shock
Causes of Cell InjuryCauses of Cell Injury
Chemical Agents and DrugsChemical Agents and Drugs
Hypertonic concentration of salt ndash Hypertonic concentration of salt ndash deranging electrolyte homeostasisderanging electrolyte homeostasis
PoisonsPoisons ndashndash arsenic cyanide or arsenic cyanide or mercuric saltsmercuric salts
Insecticides and HerbicidesInsecticides and Herbicides Air pollutant ndash Air pollutant ndash carbon monoxidecarbon monoxide Occupational hazard ndash Occupational hazard ndash asbestosasbestos Alcohol and Narcotic drugsAlcohol and Narcotic drugs
Causes of Cell InjuryCauses of Cell Injury
Infectious AgentsInfectious Agents
ParasitesParasites FungiFungi BacteriaBacteria RickettsiaeRickettsiae VirusesViruses
Causes of Cell InjuryCauses of Cell Injury
Immunologic ReactionsImmunologic Reactions
Anaphylactic reaction to Anaphylactic reaction to foreign foreign proteinprotein or or drugdrug
Reactions to endogenous self-Reactions to endogenous self-antigens ndash antigens ndash autoimmune diseasesautoimmune diseases
Causes of Cell InjuryCauses of Cell Injury
Genetics DerangementsGenetics Derangements
Congenital malformation ndash Congenital malformation ndash Down Down syndromesyndrome
Decreased life of red blood cell ndash Decreased life of red blood cell ndash Thalassemia Sickle cell anemiaThalassemia Sickle cell anemia
Inborn errors of metabolismInborn errors of metabolism
Causes of Cell InjuryCauses of Cell Injury
Nutritional ImbalancesNutritional Imbalances
Protein-calorie deficienciesProtein-calorie deficiencies Vitamin deficienciesVitamin deficiencies Anorexia nervosaAnorexia nervosa Excesses of lipids ndash Excesses of lipids ndash ObesityObesity
AtherosclerosisAtherosclerosis Metabolic diseasesMetabolic diseases ndashndash Diabetes Diabetes
Causes of Cell InjuryCauses of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury Depletion of ATPDepletion of ATP Mitochondrial DamageMitochondrial Damage Influx of Intracellular Calcium and Loss of Influx of Intracellular Calcium and Loss of
Calcium HomeostasisCalcium Homeostasis Accumulation of Oxygen-Derived free Accumulation of Oxygen-Derived free
radical (radical (Oxidative stressOxidative stress)) Defects in Membrane PermeabilityDefects in Membrane Permeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Na+K+ATPase (Na-pump) Ca2+Mg2+ ATPases (Ca-pump)
CausesCauses
Hypoxia Ischemia
Chemical Injury
Membrane transport
Protein synthesis Lipogenesis etc
ATP
ATP depletionATP depletion lt5-10 of normal lt5-10 of normalbull ATP use gt ATP synthesis is a common consequence of ATP use gt ATP synthesis is a common consequence of
both ischemic amp toxic injuryboth ischemic amp toxic injurybull ATP production occurs via 2 related mechanismATP production occurs via 2 related mechanism
Glycolysis ndash cytosolic low yield lactate production (darrpH)Glycolysis ndash cytosolic low yield lactate production (darrpH) Oxidative phosphorylation ndash mitochondrial high yieldOxidative phosphorylation ndash mitochondrial high yield
bull Hypoxia results in uarred glycolysis (depletion of glycogen amp Hypoxia results in uarred glycolysis (depletion of glycogen amp darrpH)darrpH)
bull ATP is critical forATP is critical for Membrane transportMembrane transport Maintenance of ionic gradients ( Na+ K+ Ca2+)Maintenance of ionic gradients ( Na+ K+ Ca2+) Protein synthesisProtein synthesis Cytoskeletal function (microfilaments)Cytoskeletal function (microfilaments)
Na+
K+
Ca2+
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
CausesCauses
Hypoxia Toxins
Cytosolic Ca2+
Oxidative stress
Lipid breakdown product
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
bull Mitochondrial permeability transition of inner membrane (formation of high-conductance high-conductance channelchannel)
bull Leakage of Cytochrome cCytochrome c into cytosol
ATP productionATP production
Mitochondrial Oxidative Phosphorylation
Mitochondrial damageMitochondrial damagebull May occur directly due to hypoxia or increased Ca2+ May occur directly due to hypoxia or increased Ca2+
oxidative stress or phospholipids breakdownoxidative stress or phospholipids breakdownbull Damage results in the formation of a high-Damage results in the formation of a high-
conductance channel that dissipates the H+ ion conductance channel that dissipates the H+ ion gradient across the inner membrane (mitochondrial gradient across the inner membrane (mitochondrial permeability transition (MPT)) Mitochondrial permeability transition (MPT)) Mitochondrial membrane damage can result in Cytochrome C membrane damage can result in Cytochrome C leakage which can trigger apoptosisleakage which can trigger apoptosis
Defects in membrane permeabilityDefects in membrane permeabilitybull Membranes may be damaged directly by toxins Membranes may be damaged directly by toxins
physical chemical agents activated complement physical chemical agents activated complement components and perforins components and perforins
bull Increased cell membrane permeability disrupts Increased cell membrane permeability disrupts intracellular osmolarity and enzyme activityintracellular osmolarity and enzyme activity
bull Organelle membrane defects cause organelle Organelle membrane defects cause organelle dysfunction and failure dysfunction and failure
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mitochondrial Mitochondrial DamageDamage
Influx of Intracellular Calcium Influx of Intracellular Calcium and Loss of Calcium and Loss of Calcium
HomeostasisHomeostasis
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of O2 Accumulation of O2 derived free radicalsderived free radicals
bull Partially reduced highly Partially reduced highly reactive unstable oxygen reactive unstable oxygen moieties are able tomoieties are able to
Induce the formation of Induce the formation of more free radicals more free radicals (propagation)(propagation)
Damage lipids by Damage lipids by peroxidation of double peroxidation of double bonds resulting in breakagebonds resulting in breakage
Damage protein by Damage protein by oxidation and oxidation and fragmentationfragmentation
Damage nucleic acids Damage nucleic acids ( chain breakage)( chain breakage)
bull Free radical formation occurs Free radical formation occurs byby
Absorption of radiant Absorption of radiant energy (H2O rarr O∙ + OH∙)energy (H2O rarr O∙ + OH∙)
Metabolism of exogenous Metabolism of exogenous chemicals and drugschemicals and drugs
Normal metabolic Normal metabolic oxidation-reduction oxidation-reduction reactions (O2- H2O2 OH∙)reactions (O2- H2O2 OH∙)
Transition metals (Fe Cu Transition metals (Fe Cu etc) can catalyze radical etc) can catalyze radical formationformation
Nitric oxide can act directly Nitric oxide can act directly as a free radical or be as a free radical or be converted to other highly converted to other highly reactive formsreactive forms
Free radical defenseFree radical defensebull Free radicals are highly Free radicals are highly
unstable and generally unstable and generally decay spontaneouslydecay spontaneously
bull Antioxidants block the Antioxidants block the formation or scavenge formation or scavenge them ( Vitamin E C A them ( Vitamin E C A GSH) GSH)
bull Transition metals are Transition metals are usually tightly bound to usually tightly bound to carrier proteins carrier proteins (transferring ferritin (transferring ferritin lactoferin lactoferin ceruloplasmin) release ceruloplasmin) release and use are highly and use are highly regulatedregulated
bull Free radical scavenging Free radical scavenging systems defuse radicals systems defuse radicals rapidlyrapidly
CatalaseCatalase Glutathione oxidaseGlutathione oxidase Superoxide dismutaseSuperoxide dismutase
Free RadicalsFree Radicals
11 Free radicalsFree radicals11 Unstable oxygen Unstable oxygen
speciesspecies
22 Damage and break Damage and break lipids proteins and lipids proteins and nucleic acidsnucleic acids
33 Formed by normal Formed by normal metabolismmetabolism
44 Energy absorptionEnergy absorption
55 Metabolism of Metabolism of chemicals and drugschemicals and drugs
11 Free Radical Free Radical DefenseDefense11 Spontaneous Spontaneous
decaydecay
22 AntioxidantsAntioxidants
33 Free radical Free radical scavenging scavenging systemssystems
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Cell Adaptation Injury and DeathCell Adaptation Injury and Death
Adaptation In response to stimuli the cell Adaptation In response to stimuli the cell develops a new altered state but remains develops a new altered state but remains functional (able to maintain homeostasis)functional (able to maintain homeostasis)
HyperplasiaHyperplasia - uarr cell - uarr cell HypertrophyHypertrophy - uarr cell mass - uarr cell mass AtrophyAtrophy - darr cell mass - darr cell mass Metaplasia Metaplasia ndash change from one adult ndash change from one adult
form to anotherform to another
Morphology of cell injuryMorphology of cell injury
Swelling (via increased water Swelling (via increased water content)content)
Fatty change (steatosis TG)Fatty change (steatosis TG) Necrosis (dead cells)Necrosis (dead cells) Intracellular deposits (lipid CHO Intracellular deposits (lipid CHO
protein)protein) Loss of cellular fine structure Loss of cellular fine structure
(microvilli)(microvilli) Karyolysis (DNA degradation)Karyolysis (DNA degradation) Pyknosis (nuclear shrinkage)Pyknosis (nuclear shrinkage) Karyorrhexis (nuclear Karyorrhexis (nuclear
fragmentation)fragmentation)
Subcellular response to Subcellular response to injuryinjury
1Lysosomes (heterophagy autophagy)
2Smooth ER (induction)
3Mitochondria ( number size and shape)
4Cytoskeleton ( phagocytosis locomotion)
5Nucleus (karyolysis karyorrhexis pyknosis)
6Membranes (cellular and subcellullar)
Causes of Cell InjuryCauses of Cell Injury
11 O2 deprivationO2 deprivation which impairs aerobic which impairs aerobic respiration amp the ability to produce ATP This respiration amp the ability to produce ATP This is a common cause of cell deathis a common cause of cell death
a Hypoxia- lack of O2 results in a Hypoxia- lack of O2 results in decreased aerobic respirationdecreased aerobic respirationb Ischemia- lack of O2 amp metabolic b Ischemia- lack of O2 amp metabolic substratessubstrates
22 Physical agentsPhysical agents- mechanical trauma - mechanical trauma temperature changes shock radiation etctemperature changes shock radiation etc
33 Chemical agents amp drugsChemical agents amp drugs - acids bases - acids bases toxins therapeutic drugs pollutants ldquosocial toxins therapeutic drugs pollutants ldquosocial stimulantsrdquo etcstimulantsrdquo etc
Causes of Cell InjuryCauses of Cell Injury
44 Infectious agentsInfectious agents
5 5 Immunologic reactionsImmunologic reactions
a Xeno-immune reactiona Xeno-immune reaction
b Autoimmune reactionb Autoimmune reaction
c ldquoNormalldquo immune responsec ldquoNormalldquo immune response
6 6 Genetic derangementsGenetic derangements
7 7 Nutritional imbalancesNutritional imbalances
a Deficienciesa Deficiencies
b Excessesb Excesses
Mechanisms of cell injuryMechanisms of cell injury
3 Principles3 Principles11 The cellular response to injury depends on the The cellular response to injury depends on the
type duration and severity of the injurytype duration and severity of the injury2 2 The consequences of the injury depend on the The consequences of the injury depend on the
type state and adaptability of the celltype state and adaptability of the cell33 Cell injury results from an abnormality in one or Cell injury results from an abnormality in one or
more essential cellular componentsmore essential cellular componentsbull Aerobic respiration (mitochondrial oxidation amp ATP Aerobic respiration (mitochondrial oxidation amp ATP
production)production)bull Membrane integrity (cell amp organelle membranes)Membrane integrity (cell amp organelle membranes)bull Protein synthesisProtein synthesisbull Cytoskeletal structureCytoskeletal structurebull The genetic apparatusThe genetic apparatus
Causes of Cell InjuryCauses of Cell Injury
Oxygen DeprivationOxygen Deprivation Physical AgentsPhysical Agents Chemical Agents and DrugsChemical Agents and Drugs Infectious AgentsInfectious Agents Immunologic ReactionsImmunologic Reactions Genetic DerangementsGenetic Derangements Nutritional ImbalancesNutritional Imbalances
Physical AgentsPhysical Agents
Mechanical traumaMechanical trauma Extremes of temperature ndash Extremes of temperature ndash burnsburns
deep colddeep cold RadiationRadiation Electric shockElectric shock
Causes of Cell InjuryCauses of Cell Injury
Chemical Agents and DrugsChemical Agents and Drugs
Hypertonic concentration of salt ndash Hypertonic concentration of salt ndash deranging electrolyte homeostasisderanging electrolyte homeostasis
PoisonsPoisons ndashndash arsenic cyanide or arsenic cyanide or mercuric saltsmercuric salts
Insecticides and HerbicidesInsecticides and Herbicides Air pollutant ndash Air pollutant ndash carbon monoxidecarbon monoxide Occupational hazard ndash Occupational hazard ndash asbestosasbestos Alcohol and Narcotic drugsAlcohol and Narcotic drugs
Causes of Cell InjuryCauses of Cell Injury
Infectious AgentsInfectious Agents
ParasitesParasites FungiFungi BacteriaBacteria RickettsiaeRickettsiae VirusesViruses
Causes of Cell InjuryCauses of Cell Injury
Immunologic ReactionsImmunologic Reactions
Anaphylactic reaction to Anaphylactic reaction to foreign foreign proteinprotein or or drugdrug
Reactions to endogenous self-Reactions to endogenous self-antigens ndash antigens ndash autoimmune diseasesautoimmune diseases
Causes of Cell InjuryCauses of Cell Injury
Genetics DerangementsGenetics Derangements
Congenital malformation ndash Congenital malformation ndash Down Down syndromesyndrome
Decreased life of red blood cell ndash Decreased life of red blood cell ndash Thalassemia Sickle cell anemiaThalassemia Sickle cell anemia
Inborn errors of metabolismInborn errors of metabolism
Causes of Cell InjuryCauses of Cell Injury
Nutritional ImbalancesNutritional Imbalances
Protein-calorie deficienciesProtein-calorie deficiencies Vitamin deficienciesVitamin deficiencies Anorexia nervosaAnorexia nervosa Excesses of lipids ndash Excesses of lipids ndash ObesityObesity
AtherosclerosisAtherosclerosis Metabolic diseasesMetabolic diseases ndashndash Diabetes Diabetes
Causes of Cell InjuryCauses of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury Depletion of ATPDepletion of ATP Mitochondrial DamageMitochondrial Damage Influx of Intracellular Calcium and Loss of Influx of Intracellular Calcium and Loss of
Calcium HomeostasisCalcium Homeostasis Accumulation of Oxygen-Derived free Accumulation of Oxygen-Derived free
radical (radical (Oxidative stressOxidative stress)) Defects in Membrane PermeabilityDefects in Membrane Permeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Na+K+ATPase (Na-pump) Ca2+Mg2+ ATPases (Ca-pump)
CausesCauses
Hypoxia Ischemia
Chemical Injury
Membrane transport
Protein synthesis Lipogenesis etc
ATP
ATP depletionATP depletion lt5-10 of normal lt5-10 of normalbull ATP use gt ATP synthesis is a common consequence of ATP use gt ATP synthesis is a common consequence of
both ischemic amp toxic injuryboth ischemic amp toxic injurybull ATP production occurs via 2 related mechanismATP production occurs via 2 related mechanism
Glycolysis ndash cytosolic low yield lactate production (darrpH)Glycolysis ndash cytosolic low yield lactate production (darrpH) Oxidative phosphorylation ndash mitochondrial high yieldOxidative phosphorylation ndash mitochondrial high yield
bull Hypoxia results in uarred glycolysis (depletion of glycogen amp Hypoxia results in uarred glycolysis (depletion of glycogen amp darrpH)darrpH)
bull ATP is critical forATP is critical for Membrane transportMembrane transport Maintenance of ionic gradients ( Na+ K+ Ca2+)Maintenance of ionic gradients ( Na+ K+ Ca2+) Protein synthesisProtein synthesis Cytoskeletal function (microfilaments)Cytoskeletal function (microfilaments)
Na+
K+
Ca2+
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
CausesCauses
Hypoxia Toxins
Cytosolic Ca2+
Oxidative stress
Lipid breakdown product
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
bull Mitochondrial permeability transition of inner membrane (formation of high-conductance high-conductance channelchannel)
bull Leakage of Cytochrome cCytochrome c into cytosol
ATP productionATP production
Mitochondrial Oxidative Phosphorylation
Mitochondrial damageMitochondrial damagebull May occur directly due to hypoxia or increased Ca2+ May occur directly due to hypoxia or increased Ca2+
oxidative stress or phospholipids breakdownoxidative stress or phospholipids breakdownbull Damage results in the formation of a high-Damage results in the formation of a high-
conductance channel that dissipates the H+ ion conductance channel that dissipates the H+ ion gradient across the inner membrane (mitochondrial gradient across the inner membrane (mitochondrial permeability transition (MPT)) Mitochondrial permeability transition (MPT)) Mitochondrial membrane damage can result in Cytochrome C membrane damage can result in Cytochrome C leakage which can trigger apoptosisleakage which can trigger apoptosis
Defects in membrane permeabilityDefects in membrane permeabilitybull Membranes may be damaged directly by toxins Membranes may be damaged directly by toxins
physical chemical agents activated complement physical chemical agents activated complement components and perforins components and perforins
bull Increased cell membrane permeability disrupts Increased cell membrane permeability disrupts intracellular osmolarity and enzyme activityintracellular osmolarity and enzyme activity
bull Organelle membrane defects cause organelle Organelle membrane defects cause organelle dysfunction and failure dysfunction and failure
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mitochondrial Mitochondrial DamageDamage
Influx of Intracellular Calcium Influx of Intracellular Calcium and Loss of Calcium and Loss of Calcium
HomeostasisHomeostasis
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of O2 Accumulation of O2 derived free radicalsderived free radicals
bull Partially reduced highly Partially reduced highly reactive unstable oxygen reactive unstable oxygen moieties are able tomoieties are able to
Induce the formation of Induce the formation of more free radicals more free radicals (propagation)(propagation)
Damage lipids by Damage lipids by peroxidation of double peroxidation of double bonds resulting in breakagebonds resulting in breakage
Damage protein by Damage protein by oxidation and oxidation and fragmentationfragmentation
Damage nucleic acids Damage nucleic acids ( chain breakage)( chain breakage)
bull Free radical formation occurs Free radical formation occurs byby
Absorption of radiant Absorption of radiant energy (H2O rarr O∙ + OH∙)energy (H2O rarr O∙ + OH∙)
Metabolism of exogenous Metabolism of exogenous chemicals and drugschemicals and drugs
Normal metabolic Normal metabolic oxidation-reduction oxidation-reduction reactions (O2- H2O2 OH∙)reactions (O2- H2O2 OH∙)
Transition metals (Fe Cu Transition metals (Fe Cu etc) can catalyze radical etc) can catalyze radical formationformation
Nitric oxide can act directly Nitric oxide can act directly as a free radical or be as a free radical or be converted to other highly converted to other highly reactive formsreactive forms
Free radical defenseFree radical defensebull Free radicals are highly Free radicals are highly
unstable and generally unstable and generally decay spontaneouslydecay spontaneously
bull Antioxidants block the Antioxidants block the formation or scavenge formation or scavenge them ( Vitamin E C A them ( Vitamin E C A GSH) GSH)
bull Transition metals are Transition metals are usually tightly bound to usually tightly bound to carrier proteins carrier proteins (transferring ferritin (transferring ferritin lactoferin lactoferin ceruloplasmin) release ceruloplasmin) release and use are highly and use are highly regulatedregulated
bull Free radical scavenging Free radical scavenging systems defuse radicals systems defuse radicals rapidlyrapidly
CatalaseCatalase Glutathione oxidaseGlutathione oxidase Superoxide dismutaseSuperoxide dismutase
Free RadicalsFree Radicals
11 Free radicalsFree radicals11 Unstable oxygen Unstable oxygen
speciesspecies
22 Damage and break Damage and break lipids proteins and lipids proteins and nucleic acidsnucleic acids
33 Formed by normal Formed by normal metabolismmetabolism
44 Energy absorptionEnergy absorption
55 Metabolism of Metabolism of chemicals and drugschemicals and drugs
11 Free Radical Free Radical DefenseDefense11 Spontaneous Spontaneous
decaydecay
22 AntioxidantsAntioxidants
33 Free radical Free radical scavenging scavenging systemssystems
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Morphology of cell injuryMorphology of cell injury
Swelling (via increased water Swelling (via increased water content)content)
Fatty change (steatosis TG)Fatty change (steatosis TG) Necrosis (dead cells)Necrosis (dead cells) Intracellular deposits (lipid CHO Intracellular deposits (lipid CHO
protein)protein) Loss of cellular fine structure Loss of cellular fine structure
(microvilli)(microvilli) Karyolysis (DNA degradation)Karyolysis (DNA degradation) Pyknosis (nuclear shrinkage)Pyknosis (nuclear shrinkage) Karyorrhexis (nuclear Karyorrhexis (nuclear
fragmentation)fragmentation)
Subcellular response to Subcellular response to injuryinjury
1Lysosomes (heterophagy autophagy)
2Smooth ER (induction)
3Mitochondria ( number size and shape)
4Cytoskeleton ( phagocytosis locomotion)
5Nucleus (karyolysis karyorrhexis pyknosis)
6Membranes (cellular and subcellullar)
Causes of Cell InjuryCauses of Cell Injury
11 O2 deprivationO2 deprivation which impairs aerobic which impairs aerobic respiration amp the ability to produce ATP This respiration amp the ability to produce ATP This is a common cause of cell deathis a common cause of cell death
a Hypoxia- lack of O2 results in a Hypoxia- lack of O2 results in decreased aerobic respirationdecreased aerobic respirationb Ischemia- lack of O2 amp metabolic b Ischemia- lack of O2 amp metabolic substratessubstrates
22 Physical agentsPhysical agents- mechanical trauma - mechanical trauma temperature changes shock radiation etctemperature changes shock radiation etc
33 Chemical agents amp drugsChemical agents amp drugs - acids bases - acids bases toxins therapeutic drugs pollutants ldquosocial toxins therapeutic drugs pollutants ldquosocial stimulantsrdquo etcstimulantsrdquo etc
Causes of Cell InjuryCauses of Cell Injury
44 Infectious agentsInfectious agents
5 5 Immunologic reactionsImmunologic reactions
a Xeno-immune reactiona Xeno-immune reaction
b Autoimmune reactionb Autoimmune reaction
c ldquoNormalldquo immune responsec ldquoNormalldquo immune response
6 6 Genetic derangementsGenetic derangements
7 7 Nutritional imbalancesNutritional imbalances
a Deficienciesa Deficiencies
b Excessesb Excesses
Mechanisms of cell injuryMechanisms of cell injury
3 Principles3 Principles11 The cellular response to injury depends on the The cellular response to injury depends on the
type duration and severity of the injurytype duration and severity of the injury2 2 The consequences of the injury depend on the The consequences of the injury depend on the
type state and adaptability of the celltype state and adaptability of the cell33 Cell injury results from an abnormality in one or Cell injury results from an abnormality in one or
more essential cellular componentsmore essential cellular componentsbull Aerobic respiration (mitochondrial oxidation amp ATP Aerobic respiration (mitochondrial oxidation amp ATP
production)production)bull Membrane integrity (cell amp organelle membranes)Membrane integrity (cell amp organelle membranes)bull Protein synthesisProtein synthesisbull Cytoskeletal structureCytoskeletal structurebull The genetic apparatusThe genetic apparatus
Causes of Cell InjuryCauses of Cell Injury
Oxygen DeprivationOxygen Deprivation Physical AgentsPhysical Agents Chemical Agents and DrugsChemical Agents and Drugs Infectious AgentsInfectious Agents Immunologic ReactionsImmunologic Reactions Genetic DerangementsGenetic Derangements Nutritional ImbalancesNutritional Imbalances
Physical AgentsPhysical Agents
Mechanical traumaMechanical trauma Extremes of temperature ndash Extremes of temperature ndash burnsburns
deep colddeep cold RadiationRadiation Electric shockElectric shock
Causes of Cell InjuryCauses of Cell Injury
Chemical Agents and DrugsChemical Agents and Drugs
Hypertonic concentration of salt ndash Hypertonic concentration of salt ndash deranging electrolyte homeostasisderanging electrolyte homeostasis
PoisonsPoisons ndashndash arsenic cyanide or arsenic cyanide or mercuric saltsmercuric salts
Insecticides and HerbicidesInsecticides and Herbicides Air pollutant ndash Air pollutant ndash carbon monoxidecarbon monoxide Occupational hazard ndash Occupational hazard ndash asbestosasbestos Alcohol and Narcotic drugsAlcohol and Narcotic drugs
Causes of Cell InjuryCauses of Cell Injury
Infectious AgentsInfectious Agents
ParasitesParasites FungiFungi BacteriaBacteria RickettsiaeRickettsiae VirusesViruses
Causes of Cell InjuryCauses of Cell Injury
Immunologic ReactionsImmunologic Reactions
Anaphylactic reaction to Anaphylactic reaction to foreign foreign proteinprotein or or drugdrug
Reactions to endogenous self-Reactions to endogenous self-antigens ndash antigens ndash autoimmune diseasesautoimmune diseases
Causes of Cell InjuryCauses of Cell Injury
Genetics DerangementsGenetics Derangements
Congenital malformation ndash Congenital malformation ndash Down Down syndromesyndrome
Decreased life of red blood cell ndash Decreased life of red blood cell ndash Thalassemia Sickle cell anemiaThalassemia Sickle cell anemia
Inborn errors of metabolismInborn errors of metabolism
Causes of Cell InjuryCauses of Cell Injury
Nutritional ImbalancesNutritional Imbalances
Protein-calorie deficienciesProtein-calorie deficiencies Vitamin deficienciesVitamin deficiencies Anorexia nervosaAnorexia nervosa Excesses of lipids ndash Excesses of lipids ndash ObesityObesity
AtherosclerosisAtherosclerosis Metabolic diseasesMetabolic diseases ndashndash Diabetes Diabetes
Causes of Cell InjuryCauses of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury Depletion of ATPDepletion of ATP Mitochondrial DamageMitochondrial Damage Influx of Intracellular Calcium and Loss of Influx of Intracellular Calcium and Loss of
Calcium HomeostasisCalcium Homeostasis Accumulation of Oxygen-Derived free Accumulation of Oxygen-Derived free
radical (radical (Oxidative stressOxidative stress)) Defects in Membrane PermeabilityDefects in Membrane Permeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Na+K+ATPase (Na-pump) Ca2+Mg2+ ATPases (Ca-pump)
CausesCauses
Hypoxia Ischemia
Chemical Injury
Membrane transport
Protein synthesis Lipogenesis etc
ATP
ATP depletionATP depletion lt5-10 of normal lt5-10 of normalbull ATP use gt ATP synthesis is a common consequence of ATP use gt ATP synthesis is a common consequence of
both ischemic amp toxic injuryboth ischemic amp toxic injurybull ATP production occurs via 2 related mechanismATP production occurs via 2 related mechanism
Glycolysis ndash cytosolic low yield lactate production (darrpH)Glycolysis ndash cytosolic low yield lactate production (darrpH) Oxidative phosphorylation ndash mitochondrial high yieldOxidative phosphorylation ndash mitochondrial high yield
bull Hypoxia results in uarred glycolysis (depletion of glycogen amp Hypoxia results in uarred glycolysis (depletion of glycogen amp darrpH)darrpH)
bull ATP is critical forATP is critical for Membrane transportMembrane transport Maintenance of ionic gradients ( Na+ K+ Ca2+)Maintenance of ionic gradients ( Na+ K+ Ca2+) Protein synthesisProtein synthesis Cytoskeletal function (microfilaments)Cytoskeletal function (microfilaments)
Na+
K+
Ca2+
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
CausesCauses
Hypoxia Toxins
Cytosolic Ca2+
Oxidative stress
Lipid breakdown product
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
bull Mitochondrial permeability transition of inner membrane (formation of high-conductance high-conductance channelchannel)
bull Leakage of Cytochrome cCytochrome c into cytosol
ATP productionATP production
Mitochondrial Oxidative Phosphorylation
Mitochondrial damageMitochondrial damagebull May occur directly due to hypoxia or increased Ca2+ May occur directly due to hypoxia or increased Ca2+
oxidative stress or phospholipids breakdownoxidative stress or phospholipids breakdownbull Damage results in the formation of a high-Damage results in the formation of a high-
conductance channel that dissipates the H+ ion conductance channel that dissipates the H+ ion gradient across the inner membrane (mitochondrial gradient across the inner membrane (mitochondrial permeability transition (MPT)) Mitochondrial permeability transition (MPT)) Mitochondrial membrane damage can result in Cytochrome C membrane damage can result in Cytochrome C leakage which can trigger apoptosisleakage which can trigger apoptosis
Defects in membrane permeabilityDefects in membrane permeabilitybull Membranes may be damaged directly by toxins Membranes may be damaged directly by toxins
physical chemical agents activated complement physical chemical agents activated complement components and perforins components and perforins
bull Increased cell membrane permeability disrupts Increased cell membrane permeability disrupts intracellular osmolarity and enzyme activityintracellular osmolarity and enzyme activity
bull Organelle membrane defects cause organelle Organelle membrane defects cause organelle dysfunction and failure dysfunction and failure
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mitochondrial Mitochondrial DamageDamage
Influx of Intracellular Calcium Influx of Intracellular Calcium and Loss of Calcium and Loss of Calcium
HomeostasisHomeostasis
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of O2 Accumulation of O2 derived free radicalsderived free radicals
bull Partially reduced highly Partially reduced highly reactive unstable oxygen reactive unstable oxygen moieties are able tomoieties are able to
Induce the formation of Induce the formation of more free radicals more free radicals (propagation)(propagation)
Damage lipids by Damage lipids by peroxidation of double peroxidation of double bonds resulting in breakagebonds resulting in breakage
Damage protein by Damage protein by oxidation and oxidation and fragmentationfragmentation
Damage nucleic acids Damage nucleic acids ( chain breakage)( chain breakage)
bull Free radical formation occurs Free radical formation occurs byby
Absorption of radiant Absorption of radiant energy (H2O rarr O∙ + OH∙)energy (H2O rarr O∙ + OH∙)
Metabolism of exogenous Metabolism of exogenous chemicals and drugschemicals and drugs
Normal metabolic Normal metabolic oxidation-reduction oxidation-reduction reactions (O2- H2O2 OH∙)reactions (O2- H2O2 OH∙)
Transition metals (Fe Cu Transition metals (Fe Cu etc) can catalyze radical etc) can catalyze radical formationformation
Nitric oxide can act directly Nitric oxide can act directly as a free radical or be as a free radical or be converted to other highly converted to other highly reactive formsreactive forms
Free radical defenseFree radical defensebull Free radicals are highly Free radicals are highly
unstable and generally unstable and generally decay spontaneouslydecay spontaneously
bull Antioxidants block the Antioxidants block the formation or scavenge formation or scavenge them ( Vitamin E C A them ( Vitamin E C A GSH) GSH)
bull Transition metals are Transition metals are usually tightly bound to usually tightly bound to carrier proteins carrier proteins (transferring ferritin (transferring ferritin lactoferin lactoferin ceruloplasmin) release ceruloplasmin) release and use are highly and use are highly regulatedregulated
bull Free radical scavenging Free radical scavenging systems defuse radicals systems defuse radicals rapidlyrapidly
CatalaseCatalase Glutathione oxidaseGlutathione oxidase Superoxide dismutaseSuperoxide dismutase
Free RadicalsFree Radicals
11 Free radicalsFree radicals11 Unstable oxygen Unstable oxygen
speciesspecies
22 Damage and break Damage and break lipids proteins and lipids proteins and nucleic acidsnucleic acids
33 Formed by normal Formed by normal metabolismmetabolism
44 Energy absorptionEnergy absorption
55 Metabolism of Metabolism of chemicals and drugschemicals and drugs
11 Free Radical Free Radical DefenseDefense11 Spontaneous Spontaneous
decaydecay
22 AntioxidantsAntioxidants
33 Free radical Free radical scavenging scavenging systemssystems
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Subcellular response to Subcellular response to injuryinjury
1Lysosomes (heterophagy autophagy)
2Smooth ER (induction)
3Mitochondria ( number size and shape)
4Cytoskeleton ( phagocytosis locomotion)
5Nucleus (karyolysis karyorrhexis pyknosis)
6Membranes (cellular and subcellullar)
Causes of Cell InjuryCauses of Cell Injury
11 O2 deprivationO2 deprivation which impairs aerobic which impairs aerobic respiration amp the ability to produce ATP This respiration amp the ability to produce ATP This is a common cause of cell deathis a common cause of cell death
a Hypoxia- lack of O2 results in a Hypoxia- lack of O2 results in decreased aerobic respirationdecreased aerobic respirationb Ischemia- lack of O2 amp metabolic b Ischemia- lack of O2 amp metabolic substratessubstrates
22 Physical agentsPhysical agents- mechanical trauma - mechanical trauma temperature changes shock radiation etctemperature changes shock radiation etc
33 Chemical agents amp drugsChemical agents amp drugs - acids bases - acids bases toxins therapeutic drugs pollutants ldquosocial toxins therapeutic drugs pollutants ldquosocial stimulantsrdquo etcstimulantsrdquo etc
Causes of Cell InjuryCauses of Cell Injury
44 Infectious agentsInfectious agents
5 5 Immunologic reactionsImmunologic reactions
a Xeno-immune reactiona Xeno-immune reaction
b Autoimmune reactionb Autoimmune reaction
c ldquoNormalldquo immune responsec ldquoNormalldquo immune response
6 6 Genetic derangementsGenetic derangements
7 7 Nutritional imbalancesNutritional imbalances
a Deficienciesa Deficiencies
b Excessesb Excesses
Mechanisms of cell injuryMechanisms of cell injury
3 Principles3 Principles11 The cellular response to injury depends on the The cellular response to injury depends on the
type duration and severity of the injurytype duration and severity of the injury2 2 The consequences of the injury depend on the The consequences of the injury depend on the
type state and adaptability of the celltype state and adaptability of the cell33 Cell injury results from an abnormality in one or Cell injury results from an abnormality in one or
more essential cellular componentsmore essential cellular componentsbull Aerobic respiration (mitochondrial oxidation amp ATP Aerobic respiration (mitochondrial oxidation amp ATP
production)production)bull Membrane integrity (cell amp organelle membranes)Membrane integrity (cell amp organelle membranes)bull Protein synthesisProtein synthesisbull Cytoskeletal structureCytoskeletal structurebull The genetic apparatusThe genetic apparatus
Causes of Cell InjuryCauses of Cell Injury
Oxygen DeprivationOxygen Deprivation Physical AgentsPhysical Agents Chemical Agents and DrugsChemical Agents and Drugs Infectious AgentsInfectious Agents Immunologic ReactionsImmunologic Reactions Genetic DerangementsGenetic Derangements Nutritional ImbalancesNutritional Imbalances
Physical AgentsPhysical Agents
Mechanical traumaMechanical trauma Extremes of temperature ndash Extremes of temperature ndash burnsburns
deep colddeep cold RadiationRadiation Electric shockElectric shock
Causes of Cell InjuryCauses of Cell Injury
Chemical Agents and DrugsChemical Agents and Drugs
Hypertonic concentration of salt ndash Hypertonic concentration of salt ndash deranging electrolyte homeostasisderanging electrolyte homeostasis
PoisonsPoisons ndashndash arsenic cyanide or arsenic cyanide or mercuric saltsmercuric salts
Insecticides and HerbicidesInsecticides and Herbicides Air pollutant ndash Air pollutant ndash carbon monoxidecarbon monoxide Occupational hazard ndash Occupational hazard ndash asbestosasbestos Alcohol and Narcotic drugsAlcohol and Narcotic drugs
Causes of Cell InjuryCauses of Cell Injury
Infectious AgentsInfectious Agents
ParasitesParasites FungiFungi BacteriaBacteria RickettsiaeRickettsiae VirusesViruses
Causes of Cell InjuryCauses of Cell Injury
Immunologic ReactionsImmunologic Reactions
Anaphylactic reaction to Anaphylactic reaction to foreign foreign proteinprotein or or drugdrug
Reactions to endogenous self-Reactions to endogenous self-antigens ndash antigens ndash autoimmune diseasesautoimmune diseases
Causes of Cell InjuryCauses of Cell Injury
Genetics DerangementsGenetics Derangements
Congenital malformation ndash Congenital malformation ndash Down Down syndromesyndrome
Decreased life of red blood cell ndash Decreased life of red blood cell ndash Thalassemia Sickle cell anemiaThalassemia Sickle cell anemia
Inborn errors of metabolismInborn errors of metabolism
Causes of Cell InjuryCauses of Cell Injury
Nutritional ImbalancesNutritional Imbalances
Protein-calorie deficienciesProtein-calorie deficiencies Vitamin deficienciesVitamin deficiencies Anorexia nervosaAnorexia nervosa Excesses of lipids ndash Excesses of lipids ndash ObesityObesity
AtherosclerosisAtherosclerosis Metabolic diseasesMetabolic diseases ndashndash Diabetes Diabetes
Causes of Cell InjuryCauses of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury Depletion of ATPDepletion of ATP Mitochondrial DamageMitochondrial Damage Influx of Intracellular Calcium and Loss of Influx of Intracellular Calcium and Loss of
Calcium HomeostasisCalcium Homeostasis Accumulation of Oxygen-Derived free Accumulation of Oxygen-Derived free
radical (radical (Oxidative stressOxidative stress)) Defects in Membrane PermeabilityDefects in Membrane Permeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Na+K+ATPase (Na-pump) Ca2+Mg2+ ATPases (Ca-pump)
CausesCauses
Hypoxia Ischemia
Chemical Injury
Membrane transport
Protein synthesis Lipogenesis etc
ATP
ATP depletionATP depletion lt5-10 of normal lt5-10 of normalbull ATP use gt ATP synthesis is a common consequence of ATP use gt ATP synthesis is a common consequence of
both ischemic amp toxic injuryboth ischemic amp toxic injurybull ATP production occurs via 2 related mechanismATP production occurs via 2 related mechanism
Glycolysis ndash cytosolic low yield lactate production (darrpH)Glycolysis ndash cytosolic low yield lactate production (darrpH) Oxidative phosphorylation ndash mitochondrial high yieldOxidative phosphorylation ndash mitochondrial high yield
bull Hypoxia results in uarred glycolysis (depletion of glycogen amp Hypoxia results in uarred glycolysis (depletion of glycogen amp darrpH)darrpH)
bull ATP is critical forATP is critical for Membrane transportMembrane transport Maintenance of ionic gradients ( Na+ K+ Ca2+)Maintenance of ionic gradients ( Na+ K+ Ca2+) Protein synthesisProtein synthesis Cytoskeletal function (microfilaments)Cytoskeletal function (microfilaments)
Na+
K+
Ca2+
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
CausesCauses
Hypoxia Toxins
Cytosolic Ca2+
Oxidative stress
Lipid breakdown product
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
bull Mitochondrial permeability transition of inner membrane (formation of high-conductance high-conductance channelchannel)
bull Leakage of Cytochrome cCytochrome c into cytosol
ATP productionATP production
Mitochondrial Oxidative Phosphorylation
Mitochondrial damageMitochondrial damagebull May occur directly due to hypoxia or increased Ca2+ May occur directly due to hypoxia or increased Ca2+
oxidative stress or phospholipids breakdownoxidative stress or phospholipids breakdownbull Damage results in the formation of a high-Damage results in the formation of a high-
conductance channel that dissipates the H+ ion conductance channel that dissipates the H+ ion gradient across the inner membrane (mitochondrial gradient across the inner membrane (mitochondrial permeability transition (MPT)) Mitochondrial permeability transition (MPT)) Mitochondrial membrane damage can result in Cytochrome C membrane damage can result in Cytochrome C leakage which can trigger apoptosisleakage which can trigger apoptosis
Defects in membrane permeabilityDefects in membrane permeabilitybull Membranes may be damaged directly by toxins Membranes may be damaged directly by toxins
physical chemical agents activated complement physical chemical agents activated complement components and perforins components and perforins
bull Increased cell membrane permeability disrupts Increased cell membrane permeability disrupts intracellular osmolarity and enzyme activityintracellular osmolarity and enzyme activity
bull Organelle membrane defects cause organelle Organelle membrane defects cause organelle dysfunction and failure dysfunction and failure
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mitochondrial Mitochondrial DamageDamage
Influx of Intracellular Calcium Influx of Intracellular Calcium and Loss of Calcium and Loss of Calcium
HomeostasisHomeostasis
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of O2 Accumulation of O2 derived free radicalsderived free radicals
bull Partially reduced highly Partially reduced highly reactive unstable oxygen reactive unstable oxygen moieties are able tomoieties are able to
Induce the formation of Induce the formation of more free radicals more free radicals (propagation)(propagation)
Damage lipids by Damage lipids by peroxidation of double peroxidation of double bonds resulting in breakagebonds resulting in breakage
Damage protein by Damage protein by oxidation and oxidation and fragmentationfragmentation
Damage nucleic acids Damage nucleic acids ( chain breakage)( chain breakage)
bull Free radical formation occurs Free radical formation occurs byby
Absorption of radiant Absorption of radiant energy (H2O rarr O∙ + OH∙)energy (H2O rarr O∙ + OH∙)
Metabolism of exogenous Metabolism of exogenous chemicals and drugschemicals and drugs
Normal metabolic Normal metabolic oxidation-reduction oxidation-reduction reactions (O2- H2O2 OH∙)reactions (O2- H2O2 OH∙)
Transition metals (Fe Cu Transition metals (Fe Cu etc) can catalyze radical etc) can catalyze radical formationformation
Nitric oxide can act directly Nitric oxide can act directly as a free radical or be as a free radical or be converted to other highly converted to other highly reactive formsreactive forms
Free radical defenseFree radical defensebull Free radicals are highly Free radicals are highly
unstable and generally unstable and generally decay spontaneouslydecay spontaneously
bull Antioxidants block the Antioxidants block the formation or scavenge formation or scavenge them ( Vitamin E C A them ( Vitamin E C A GSH) GSH)
bull Transition metals are Transition metals are usually tightly bound to usually tightly bound to carrier proteins carrier proteins (transferring ferritin (transferring ferritin lactoferin lactoferin ceruloplasmin) release ceruloplasmin) release and use are highly and use are highly regulatedregulated
bull Free radical scavenging Free radical scavenging systems defuse radicals systems defuse radicals rapidlyrapidly
CatalaseCatalase Glutathione oxidaseGlutathione oxidase Superoxide dismutaseSuperoxide dismutase
Free RadicalsFree Radicals
11 Free radicalsFree radicals11 Unstable oxygen Unstable oxygen
speciesspecies
22 Damage and break Damage and break lipids proteins and lipids proteins and nucleic acidsnucleic acids
33 Formed by normal Formed by normal metabolismmetabolism
44 Energy absorptionEnergy absorption
55 Metabolism of Metabolism of chemicals and drugschemicals and drugs
11 Free Radical Free Radical DefenseDefense11 Spontaneous Spontaneous
decaydecay
22 AntioxidantsAntioxidants
33 Free radical Free radical scavenging scavenging systemssystems
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Causes of Cell InjuryCauses of Cell Injury
11 O2 deprivationO2 deprivation which impairs aerobic which impairs aerobic respiration amp the ability to produce ATP This respiration amp the ability to produce ATP This is a common cause of cell deathis a common cause of cell death
a Hypoxia- lack of O2 results in a Hypoxia- lack of O2 results in decreased aerobic respirationdecreased aerobic respirationb Ischemia- lack of O2 amp metabolic b Ischemia- lack of O2 amp metabolic substratessubstrates
22 Physical agentsPhysical agents- mechanical trauma - mechanical trauma temperature changes shock radiation etctemperature changes shock radiation etc
33 Chemical agents amp drugsChemical agents amp drugs - acids bases - acids bases toxins therapeutic drugs pollutants ldquosocial toxins therapeutic drugs pollutants ldquosocial stimulantsrdquo etcstimulantsrdquo etc
Causes of Cell InjuryCauses of Cell Injury
44 Infectious agentsInfectious agents
5 5 Immunologic reactionsImmunologic reactions
a Xeno-immune reactiona Xeno-immune reaction
b Autoimmune reactionb Autoimmune reaction
c ldquoNormalldquo immune responsec ldquoNormalldquo immune response
6 6 Genetic derangementsGenetic derangements
7 7 Nutritional imbalancesNutritional imbalances
a Deficienciesa Deficiencies
b Excessesb Excesses
Mechanisms of cell injuryMechanisms of cell injury
3 Principles3 Principles11 The cellular response to injury depends on the The cellular response to injury depends on the
type duration and severity of the injurytype duration and severity of the injury2 2 The consequences of the injury depend on the The consequences of the injury depend on the
type state and adaptability of the celltype state and adaptability of the cell33 Cell injury results from an abnormality in one or Cell injury results from an abnormality in one or
more essential cellular componentsmore essential cellular componentsbull Aerobic respiration (mitochondrial oxidation amp ATP Aerobic respiration (mitochondrial oxidation amp ATP
production)production)bull Membrane integrity (cell amp organelle membranes)Membrane integrity (cell amp organelle membranes)bull Protein synthesisProtein synthesisbull Cytoskeletal structureCytoskeletal structurebull The genetic apparatusThe genetic apparatus
Causes of Cell InjuryCauses of Cell Injury
Oxygen DeprivationOxygen Deprivation Physical AgentsPhysical Agents Chemical Agents and DrugsChemical Agents and Drugs Infectious AgentsInfectious Agents Immunologic ReactionsImmunologic Reactions Genetic DerangementsGenetic Derangements Nutritional ImbalancesNutritional Imbalances
Physical AgentsPhysical Agents
Mechanical traumaMechanical trauma Extremes of temperature ndash Extremes of temperature ndash burnsburns
deep colddeep cold RadiationRadiation Electric shockElectric shock
Causes of Cell InjuryCauses of Cell Injury
Chemical Agents and DrugsChemical Agents and Drugs
Hypertonic concentration of salt ndash Hypertonic concentration of salt ndash deranging electrolyte homeostasisderanging electrolyte homeostasis
PoisonsPoisons ndashndash arsenic cyanide or arsenic cyanide or mercuric saltsmercuric salts
Insecticides and HerbicidesInsecticides and Herbicides Air pollutant ndash Air pollutant ndash carbon monoxidecarbon monoxide Occupational hazard ndash Occupational hazard ndash asbestosasbestos Alcohol and Narcotic drugsAlcohol and Narcotic drugs
Causes of Cell InjuryCauses of Cell Injury
Infectious AgentsInfectious Agents
ParasitesParasites FungiFungi BacteriaBacteria RickettsiaeRickettsiae VirusesViruses
Causes of Cell InjuryCauses of Cell Injury
Immunologic ReactionsImmunologic Reactions
Anaphylactic reaction to Anaphylactic reaction to foreign foreign proteinprotein or or drugdrug
Reactions to endogenous self-Reactions to endogenous self-antigens ndash antigens ndash autoimmune diseasesautoimmune diseases
Causes of Cell InjuryCauses of Cell Injury
Genetics DerangementsGenetics Derangements
Congenital malformation ndash Congenital malformation ndash Down Down syndromesyndrome
Decreased life of red blood cell ndash Decreased life of red blood cell ndash Thalassemia Sickle cell anemiaThalassemia Sickle cell anemia
Inborn errors of metabolismInborn errors of metabolism
Causes of Cell InjuryCauses of Cell Injury
Nutritional ImbalancesNutritional Imbalances
Protein-calorie deficienciesProtein-calorie deficiencies Vitamin deficienciesVitamin deficiencies Anorexia nervosaAnorexia nervosa Excesses of lipids ndash Excesses of lipids ndash ObesityObesity
AtherosclerosisAtherosclerosis Metabolic diseasesMetabolic diseases ndashndash Diabetes Diabetes
Causes of Cell InjuryCauses of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury Depletion of ATPDepletion of ATP Mitochondrial DamageMitochondrial Damage Influx of Intracellular Calcium and Loss of Influx of Intracellular Calcium and Loss of
Calcium HomeostasisCalcium Homeostasis Accumulation of Oxygen-Derived free Accumulation of Oxygen-Derived free
radical (radical (Oxidative stressOxidative stress)) Defects in Membrane PermeabilityDefects in Membrane Permeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Na+K+ATPase (Na-pump) Ca2+Mg2+ ATPases (Ca-pump)
CausesCauses
Hypoxia Ischemia
Chemical Injury
Membrane transport
Protein synthesis Lipogenesis etc
ATP
ATP depletionATP depletion lt5-10 of normal lt5-10 of normalbull ATP use gt ATP synthesis is a common consequence of ATP use gt ATP synthesis is a common consequence of
both ischemic amp toxic injuryboth ischemic amp toxic injurybull ATP production occurs via 2 related mechanismATP production occurs via 2 related mechanism
Glycolysis ndash cytosolic low yield lactate production (darrpH)Glycolysis ndash cytosolic low yield lactate production (darrpH) Oxidative phosphorylation ndash mitochondrial high yieldOxidative phosphorylation ndash mitochondrial high yield
bull Hypoxia results in uarred glycolysis (depletion of glycogen amp Hypoxia results in uarred glycolysis (depletion of glycogen amp darrpH)darrpH)
bull ATP is critical forATP is critical for Membrane transportMembrane transport Maintenance of ionic gradients ( Na+ K+ Ca2+)Maintenance of ionic gradients ( Na+ K+ Ca2+) Protein synthesisProtein synthesis Cytoskeletal function (microfilaments)Cytoskeletal function (microfilaments)
Na+
K+
Ca2+
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
CausesCauses
Hypoxia Toxins
Cytosolic Ca2+
Oxidative stress
Lipid breakdown product
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
bull Mitochondrial permeability transition of inner membrane (formation of high-conductance high-conductance channelchannel)
bull Leakage of Cytochrome cCytochrome c into cytosol
ATP productionATP production
Mitochondrial Oxidative Phosphorylation
Mitochondrial damageMitochondrial damagebull May occur directly due to hypoxia or increased Ca2+ May occur directly due to hypoxia or increased Ca2+
oxidative stress or phospholipids breakdownoxidative stress or phospholipids breakdownbull Damage results in the formation of a high-Damage results in the formation of a high-
conductance channel that dissipates the H+ ion conductance channel that dissipates the H+ ion gradient across the inner membrane (mitochondrial gradient across the inner membrane (mitochondrial permeability transition (MPT)) Mitochondrial permeability transition (MPT)) Mitochondrial membrane damage can result in Cytochrome C membrane damage can result in Cytochrome C leakage which can trigger apoptosisleakage which can trigger apoptosis
Defects in membrane permeabilityDefects in membrane permeabilitybull Membranes may be damaged directly by toxins Membranes may be damaged directly by toxins
physical chemical agents activated complement physical chemical agents activated complement components and perforins components and perforins
bull Increased cell membrane permeability disrupts Increased cell membrane permeability disrupts intracellular osmolarity and enzyme activityintracellular osmolarity and enzyme activity
bull Organelle membrane defects cause organelle Organelle membrane defects cause organelle dysfunction and failure dysfunction and failure
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mitochondrial Mitochondrial DamageDamage
Influx of Intracellular Calcium Influx of Intracellular Calcium and Loss of Calcium and Loss of Calcium
HomeostasisHomeostasis
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of O2 Accumulation of O2 derived free radicalsderived free radicals
bull Partially reduced highly Partially reduced highly reactive unstable oxygen reactive unstable oxygen moieties are able tomoieties are able to
Induce the formation of Induce the formation of more free radicals more free radicals (propagation)(propagation)
Damage lipids by Damage lipids by peroxidation of double peroxidation of double bonds resulting in breakagebonds resulting in breakage
Damage protein by Damage protein by oxidation and oxidation and fragmentationfragmentation
Damage nucleic acids Damage nucleic acids ( chain breakage)( chain breakage)
bull Free radical formation occurs Free radical formation occurs byby
Absorption of radiant Absorption of radiant energy (H2O rarr O∙ + OH∙)energy (H2O rarr O∙ + OH∙)
Metabolism of exogenous Metabolism of exogenous chemicals and drugschemicals and drugs
Normal metabolic Normal metabolic oxidation-reduction oxidation-reduction reactions (O2- H2O2 OH∙)reactions (O2- H2O2 OH∙)
Transition metals (Fe Cu Transition metals (Fe Cu etc) can catalyze radical etc) can catalyze radical formationformation
Nitric oxide can act directly Nitric oxide can act directly as a free radical or be as a free radical or be converted to other highly converted to other highly reactive formsreactive forms
Free radical defenseFree radical defensebull Free radicals are highly Free radicals are highly
unstable and generally unstable and generally decay spontaneouslydecay spontaneously
bull Antioxidants block the Antioxidants block the formation or scavenge formation or scavenge them ( Vitamin E C A them ( Vitamin E C A GSH) GSH)
bull Transition metals are Transition metals are usually tightly bound to usually tightly bound to carrier proteins carrier proteins (transferring ferritin (transferring ferritin lactoferin lactoferin ceruloplasmin) release ceruloplasmin) release and use are highly and use are highly regulatedregulated
bull Free radical scavenging Free radical scavenging systems defuse radicals systems defuse radicals rapidlyrapidly
CatalaseCatalase Glutathione oxidaseGlutathione oxidase Superoxide dismutaseSuperoxide dismutase
Free RadicalsFree Radicals
11 Free radicalsFree radicals11 Unstable oxygen Unstable oxygen
speciesspecies
22 Damage and break Damage and break lipids proteins and lipids proteins and nucleic acidsnucleic acids
33 Formed by normal Formed by normal metabolismmetabolism
44 Energy absorptionEnergy absorption
55 Metabolism of Metabolism of chemicals and drugschemicals and drugs
11 Free Radical Free Radical DefenseDefense11 Spontaneous Spontaneous
decaydecay
22 AntioxidantsAntioxidants
33 Free radical Free radical scavenging scavenging systemssystems
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Causes of Cell InjuryCauses of Cell Injury
44 Infectious agentsInfectious agents
5 5 Immunologic reactionsImmunologic reactions
a Xeno-immune reactiona Xeno-immune reaction
b Autoimmune reactionb Autoimmune reaction
c ldquoNormalldquo immune responsec ldquoNormalldquo immune response
6 6 Genetic derangementsGenetic derangements
7 7 Nutritional imbalancesNutritional imbalances
a Deficienciesa Deficiencies
b Excessesb Excesses
Mechanisms of cell injuryMechanisms of cell injury
3 Principles3 Principles11 The cellular response to injury depends on the The cellular response to injury depends on the
type duration and severity of the injurytype duration and severity of the injury2 2 The consequences of the injury depend on the The consequences of the injury depend on the
type state and adaptability of the celltype state and adaptability of the cell33 Cell injury results from an abnormality in one or Cell injury results from an abnormality in one or
more essential cellular componentsmore essential cellular componentsbull Aerobic respiration (mitochondrial oxidation amp ATP Aerobic respiration (mitochondrial oxidation amp ATP
production)production)bull Membrane integrity (cell amp organelle membranes)Membrane integrity (cell amp organelle membranes)bull Protein synthesisProtein synthesisbull Cytoskeletal structureCytoskeletal structurebull The genetic apparatusThe genetic apparatus
Causes of Cell InjuryCauses of Cell Injury
Oxygen DeprivationOxygen Deprivation Physical AgentsPhysical Agents Chemical Agents and DrugsChemical Agents and Drugs Infectious AgentsInfectious Agents Immunologic ReactionsImmunologic Reactions Genetic DerangementsGenetic Derangements Nutritional ImbalancesNutritional Imbalances
Physical AgentsPhysical Agents
Mechanical traumaMechanical trauma Extremes of temperature ndash Extremes of temperature ndash burnsburns
deep colddeep cold RadiationRadiation Electric shockElectric shock
Causes of Cell InjuryCauses of Cell Injury
Chemical Agents and DrugsChemical Agents and Drugs
Hypertonic concentration of salt ndash Hypertonic concentration of salt ndash deranging electrolyte homeostasisderanging electrolyte homeostasis
PoisonsPoisons ndashndash arsenic cyanide or arsenic cyanide or mercuric saltsmercuric salts
Insecticides and HerbicidesInsecticides and Herbicides Air pollutant ndash Air pollutant ndash carbon monoxidecarbon monoxide Occupational hazard ndash Occupational hazard ndash asbestosasbestos Alcohol and Narcotic drugsAlcohol and Narcotic drugs
Causes of Cell InjuryCauses of Cell Injury
Infectious AgentsInfectious Agents
ParasitesParasites FungiFungi BacteriaBacteria RickettsiaeRickettsiae VirusesViruses
Causes of Cell InjuryCauses of Cell Injury
Immunologic ReactionsImmunologic Reactions
Anaphylactic reaction to Anaphylactic reaction to foreign foreign proteinprotein or or drugdrug
Reactions to endogenous self-Reactions to endogenous self-antigens ndash antigens ndash autoimmune diseasesautoimmune diseases
Causes of Cell InjuryCauses of Cell Injury
Genetics DerangementsGenetics Derangements
Congenital malformation ndash Congenital malformation ndash Down Down syndromesyndrome
Decreased life of red blood cell ndash Decreased life of red blood cell ndash Thalassemia Sickle cell anemiaThalassemia Sickle cell anemia
Inborn errors of metabolismInborn errors of metabolism
Causes of Cell InjuryCauses of Cell Injury
Nutritional ImbalancesNutritional Imbalances
Protein-calorie deficienciesProtein-calorie deficiencies Vitamin deficienciesVitamin deficiencies Anorexia nervosaAnorexia nervosa Excesses of lipids ndash Excesses of lipids ndash ObesityObesity
AtherosclerosisAtherosclerosis Metabolic diseasesMetabolic diseases ndashndash Diabetes Diabetes
Causes of Cell InjuryCauses of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury Depletion of ATPDepletion of ATP Mitochondrial DamageMitochondrial Damage Influx of Intracellular Calcium and Loss of Influx of Intracellular Calcium and Loss of
Calcium HomeostasisCalcium Homeostasis Accumulation of Oxygen-Derived free Accumulation of Oxygen-Derived free
radical (radical (Oxidative stressOxidative stress)) Defects in Membrane PermeabilityDefects in Membrane Permeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Na+K+ATPase (Na-pump) Ca2+Mg2+ ATPases (Ca-pump)
CausesCauses
Hypoxia Ischemia
Chemical Injury
Membrane transport
Protein synthesis Lipogenesis etc
ATP
ATP depletionATP depletion lt5-10 of normal lt5-10 of normalbull ATP use gt ATP synthesis is a common consequence of ATP use gt ATP synthesis is a common consequence of
both ischemic amp toxic injuryboth ischemic amp toxic injurybull ATP production occurs via 2 related mechanismATP production occurs via 2 related mechanism
Glycolysis ndash cytosolic low yield lactate production (darrpH)Glycolysis ndash cytosolic low yield lactate production (darrpH) Oxidative phosphorylation ndash mitochondrial high yieldOxidative phosphorylation ndash mitochondrial high yield
bull Hypoxia results in uarred glycolysis (depletion of glycogen amp Hypoxia results in uarred glycolysis (depletion of glycogen amp darrpH)darrpH)
bull ATP is critical forATP is critical for Membrane transportMembrane transport Maintenance of ionic gradients ( Na+ K+ Ca2+)Maintenance of ionic gradients ( Na+ K+ Ca2+) Protein synthesisProtein synthesis Cytoskeletal function (microfilaments)Cytoskeletal function (microfilaments)
Na+
K+
Ca2+
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
CausesCauses
Hypoxia Toxins
Cytosolic Ca2+
Oxidative stress
Lipid breakdown product
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
bull Mitochondrial permeability transition of inner membrane (formation of high-conductance high-conductance channelchannel)
bull Leakage of Cytochrome cCytochrome c into cytosol
ATP productionATP production
Mitochondrial Oxidative Phosphorylation
Mitochondrial damageMitochondrial damagebull May occur directly due to hypoxia or increased Ca2+ May occur directly due to hypoxia or increased Ca2+
oxidative stress or phospholipids breakdownoxidative stress or phospholipids breakdownbull Damage results in the formation of a high-Damage results in the formation of a high-
conductance channel that dissipates the H+ ion conductance channel that dissipates the H+ ion gradient across the inner membrane (mitochondrial gradient across the inner membrane (mitochondrial permeability transition (MPT)) Mitochondrial permeability transition (MPT)) Mitochondrial membrane damage can result in Cytochrome C membrane damage can result in Cytochrome C leakage which can trigger apoptosisleakage which can trigger apoptosis
Defects in membrane permeabilityDefects in membrane permeabilitybull Membranes may be damaged directly by toxins Membranes may be damaged directly by toxins
physical chemical agents activated complement physical chemical agents activated complement components and perforins components and perforins
bull Increased cell membrane permeability disrupts Increased cell membrane permeability disrupts intracellular osmolarity and enzyme activityintracellular osmolarity and enzyme activity
bull Organelle membrane defects cause organelle Organelle membrane defects cause organelle dysfunction and failure dysfunction and failure
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mitochondrial Mitochondrial DamageDamage
Influx of Intracellular Calcium Influx of Intracellular Calcium and Loss of Calcium and Loss of Calcium
HomeostasisHomeostasis
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of O2 Accumulation of O2 derived free radicalsderived free radicals
bull Partially reduced highly Partially reduced highly reactive unstable oxygen reactive unstable oxygen moieties are able tomoieties are able to
Induce the formation of Induce the formation of more free radicals more free radicals (propagation)(propagation)
Damage lipids by Damage lipids by peroxidation of double peroxidation of double bonds resulting in breakagebonds resulting in breakage
Damage protein by Damage protein by oxidation and oxidation and fragmentationfragmentation
Damage nucleic acids Damage nucleic acids ( chain breakage)( chain breakage)
bull Free radical formation occurs Free radical formation occurs byby
Absorption of radiant Absorption of radiant energy (H2O rarr O∙ + OH∙)energy (H2O rarr O∙ + OH∙)
Metabolism of exogenous Metabolism of exogenous chemicals and drugschemicals and drugs
Normal metabolic Normal metabolic oxidation-reduction oxidation-reduction reactions (O2- H2O2 OH∙)reactions (O2- H2O2 OH∙)
Transition metals (Fe Cu Transition metals (Fe Cu etc) can catalyze radical etc) can catalyze radical formationformation
Nitric oxide can act directly Nitric oxide can act directly as a free radical or be as a free radical or be converted to other highly converted to other highly reactive formsreactive forms
Free radical defenseFree radical defensebull Free radicals are highly Free radicals are highly
unstable and generally unstable and generally decay spontaneouslydecay spontaneously
bull Antioxidants block the Antioxidants block the formation or scavenge formation or scavenge them ( Vitamin E C A them ( Vitamin E C A GSH) GSH)
bull Transition metals are Transition metals are usually tightly bound to usually tightly bound to carrier proteins carrier proteins (transferring ferritin (transferring ferritin lactoferin lactoferin ceruloplasmin) release ceruloplasmin) release and use are highly and use are highly regulatedregulated
bull Free radical scavenging Free radical scavenging systems defuse radicals systems defuse radicals rapidlyrapidly
CatalaseCatalase Glutathione oxidaseGlutathione oxidase Superoxide dismutaseSuperoxide dismutase
Free RadicalsFree Radicals
11 Free radicalsFree radicals11 Unstable oxygen Unstable oxygen
speciesspecies
22 Damage and break Damage and break lipids proteins and lipids proteins and nucleic acidsnucleic acids
33 Formed by normal Formed by normal metabolismmetabolism
44 Energy absorptionEnergy absorption
55 Metabolism of Metabolism of chemicals and drugschemicals and drugs
11 Free Radical Free Radical DefenseDefense11 Spontaneous Spontaneous
decaydecay
22 AntioxidantsAntioxidants
33 Free radical Free radical scavenging scavenging systemssystems
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Mechanisms of cell injuryMechanisms of cell injury
3 Principles3 Principles11 The cellular response to injury depends on the The cellular response to injury depends on the
type duration and severity of the injurytype duration and severity of the injury2 2 The consequences of the injury depend on the The consequences of the injury depend on the
type state and adaptability of the celltype state and adaptability of the cell33 Cell injury results from an abnormality in one or Cell injury results from an abnormality in one or
more essential cellular componentsmore essential cellular componentsbull Aerobic respiration (mitochondrial oxidation amp ATP Aerobic respiration (mitochondrial oxidation amp ATP
production)production)bull Membrane integrity (cell amp organelle membranes)Membrane integrity (cell amp organelle membranes)bull Protein synthesisProtein synthesisbull Cytoskeletal structureCytoskeletal structurebull The genetic apparatusThe genetic apparatus
Causes of Cell InjuryCauses of Cell Injury
Oxygen DeprivationOxygen Deprivation Physical AgentsPhysical Agents Chemical Agents and DrugsChemical Agents and Drugs Infectious AgentsInfectious Agents Immunologic ReactionsImmunologic Reactions Genetic DerangementsGenetic Derangements Nutritional ImbalancesNutritional Imbalances
Physical AgentsPhysical Agents
Mechanical traumaMechanical trauma Extremes of temperature ndash Extremes of temperature ndash burnsburns
deep colddeep cold RadiationRadiation Electric shockElectric shock
Causes of Cell InjuryCauses of Cell Injury
Chemical Agents and DrugsChemical Agents and Drugs
Hypertonic concentration of salt ndash Hypertonic concentration of salt ndash deranging electrolyte homeostasisderanging electrolyte homeostasis
PoisonsPoisons ndashndash arsenic cyanide or arsenic cyanide or mercuric saltsmercuric salts
Insecticides and HerbicidesInsecticides and Herbicides Air pollutant ndash Air pollutant ndash carbon monoxidecarbon monoxide Occupational hazard ndash Occupational hazard ndash asbestosasbestos Alcohol and Narcotic drugsAlcohol and Narcotic drugs
Causes of Cell InjuryCauses of Cell Injury
Infectious AgentsInfectious Agents
ParasitesParasites FungiFungi BacteriaBacteria RickettsiaeRickettsiae VirusesViruses
Causes of Cell InjuryCauses of Cell Injury
Immunologic ReactionsImmunologic Reactions
Anaphylactic reaction to Anaphylactic reaction to foreign foreign proteinprotein or or drugdrug
Reactions to endogenous self-Reactions to endogenous self-antigens ndash antigens ndash autoimmune diseasesautoimmune diseases
Causes of Cell InjuryCauses of Cell Injury
Genetics DerangementsGenetics Derangements
Congenital malformation ndash Congenital malformation ndash Down Down syndromesyndrome
Decreased life of red blood cell ndash Decreased life of red blood cell ndash Thalassemia Sickle cell anemiaThalassemia Sickle cell anemia
Inborn errors of metabolismInborn errors of metabolism
Causes of Cell InjuryCauses of Cell Injury
Nutritional ImbalancesNutritional Imbalances
Protein-calorie deficienciesProtein-calorie deficiencies Vitamin deficienciesVitamin deficiencies Anorexia nervosaAnorexia nervosa Excesses of lipids ndash Excesses of lipids ndash ObesityObesity
AtherosclerosisAtherosclerosis Metabolic diseasesMetabolic diseases ndashndash Diabetes Diabetes
Causes of Cell InjuryCauses of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury Depletion of ATPDepletion of ATP Mitochondrial DamageMitochondrial Damage Influx of Intracellular Calcium and Loss of Influx of Intracellular Calcium and Loss of
Calcium HomeostasisCalcium Homeostasis Accumulation of Oxygen-Derived free Accumulation of Oxygen-Derived free
radical (radical (Oxidative stressOxidative stress)) Defects in Membrane PermeabilityDefects in Membrane Permeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Na+K+ATPase (Na-pump) Ca2+Mg2+ ATPases (Ca-pump)
CausesCauses
Hypoxia Ischemia
Chemical Injury
Membrane transport
Protein synthesis Lipogenesis etc
ATP
ATP depletionATP depletion lt5-10 of normal lt5-10 of normalbull ATP use gt ATP synthesis is a common consequence of ATP use gt ATP synthesis is a common consequence of
both ischemic amp toxic injuryboth ischemic amp toxic injurybull ATP production occurs via 2 related mechanismATP production occurs via 2 related mechanism
Glycolysis ndash cytosolic low yield lactate production (darrpH)Glycolysis ndash cytosolic low yield lactate production (darrpH) Oxidative phosphorylation ndash mitochondrial high yieldOxidative phosphorylation ndash mitochondrial high yield
bull Hypoxia results in uarred glycolysis (depletion of glycogen amp Hypoxia results in uarred glycolysis (depletion of glycogen amp darrpH)darrpH)
bull ATP is critical forATP is critical for Membrane transportMembrane transport Maintenance of ionic gradients ( Na+ K+ Ca2+)Maintenance of ionic gradients ( Na+ K+ Ca2+) Protein synthesisProtein synthesis Cytoskeletal function (microfilaments)Cytoskeletal function (microfilaments)
Na+
K+
Ca2+
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
CausesCauses
Hypoxia Toxins
Cytosolic Ca2+
Oxidative stress
Lipid breakdown product
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
bull Mitochondrial permeability transition of inner membrane (formation of high-conductance high-conductance channelchannel)
bull Leakage of Cytochrome cCytochrome c into cytosol
ATP productionATP production
Mitochondrial Oxidative Phosphorylation
Mitochondrial damageMitochondrial damagebull May occur directly due to hypoxia or increased Ca2+ May occur directly due to hypoxia or increased Ca2+
oxidative stress or phospholipids breakdownoxidative stress or phospholipids breakdownbull Damage results in the formation of a high-Damage results in the formation of a high-
conductance channel that dissipates the H+ ion conductance channel that dissipates the H+ ion gradient across the inner membrane (mitochondrial gradient across the inner membrane (mitochondrial permeability transition (MPT)) Mitochondrial permeability transition (MPT)) Mitochondrial membrane damage can result in Cytochrome C membrane damage can result in Cytochrome C leakage which can trigger apoptosisleakage which can trigger apoptosis
Defects in membrane permeabilityDefects in membrane permeabilitybull Membranes may be damaged directly by toxins Membranes may be damaged directly by toxins
physical chemical agents activated complement physical chemical agents activated complement components and perforins components and perforins
bull Increased cell membrane permeability disrupts Increased cell membrane permeability disrupts intracellular osmolarity and enzyme activityintracellular osmolarity and enzyme activity
bull Organelle membrane defects cause organelle Organelle membrane defects cause organelle dysfunction and failure dysfunction and failure
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mitochondrial Mitochondrial DamageDamage
Influx of Intracellular Calcium Influx of Intracellular Calcium and Loss of Calcium and Loss of Calcium
HomeostasisHomeostasis
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of O2 Accumulation of O2 derived free radicalsderived free radicals
bull Partially reduced highly Partially reduced highly reactive unstable oxygen reactive unstable oxygen moieties are able tomoieties are able to
Induce the formation of Induce the formation of more free radicals more free radicals (propagation)(propagation)
Damage lipids by Damage lipids by peroxidation of double peroxidation of double bonds resulting in breakagebonds resulting in breakage
Damage protein by Damage protein by oxidation and oxidation and fragmentationfragmentation
Damage nucleic acids Damage nucleic acids ( chain breakage)( chain breakage)
bull Free radical formation occurs Free radical formation occurs byby
Absorption of radiant Absorption of radiant energy (H2O rarr O∙ + OH∙)energy (H2O rarr O∙ + OH∙)
Metabolism of exogenous Metabolism of exogenous chemicals and drugschemicals and drugs
Normal metabolic Normal metabolic oxidation-reduction oxidation-reduction reactions (O2- H2O2 OH∙)reactions (O2- H2O2 OH∙)
Transition metals (Fe Cu Transition metals (Fe Cu etc) can catalyze radical etc) can catalyze radical formationformation
Nitric oxide can act directly Nitric oxide can act directly as a free radical or be as a free radical or be converted to other highly converted to other highly reactive formsreactive forms
Free radical defenseFree radical defensebull Free radicals are highly Free radicals are highly
unstable and generally unstable and generally decay spontaneouslydecay spontaneously
bull Antioxidants block the Antioxidants block the formation or scavenge formation or scavenge them ( Vitamin E C A them ( Vitamin E C A GSH) GSH)
bull Transition metals are Transition metals are usually tightly bound to usually tightly bound to carrier proteins carrier proteins (transferring ferritin (transferring ferritin lactoferin lactoferin ceruloplasmin) release ceruloplasmin) release and use are highly and use are highly regulatedregulated
bull Free radical scavenging Free radical scavenging systems defuse radicals systems defuse radicals rapidlyrapidly
CatalaseCatalase Glutathione oxidaseGlutathione oxidase Superoxide dismutaseSuperoxide dismutase
Free RadicalsFree Radicals
11 Free radicalsFree radicals11 Unstable oxygen Unstable oxygen
speciesspecies
22 Damage and break Damage and break lipids proteins and lipids proteins and nucleic acidsnucleic acids
33 Formed by normal Formed by normal metabolismmetabolism
44 Energy absorptionEnergy absorption
55 Metabolism of Metabolism of chemicals and drugschemicals and drugs
11 Free Radical Free Radical DefenseDefense11 Spontaneous Spontaneous
decaydecay
22 AntioxidantsAntioxidants
33 Free radical Free radical scavenging scavenging systemssystems
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Causes of Cell InjuryCauses of Cell Injury
Oxygen DeprivationOxygen Deprivation Physical AgentsPhysical Agents Chemical Agents and DrugsChemical Agents and Drugs Infectious AgentsInfectious Agents Immunologic ReactionsImmunologic Reactions Genetic DerangementsGenetic Derangements Nutritional ImbalancesNutritional Imbalances
Physical AgentsPhysical Agents
Mechanical traumaMechanical trauma Extremes of temperature ndash Extremes of temperature ndash burnsburns
deep colddeep cold RadiationRadiation Electric shockElectric shock
Causes of Cell InjuryCauses of Cell Injury
Chemical Agents and DrugsChemical Agents and Drugs
Hypertonic concentration of salt ndash Hypertonic concentration of salt ndash deranging electrolyte homeostasisderanging electrolyte homeostasis
PoisonsPoisons ndashndash arsenic cyanide or arsenic cyanide or mercuric saltsmercuric salts
Insecticides and HerbicidesInsecticides and Herbicides Air pollutant ndash Air pollutant ndash carbon monoxidecarbon monoxide Occupational hazard ndash Occupational hazard ndash asbestosasbestos Alcohol and Narcotic drugsAlcohol and Narcotic drugs
Causes of Cell InjuryCauses of Cell Injury
Infectious AgentsInfectious Agents
ParasitesParasites FungiFungi BacteriaBacteria RickettsiaeRickettsiae VirusesViruses
Causes of Cell InjuryCauses of Cell Injury
Immunologic ReactionsImmunologic Reactions
Anaphylactic reaction to Anaphylactic reaction to foreign foreign proteinprotein or or drugdrug
Reactions to endogenous self-Reactions to endogenous self-antigens ndash antigens ndash autoimmune diseasesautoimmune diseases
Causes of Cell InjuryCauses of Cell Injury
Genetics DerangementsGenetics Derangements
Congenital malformation ndash Congenital malformation ndash Down Down syndromesyndrome
Decreased life of red blood cell ndash Decreased life of red blood cell ndash Thalassemia Sickle cell anemiaThalassemia Sickle cell anemia
Inborn errors of metabolismInborn errors of metabolism
Causes of Cell InjuryCauses of Cell Injury
Nutritional ImbalancesNutritional Imbalances
Protein-calorie deficienciesProtein-calorie deficiencies Vitamin deficienciesVitamin deficiencies Anorexia nervosaAnorexia nervosa Excesses of lipids ndash Excesses of lipids ndash ObesityObesity
AtherosclerosisAtherosclerosis Metabolic diseasesMetabolic diseases ndashndash Diabetes Diabetes
Causes of Cell InjuryCauses of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury Depletion of ATPDepletion of ATP Mitochondrial DamageMitochondrial Damage Influx of Intracellular Calcium and Loss of Influx of Intracellular Calcium and Loss of
Calcium HomeostasisCalcium Homeostasis Accumulation of Oxygen-Derived free Accumulation of Oxygen-Derived free
radical (radical (Oxidative stressOxidative stress)) Defects in Membrane PermeabilityDefects in Membrane Permeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Na+K+ATPase (Na-pump) Ca2+Mg2+ ATPases (Ca-pump)
CausesCauses
Hypoxia Ischemia
Chemical Injury
Membrane transport
Protein synthesis Lipogenesis etc
ATP
ATP depletionATP depletion lt5-10 of normal lt5-10 of normalbull ATP use gt ATP synthesis is a common consequence of ATP use gt ATP synthesis is a common consequence of
both ischemic amp toxic injuryboth ischemic amp toxic injurybull ATP production occurs via 2 related mechanismATP production occurs via 2 related mechanism
Glycolysis ndash cytosolic low yield lactate production (darrpH)Glycolysis ndash cytosolic low yield lactate production (darrpH) Oxidative phosphorylation ndash mitochondrial high yieldOxidative phosphorylation ndash mitochondrial high yield
bull Hypoxia results in uarred glycolysis (depletion of glycogen amp Hypoxia results in uarred glycolysis (depletion of glycogen amp darrpH)darrpH)
bull ATP is critical forATP is critical for Membrane transportMembrane transport Maintenance of ionic gradients ( Na+ K+ Ca2+)Maintenance of ionic gradients ( Na+ K+ Ca2+) Protein synthesisProtein synthesis Cytoskeletal function (microfilaments)Cytoskeletal function (microfilaments)
Na+
K+
Ca2+
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
CausesCauses
Hypoxia Toxins
Cytosolic Ca2+
Oxidative stress
Lipid breakdown product
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
bull Mitochondrial permeability transition of inner membrane (formation of high-conductance high-conductance channelchannel)
bull Leakage of Cytochrome cCytochrome c into cytosol
ATP productionATP production
Mitochondrial Oxidative Phosphorylation
Mitochondrial damageMitochondrial damagebull May occur directly due to hypoxia or increased Ca2+ May occur directly due to hypoxia or increased Ca2+
oxidative stress or phospholipids breakdownoxidative stress or phospholipids breakdownbull Damage results in the formation of a high-Damage results in the formation of a high-
conductance channel that dissipates the H+ ion conductance channel that dissipates the H+ ion gradient across the inner membrane (mitochondrial gradient across the inner membrane (mitochondrial permeability transition (MPT)) Mitochondrial permeability transition (MPT)) Mitochondrial membrane damage can result in Cytochrome C membrane damage can result in Cytochrome C leakage which can trigger apoptosisleakage which can trigger apoptosis
Defects in membrane permeabilityDefects in membrane permeabilitybull Membranes may be damaged directly by toxins Membranes may be damaged directly by toxins
physical chemical agents activated complement physical chemical agents activated complement components and perforins components and perforins
bull Increased cell membrane permeability disrupts Increased cell membrane permeability disrupts intracellular osmolarity and enzyme activityintracellular osmolarity and enzyme activity
bull Organelle membrane defects cause organelle Organelle membrane defects cause organelle dysfunction and failure dysfunction and failure
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mitochondrial Mitochondrial DamageDamage
Influx of Intracellular Calcium Influx of Intracellular Calcium and Loss of Calcium and Loss of Calcium
HomeostasisHomeostasis
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of O2 Accumulation of O2 derived free radicalsderived free radicals
bull Partially reduced highly Partially reduced highly reactive unstable oxygen reactive unstable oxygen moieties are able tomoieties are able to
Induce the formation of Induce the formation of more free radicals more free radicals (propagation)(propagation)
Damage lipids by Damage lipids by peroxidation of double peroxidation of double bonds resulting in breakagebonds resulting in breakage
Damage protein by Damage protein by oxidation and oxidation and fragmentationfragmentation
Damage nucleic acids Damage nucleic acids ( chain breakage)( chain breakage)
bull Free radical formation occurs Free radical formation occurs byby
Absorption of radiant Absorption of radiant energy (H2O rarr O∙ + OH∙)energy (H2O rarr O∙ + OH∙)
Metabolism of exogenous Metabolism of exogenous chemicals and drugschemicals and drugs
Normal metabolic Normal metabolic oxidation-reduction oxidation-reduction reactions (O2- H2O2 OH∙)reactions (O2- H2O2 OH∙)
Transition metals (Fe Cu Transition metals (Fe Cu etc) can catalyze radical etc) can catalyze radical formationformation
Nitric oxide can act directly Nitric oxide can act directly as a free radical or be as a free radical or be converted to other highly converted to other highly reactive formsreactive forms
Free radical defenseFree radical defensebull Free radicals are highly Free radicals are highly
unstable and generally unstable and generally decay spontaneouslydecay spontaneously
bull Antioxidants block the Antioxidants block the formation or scavenge formation or scavenge them ( Vitamin E C A them ( Vitamin E C A GSH) GSH)
bull Transition metals are Transition metals are usually tightly bound to usually tightly bound to carrier proteins carrier proteins (transferring ferritin (transferring ferritin lactoferin lactoferin ceruloplasmin) release ceruloplasmin) release and use are highly and use are highly regulatedregulated
bull Free radical scavenging Free radical scavenging systems defuse radicals systems defuse radicals rapidlyrapidly
CatalaseCatalase Glutathione oxidaseGlutathione oxidase Superoxide dismutaseSuperoxide dismutase
Free RadicalsFree Radicals
11 Free radicalsFree radicals11 Unstable oxygen Unstable oxygen
speciesspecies
22 Damage and break Damage and break lipids proteins and lipids proteins and nucleic acidsnucleic acids
33 Formed by normal Formed by normal metabolismmetabolism
44 Energy absorptionEnergy absorption
55 Metabolism of Metabolism of chemicals and drugschemicals and drugs
11 Free Radical Free Radical DefenseDefense11 Spontaneous Spontaneous
decaydecay
22 AntioxidantsAntioxidants
33 Free radical Free radical scavenging scavenging systemssystems
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Physical AgentsPhysical Agents
Mechanical traumaMechanical trauma Extremes of temperature ndash Extremes of temperature ndash burnsburns
deep colddeep cold RadiationRadiation Electric shockElectric shock
Causes of Cell InjuryCauses of Cell Injury
Chemical Agents and DrugsChemical Agents and Drugs
Hypertonic concentration of salt ndash Hypertonic concentration of salt ndash deranging electrolyte homeostasisderanging electrolyte homeostasis
PoisonsPoisons ndashndash arsenic cyanide or arsenic cyanide or mercuric saltsmercuric salts
Insecticides and HerbicidesInsecticides and Herbicides Air pollutant ndash Air pollutant ndash carbon monoxidecarbon monoxide Occupational hazard ndash Occupational hazard ndash asbestosasbestos Alcohol and Narcotic drugsAlcohol and Narcotic drugs
Causes of Cell InjuryCauses of Cell Injury
Infectious AgentsInfectious Agents
ParasitesParasites FungiFungi BacteriaBacteria RickettsiaeRickettsiae VirusesViruses
Causes of Cell InjuryCauses of Cell Injury
Immunologic ReactionsImmunologic Reactions
Anaphylactic reaction to Anaphylactic reaction to foreign foreign proteinprotein or or drugdrug
Reactions to endogenous self-Reactions to endogenous self-antigens ndash antigens ndash autoimmune diseasesautoimmune diseases
Causes of Cell InjuryCauses of Cell Injury
Genetics DerangementsGenetics Derangements
Congenital malformation ndash Congenital malformation ndash Down Down syndromesyndrome
Decreased life of red blood cell ndash Decreased life of red blood cell ndash Thalassemia Sickle cell anemiaThalassemia Sickle cell anemia
Inborn errors of metabolismInborn errors of metabolism
Causes of Cell InjuryCauses of Cell Injury
Nutritional ImbalancesNutritional Imbalances
Protein-calorie deficienciesProtein-calorie deficiencies Vitamin deficienciesVitamin deficiencies Anorexia nervosaAnorexia nervosa Excesses of lipids ndash Excesses of lipids ndash ObesityObesity
AtherosclerosisAtherosclerosis Metabolic diseasesMetabolic diseases ndashndash Diabetes Diabetes
Causes of Cell InjuryCauses of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury Depletion of ATPDepletion of ATP Mitochondrial DamageMitochondrial Damage Influx of Intracellular Calcium and Loss of Influx of Intracellular Calcium and Loss of
Calcium HomeostasisCalcium Homeostasis Accumulation of Oxygen-Derived free Accumulation of Oxygen-Derived free
radical (radical (Oxidative stressOxidative stress)) Defects in Membrane PermeabilityDefects in Membrane Permeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Na+K+ATPase (Na-pump) Ca2+Mg2+ ATPases (Ca-pump)
CausesCauses
Hypoxia Ischemia
Chemical Injury
Membrane transport
Protein synthesis Lipogenesis etc
ATP
ATP depletionATP depletion lt5-10 of normal lt5-10 of normalbull ATP use gt ATP synthesis is a common consequence of ATP use gt ATP synthesis is a common consequence of
both ischemic amp toxic injuryboth ischemic amp toxic injurybull ATP production occurs via 2 related mechanismATP production occurs via 2 related mechanism
Glycolysis ndash cytosolic low yield lactate production (darrpH)Glycolysis ndash cytosolic low yield lactate production (darrpH) Oxidative phosphorylation ndash mitochondrial high yieldOxidative phosphorylation ndash mitochondrial high yield
bull Hypoxia results in uarred glycolysis (depletion of glycogen amp Hypoxia results in uarred glycolysis (depletion of glycogen amp darrpH)darrpH)
bull ATP is critical forATP is critical for Membrane transportMembrane transport Maintenance of ionic gradients ( Na+ K+ Ca2+)Maintenance of ionic gradients ( Na+ K+ Ca2+) Protein synthesisProtein synthesis Cytoskeletal function (microfilaments)Cytoskeletal function (microfilaments)
Na+
K+
Ca2+
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
CausesCauses
Hypoxia Toxins
Cytosolic Ca2+
Oxidative stress
Lipid breakdown product
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
bull Mitochondrial permeability transition of inner membrane (formation of high-conductance high-conductance channelchannel)
bull Leakage of Cytochrome cCytochrome c into cytosol
ATP productionATP production
Mitochondrial Oxidative Phosphorylation
Mitochondrial damageMitochondrial damagebull May occur directly due to hypoxia or increased Ca2+ May occur directly due to hypoxia or increased Ca2+
oxidative stress or phospholipids breakdownoxidative stress or phospholipids breakdownbull Damage results in the formation of a high-Damage results in the formation of a high-
conductance channel that dissipates the H+ ion conductance channel that dissipates the H+ ion gradient across the inner membrane (mitochondrial gradient across the inner membrane (mitochondrial permeability transition (MPT)) Mitochondrial permeability transition (MPT)) Mitochondrial membrane damage can result in Cytochrome C membrane damage can result in Cytochrome C leakage which can trigger apoptosisleakage which can trigger apoptosis
Defects in membrane permeabilityDefects in membrane permeabilitybull Membranes may be damaged directly by toxins Membranes may be damaged directly by toxins
physical chemical agents activated complement physical chemical agents activated complement components and perforins components and perforins
bull Increased cell membrane permeability disrupts Increased cell membrane permeability disrupts intracellular osmolarity and enzyme activityintracellular osmolarity and enzyme activity
bull Organelle membrane defects cause organelle Organelle membrane defects cause organelle dysfunction and failure dysfunction and failure
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mitochondrial Mitochondrial DamageDamage
Influx of Intracellular Calcium Influx of Intracellular Calcium and Loss of Calcium and Loss of Calcium
HomeostasisHomeostasis
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of O2 Accumulation of O2 derived free radicalsderived free radicals
bull Partially reduced highly Partially reduced highly reactive unstable oxygen reactive unstable oxygen moieties are able tomoieties are able to
Induce the formation of Induce the formation of more free radicals more free radicals (propagation)(propagation)
Damage lipids by Damage lipids by peroxidation of double peroxidation of double bonds resulting in breakagebonds resulting in breakage
Damage protein by Damage protein by oxidation and oxidation and fragmentationfragmentation
Damage nucleic acids Damage nucleic acids ( chain breakage)( chain breakage)
bull Free radical formation occurs Free radical formation occurs byby
Absorption of radiant Absorption of radiant energy (H2O rarr O∙ + OH∙)energy (H2O rarr O∙ + OH∙)
Metabolism of exogenous Metabolism of exogenous chemicals and drugschemicals and drugs
Normal metabolic Normal metabolic oxidation-reduction oxidation-reduction reactions (O2- H2O2 OH∙)reactions (O2- H2O2 OH∙)
Transition metals (Fe Cu Transition metals (Fe Cu etc) can catalyze radical etc) can catalyze radical formationformation
Nitric oxide can act directly Nitric oxide can act directly as a free radical or be as a free radical or be converted to other highly converted to other highly reactive formsreactive forms
Free radical defenseFree radical defensebull Free radicals are highly Free radicals are highly
unstable and generally unstable and generally decay spontaneouslydecay spontaneously
bull Antioxidants block the Antioxidants block the formation or scavenge formation or scavenge them ( Vitamin E C A them ( Vitamin E C A GSH) GSH)
bull Transition metals are Transition metals are usually tightly bound to usually tightly bound to carrier proteins carrier proteins (transferring ferritin (transferring ferritin lactoferin lactoferin ceruloplasmin) release ceruloplasmin) release and use are highly and use are highly regulatedregulated
bull Free radical scavenging Free radical scavenging systems defuse radicals systems defuse radicals rapidlyrapidly
CatalaseCatalase Glutathione oxidaseGlutathione oxidase Superoxide dismutaseSuperoxide dismutase
Free RadicalsFree Radicals
11 Free radicalsFree radicals11 Unstable oxygen Unstable oxygen
speciesspecies
22 Damage and break Damage and break lipids proteins and lipids proteins and nucleic acidsnucleic acids
33 Formed by normal Formed by normal metabolismmetabolism
44 Energy absorptionEnergy absorption
55 Metabolism of Metabolism of chemicals and drugschemicals and drugs
11 Free Radical Free Radical DefenseDefense11 Spontaneous Spontaneous
decaydecay
22 AntioxidantsAntioxidants
33 Free radical Free radical scavenging scavenging systemssystems
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Chemical Agents and DrugsChemical Agents and Drugs
Hypertonic concentration of salt ndash Hypertonic concentration of salt ndash deranging electrolyte homeostasisderanging electrolyte homeostasis
PoisonsPoisons ndashndash arsenic cyanide or arsenic cyanide or mercuric saltsmercuric salts
Insecticides and HerbicidesInsecticides and Herbicides Air pollutant ndash Air pollutant ndash carbon monoxidecarbon monoxide Occupational hazard ndash Occupational hazard ndash asbestosasbestos Alcohol and Narcotic drugsAlcohol and Narcotic drugs
Causes of Cell InjuryCauses of Cell Injury
Infectious AgentsInfectious Agents
ParasitesParasites FungiFungi BacteriaBacteria RickettsiaeRickettsiae VirusesViruses
Causes of Cell InjuryCauses of Cell Injury
Immunologic ReactionsImmunologic Reactions
Anaphylactic reaction to Anaphylactic reaction to foreign foreign proteinprotein or or drugdrug
Reactions to endogenous self-Reactions to endogenous self-antigens ndash antigens ndash autoimmune diseasesautoimmune diseases
Causes of Cell InjuryCauses of Cell Injury
Genetics DerangementsGenetics Derangements
Congenital malformation ndash Congenital malformation ndash Down Down syndromesyndrome
Decreased life of red blood cell ndash Decreased life of red blood cell ndash Thalassemia Sickle cell anemiaThalassemia Sickle cell anemia
Inborn errors of metabolismInborn errors of metabolism
Causes of Cell InjuryCauses of Cell Injury
Nutritional ImbalancesNutritional Imbalances
Protein-calorie deficienciesProtein-calorie deficiencies Vitamin deficienciesVitamin deficiencies Anorexia nervosaAnorexia nervosa Excesses of lipids ndash Excesses of lipids ndash ObesityObesity
AtherosclerosisAtherosclerosis Metabolic diseasesMetabolic diseases ndashndash Diabetes Diabetes
Causes of Cell InjuryCauses of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury Depletion of ATPDepletion of ATP Mitochondrial DamageMitochondrial Damage Influx of Intracellular Calcium and Loss of Influx of Intracellular Calcium and Loss of
Calcium HomeostasisCalcium Homeostasis Accumulation of Oxygen-Derived free Accumulation of Oxygen-Derived free
radical (radical (Oxidative stressOxidative stress)) Defects in Membrane PermeabilityDefects in Membrane Permeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Na+K+ATPase (Na-pump) Ca2+Mg2+ ATPases (Ca-pump)
CausesCauses
Hypoxia Ischemia
Chemical Injury
Membrane transport
Protein synthesis Lipogenesis etc
ATP
ATP depletionATP depletion lt5-10 of normal lt5-10 of normalbull ATP use gt ATP synthesis is a common consequence of ATP use gt ATP synthesis is a common consequence of
both ischemic amp toxic injuryboth ischemic amp toxic injurybull ATP production occurs via 2 related mechanismATP production occurs via 2 related mechanism
Glycolysis ndash cytosolic low yield lactate production (darrpH)Glycolysis ndash cytosolic low yield lactate production (darrpH) Oxidative phosphorylation ndash mitochondrial high yieldOxidative phosphorylation ndash mitochondrial high yield
bull Hypoxia results in uarred glycolysis (depletion of glycogen amp Hypoxia results in uarred glycolysis (depletion of glycogen amp darrpH)darrpH)
bull ATP is critical forATP is critical for Membrane transportMembrane transport Maintenance of ionic gradients ( Na+ K+ Ca2+)Maintenance of ionic gradients ( Na+ K+ Ca2+) Protein synthesisProtein synthesis Cytoskeletal function (microfilaments)Cytoskeletal function (microfilaments)
Na+
K+
Ca2+
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
CausesCauses
Hypoxia Toxins
Cytosolic Ca2+
Oxidative stress
Lipid breakdown product
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
bull Mitochondrial permeability transition of inner membrane (formation of high-conductance high-conductance channelchannel)
bull Leakage of Cytochrome cCytochrome c into cytosol
ATP productionATP production
Mitochondrial Oxidative Phosphorylation
Mitochondrial damageMitochondrial damagebull May occur directly due to hypoxia or increased Ca2+ May occur directly due to hypoxia or increased Ca2+
oxidative stress or phospholipids breakdownoxidative stress or phospholipids breakdownbull Damage results in the formation of a high-Damage results in the formation of a high-
conductance channel that dissipates the H+ ion conductance channel that dissipates the H+ ion gradient across the inner membrane (mitochondrial gradient across the inner membrane (mitochondrial permeability transition (MPT)) Mitochondrial permeability transition (MPT)) Mitochondrial membrane damage can result in Cytochrome C membrane damage can result in Cytochrome C leakage which can trigger apoptosisleakage which can trigger apoptosis
Defects in membrane permeabilityDefects in membrane permeabilitybull Membranes may be damaged directly by toxins Membranes may be damaged directly by toxins
physical chemical agents activated complement physical chemical agents activated complement components and perforins components and perforins
bull Increased cell membrane permeability disrupts Increased cell membrane permeability disrupts intracellular osmolarity and enzyme activityintracellular osmolarity and enzyme activity
bull Organelle membrane defects cause organelle Organelle membrane defects cause organelle dysfunction and failure dysfunction and failure
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mitochondrial Mitochondrial DamageDamage
Influx of Intracellular Calcium Influx of Intracellular Calcium and Loss of Calcium and Loss of Calcium
HomeostasisHomeostasis
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of O2 Accumulation of O2 derived free radicalsderived free radicals
bull Partially reduced highly Partially reduced highly reactive unstable oxygen reactive unstable oxygen moieties are able tomoieties are able to
Induce the formation of Induce the formation of more free radicals more free radicals (propagation)(propagation)
Damage lipids by Damage lipids by peroxidation of double peroxidation of double bonds resulting in breakagebonds resulting in breakage
Damage protein by Damage protein by oxidation and oxidation and fragmentationfragmentation
Damage nucleic acids Damage nucleic acids ( chain breakage)( chain breakage)
bull Free radical formation occurs Free radical formation occurs byby
Absorption of radiant Absorption of radiant energy (H2O rarr O∙ + OH∙)energy (H2O rarr O∙ + OH∙)
Metabolism of exogenous Metabolism of exogenous chemicals and drugschemicals and drugs
Normal metabolic Normal metabolic oxidation-reduction oxidation-reduction reactions (O2- H2O2 OH∙)reactions (O2- H2O2 OH∙)
Transition metals (Fe Cu Transition metals (Fe Cu etc) can catalyze radical etc) can catalyze radical formationformation
Nitric oxide can act directly Nitric oxide can act directly as a free radical or be as a free radical or be converted to other highly converted to other highly reactive formsreactive forms
Free radical defenseFree radical defensebull Free radicals are highly Free radicals are highly
unstable and generally unstable and generally decay spontaneouslydecay spontaneously
bull Antioxidants block the Antioxidants block the formation or scavenge formation or scavenge them ( Vitamin E C A them ( Vitamin E C A GSH) GSH)
bull Transition metals are Transition metals are usually tightly bound to usually tightly bound to carrier proteins carrier proteins (transferring ferritin (transferring ferritin lactoferin lactoferin ceruloplasmin) release ceruloplasmin) release and use are highly and use are highly regulatedregulated
bull Free radical scavenging Free radical scavenging systems defuse radicals systems defuse radicals rapidlyrapidly
CatalaseCatalase Glutathione oxidaseGlutathione oxidase Superoxide dismutaseSuperoxide dismutase
Free RadicalsFree Radicals
11 Free radicalsFree radicals11 Unstable oxygen Unstable oxygen
speciesspecies
22 Damage and break Damage and break lipids proteins and lipids proteins and nucleic acidsnucleic acids
33 Formed by normal Formed by normal metabolismmetabolism
44 Energy absorptionEnergy absorption
55 Metabolism of Metabolism of chemicals and drugschemicals and drugs
11 Free Radical Free Radical DefenseDefense11 Spontaneous Spontaneous
decaydecay
22 AntioxidantsAntioxidants
33 Free radical Free radical scavenging scavenging systemssystems
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Infectious AgentsInfectious Agents
ParasitesParasites FungiFungi BacteriaBacteria RickettsiaeRickettsiae VirusesViruses
Causes of Cell InjuryCauses of Cell Injury
Immunologic ReactionsImmunologic Reactions
Anaphylactic reaction to Anaphylactic reaction to foreign foreign proteinprotein or or drugdrug
Reactions to endogenous self-Reactions to endogenous self-antigens ndash antigens ndash autoimmune diseasesautoimmune diseases
Causes of Cell InjuryCauses of Cell Injury
Genetics DerangementsGenetics Derangements
Congenital malformation ndash Congenital malformation ndash Down Down syndromesyndrome
Decreased life of red blood cell ndash Decreased life of red blood cell ndash Thalassemia Sickle cell anemiaThalassemia Sickle cell anemia
Inborn errors of metabolismInborn errors of metabolism
Causes of Cell InjuryCauses of Cell Injury
Nutritional ImbalancesNutritional Imbalances
Protein-calorie deficienciesProtein-calorie deficiencies Vitamin deficienciesVitamin deficiencies Anorexia nervosaAnorexia nervosa Excesses of lipids ndash Excesses of lipids ndash ObesityObesity
AtherosclerosisAtherosclerosis Metabolic diseasesMetabolic diseases ndashndash Diabetes Diabetes
Causes of Cell InjuryCauses of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury Depletion of ATPDepletion of ATP Mitochondrial DamageMitochondrial Damage Influx of Intracellular Calcium and Loss of Influx of Intracellular Calcium and Loss of
Calcium HomeostasisCalcium Homeostasis Accumulation of Oxygen-Derived free Accumulation of Oxygen-Derived free
radical (radical (Oxidative stressOxidative stress)) Defects in Membrane PermeabilityDefects in Membrane Permeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Na+K+ATPase (Na-pump) Ca2+Mg2+ ATPases (Ca-pump)
CausesCauses
Hypoxia Ischemia
Chemical Injury
Membrane transport
Protein synthesis Lipogenesis etc
ATP
ATP depletionATP depletion lt5-10 of normal lt5-10 of normalbull ATP use gt ATP synthesis is a common consequence of ATP use gt ATP synthesis is a common consequence of
both ischemic amp toxic injuryboth ischemic amp toxic injurybull ATP production occurs via 2 related mechanismATP production occurs via 2 related mechanism
Glycolysis ndash cytosolic low yield lactate production (darrpH)Glycolysis ndash cytosolic low yield lactate production (darrpH) Oxidative phosphorylation ndash mitochondrial high yieldOxidative phosphorylation ndash mitochondrial high yield
bull Hypoxia results in uarred glycolysis (depletion of glycogen amp Hypoxia results in uarred glycolysis (depletion of glycogen amp darrpH)darrpH)
bull ATP is critical forATP is critical for Membrane transportMembrane transport Maintenance of ionic gradients ( Na+ K+ Ca2+)Maintenance of ionic gradients ( Na+ K+ Ca2+) Protein synthesisProtein synthesis Cytoskeletal function (microfilaments)Cytoskeletal function (microfilaments)
Na+
K+
Ca2+
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
CausesCauses
Hypoxia Toxins
Cytosolic Ca2+
Oxidative stress
Lipid breakdown product
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
bull Mitochondrial permeability transition of inner membrane (formation of high-conductance high-conductance channelchannel)
bull Leakage of Cytochrome cCytochrome c into cytosol
ATP productionATP production
Mitochondrial Oxidative Phosphorylation
Mitochondrial damageMitochondrial damagebull May occur directly due to hypoxia or increased Ca2+ May occur directly due to hypoxia or increased Ca2+
oxidative stress or phospholipids breakdownoxidative stress or phospholipids breakdownbull Damage results in the formation of a high-Damage results in the formation of a high-
conductance channel that dissipates the H+ ion conductance channel that dissipates the H+ ion gradient across the inner membrane (mitochondrial gradient across the inner membrane (mitochondrial permeability transition (MPT)) Mitochondrial permeability transition (MPT)) Mitochondrial membrane damage can result in Cytochrome C membrane damage can result in Cytochrome C leakage which can trigger apoptosisleakage which can trigger apoptosis
Defects in membrane permeabilityDefects in membrane permeabilitybull Membranes may be damaged directly by toxins Membranes may be damaged directly by toxins
physical chemical agents activated complement physical chemical agents activated complement components and perforins components and perforins
bull Increased cell membrane permeability disrupts Increased cell membrane permeability disrupts intracellular osmolarity and enzyme activityintracellular osmolarity and enzyme activity
bull Organelle membrane defects cause organelle Organelle membrane defects cause organelle dysfunction and failure dysfunction and failure
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mitochondrial Mitochondrial DamageDamage
Influx of Intracellular Calcium Influx of Intracellular Calcium and Loss of Calcium and Loss of Calcium
HomeostasisHomeostasis
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of O2 Accumulation of O2 derived free radicalsderived free radicals
bull Partially reduced highly Partially reduced highly reactive unstable oxygen reactive unstable oxygen moieties are able tomoieties are able to
Induce the formation of Induce the formation of more free radicals more free radicals (propagation)(propagation)
Damage lipids by Damage lipids by peroxidation of double peroxidation of double bonds resulting in breakagebonds resulting in breakage
Damage protein by Damage protein by oxidation and oxidation and fragmentationfragmentation
Damage nucleic acids Damage nucleic acids ( chain breakage)( chain breakage)
bull Free radical formation occurs Free radical formation occurs byby
Absorption of radiant Absorption of radiant energy (H2O rarr O∙ + OH∙)energy (H2O rarr O∙ + OH∙)
Metabolism of exogenous Metabolism of exogenous chemicals and drugschemicals and drugs
Normal metabolic Normal metabolic oxidation-reduction oxidation-reduction reactions (O2- H2O2 OH∙)reactions (O2- H2O2 OH∙)
Transition metals (Fe Cu Transition metals (Fe Cu etc) can catalyze radical etc) can catalyze radical formationformation
Nitric oxide can act directly Nitric oxide can act directly as a free radical or be as a free radical or be converted to other highly converted to other highly reactive formsreactive forms
Free radical defenseFree radical defensebull Free radicals are highly Free radicals are highly
unstable and generally unstable and generally decay spontaneouslydecay spontaneously
bull Antioxidants block the Antioxidants block the formation or scavenge formation or scavenge them ( Vitamin E C A them ( Vitamin E C A GSH) GSH)
bull Transition metals are Transition metals are usually tightly bound to usually tightly bound to carrier proteins carrier proteins (transferring ferritin (transferring ferritin lactoferin lactoferin ceruloplasmin) release ceruloplasmin) release and use are highly and use are highly regulatedregulated
bull Free radical scavenging Free radical scavenging systems defuse radicals systems defuse radicals rapidlyrapidly
CatalaseCatalase Glutathione oxidaseGlutathione oxidase Superoxide dismutaseSuperoxide dismutase
Free RadicalsFree Radicals
11 Free radicalsFree radicals11 Unstable oxygen Unstable oxygen
speciesspecies
22 Damage and break Damage and break lipids proteins and lipids proteins and nucleic acidsnucleic acids
33 Formed by normal Formed by normal metabolismmetabolism
44 Energy absorptionEnergy absorption
55 Metabolism of Metabolism of chemicals and drugschemicals and drugs
11 Free Radical Free Radical DefenseDefense11 Spontaneous Spontaneous
decaydecay
22 AntioxidantsAntioxidants
33 Free radical Free radical scavenging scavenging systemssystems
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Immunologic ReactionsImmunologic Reactions
Anaphylactic reaction to Anaphylactic reaction to foreign foreign proteinprotein or or drugdrug
Reactions to endogenous self-Reactions to endogenous self-antigens ndash antigens ndash autoimmune diseasesautoimmune diseases
Causes of Cell InjuryCauses of Cell Injury
Genetics DerangementsGenetics Derangements
Congenital malformation ndash Congenital malformation ndash Down Down syndromesyndrome
Decreased life of red blood cell ndash Decreased life of red blood cell ndash Thalassemia Sickle cell anemiaThalassemia Sickle cell anemia
Inborn errors of metabolismInborn errors of metabolism
Causes of Cell InjuryCauses of Cell Injury
Nutritional ImbalancesNutritional Imbalances
Protein-calorie deficienciesProtein-calorie deficiencies Vitamin deficienciesVitamin deficiencies Anorexia nervosaAnorexia nervosa Excesses of lipids ndash Excesses of lipids ndash ObesityObesity
AtherosclerosisAtherosclerosis Metabolic diseasesMetabolic diseases ndashndash Diabetes Diabetes
Causes of Cell InjuryCauses of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury Depletion of ATPDepletion of ATP Mitochondrial DamageMitochondrial Damage Influx of Intracellular Calcium and Loss of Influx of Intracellular Calcium and Loss of
Calcium HomeostasisCalcium Homeostasis Accumulation of Oxygen-Derived free Accumulation of Oxygen-Derived free
radical (radical (Oxidative stressOxidative stress)) Defects in Membrane PermeabilityDefects in Membrane Permeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Na+K+ATPase (Na-pump) Ca2+Mg2+ ATPases (Ca-pump)
CausesCauses
Hypoxia Ischemia
Chemical Injury
Membrane transport
Protein synthesis Lipogenesis etc
ATP
ATP depletionATP depletion lt5-10 of normal lt5-10 of normalbull ATP use gt ATP synthesis is a common consequence of ATP use gt ATP synthesis is a common consequence of
both ischemic amp toxic injuryboth ischemic amp toxic injurybull ATP production occurs via 2 related mechanismATP production occurs via 2 related mechanism
Glycolysis ndash cytosolic low yield lactate production (darrpH)Glycolysis ndash cytosolic low yield lactate production (darrpH) Oxidative phosphorylation ndash mitochondrial high yieldOxidative phosphorylation ndash mitochondrial high yield
bull Hypoxia results in uarred glycolysis (depletion of glycogen amp Hypoxia results in uarred glycolysis (depletion of glycogen amp darrpH)darrpH)
bull ATP is critical forATP is critical for Membrane transportMembrane transport Maintenance of ionic gradients ( Na+ K+ Ca2+)Maintenance of ionic gradients ( Na+ K+ Ca2+) Protein synthesisProtein synthesis Cytoskeletal function (microfilaments)Cytoskeletal function (microfilaments)
Na+
K+
Ca2+
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
CausesCauses
Hypoxia Toxins
Cytosolic Ca2+
Oxidative stress
Lipid breakdown product
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
bull Mitochondrial permeability transition of inner membrane (formation of high-conductance high-conductance channelchannel)
bull Leakage of Cytochrome cCytochrome c into cytosol
ATP productionATP production
Mitochondrial Oxidative Phosphorylation
Mitochondrial damageMitochondrial damagebull May occur directly due to hypoxia or increased Ca2+ May occur directly due to hypoxia or increased Ca2+
oxidative stress or phospholipids breakdownoxidative stress or phospholipids breakdownbull Damage results in the formation of a high-Damage results in the formation of a high-
conductance channel that dissipates the H+ ion conductance channel that dissipates the H+ ion gradient across the inner membrane (mitochondrial gradient across the inner membrane (mitochondrial permeability transition (MPT)) Mitochondrial permeability transition (MPT)) Mitochondrial membrane damage can result in Cytochrome C membrane damage can result in Cytochrome C leakage which can trigger apoptosisleakage which can trigger apoptosis
Defects in membrane permeabilityDefects in membrane permeabilitybull Membranes may be damaged directly by toxins Membranes may be damaged directly by toxins
physical chemical agents activated complement physical chemical agents activated complement components and perforins components and perforins
bull Increased cell membrane permeability disrupts Increased cell membrane permeability disrupts intracellular osmolarity and enzyme activityintracellular osmolarity and enzyme activity
bull Organelle membrane defects cause organelle Organelle membrane defects cause organelle dysfunction and failure dysfunction and failure
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mitochondrial Mitochondrial DamageDamage
Influx of Intracellular Calcium Influx of Intracellular Calcium and Loss of Calcium and Loss of Calcium
HomeostasisHomeostasis
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of O2 Accumulation of O2 derived free radicalsderived free radicals
bull Partially reduced highly Partially reduced highly reactive unstable oxygen reactive unstable oxygen moieties are able tomoieties are able to
Induce the formation of Induce the formation of more free radicals more free radicals (propagation)(propagation)
Damage lipids by Damage lipids by peroxidation of double peroxidation of double bonds resulting in breakagebonds resulting in breakage
Damage protein by Damage protein by oxidation and oxidation and fragmentationfragmentation
Damage nucleic acids Damage nucleic acids ( chain breakage)( chain breakage)
bull Free radical formation occurs Free radical formation occurs byby
Absorption of radiant Absorption of radiant energy (H2O rarr O∙ + OH∙)energy (H2O rarr O∙ + OH∙)
Metabolism of exogenous Metabolism of exogenous chemicals and drugschemicals and drugs
Normal metabolic Normal metabolic oxidation-reduction oxidation-reduction reactions (O2- H2O2 OH∙)reactions (O2- H2O2 OH∙)
Transition metals (Fe Cu Transition metals (Fe Cu etc) can catalyze radical etc) can catalyze radical formationformation
Nitric oxide can act directly Nitric oxide can act directly as a free radical or be as a free radical or be converted to other highly converted to other highly reactive formsreactive forms
Free radical defenseFree radical defensebull Free radicals are highly Free radicals are highly
unstable and generally unstable and generally decay spontaneouslydecay spontaneously
bull Antioxidants block the Antioxidants block the formation or scavenge formation or scavenge them ( Vitamin E C A them ( Vitamin E C A GSH) GSH)
bull Transition metals are Transition metals are usually tightly bound to usually tightly bound to carrier proteins carrier proteins (transferring ferritin (transferring ferritin lactoferin lactoferin ceruloplasmin) release ceruloplasmin) release and use are highly and use are highly regulatedregulated
bull Free radical scavenging Free radical scavenging systems defuse radicals systems defuse radicals rapidlyrapidly
CatalaseCatalase Glutathione oxidaseGlutathione oxidase Superoxide dismutaseSuperoxide dismutase
Free RadicalsFree Radicals
11 Free radicalsFree radicals11 Unstable oxygen Unstable oxygen
speciesspecies
22 Damage and break Damage and break lipids proteins and lipids proteins and nucleic acidsnucleic acids
33 Formed by normal Formed by normal metabolismmetabolism
44 Energy absorptionEnergy absorption
55 Metabolism of Metabolism of chemicals and drugschemicals and drugs
11 Free Radical Free Radical DefenseDefense11 Spontaneous Spontaneous
decaydecay
22 AntioxidantsAntioxidants
33 Free radical Free radical scavenging scavenging systemssystems
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Genetics DerangementsGenetics Derangements
Congenital malformation ndash Congenital malformation ndash Down Down syndromesyndrome
Decreased life of red blood cell ndash Decreased life of red blood cell ndash Thalassemia Sickle cell anemiaThalassemia Sickle cell anemia
Inborn errors of metabolismInborn errors of metabolism
Causes of Cell InjuryCauses of Cell Injury
Nutritional ImbalancesNutritional Imbalances
Protein-calorie deficienciesProtein-calorie deficiencies Vitamin deficienciesVitamin deficiencies Anorexia nervosaAnorexia nervosa Excesses of lipids ndash Excesses of lipids ndash ObesityObesity
AtherosclerosisAtherosclerosis Metabolic diseasesMetabolic diseases ndashndash Diabetes Diabetes
Causes of Cell InjuryCauses of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury Depletion of ATPDepletion of ATP Mitochondrial DamageMitochondrial Damage Influx of Intracellular Calcium and Loss of Influx of Intracellular Calcium and Loss of
Calcium HomeostasisCalcium Homeostasis Accumulation of Oxygen-Derived free Accumulation of Oxygen-Derived free
radical (radical (Oxidative stressOxidative stress)) Defects in Membrane PermeabilityDefects in Membrane Permeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Na+K+ATPase (Na-pump) Ca2+Mg2+ ATPases (Ca-pump)
CausesCauses
Hypoxia Ischemia
Chemical Injury
Membrane transport
Protein synthesis Lipogenesis etc
ATP
ATP depletionATP depletion lt5-10 of normal lt5-10 of normalbull ATP use gt ATP synthesis is a common consequence of ATP use gt ATP synthesis is a common consequence of
both ischemic amp toxic injuryboth ischemic amp toxic injurybull ATP production occurs via 2 related mechanismATP production occurs via 2 related mechanism
Glycolysis ndash cytosolic low yield lactate production (darrpH)Glycolysis ndash cytosolic low yield lactate production (darrpH) Oxidative phosphorylation ndash mitochondrial high yieldOxidative phosphorylation ndash mitochondrial high yield
bull Hypoxia results in uarred glycolysis (depletion of glycogen amp Hypoxia results in uarred glycolysis (depletion of glycogen amp darrpH)darrpH)
bull ATP is critical forATP is critical for Membrane transportMembrane transport Maintenance of ionic gradients ( Na+ K+ Ca2+)Maintenance of ionic gradients ( Na+ K+ Ca2+) Protein synthesisProtein synthesis Cytoskeletal function (microfilaments)Cytoskeletal function (microfilaments)
Na+
K+
Ca2+
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
CausesCauses
Hypoxia Toxins
Cytosolic Ca2+
Oxidative stress
Lipid breakdown product
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
bull Mitochondrial permeability transition of inner membrane (formation of high-conductance high-conductance channelchannel)
bull Leakage of Cytochrome cCytochrome c into cytosol
ATP productionATP production
Mitochondrial Oxidative Phosphorylation
Mitochondrial damageMitochondrial damagebull May occur directly due to hypoxia or increased Ca2+ May occur directly due to hypoxia or increased Ca2+
oxidative stress or phospholipids breakdownoxidative stress or phospholipids breakdownbull Damage results in the formation of a high-Damage results in the formation of a high-
conductance channel that dissipates the H+ ion conductance channel that dissipates the H+ ion gradient across the inner membrane (mitochondrial gradient across the inner membrane (mitochondrial permeability transition (MPT)) Mitochondrial permeability transition (MPT)) Mitochondrial membrane damage can result in Cytochrome C membrane damage can result in Cytochrome C leakage which can trigger apoptosisleakage which can trigger apoptosis
Defects in membrane permeabilityDefects in membrane permeabilitybull Membranes may be damaged directly by toxins Membranes may be damaged directly by toxins
physical chemical agents activated complement physical chemical agents activated complement components and perforins components and perforins
bull Increased cell membrane permeability disrupts Increased cell membrane permeability disrupts intracellular osmolarity and enzyme activityintracellular osmolarity and enzyme activity
bull Organelle membrane defects cause organelle Organelle membrane defects cause organelle dysfunction and failure dysfunction and failure
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mitochondrial Mitochondrial DamageDamage
Influx of Intracellular Calcium Influx of Intracellular Calcium and Loss of Calcium and Loss of Calcium
HomeostasisHomeostasis
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of O2 Accumulation of O2 derived free radicalsderived free radicals
bull Partially reduced highly Partially reduced highly reactive unstable oxygen reactive unstable oxygen moieties are able tomoieties are able to
Induce the formation of Induce the formation of more free radicals more free radicals (propagation)(propagation)
Damage lipids by Damage lipids by peroxidation of double peroxidation of double bonds resulting in breakagebonds resulting in breakage
Damage protein by Damage protein by oxidation and oxidation and fragmentationfragmentation
Damage nucleic acids Damage nucleic acids ( chain breakage)( chain breakage)
bull Free radical formation occurs Free radical formation occurs byby
Absorption of radiant Absorption of radiant energy (H2O rarr O∙ + OH∙)energy (H2O rarr O∙ + OH∙)
Metabolism of exogenous Metabolism of exogenous chemicals and drugschemicals and drugs
Normal metabolic Normal metabolic oxidation-reduction oxidation-reduction reactions (O2- H2O2 OH∙)reactions (O2- H2O2 OH∙)
Transition metals (Fe Cu Transition metals (Fe Cu etc) can catalyze radical etc) can catalyze radical formationformation
Nitric oxide can act directly Nitric oxide can act directly as a free radical or be as a free radical or be converted to other highly converted to other highly reactive formsreactive forms
Free radical defenseFree radical defensebull Free radicals are highly Free radicals are highly
unstable and generally unstable and generally decay spontaneouslydecay spontaneously
bull Antioxidants block the Antioxidants block the formation or scavenge formation or scavenge them ( Vitamin E C A them ( Vitamin E C A GSH) GSH)
bull Transition metals are Transition metals are usually tightly bound to usually tightly bound to carrier proteins carrier proteins (transferring ferritin (transferring ferritin lactoferin lactoferin ceruloplasmin) release ceruloplasmin) release and use are highly and use are highly regulatedregulated
bull Free radical scavenging Free radical scavenging systems defuse radicals systems defuse radicals rapidlyrapidly
CatalaseCatalase Glutathione oxidaseGlutathione oxidase Superoxide dismutaseSuperoxide dismutase
Free RadicalsFree Radicals
11 Free radicalsFree radicals11 Unstable oxygen Unstable oxygen
speciesspecies
22 Damage and break Damage and break lipids proteins and lipids proteins and nucleic acidsnucleic acids
33 Formed by normal Formed by normal metabolismmetabolism
44 Energy absorptionEnergy absorption
55 Metabolism of Metabolism of chemicals and drugschemicals and drugs
11 Free Radical Free Radical DefenseDefense11 Spontaneous Spontaneous
decaydecay
22 AntioxidantsAntioxidants
33 Free radical Free radical scavenging scavenging systemssystems
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Nutritional ImbalancesNutritional Imbalances
Protein-calorie deficienciesProtein-calorie deficiencies Vitamin deficienciesVitamin deficiencies Anorexia nervosaAnorexia nervosa Excesses of lipids ndash Excesses of lipids ndash ObesityObesity
AtherosclerosisAtherosclerosis Metabolic diseasesMetabolic diseases ndashndash Diabetes Diabetes
Causes of Cell InjuryCauses of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury Depletion of ATPDepletion of ATP Mitochondrial DamageMitochondrial Damage Influx of Intracellular Calcium and Loss of Influx of Intracellular Calcium and Loss of
Calcium HomeostasisCalcium Homeostasis Accumulation of Oxygen-Derived free Accumulation of Oxygen-Derived free
radical (radical (Oxidative stressOxidative stress)) Defects in Membrane PermeabilityDefects in Membrane Permeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Na+K+ATPase (Na-pump) Ca2+Mg2+ ATPases (Ca-pump)
CausesCauses
Hypoxia Ischemia
Chemical Injury
Membrane transport
Protein synthesis Lipogenesis etc
ATP
ATP depletionATP depletion lt5-10 of normal lt5-10 of normalbull ATP use gt ATP synthesis is a common consequence of ATP use gt ATP synthesis is a common consequence of
both ischemic amp toxic injuryboth ischemic amp toxic injurybull ATP production occurs via 2 related mechanismATP production occurs via 2 related mechanism
Glycolysis ndash cytosolic low yield lactate production (darrpH)Glycolysis ndash cytosolic low yield lactate production (darrpH) Oxidative phosphorylation ndash mitochondrial high yieldOxidative phosphorylation ndash mitochondrial high yield
bull Hypoxia results in uarred glycolysis (depletion of glycogen amp Hypoxia results in uarred glycolysis (depletion of glycogen amp darrpH)darrpH)
bull ATP is critical forATP is critical for Membrane transportMembrane transport Maintenance of ionic gradients ( Na+ K+ Ca2+)Maintenance of ionic gradients ( Na+ K+ Ca2+) Protein synthesisProtein synthesis Cytoskeletal function (microfilaments)Cytoskeletal function (microfilaments)
Na+
K+
Ca2+
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
CausesCauses
Hypoxia Toxins
Cytosolic Ca2+
Oxidative stress
Lipid breakdown product
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
bull Mitochondrial permeability transition of inner membrane (formation of high-conductance high-conductance channelchannel)
bull Leakage of Cytochrome cCytochrome c into cytosol
ATP productionATP production
Mitochondrial Oxidative Phosphorylation
Mitochondrial damageMitochondrial damagebull May occur directly due to hypoxia or increased Ca2+ May occur directly due to hypoxia or increased Ca2+
oxidative stress or phospholipids breakdownoxidative stress or phospholipids breakdownbull Damage results in the formation of a high-Damage results in the formation of a high-
conductance channel that dissipates the H+ ion conductance channel that dissipates the H+ ion gradient across the inner membrane (mitochondrial gradient across the inner membrane (mitochondrial permeability transition (MPT)) Mitochondrial permeability transition (MPT)) Mitochondrial membrane damage can result in Cytochrome C membrane damage can result in Cytochrome C leakage which can trigger apoptosisleakage which can trigger apoptosis
Defects in membrane permeabilityDefects in membrane permeabilitybull Membranes may be damaged directly by toxins Membranes may be damaged directly by toxins
physical chemical agents activated complement physical chemical agents activated complement components and perforins components and perforins
bull Increased cell membrane permeability disrupts Increased cell membrane permeability disrupts intracellular osmolarity and enzyme activityintracellular osmolarity and enzyme activity
bull Organelle membrane defects cause organelle Organelle membrane defects cause organelle dysfunction and failure dysfunction and failure
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mitochondrial Mitochondrial DamageDamage
Influx of Intracellular Calcium Influx of Intracellular Calcium and Loss of Calcium and Loss of Calcium
HomeostasisHomeostasis
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of O2 Accumulation of O2 derived free radicalsderived free radicals
bull Partially reduced highly Partially reduced highly reactive unstable oxygen reactive unstable oxygen moieties are able tomoieties are able to
Induce the formation of Induce the formation of more free radicals more free radicals (propagation)(propagation)
Damage lipids by Damage lipids by peroxidation of double peroxidation of double bonds resulting in breakagebonds resulting in breakage
Damage protein by Damage protein by oxidation and oxidation and fragmentationfragmentation
Damage nucleic acids Damage nucleic acids ( chain breakage)( chain breakage)
bull Free radical formation occurs Free radical formation occurs byby
Absorption of radiant Absorption of radiant energy (H2O rarr O∙ + OH∙)energy (H2O rarr O∙ + OH∙)
Metabolism of exogenous Metabolism of exogenous chemicals and drugschemicals and drugs
Normal metabolic Normal metabolic oxidation-reduction oxidation-reduction reactions (O2- H2O2 OH∙)reactions (O2- H2O2 OH∙)
Transition metals (Fe Cu Transition metals (Fe Cu etc) can catalyze radical etc) can catalyze radical formationformation
Nitric oxide can act directly Nitric oxide can act directly as a free radical or be as a free radical or be converted to other highly converted to other highly reactive formsreactive forms
Free radical defenseFree radical defensebull Free radicals are highly Free radicals are highly
unstable and generally unstable and generally decay spontaneouslydecay spontaneously
bull Antioxidants block the Antioxidants block the formation or scavenge formation or scavenge them ( Vitamin E C A them ( Vitamin E C A GSH) GSH)
bull Transition metals are Transition metals are usually tightly bound to usually tightly bound to carrier proteins carrier proteins (transferring ferritin (transferring ferritin lactoferin lactoferin ceruloplasmin) release ceruloplasmin) release and use are highly and use are highly regulatedregulated
bull Free radical scavenging Free radical scavenging systems defuse radicals systems defuse radicals rapidlyrapidly
CatalaseCatalase Glutathione oxidaseGlutathione oxidase Superoxide dismutaseSuperoxide dismutase
Free RadicalsFree Radicals
11 Free radicalsFree radicals11 Unstable oxygen Unstable oxygen
speciesspecies
22 Damage and break Damage and break lipids proteins and lipids proteins and nucleic acidsnucleic acids
33 Formed by normal Formed by normal metabolismmetabolism
44 Energy absorptionEnergy absorption
55 Metabolism of Metabolism of chemicals and drugschemicals and drugs
11 Free Radical Free Radical DefenseDefense11 Spontaneous Spontaneous
decaydecay
22 AntioxidantsAntioxidants
33 Free radical Free radical scavenging scavenging systemssystems
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Mechanisms of Cell InjuryMechanisms of Cell Injury Depletion of ATPDepletion of ATP Mitochondrial DamageMitochondrial Damage Influx of Intracellular Calcium and Loss of Influx of Intracellular Calcium and Loss of
Calcium HomeostasisCalcium Homeostasis Accumulation of Oxygen-Derived free Accumulation of Oxygen-Derived free
radical (radical (Oxidative stressOxidative stress)) Defects in Membrane PermeabilityDefects in Membrane Permeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Na+K+ATPase (Na-pump) Ca2+Mg2+ ATPases (Ca-pump)
CausesCauses
Hypoxia Ischemia
Chemical Injury
Membrane transport
Protein synthesis Lipogenesis etc
ATP
ATP depletionATP depletion lt5-10 of normal lt5-10 of normalbull ATP use gt ATP synthesis is a common consequence of ATP use gt ATP synthesis is a common consequence of
both ischemic amp toxic injuryboth ischemic amp toxic injurybull ATP production occurs via 2 related mechanismATP production occurs via 2 related mechanism
Glycolysis ndash cytosolic low yield lactate production (darrpH)Glycolysis ndash cytosolic low yield lactate production (darrpH) Oxidative phosphorylation ndash mitochondrial high yieldOxidative phosphorylation ndash mitochondrial high yield
bull Hypoxia results in uarred glycolysis (depletion of glycogen amp Hypoxia results in uarred glycolysis (depletion of glycogen amp darrpH)darrpH)
bull ATP is critical forATP is critical for Membrane transportMembrane transport Maintenance of ionic gradients ( Na+ K+ Ca2+)Maintenance of ionic gradients ( Na+ K+ Ca2+) Protein synthesisProtein synthesis Cytoskeletal function (microfilaments)Cytoskeletal function (microfilaments)
Na+
K+
Ca2+
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
CausesCauses
Hypoxia Toxins
Cytosolic Ca2+
Oxidative stress
Lipid breakdown product
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
bull Mitochondrial permeability transition of inner membrane (formation of high-conductance high-conductance channelchannel)
bull Leakage of Cytochrome cCytochrome c into cytosol
ATP productionATP production
Mitochondrial Oxidative Phosphorylation
Mitochondrial damageMitochondrial damagebull May occur directly due to hypoxia or increased Ca2+ May occur directly due to hypoxia or increased Ca2+
oxidative stress or phospholipids breakdownoxidative stress or phospholipids breakdownbull Damage results in the formation of a high-Damage results in the formation of a high-
conductance channel that dissipates the H+ ion conductance channel that dissipates the H+ ion gradient across the inner membrane (mitochondrial gradient across the inner membrane (mitochondrial permeability transition (MPT)) Mitochondrial permeability transition (MPT)) Mitochondrial membrane damage can result in Cytochrome C membrane damage can result in Cytochrome C leakage which can trigger apoptosisleakage which can trigger apoptosis
Defects in membrane permeabilityDefects in membrane permeabilitybull Membranes may be damaged directly by toxins Membranes may be damaged directly by toxins
physical chemical agents activated complement physical chemical agents activated complement components and perforins components and perforins
bull Increased cell membrane permeability disrupts Increased cell membrane permeability disrupts intracellular osmolarity and enzyme activityintracellular osmolarity and enzyme activity
bull Organelle membrane defects cause organelle Organelle membrane defects cause organelle dysfunction and failure dysfunction and failure
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mitochondrial Mitochondrial DamageDamage
Influx of Intracellular Calcium Influx of Intracellular Calcium and Loss of Calcium and Loss of Calcium
HomeostasisHomeostasis
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of O2 Accumulation of O2 derived free radicalsderived free radicals
bull Partially reduced highly Partially reduced highly reactive unstable oxygen reactive unstable oxygen moieties are able tomoieties are able to
Induce the formation of Induce the formation of more free radicals more free radicals (propagation)(propagation)
Damage lipids by Damage lipids by peroxidation of double peroxidation of double bonds resulting in breakagebonds resulting in breakage
Damage protein by Damage protein by oxidation and oxidation and fragmentationfragmentation
Damage nucleic acids Damage nucleic acids ( chain breakage)( chain breakage)
bull Free radical formation occurs Free radical formation occurs byby
Absorption of radiant Absorption of radiant energy (H2O rarr O∙ + OH∙)energy (H2O rarr O∙ + OH∙)
Metabolism of exogenous Metabolism of exogenous chemicals and drugschemicals and drugs
Normal metabolic Normal metabolic oxidation-reduction oxidation-reduction reactions (O2- H2O2 OH∙)reactions (O2- H2O2 OH∙)
Transition metals (Fe Cu Transition metals (Fe Cu etc) can catalyze radical etc) can catalyze radical formationformation
Nitric oxide can act directly Nitric oxide can act directly as a free radical or be as a free radical or be converted to other highly converted to other highly reactive formsreactive forms
Free radical defenseFree radical defensebull Free radicals are highly Free radicals are highly
unstable and generally unstable and generally decay spontaneouslydecay spontaneously
bull Antioxidants block the Antioxidants block the formation or scavenge formation or scavenge them ( Vitamin E C A them ( Vitamin E C A GSH) GSH)
bull Transition metals are Transition metals are usually tightly bound to usually tightly bound to carrier proteins carrier proteins (transferring ferritin (transferring ferritin lactoferin lactoferin ceruloplasmin) release ceruloplasmin) release and use are highly and use are highly regulatedregulated
bull Free radical scavenging Free radical scavenging systems defuse radicals systems defuse radicals rapidlyrapidly
CatalaseCatalase Glutathione oxidaseGlutathione oxidase Superoxide dismutaseSuperoxide dismutase
Free RadicalsFree Radicals
11 Free radicalsFree radicals11 Unstable oxygen Unstable oxygen
speciesspecies
22 Damage and break Damage and break lipids proteins and lipids proteins and nucleic acidsnucleic acids
33 Formed by normal Formed by normal metabolismmetabolism
44 Energy absorptionEnergy absorption
55 Metabolism of Metabolism of chemicals and drugschemicals and drugs
11 Free Radical Free Radical DefenseDefense11 Spontaneous Spontaneous
decaydecay
22 AntioxidantsAntioxidants
33 Free radical Free radical scavenging scavenging systemssystems
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Na+K+ATPase (Na-pump) Ca2+Mg2+ ATPases (Ca-pump)
CausesCauses
Hypoxia Ischemia
Chemical Injury
Membrane transport
Protein synthesis Lipogenesis etc
ATP
ATP depletionATP depletion lt5-10 of normal lt5-10 of normalbull ATP use gt ATP synthesis is a common consequence of ATP use gt ATP synthesis is a common consequence of
both ischemic amp toxic injuryboth ischemic amp toxic injurybull ATP production occurs via 2 related mechanismATP production occurs via 2 related mechanism
Glycolysis ndash cytosolic low yield lactate production (darrpH)Glycolysis ndash cytosolic low yield lactate production (darrpH) Oxidative phosphorylation ndash mitochondrial high yieldOxidative phosphorylation ndash mitochondrial high yield
bull Hypoxia results in uarred glycolysis (depletion of glycogen amp Hypoxia results in uarred glycolysis (depletion of glycogen amp darrpH)darrpH)
bull ATP is critical forATP is critical for Membrane transportMembrane transport Maintenance of ionic gradients ( Na+ K+ Ca2+)Maintenance of ionic gradients ( Na+ K+ Ca2+) Protein synthesisProtein synthesis Cytoskeletal function (microfilaments)Cytoskeletal function (microfilaments)
Na+
K+
Ca2+
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
CausesCauses
Hypoxia Toxins
Cytosolic Ca2+
Oxidative stress
Lipid breakdown product
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
bull Mitochondrial permeability transition of inner membrane (formation of high-conductance high-conductance channelchannel)
bull Leakage of Cytochrome cCytochrome c into cytosol
ATP productionATP production
Mitochondrial Oxidative Phosphorylation
Mitochondrial damageMitochondrial damagebull May occur directly due to hypoxia or increased Ca2+ May occur directly due to hypoxia or increased Ca2+
oxidative stress or phospholipids breakdownoxidative stress or phospholipids breakdownbull Damage results in the formation of a high-Damage results in the formation of a high-
conductance channel that dissipates the H+ ion conductance channel that dissipates the H+ ion gradient across the inner membrane (mitochondrial gradient across the inner membrane (mitochondrial permeability transition (MPT)) Mitochondrial permeability transition (MPT)) Mitochondrial membrane damage can result in Cytochrome C membrane damage can result in Cytochrome C leakage which can trigger apoptosisleakage which can trigger apoptosis
Defects in membrane permeabilityDefects in membrane permeabilitybull Membranes may be damaged directly by toxins Membranes may be damaged directly by toxins
physical chemical agents activated complement physical chemical agents activated complement components and perforins components and perforins
bull Increased cell membrane permeability disrupts Increased cell membrane permeability disrupts intracellular osmolarity and enzyme activityintracellular osmolarity and enzyme activity
bull Organelle membrane defects cause organelle Organelle membrane defects cause organelle dysfunction and failure dysfunction and failure
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mitochondrial Mitochondrial DamageDamage
Influx of Intracellular Calcium Influx of Intracellular Calcium and Loss of Calcium and Loss of Calcium
HomeostasisHomeostasis
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of O2 Accumulation of O2 derived free radicalsderived free radicals
bull Partially reduced highly Partially reduced highly reactive unstable oxygen reactive unstable oxygen moieties are able tomoieties are able to
Induce the formation of Induce the formation of more free radicals more free radicals (propagation)(propagation)
Damage lipids by Damage lipids by peroxidation of double peroxidation of double bonds resulting in breakagebonds resulting in breakage
Damage protein by Damage protein by oxidation and oxidation and fragmentationfragmentation
Damage nucleic acids Damage nucleic acids ( chain breakage)( chain breakage)
bull Free radical formation occurs Free radical formation occurs byby
Absorption of radiant Absorption of radiant energy (H2O rarr O∙ + OH∙)energy (H2O rarr O∙ + OH∙)
Metabolism of exogenous Metabolism of exogenous chemicals and drugschemicals and drugs
Normal metabolic Normal metabolic oxidation-reduction oxidation-reduction reactions (O2- H2O2 OH∙)reactions (O2- H2O2 OH∙)
Transition metals (Fe Cu Transition metals (Fe Cu etc) can catalyze radical etc) can catalyze radical formationformation
Nitric oxide can act directly Nitric oxide can act directly as a free radical or be as a free radical or be converted to other highly converted to other highly reactive formsreactive forms
Free radical defenseFree radical defensebull Free radicals are highly Free radicals are highly
unstable and generally unstable and generally decay spontaneouslydecay spontaneously
bull Antioxidants block the Antioxidants block the formation or scavenge formation or scavenge them ( Vitamin E C A them ( Vitamin E C A GSH) GSH)
bull Transition metals are Transition metals are usually tightly bound to usually tightly bound to carrier proteins carrier proteins (transferring ferritin (transferring ferritin lactoferin lactoferin ceruloplasmin) release ceruloplasmin) release and use are highly and use are highly regulatedregulated
bull Free radical scavenging Free radical scavenging systems defuse radicals systems defuse radicals rapidlyrapidly
CatalaseCatalase Glutathione oxidaseGlutathione oxidase Superoxide dismutaseSuperoxide dismutase
Free RadicalsFree Radicals
11 Free radicalsFree radicals11 Unstable oxygen Unstable oxygen
speciesspecies
22 Damage and break Damage and break lipids proteins and lipids proteins and nucleic acidsnucleic acids
33 Formed by normal Formed by normal metabolismmetabolism
44 Energy absorptionEnergy absorption
55 Metabolism of Metabolism of chemicals and drugschemicals and drugs
11 Free Radical Free Radical DefenseDefense11 Spontaneous Spontaneous
decaydecay
22 AntioxidantsAntioxidants
33 Free radical Free radical scavenging scavenging systemssystems
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
ATP depletionATP depletion lt5-10 of normal lt5-10 of normalbull ATP use gt ATP synthesis is a common consequence of ATP use gt ATP synthesis is a common consequence of
both ischemic amp toxic injuryboth ischemic amp toxic injurybull ATP production occurs via 2 related mechanismATP production occurs via 2 related mechanism
Glycolysis ndash cytosolic low yield lactate production (darrpH)Glycolysis ndash cytosolic low yield lactate production (darrpH) Oxidative phosphorylation ndash mitochondrial high yieldOxidative phosphorylation ndash mitochondrial high yield
bull Hypoxia results in uarred glycolysis (depletion of glycogen amp Hypoxia results in uarred glycolysis (depletion of glycogen amp darrpH)darrpH)
bull ATP is critical forATP is critical for Membrane transportMembrane transport Maintenance of ionic gradients ( Na+ K+ Ca2+)Maintenance of ionic gradients ( Na+ K+ Ca2+) Protein synthesisProtein synthesis Cytoskeletal function (microfilaments)Cytoskeletal function (microfilaments)
Na+
K+
Ca2+
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
CausesCauses
Hypoxia Toxins
Cytosolic Ca2+
Oxidative stress
Lipid breakdown product
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
bull Mitochondrial permeability transition of inner membrane (formation of high-conductance high-conductance channelchannel)
bull Leakage of Cytochrome cCytochrome c into cytosol
ATP productionATP production
Mitochondrial Oxidative Phosphorylation
Mitochondrial damageMitochondrial damagebull May occur directly due to hypoxia or increased Ca2+ May occur directly due to hypoxia or increased Ca2+
oxidative stress or phospholipids breakdownoxidative stress or phospholipids breakdownbull Damage results in the formation of a high-Damage results in the formation of a high-
conductance channel that dissipates the H+ ion conductance channel that dissipates the H+ ion gradient across the inner membrane (mitochondrial gradient across the inner membrane (mitochondrial permeability transition (MPT)) Mitochondrial permeability transition (MPT)) Mitochondrial membrane damage can result in Cytochrome C membrane damage can result in Cytochrome C leakage which can trigger apoptosisleakage which can trigger apoptosis
Defects in membrane permeabilityDefects in membrane permeabilitybull Membranes may be damaged directly by toxins Membranes may be damaged directly by toxins
physical chemical agents activated complement physical chemical agents activated complement components and perforins components and perforins
bull Increased cell membrane permeability disrupts Increased cell membrane permeability disrupts intracellular osmolarity and enzyme activityintracellular osmolarity and enzyme activity
bull Organelle membrane defects cause organelle Organelle membrane defects cause organelle dysfunction and failure dysfunction and failure
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mitochondrial Mitochondrial DamageDamage
Influx of Intracellular Calcium Influx of Intracellular Calcium and Loss of Calcium and Loss of Calcium
HomeostasisHomeostasis
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of O2 Accumulation of O2 derived free radicalsderived free radicals
bull Partially reduced highly Partially reduced highly reactive unstable oxygen reactive unstable oxygen moieties are able tomoieties are able to
Induce the formation of Induce the formation of more free radicals more free radicals (propagation)(propagation)
Damage lipids by Damage lipids by peroxidation of double peroxidation of double bonds resulting in breakagebonds resulting in breakage
Damage protein by Damage protein by oxidation and oxidation and fragmentationfragmentation
Damage nucleic acids Damage nucleic acids ( chain breakage)( chain breakage)
bull Free radical formation occurs Free radical formation occurs byby
Absorption of radiant Absorption of radiant energy (H2O rarr O∙ + OH∙)energy (H2O rarr O∙ + OH∙)
Metabolism of exogenous Metabolism of exogenous chemicals and drugschemicals and drugs
Normal metabolic Normal metabolic oxidation-reduction oxidation-reduction reactions (O2- H2O2 OH∙)reactions (O2- H2O2 OH∙)
Transition metals (Fe Cu Transition metals (Fe Cu etc) can catalyze radical etc) can catalyze radical formationformation
Nitric oxide can act directly Nitric oxide can act directly as a free radical or be as a free radical or be converted to other highly converted to other highly reactive formsreactive forms
Free radical defenseFree radical defensebull Free radicals are highly Free radicals are highly
unstable and generally unstable and generally decay spontaneouslydecay spontaneously
bull Antioxidants block the Antioxidants block the formation or scavenge formation or scavenge them ( Vitamin E C A them ( Vitamin E C A GSH) GSH)
bull Transition metals are Transition metals are usually tightly bound to usually tightly bound to carrier proteins carrier proteins (transferring ferritin (transferring ferritin lactoferin lactoferin ceruloplasmin) release ceruloplasmin) release and use are highly and use are highly regulatedregulated
bull Free radical scavenging Free radical scavenging systems defuse radicals systems defuse radicals rapidlyrapidly
CatalaseCatalase Glutathione oxidaseGlutathione oxidase Superoxide dismutaseSuperoxide dismutase
Free RadicalsFree Radicals
11 Free radicalsFree radicals11 Unstable oxygen Unstable oxygen
speciesspecies
22 Damage and break Damage and break lipids proteins and lipids proteins and nucleic acidsnucleic acids
33 Formed by normal Formed by normal metabolismmetabolism
44 Energy absorptionEnergy absorption
55 Metabolism of Metabolism of chemicals and drugschemicals and drugs
11 Free Radical Free Radical DefenseDefense11 Spontaneous Spontaneous
decaydecay
22 AntioxidantsAntioxidants
33 Free radical Free radical scavenging scavenging systemssystems
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Na+
K+
Ca2+
Mechanisms of Cell InjuryMechanisms of Cell Injury
Depletion of ATPDepletion of ATP
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
CausesCauses
Hypoxia Toxins
Cytosolic Ca2+
Oxidative stress
Lipid breakdown product
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
bull Mitochondrial permeability transition of inner membrane (formation of high-conductance high-conductance channelchannel)
bull Leakage of Cytochrome cCytochrome c into cytosol
ATP productionATP production
Mitochondrial Oxidative Phosphorylation
Mitochondrial damageMitochondrial damagebull May occur directly due to hypoxia or increased Ca2+ May occur directly due to hypoxia or increased Ca2+
oxidative stress or phospholipids breakdownoxidative stress or phospholipids breakdownbull Damage results in the formation of a high-Damage results in the formation of a high-
conductance channel that dissipates the H+ ion conductance channel that dissipates the H+ ion gradient across the inner membrane (mitochondrial gradient across the inner membrane (mitochondrial permeability transition (MPT)) Mitochondrial permeability transition (MPT)) Mitochondrial membrane damage can result in Cytochrome C membrane damage can result in Cytochrome C leakage which can trigger apoptosisleakage which can trigger apoptosis
Defects in membrane permeabilityDefects in membrane permeabilitybull Membranes may be damaged directly by toxins Membranes may be damaged directly by toxins
physical chemical agents activated complement physical chemical agents activated complement components and perforins components and perforins
bull Increased cell membrane permeability disrupts Increased cell membrane permeability disrupts intracellular osmolarity and enzyme activityintracellular osmolarity and enzyme activity
bull Organelle membrane defects cause organelle Organelle membrane defects cause organelle dysfunction and failure dysfunction and failure
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mitochondrial Mitochondrial DamageDamage
Influx of Intracellular Calcium Influx of Intracellular Calcium and Loss of Calcium and Loss of Calcium
HomeostasisHomeostasis
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of O2 Accumulation of O2 derived free radicalsderived free radicals
bull Partially reduced highly Partially reduced highly reactive unstable oxygen reactive unstable oxygen moieties are able tomoieties are able to
Induce the formation of Induce the formation of more free radicals more free radicals (propagation)(propagation)
Damage lipids by Damage lipids by peroxidation of double peroxidation of double bonds resulting in breakagebonds resulting in breakage
Damage protein by Damage protein by oxidation and oxidation and fragmentationfragmentation
Damage nucleic acids Damage nucleic acids ( chain breakage)( chain breakage)
bull Free radical formation occurs Free radical formation occurs byby
Absorption of radiant Absorption of radiant energy (H2O rarr O∙ + OH∙)energy (H2O rarr O∙ + OH∙)
Metabolism of exogenous Metabolism of exogenous chemicals and drugschemicals and drugs
Normal metabolic Normal metabolic oxidation-reduction oxidation-reduction reactions (O2- H2O2 OH∙)reactions (O2- H2O2 OH∙)
Transition metals (Fe Cu Transition metals (Fe Cu etc) can catalyze radical etc) can catalyze radical formationformation
Nitric oxide can act directly Nitric oxide can act directly as a free radical or be as a free radical or be converted to other highly converted to other highly reactive formsreactive forms
Free radical defenseFree radical defensebull Free radicals are highly Free radicals are highly
unstable and generally unstable and generally decay spontaneouslydecay spontaneously
bull Antioxidants block the Antioxidants block the formation or scavenge formation or scavenge them ( Vitamin E C A them ( Vitamin E C A GSH) GSH)
bull Transition metals are Transition metals are usually tightly bound to usually tightly bound to carrier proteins carrier proteins (transferring ferritin (transferring ferritin lactoferin lactoferin ceruloplasmin) release ceruloplasmin) release and use are highly and use are highly regulatedregulated
bull Free radical scavenging Free radical scavenging systems defuse radicals systems defuse radicals rapidlyrapidly
CatalaseCatalase Glutathione oxidaseGlutathione oxidase Superoxide dismutaseSuperoxide dismutase
Free RadicalsFree Radicals
11 Free radicalsFree radicals11 Unstable oxygen Unstable oxygen
speciesspecies
22 Damage and break Damage and break lipids proteins and lipids proteins and nucleic acidsnucleic acids
33 Formed by normal Formed by normal metabolismmetabolism
44 Energy absorptionEnergy absorption
55 Metabolism of Metabolism of chemicals and drugschemicals and drugs
11 Free Radical Free Radical DefenseDefense11 Spontaneous Spontaneous
decaydecay
22 AntioxidantsAntioxidants
33 Free radical Free radical scavenging scavenging systemssystems
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
CausesCauses
Hypoxia Toxins
Cytosolic Ca2+
Oxidative stress
Lipid breakdown product
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
bull Mitochondrial permeability transition of inner membrane (formation of high-conductance high-conductance channelchannel)
bull Leakage of Cytochrome cCytochrome c into cytosol
ATP productionATP production
Mitochondrial Oxidative Phosphorylation
Mitochondrial damageMitochondrial damagebull May occur directly due to hypoxia or increased Ca2+ May occur directly due to hypoxia or increased Ca2+
oxidative stress or phospholipids breakdownoxidative stress or phospholipids breakdownbull Damage results in the formation of a high-Damage results in the formation of a high-
conductance channel that dissipates the H+ ion conductance channel that dissipates the H+ ion gradient across the inner membrane (mitochondrial gradient across the inner membrane (mitochondrial permeability transition (MPT)) Mitochondrial permeability transition (MPT)) Mitochondrial membrane damage can result in Cytochrome C membrane damage can result in Cytochrome C leakage which can trigger apoptosisleakage which can trigger apoptosis
Defects in membrane permeabilityDefects in membrane permeabilitybull Membranes may be damaged directly by toxins Membranes may be damaged directly by toxins
physical chemical agents activated complement physical chemical agents activated complement components and perforins components and perforins
bull Increased cell membrane permeability disrupts Increased cell membrane permeability disrupts intracellular osmolarity and enzyme activityintracellular osmolarity and enzyme activity
bull Organelle membrane defects cause organelle Organelle membrane defects cause organelle dysfunction and failure dysfunction and failure
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mitochondrial Mitochondrial DamageDamage
Influx of Intracellular Calcium Influx of Intracellular Calcium and Loss of Calcium and Loss of Calcium
HomeostasisHomeostasis
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of O2 Accumulation of O2 derived free radicalsderived free radicals
bull Partially reduced highly Partially reduced highly reactive unstable oxygen reactive unstable oxygen moieties are able tomoieties are able to
Induce the formation of Induce the formation of more free radicals more free radicals (propagation)(propagation)
Damage lipids by Damage lipids by peroxidation of double peroxidation of double bonds resulting in breakagebonds resulting in breakage
Damage protein by Damage protein by oxidation and oxidation and fragmentationfragmentation
Damage nucleic acids Damage nucleic acids ( chain breakage)( chain breakage)
bull Free radical formation occurs Free radical formation occurs byby
Absorption of radiant Absorption of radiant energy (H2O rarr O∙ + OH∙)energy (H2O rarr O∙ + OH∙)
Metabolism of exogenous Metabolism of exogenous chemicals and drugschemicals and drugs
Normal metabolic Normal metabolic oxidation-reduction oxidation-reduction reactions (O2- H2O2 OH∙)reactions (O2- H2O2 OH∙)
Transition metals (Fe Cu Transition metals (Fe Cu etc) can catalyze radical etc) can catalyze radical formationformation
Nitric oxide can act directly Nitric oxide can act directly as a free radical or be as a free radical or be converted to other highly converted to other highly reactive formsreactive forms
Free radical defenseFree radical defensebull Free radicals are highly Free radicals are highly
unstable and generally unstable and generally decay spontaneouslydecay spontaneously
bull Antioxidants block the Antioxidants block the formation or scavenge formation or scavenge them ( Vitamin E C A them ( Vitamin E C A GSH) GSH)
bull Transition metals are Transition metals are usually tightly bound to usually tightly bound to carrier proteins carrier proteins (transferring ferritin (transferring ferritin lactoferin lactoferin ceruloplasmin) release ceruloplasmin) release and use are highly and use are highly regulatedregulated
bull Free radical scavenging Free radical scavenging systems defuse radicals systems defuse radicals rapidlyrapidly
CatalaseCatalase Glutathione oxidaseGlutathione oxidase Superoxide dismutaseSuperoxide dismutase
Free RadicalsFree Radicals
11 Free radicalsFree radicals11 Unstable oxygen Unstable oxygen
speciesspecies
22 Damage and break Damage and break lipids proteins and lipids proteins and nucleic acidsnucleic acids
33 Formed by normal Formed by normal metabolismmetabolism
44 Energy absorptionEnergy absorption
55 Metabolism of Metabolism of chemicals and drugschemicals and drugs
11 Free Radical Free Radical DefenseDefense11 Spontaneous Spontaneous
decaydecay
22 AntioxidantsAntioxidants
33 Free radical Free radical scavenging scavenging systemssystems
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury
bull Mitochondrial permeability transition of inner membrane (formation of high-conductance high-conductance channelchannel)
bull Leakage of Cytochrome cCytochrome c into cytosol
ATP productionATP production
Mitochondrial Oxidative Phosphorylation
Mitochondrial damageMitochondrial damagebull May occur directly due to hypoxia or increased Ca2+ May occur directly due to hypoxia or increased Ca2+
oxidative stress or phospholipids breakdownoxidative stress or phospholipids breakdownbull Damage results in the formation of a high-Damage results in the formation of a high-
conductance channel that dissipates the H+ ion conductance channel that dissipates the H+ ion gradient across the inner membrane (mitochondrial gradient across the inner membrane (mitochondrial permeability transition (MPT)) Mitochondrial permeability transition (MPT)) Mitochondrial membrane damage can result in Cytochrome C membrane damage can result in Cytochrome C leakage which can trigger apoptosisleakage which can trigger apoptosis
Defects in membrane permeabilityDefects in membrane permeabilitybull Membranes may be damaged directly by toxins Membranes may be damaged directly by toxins
physical chemical agents activated complement physical chemical agents activated complement components and perforins components and perforins
bull Increased cell membrane permeability disrupts Increased cell membrane permeability disrupts intracellular osmolarity and enzyme activityintracellular osmolarity and enzyme activity
bull Organelle membrane defects cause organelle Organelle membrane defects cause organelle dysfunction and failure dysfunction and failure
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mitochondrial Mitochondrial DamageDamage
Influx of Intracellular Calcium Influx of Intracellular Calcium and Loss of Calcium and Loss of Calcium
HomeostasisHomeostasis
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of O2 Accumulation of O2 derived free radicalsderived free radicals
bull Partially reduced highly Partially reduced highly reactive unstable oxygen reactive unstable oxygen moieties are able tomoieties are able to
Induce the formation of Induce the formation of more free radicals more free radicals (propagation)(propagation)
Damage lipids by Damage lipids by peroxidation of double peroxidation of double bonds resulting in breakagebonds resulting in breakage
Damage protein by Damage protein by oxidation and oxidation and fragmentationfragmentation
Damage nucleic acids Damage nucleic acids ( chain breakage)( chain breakage)
bull Free radical formation occurs Free radical formation occurs byby
Absorption of radiant Absorption of radiant energy (H2O rarr O∙ + OH∙)energy (H2O rarr O∙ + OH∙)
Metabolism of exogenous Metabolism of exogenous chemicals and drugschemicals and drugs
Normal metabolic Normal metabolic oxidation-reduction oxidation-reduction reactions (O2- H2O2 OH∙)reactions (O2- H2O2 OH∙)
Transition metals (Fe Cu Transition metals (Fe Cu etc) can catalyze radical etc) can catalyze radical formationformation
Nitric oxide can act directly Nitric oxide can act directly as a free radical or be as a free radical or be converted to other highly converted to other highly reactive formsreactive forms
Free radical defenseFree radical defensebull Free radicals are highly Free radicals are highly
unstable and generally unstable and generally decay spontaneouslydecay spontaneously
bull Antioxidants block the Antioxidants block the formation or scavenge formation or scavenge them ( Vitamin E C A them ( Vitamin E C A GSH) GSH)
bull Transition metals are Transition metals are usually tightly bound to usually tightly bound to carrier proteins carrier proteins (transferring ferritin (transferring ferritin lactoferin lactoferin ceruloplasmin) release ceruloplasmin) release and use are highly and use are highly regulatedregulated
bull Free radical scavenging Free radical scavenging systems defuse radicals systems defuse radicals rapidlyrapidly
CatalaseCatalase Glutathione oxidaseGlutathione oxidase Superoxide dismutaseSuperoxide dismutase
Free RadicalsFree Radicals
11 Free radicalsFree radicals11 Unstable oxygen Unstable oxygen
speciesspecies
22 Damage and break Damage and break lipids proteins and lipids proteins and nucleic acidsnucleic acids
33 Formed by normal Formed by normal metabolismmetabolism
44 Energy absorptionEnergy absorption
55 Metabolism of Metabolism of chemicals and drugschemicals and drugs
11 Free Radical Free Radical DefenseDefense11 Spontaneous Spontaneous
decaydecay
22 AntioxidantsAntioxidants
33 Free radical Free radical scavenging scavenging systemssystems
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Mitochondrial damageMitochondrial damagebull May occur directly due to hypoxia or increased Ca2+ May occur directly due to hypoxia or increased Ca2+
oxidative stress or phospholipids breakdownoxidative stress or phospholipids breakdownbull Damage results in the formation of a high-Damage results in the formation of a high-
conductance channel that dissipates the H+ ion conductance channel that dissipates the H+ ion gradient across the inner membrane (mitochondrial gradient across the inner membrane (mitochondrial permeability transition (MPT)) Mitochondrial permeability transition (MPT)) Mitochondrial membrane damage can result in Cytochrome C membrane damage can result in Cytochrome C leakage which can trigger apoptosisleakage which can trigger apoptosis
Defects in membrane permeabilityDefects in membrane permeabilitybull Membranes may be damaged directly by toxins Membranes may be damaged directly by toxins
physical chemical agents activated complement physical chemical agents activated complement components and perforins components and perforins
bull Increased cell membrane permeability disrupts Increased cell membrane permeability disrupts intracellular osmolarity and enzyme activityintracellular osmolarity and enzyme activity
bull Organelle membrane defects cause organelle Organelle membrane defects cause organelle dysfunction and failure dysfunction and failure
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mitochondrial Mitochondrial DamageDamage
Influx of Intracellular Calcium Influx of Intracellular Calcium and Loss of Calcium and Loss of Calcium
HomeostasisHomeostasis
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of O2 Accumulation of O2 derived free radicalsderived free radicals
bull Partially reduced highly Partially reduced highly reactive unstable oxygen reactive unstable oxygen moieties are able tomoieties are able to
Induce the formation of Induce the formation of more free radicals more free radicals (propagation)(propagation)
Damage lipids by Damage lipids by peroxidation of double peroxidation of double bonds resulting in breakagebonds resulting in breakage
Damage protein by Damage protein by oxidation and oxidation and fragmentationfragmentation
Damage nucleic acids Damage nucleic acids ( chain breakage)( chain breakage)
bull Free radical formation occurs Free radical formation occurs byby
Absorption of radiant Absorption of radiant energy (H2O rarr O∙ + OH∙)energy (H2O rarr O∙ + OH∙)
Metabolism of exogenous Metabolism of exogenous chemicals and drugschemicals and drugs
Normal metabolic Normal metabolic oxidation-reduction oxidation-reduction reactions (O2- H2O2 OH∙)reactions (O2- H2O2 OH∙)
Transition metals (Fe Cu Transition metals (Fe Cu etc) can catalyze radical etc) can catalyze radical formationformation
Nitric oxide can act directly Nitric oxide can act directly as a free radical or be as a free radical or be converted to other highly converted to other highly reactive formsreactive forms
Free radical defenseFree radical defensebull Free radicals are highly Free radicals are highly
unstable and generally unstable and generally decay spontaneouslydecay spontaneously
bull Antioxidants block the Antioxidants block the formation or scavenge formation or scavenge them ( Vitamin E C A them ( Vitamin E C A GSH) GSH)
bull Transition metals are Transition metals are usually tightly bound to usually tightly bound to carrier proteins carrier proteins (transferring ferritin (transferring ferritin lactoferin lactoferin ceruloplasmin) release ceruloplasmin) release and use are highly and use are highly regulatedregulated
bull Free radical scavenging Free radical scavenging systems defuse radicals systems defuse radicals rapidlyrapidly
CatalaseCatalase Glutathione oxidaseGlutathione oxidase Superoxide dismutaseSuperoxide dismutase
Free RadicalsFree Radicals
11 Free radicalsFree radicals11 Unstable oxygen Unstable oxygen
speciesspecies
22 Damage and break Damage and break lipids proteins and lipids proteins and nucleic acidsnucleic acids
33 Formed by normal Formed by normal metabolismmetabolism
44 Energy absorptionEnergy absorption
55 Metabolism of Metabolism of chemicals and drugschemicals and drugs
11 Free Radical Free Radical DefenseDefense11 Spontaneous Spontaneous
decaydecay
22 AntioxidantsAntioxidants
33 Free radical Free radical scavenging scavenging systemssystems
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mitochondrial Mitochondrial DamageDamage
Influx of Intracellular Calcium Influx of Intracellular Calcium and Loss of Calcium and Loss of Calcium
HomeostasisHomeostasis
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of O2 Accumulation of O2 derived free radicalsderived free radicals
bull Partially reduced highly Partially reduced highly reactive unstable oxygen reactive unstable oxygen moieties are able tomoieties are able to
Induce the formation of Induce the formation of more free radicals more free radicals (propagation)(propagation)
Damage lipids by Damage lipids by peroxidation of double peroxidation of double bonds resulting in breakagebonds resulting in breakage
Damage protein by Damage protein by oxidation and oxidation and fragmentationfragmentation
Damage nucleic acids Damage nucleic acids ( chain breakage)( chain breakage)
bull Free radical formation occurs Free radical formation occurs byby
Absorption of radiant Absorption of radiant energy (H2O rarr O∙ + OH∙)energy (H2O rarr O∙ + OH∙)
Metabolism of exogenous Metabolism of exogenous chemicals and drugschemicals and drugs
Normal metabolic Normal metabolic oxidation-reduction oxidation-reduction reactions (O2- H2O2 OH∙)reactions (O2- H2O2 OH∙)
Transition metals (Fe Cu Transition metals (Fe Cu etc) can catalyze radical etc) can catalyze radical formationformation
Nitric oxide can act directly Nitric oxide can act directly as a free radical or be as a free radical or be converted to other highly converted to other highly reactive formsreactive forms
Free radical defenseFree radical defensebull Free radicals are highly Free radicals are highly
unstable and generally unstable and generally decay spontaneouslydecay spontaneously
bull Antioxidants block the Antioxidants block the formation or scavenge formation or scavenge them ( Vitamin E C A them ( Vitamin E C A GSH) GSH)
bull Transition metals are Transition metals are usually tightly bound to usually tightly bound to carrier proteins carrier proteins (transferring ferritin (transferring ferritin lactoferin lactoferin ceruloplasmin) release ceruloplasmin) release and use are highly and use are highly regulatedregulated
bull Free radical scavenging Free radical scavenging systems defuse radicals systems defuse radicals rapidlyrapidly
CatalaseCatalase Glutathione oxidaseGlutathione oxidase Superoxide dismutaseSuperoxide dismutase
Free RadicalsFree Radicals
11 Free radicalsFree radicals11 Unstable oxygen Unstable oxygen
speciesspecies
22 Damage and break Damage and break lipids proteins and lipids proteins and nucleic acidsnucleic acids
33 Formed by normal Formed by normal metabolismmetabolism
44 Energy absorptionEnergy absorption
55 Metabolism of Metabolism of chemicals and drugschemicals and drugs
11 Free Radical Free Radical DefenseDefense11 Spontaneous Spontaneous
decaydecay
22 AntioxidantsAntioxidants
33 Free radical Free radical scavenging scavenging systemssystems
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Influx of Intracellular Calcium Influx of Intracellular Calcium and Loss of Calcium and Loss of Calcium
HomeostasisHomeostasis
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of O2 Accumulation of O2 derived free radicalsderived free radicals
bull Partially reduced highly Partially reduced highly reactive unstable oxygen reactive unstable oxygen moieties are able tomoieties are able to
Induce the formation of Induce the formation of more free radicals more free radicals (propagation)(propagation)
Damage lipids by Damage lipids by peroxidation of double peroxidation of double bonds resulting in breakagebonds resulting in breakage
Damage protein by Damage protein by oxidation and oxidation and fragmentationfragmentation
Damage nucleic acids Damage nucleic acids ( chain breakage)( chain breakage)
bull Free radical formation occurs Free radical formation occurs byby
Absorption of radiant Absorption of radiant energy (H2O rarr O∙ + OH∙)energy (H2O rarr O∙ + OH∙)
Metabolism of exogenous Metabolism of exogenous chemicals and drugschemicals and drugs
Normal metabolic Normal metabolic oxidation-reduction oxidation-reduction reactions (O2- H2O2 OH∙)reactions (O2- H2O2 OH∙)
Transition metals (Fe Cu Transition metals (Fe Cu etc) can catalyze radical etc) can catalyze radical formationformation
Nitric oxide can act directly Nitric oxide can act directly as a free radical or be as a free radical or be converted to other highly converted to other highly reactive formsreactive forms
Free radical defenseFree radical defensebull Free radicals are highly Free radicals are highly
unstable and generally unstable and generally decay spontaneouslydecay spontaneously
bull Antioxidants block the Antioxidants block the formation or scavenge formation or scavenge them ( Vitamin E C A them ( Vitamin E C A GSH) GSH)
bull Transition metals are Transition metals are usually tightly bound to usually tightly bound to carrier proteins carrier proteins (transferring ferritin (transferring ferritin lactoferin lactoferin ceruloplasmin) release ceruloplasmin) release and use are highly and use are highly regulatedregulated
bull Free radical scavenging Free radical scavenging systems defuse radicals systems defuse radicals rapidlyrapidly
CatalaseCatalase Glutathione oxidaseGlutathione oxidase Superoxide dismutaseSuperoxide dismutase
Free RadicalsFree Radicals
11 Free radicalsFree radicals11 Unstable oxygen Unstable oxygen
speciesspecies
22 Damage and break Damage and break lipids proteins and lipids proteins and nucleic acidsnucleic acids
33 Formed by normal Formed by normal metabolismmetabolism
44 Energy absorptionEnergy absorption
55 Metabolism of Metabolism of chemicals and drugschemicals and drugs
11 Free Radical Free Radical DefenseDefense11 Spontaneous Spontaneous
decaydecay
22 AntioxidantsAntioxidants
33 Free radical Free radical scavenging scavenging systemssystems
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of O2 Accumulation of O2 derived free radicalsderived free radicals
bull Partially reduced highly Partially reduced highly reactive unstable oxygen reactive unstable oxygen moieties are able tomoieties are able to
Induce the formation of Induce the formation of more free radicals more free radicals (propagation)(propagation)
Damage lipids by Damage lipids by peroxidation of double peroxidation of double bonds resulting in breakagebonds resulting in breakage
Damage protein by Damage protein by oxidation and oxidation and fragmentationfragmentation
Damage nucleic acids Damage nucleic acids ( chain breakage)( chain breakage)
bull Free radical formation occurs Free radical formation occurs byby
Absorption of radiant Absorption of radiant energy (H2O rarr O∙ + OH∙)energy (H2O rarr O∙ + OH∙)
Metabolism of exogenous Metabolism of exogenous chemicals and drugschemicals and drugs
Normal metabolic Normal metabolic oxidation-reduction oxidation-reduction reactions (O2- H2O2 OH∙)reactions (O2- H2O2 OH∙)
Transition metals (Fe Cu Transition metals (Fe Cu etc) can catalyze radical etc) can catalyze radical formationformation
Nitric oxide can act directly Nitric oxide can act directly as a free radical or be as a free radical or be converted to other highly converted to other highly reactive formsreactive forms
Free radical defenseFree radical defensebull Free radicals are highly Free radicals are highly
unstable and generally unstable and generally decay spontaneouslydecay spontaneously
bull Antioxidants block the Antioxidants block the formation or scavenge formation or scavenge them ( Vitamin E C A them ( Vitamin E C A GSH) GSH)
bull Transition metals are Transition metals are usually tightly bound to usually tightly bound to carrier proteins carrier proteins (transferring ferritin (transferring ferritin lactoferin lactoferin ceruloplasmin) release ceruloplasmin) release and use are highly and use are highly regulatedregulated
bull Free radical scavenging Free radical scavenging systems defuse radicals systems defuse radicals rapidlyrapidly
CatalaseCatalase Glutathione oxidaseGlutathione oxidase Superoxide dismutaseSuperoxide dismutase
Free RadicalsFree Radicals
11 Free radicalsFree radicals11 Unstable oxygen Unstable oxygen
speciesspecies
22 Damage and break Damage and break lipids proteins and lipids proteins and nucleic acidsnucleic acids
33 Formed by normal Formed by normal metabolismmetabolism
44 Energy absorptionEnergy absorption
55 Metabolism of Metabolism of chemicals and drugschemicals and drugs
11 Free Radical Free Radical DefenseDefense11 Spontaneous Spontaneous
decaydecay
22 AntioxidantsAntioxidants
33 Free radical Free radical scavenging scavenging systemssystems
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Accumulation of O2 Accumulation of O2 derived free radicalsderived free radicals
bull Partially reduced highly Partially reduced highly reactive unstable oxygen reactive unstable oxygen moieties are able tomoieties are able to
Induce the formation of Induce the formation of more free radicals more free radicals (propagation)(propagation)
Damage lipids by Damage lipids by peroxidation of double peroxidation of double bonds resulting in breakagebonds resulting in breakage
Damage protein by Damage protein by oxidation and oxidation and fragmentationfragmentation
Damage nucleic acids Damage nucleic acids ( chain breakage)( chain breakage)
bull Free radical formation occurs Free radical formation occurs byby
Absorption of radiant Absorption of radiant energy (H2O rarr O∙ + OH∙)energy (H2O rarr O∙ + OH∙)
Metabolism of exogenous Metabolism of exogenous chemicals and drugschemicals and drugs
Normal metabolic Normal metabolic oxidation-reduction oxidation-reduction reactions (O2- H2O2 OH∙)reactions (O2- H2O2 OH∙)
Transition metals (Fe Cu Transition metals (Fe Cu etc) can catalyze radical etc) can catalyze radical formationformation
Nitric oxide can act directly Nitric oxide can act directly as a free radical or be as a free radical or be converted to other highly converted to other highly reactive formsreactive forms
Free radical defenseFree radical defensebull Free radicals are highly Free radicals are highly
unstable and generally unstable and generally decay spontaneouslydecay spontaneously
bull Antioxidants block the Antioxidants block the formation or scavenge formation or scavenge them ( Vitamin E C A them ( Vitamin E C A GSH) GSH)
bull Transition metals are Transition metals are usually tightly bound to usually tightly bound to carrier proteins carrier proteins (transferring ferritin (transferring ferritin lactoferin lactoferin ceruloplasmin) release ceruloplasmin) release and use are highly and use are highly regulatedregulated
bull Free radical scavenging Free radical scavenging systems defuse radicals systems defuse radicals rapidlyrapidly
CatalaseCatalase Glutathione oxidaseGlutathione oxidase Superoxide dismutaseSuperoxide dismutase
Free RadicalsFree Radicals
11 Free radicalsFree radicals11 Unstable oxygen Unstable oxygen
speciesspecies
22 Damage and break Damage and break lipids proteins and lipids proteins and nucleic acidsnucleic acids
33 Formed by normal Formed by normal metabolismmetabolism
44 Energy absorptionEnergy absorption
55 Metabolism of Metabolism of chemicals and drugschemicals and drugs
11 Free Radical Free Radical DefenseDefense11 Spontaneous Spontaneous
decaydecay
22 AntioxidantsAntioxidants
33 Free radical Free radical scavenging scavenging systemssystems
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Free RadicalsFree Radicals
11 Free radicalsFree radicals11 Unstable oxygen Unstable oxygen
speciesspecies
22 Damage and break Damage and break lipids proteins and lipids proteins and nucleic acidsnucleic acids
33 Formed by normal Formed by normal metabolismmetabolism
44 Energy absorptionEnergy absorption
55 Metabolism of Metabolism of chemicals and drugschemicals and drugs
11 Free Radical Free Radical DefenseDefense11 Spontaneous Spontaneous
decaydecay
22 AntioxidantsAntioxidants
33 Free radical Free radical scavenging scavenging systemssystems
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
A CENTRAL ROLEOFFREERADICALSINCELL DEATH
Sources Mitochondrial respiration
Xanthine oxidase (purine metabolism ndashgt uric acid O2-)
Peroxisomes (long chain FA ndashgt H2O2)
NADPH oxidase (respiratory burst)
Cyt P450 mixed function oxidase
Defense
Glutathione
Catalase (H2O2) ndash peroxisomes
Mn-superoxide dismutase ndash mitochondria
CuZn-SOD - cytosol
Antioxidants
Metal sequestration
Metallothionein
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction
(normal metabolic processes)(normal metabolic processes)
-superoxide anion (O-superoxide anion (O22--))
-hydrogen peroxide (H-hydrogen peroxide (H22OO22))
-hydroxyl ion (OH )-hydroxyl ion (OH )
Mechanisms of Cell InjuryMechanisms of Cell Injury
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy
(ultraviolet light UV X-ray)(ultraviolet light UV X-ray)
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH2200
Ionizing radiationIonizing radiation
OHOH HH
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals
(Oxidative Stress)(Oxidative Stress) Transition Metals ndash Transition Metals ndash ironiron coppercopper
Mechanisms of Cell InjuryMechanisms of Cell Injury
HH220022 OHOH--OHOHFe3+Fe2+
ldquoFenton reactionrdquo
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Lipid peroxidation of MembranesLipid peroxidation of Membranes
- Plasma membrane- Plasma membrane
- Organellar membrane- Organellar membrane
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicals on cell injuryEffects of the free radicals on cell injury
Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids
membrane damagemembrane damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains
Protein-protein cross-linkagesProtein-protein cross-linkages --Oxidation of the protein backboneOxidation of the protein backbone
Protein fragmentationProtein fragmentation
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)
Mechanisms of Cell InjuryMechanisms of Cell Injury
Effects of the free radicalsEffects of the free radicals Lesions in DNALesions in DNA
Reaction with Reaction with ThymineThymine
DNA single-stranded breakDNA single-stranded break
DNA fragmentationDNA fragmentation
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Superoxide dismutase Superoxide dismutase (SOD)(SOD)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mitochondrial DysfunctionMitochondrial Dysfunction
-Decreased phospholipid synthesis-Decreased phospholipid synthesis
-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Cytoskeletal AbnormalityCytoskeletal Abnormality
Reactive Oxygen speciesReactive Oxygen species
Lipid breakdown productsLipid breakdown products
(detergen effect on membrane)(detergen effect on membrane)
Defects in Membrane Defects in Membrane PermeabilityPermeability
Mechanisms of Cell InjuryMechanisms of Cell Injury
Mechanism of Membrane damage in Cell Injury
Cytosolic Ca+ proteaseprotease
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell
injuryinjury
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Cellular adaptationCellular adaptation
HyperplasiaHyperplasiabull An organized increase in number of cells An organized increase in number of cells
(versus dysplasia which is disorganized (versus dysplasia which is disorganized growth and neoplasia which is new growth and neoplasia which is new growth)growth)
bull Can be physiologic or pathologicCan be physiologic or pathologic HypertrophyHypertrophy
bull An increase in cell sizeAn increase in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
Hyperplasia and hypertrophy can be Hyperplasia and hypertrophy can be difficult to separate--not possible by difficult to separate--not possible by gross exam difficult by microscopic gross exam difficult by microscopic exam In some cases both hyperplasia exam In some cases both hyperplasia and hypertrophy occur together (eg and hypertrophy occur together (eg breast and uterus during pregnancy)breast and uterus during pregnancy)
Hyperplasia essentially does not occur Hyperplasia essentially does not occur in the brain and heartin the brain and heart
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Cellular adaptation (conrsquot)Cellular adaptation (conrsquot)
AtrophyAtrophybull Decrease in cell sizeDecrease in cell sizebull Can be physiologic or pathologicCan be physiologic or pathologic
Metaplasia Change in type of Metaplasia Change in type of epithelium (eg squamous epithelium (eg squamous epithelium to glandular epithelium)epithelium to glandular epithelium)
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
HyperplasiaHyperplasia PhysiologicPhysiologic
bull Breast enlargement during pregnancy (and Breast enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Uterine enlargement during pregnancy (and Uterine enlargement during pregnancy (and hypertrophy)hypertrophy)
bull Liver regrowth after partial resectionLiver regrowth after partial resectionbull Inflammation repairInflammation repair
PathologicPathologicbull Ductal hyperplasia of breast (due to estrogen)Ductal hyperplasia of breast (due to estrogen)bull Benign prostatic hyperplasiaBenign prostatic hyperplasiabull Endometrial hyperplasia (due to estrogen)Endometrial hyperplasia (due to estrogen)bull Viral infectionsViral infectionsbull Endocrine organs with increased stimulus (eg Endocrine organs with increased stimulus (eg
adrenal gland enlargement due to ACTH-secreting adrenal gland enlargement due to ACTH-secreting pituitary adenoma goiter)pituitary adenoma goiter)
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
HypertrophyHypertrophy
PhysiologicPhysiologicbull Skeletal muscle hypertrophy associated Skeletal muscle hypertrophy associated
with exercisewith exercisebull Compensatory hypertrophy of kidney after Compensatory hypertrophy of kidney after
removal of other kidneyremoval of other kidney PathologicPathologic
bull Cardiac hypertrophy due to hypertension Cardiac hypertrophy due to hypertension valvular stenosis or insufficiencyvalvular stenosis or insufficiency
bull Asthma--smooth muscle hypertrophyAsthma--smooth muscle hypertrophybull Hypertrophy of bladder associated with Hypertrophy of bladder associated with
prostatic gland hyperplasiaprostatic gland hyperplasia
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
AtrophyAtrophy
PhysiologicPhysiologicbull Regression in size of breasts and uterus Regression in size of breasts and uterus
after pregnancyafter pregnancy PathologicPathologic
bull Disuse (skeletal muscle atrophy)Disuse (skeletal muscle atrophy)bull Loss of endocrine stimulus (adrenal atrophy Loss of endocrine stimulus (adrenal atrophy
in patients on steroids)in patients on steroids)bull Denervation (physical therapists vs forensic Denervation (physical therapists vs forensic
pathologists)pathologists)bull Inadequate nutritionInadequate nutritionbull Ischemia (atrophy of kidney due to renal Ischemia (atrophy of kidney due to renal
artery stenosis)artery stenosis)
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
MetaplasiaMetaplasia
Always pathologicAlways pathologic ExamplesExamples
bull Squamous metaplasia of the lungsSquamous metaplasia of the lungsbull Glandular metaplasia of the Glandular metaplasia of the
esophagus (Barrett esophagus)esophagus (Barrett esophagus)
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Cellular accumulationsCellular accumulations
LipofuscinLipofuscin CalciumCalcium FatFat IronIron Protein cholesterol glycogenProtein cholesterol glycogen PigmentsPigments
bull Exogenous Anthracosis tattoosExogenous Anthracosis tattoosbull Endogenous Bile melaninEndogenous Bile melanin
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Why do cells accumulate Why do cells accumulate substancessubstances
Too much producedToo much produced Too slow of clearanceToo slow of clearance
bull Lack of enzyme decreased enzyme activityLack of enzyme decreased enzyme activitybull Blockage of outletBlockage of outlet
Cellular accumulations are a sign of Cellular accumulations are a sign of injury cellular accumulations result injury cellular accumulations result from injury or their accumulation can from injury or their accumulation can cause cellular injurycause cellular injury
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Common locations of various Common locations of various cellular accumulationscellular accumulations
Lipofuscin (wear and tear pigment)Lipofuscin (wear and tear pigment)bull Heart liverHeart liver
FatFatbull Liver heart kidneyLiver heart kidney
IronIronbull Lung (in patients with congestive heart Lung (in patients with congestive heart
failure)failure)bull At site of past hemorrhageAt site of past hemorrhagebull In patients with hemochromatosisIn patients with hemochromatosis
Liver heart pancreasLiver heart pancreas CholesterolCholesterol
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Protein accumulationProtein accumulation
Alzheimer disease (tau protein)Alzheimer disease (tau protein) Mallory hyaline (intermediate Mallory hyaline (intermediate
filaments in alcoholic liver filaments in alcoholic liver disease)disease)
In kidney (as result of proteinuria)In kidney (as result of proteinuria)
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
PigmentsPigments
EndogenousEndogenousbull Bilirubin melaninBilirubin melaninbull Accumulation of bilirubinAccumulation of bilirubin
Too much produced (eg hemolysis)Too much produced (eg hemolysis) Not processed (eg cirrhosis)Not processed (eg cirrhosis) Outflow blocked (eg choledocholithiasis)Outflow blocked (eg choledocholithiasis)
ExogenousExogenousbull Anthracosis (cigarette smoking urban Anthracosis (cigarette smoking urban
living)living)bull TattooTattoo
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
CalcificationCalcification
DystrophicDystrophicbull Patients have a normal calcium levelPatients have a normal calcium levelbull Calcification affects previously damaged Calcification affects previously damaged
tissuetissue MetastaticMetastatic
bull Patients have an elevated level of calciumPatients have an elevated level of calcium Causes Hyperparathyroidism bony metastasesCauses Hyperparathyroidism bony metastases
bull Calcification affects normal tissue and Calcification affects normal tissue and previously damaged tissuepreviously damaged tissue
Out of all forms of cellular adaptation Out of all forms of cellular adaptation calcification is the only one which is not calcification is the only one which is not routinely reversibleroutinely reversible
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
DysplasiaDysplasia
Definition Disorganized growth Definition Disorganized growth hyperplasia leads to dysplasia which hyperplasia leads to dysplasia which leads to neoplasialeads to neoplasia
Importance Precursor of malignancy Importance Precursor of malignancy but is reversiblebut is reversible
Common locationsCommon locationsbull CervixCervixbull Gastrointestinal tractGastrointestinal tract
Not commonly seen by forensic Not commonly seen by forensic pathologistspathologists
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (biased)forensic pathologists (biased) HyperplasiaHyperplasia
bull Benign prostatic hyperplasia (uncommon)Benign prostatic hyperplasia (uncommon)bull Adrenal gland hyperplasia (common to Adrenal gland hyperplasia (common to
uncommon)uncommon) HypertrophyHypertrophy
bull Cardiac (common)Cardiac (common) AtrophyAtrophy MetaplasiaMetaplasia
bull Squamous metaplasia of lung and Barrett Squamous metaplasia of lung and Barrett esophagus (uncommon)esophagus (uncommon)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologists (conrsquot)forensic pathologists (conrsquot) FatFatbull Hepatic steatosis (common)Hepatic steatosis (common)
IronIronbull Congestive heart failure sites of Congestive heart failure sites of
hemorrhage (common)hemorrhage (common)bull Hereditary hemochromatosis is rarely seenHereditary hemochromatosis is rarely seen
Protein accumulationProtein accumulationbull Mallory hyaline (uncommon)Mallory hyaline (uncommon)bull Tangles and plaques in Alzheimer dz Tangles and plaques in Alzheimer dz
(uncommon)(uncommon) CholesterolCholesterol
bull Atherosclerosis (common)Atherosclerosis (common)
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Cellular adaptations Cellular adaptations commonlyuncommonly seen by commonlyuncommonly seen by
forensic pathologistsforensic pathologists PigmentsPigments
bull Anthracosis (common)Anthracosis (common)bull Bile (uncommon)Bile (uncommon)
CalcificationCalcificationbull Atherosclerosis (common)Atherosclerosis (common)bull Aortic stenosis (uncommon)Aortic stenosis (uncommon)
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Morphology of Cell Injury and Morphology of Cell Injury and NecrosisNecrosis
Cell Injury ndash ReversibleCell Injury ndash Reversible
ndash ndash IrreversibleIrreversible
Cell Death ndash NecrosisCell Death ndash Necrosis
ndash ndash ApoptosisApoptosis
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Morphology of Cell InjuryMorphology of Cell Injury
Plasma membrane alterationPlasma membrane alteration Mitochondrial ChangesMitochondrial Changes Dilation of Endoplasmic reticulumDilation of Endoplasmic reticulum Nuclear AlterationNuclear Alteration
Reversible InjuryReversible InjuryCellular swelling
Fatty change
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
NecrosisNecrosis
CoagulativeCoagulative LiquefactiveLiquefactive CaseousCaseous FatFat
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Reversible vs irreversible Reversible vs irreversible cell injurycell injury
Reversible Reversible injuryinjury
Decreased Decreased ATP levelsATP levels
Ion Ion imbalanceimbalance
Swelling Swelling Decreased pHDecreased pH Fatty change Fatty change
(liver)(liver)
Irreversible Irreversible injuryinjury
Amorphous Amorphous densitiesdensities in in mitochondriamitochondria
Severe Severe membrane membrane damagedamage
Lysosomal Lysosomal rupturerupture
Extensive Extensive DNA damageDNA damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Morphology of Necrotic CellsMorphology of Necrotic Cells Increased EosinophiliaIncreased Eosinophilia - loss of RNA (basophilia)- loss of RNA (basophilia) - denatured cytoplasmic protein- denatured cytoplasmic protein Nuclear ChangesNuclear Changes - Pyknosis- Pyknosis - Karyorrhexis- Karyorrhexis - Karyolysis- Karyolysis Myelin figure Myelin figure ndash ndash large whorled phospholipid large whorled phospholipid
mass (phospholipid precipitate)mass (phospholipid precipitate)
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
HISTOLOGIC FEATURES OF HISTOLOGIC FEATURES OF COAGULATIVE NECROSISCOAGULATIVE NECROSIS
Normal cellNormal cell
Reversible Reversible cell injurycell injury with with cytoplasmic amp cytoplasmic amp organelle organelle swelling swelling blebbing amp blebbing amp ribosome ribosome detachmentdetachment
Irreversible Irreversible cell injurycell injury with rupture of with rupture of membrane amp membrane amp organelles amp organelles amp nuclear nuclear
pyknosispyknosis
KaryorrhexisKaryorrhexis
KaryolysisKaryolysis
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis Liquefactive necrosisLiquefactive necrosis Caseous necrosisCaseous necrosis Fat necrosisFat necrosis
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Coagulative NecrosisCoagulative Necrosis
intracellular acidosis intracellular acidosis
ndash ndash protein denaturedprotein denatured
ndash ndash proteolysis inhibited proteolysis inhibited
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Coagulative necrosisCoagulative necrosis
Preservation Preservation of structureof structure
Firm Firm Protein Protein
denaturationdenaturation Hypoxic Hypoxic
tissue death tissue death (except brain)(except brain)
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
This is an example of coagulative necrosis This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia) Here there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal cellular debris creating a renal abscess that obliterates the normal
architecturearchitecture
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Ischemic necrosis of the myocardium
A Normal myocardium
B Myocardium with coagulation necrosis
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Liquefactive NecrosisLiquefactive Necrosis
focal bacterial (or fungal) infectionsfocal bacterial (or fungal) infections
ndash ndash accumulation of inflammatory accumulation of inflammatory
cellscells
hypoxic death of cells within CNShypoxic death of cells within CNS
Morphologic pattern of Necrotic Morphologic pattern of Necrotic Cell massCell mass
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Liquefactive necrosisLiquefactive necrosis Enzymatic Enzymatic
digestiondigestionbull Autolysis + Autolysis +
WBCWBC Liquid viscous Liquid viscous
massmass May contain May contain
puspus Bacterial Bacterial
infections (via infections (via inflammation)inflammation)
Hypoxic brain Hypoxic brain injuryinjury
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Coagulative and liquefactive necrosisA Kidney infarct exhibiting coagulative necrosis
B A focus of liquefactive necrosis in the kidney
Figure 1-19 Coagulative and liquefactive necrosis A Kidney infarct exhibiting coagulative necrosis with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture B A focus of liquefactive necrosis in the kidney
caused by fungal infection The focus is filled with white cells and cellular debris creating a renal abscess that obliterates the normal architecture
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
The liver shows a small abscess here filled with many neutrophils This abscess is an example of localized liquefactive necrosis
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Caseous necrosisCaseous necrosis
gross appearancegross appearance
microscopic ndash granulomatous microscopic ndash granulomatous inflammation inflammation
Morphologic Pattern of Necrotic Morphologic Pattern of Necrotic Cell MassCell Mass
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Caseous necrosisCaseous necrosis
Subset of Subset of coagulative necrosiscoagulative necrosis
TBTB Cheesy white Cheesy white Surrounded by Surrounded by
inflammatory cells inflammatory cells (granulomatous (granulomatous reaction)reaction)
Complete Complete destruction of tissue destruction of tissue
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
A tuberculous lung with a large area of caseous necrosis
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis The node has a cheesy tan to white appearance Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
T uberculous granuloma showing an area of central nec - rosis epithelioid cells multiple Langhans type giant ce
lls and lymphocytes
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Fat necrosisFat necrosis
Not a specific Not a specific patternpattern
Focal areas of Focal areas of fat digestionfat digestion
Ususally via Ususally via release of release of lipases from lipases from pancreaspancreas
FFA combine FFA combine with Ca to with Ca to produce produce ldquosoapsrdquoldquosoapsrdquo
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Foci of fat necrosisfat necrosis with saponification in the mesentery
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Ischemic injuryIschemic injury
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Mechanisms of Cell InjuryMechanisms of Cell Injury
Ischemic injuryIschemic injury
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Figure Sequence of events leading to fatty fatty changechange and cell necrosiscell necrosis in carbon tetrachloride (CCl4) toxicity RER rough endoplasmic reticulum SER smoothendoplasmic reticulum
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0523 PM)
copy 2005 Elsevier
Chemical Chemical injuryinjury
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
ApoptosisApoptosis
Cell death that is induced by a tightly Cell death that is induced by a tightly regulated intracellular programregulated intracellular program
ldquo ldquoProgrammed Cell DeathProgrammed Cell Deathrdquordquo
Causes of ApoptosisCauses of Apoptosis - Physiologic situations- Physiologic situations - Pathologic conditions- Pathologic conditions
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Morphology of Apoptosis
Cell shrinkageCell shrinkage
Chromosome Chromosome condensationcondensation
Formation of Formation of cytoplasmic blebs cytoplasmic blebs and apoptotic and apoptotic bodiesbodies
Phagocytosis of Phagocytosis of apoptotic cells or apoptotic cells or cell bodiescell bodies
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations
Programmed destruction of cell during Programmed destruction of cell during embryogenesisembryogenesis
Hormone-dependent involutionHormone-dependent involution - - endometrial cellsendometrial cells (menstrual cycle) (menstrual cycle) Cell deletion in Cell deletion in proliferating cellproliferating cell population population
autoreactive T cellsautoreactive T cells Death of host cells - Death of host cells - neutrophilsneutrophils Elimination of Elimination of self reactive lymphocyteself reactive lymphocyte Cell death induced by cytotoxic T-cellsCell death induced by cytotoxic T-cells - - viral infectedviral infected or or tumortumor cells cells
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions
Cell death produced by injurious Cell death produced by injurious stimuli ndash radiation cytotoxic drugstimuli ndash radiation cytotoxic drug
Cell injury in certain viral diseases ndash Cell injury in certain viral diseases ndash viral hepatitisviral hepatitis
Pathologic atrophyPathologic atrophy Cell death in tumorsCell death in tumors
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Apoptosis Apoptosis vs Coagulation vs Coagulation Necrosis Necrosis
Cell sizeCell size Enlarged Enlarged Reduced Reduced
NucleusNucleus Pyknosis karyorrhexis karyolysisPyknosis karyorrhexis karyolysis FragmentationFragmentation
Plasma membranePlasma membrane DisruptedDisrupted Intact Intact
Cellular contentsCellular contents Enzymatic digestionEnzymatic digestion IntactIntact
InflammationInflammation FrequentFrequent NoneNone
PhysiologicpathologicPhysiologicpathologic Pathologic Pathologic PhysiologicPhysiologic
Feature Necrosis Apoptosis
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Labeled (1) are some of the major inducers of apoptosis These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand) withdrawal of growth factors or hormones and injurious agents (eg radiation) (2) Control and regulation are influenced by members of the Bcl-2 family of proteins
which can either inhibit or promote the cells death (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins This results in a cascade
of intracellular degradation including fragmentation of nuclear chromatin and breakdown of the cytoskeleton (4) The end result is formation of apoptotic bodies containing intracellular organelles and
other cytosolic components these bodies also express new ligands for binding and uptake by phagocytic cells
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Caspases are synthesized as inactive zymogen Caspases are synthesized as inactive zymogen pro-domain p20 and p10 domains Activated pro-domain p20 and p10 domains Activated by cleavage between p20 and p10 and pro-by cleavage between p20 and p10 and pro-domain and p20 Active as tetramer of 2 p10 domain and p20 Active as tetramer of 2 p10 and 2 p20 domains Three models for caspase and 2 p20 domains Three models for caspase activation i) caspase cascade eg downstream activation i) caspase cascade eg downstream effectors caspase-3 -6 -7 ii) induced proximity effectors caspase-3 -6 -7 ii) induced proximity eg on ligand binding CD95 receptors eg on ligand binding CD95 receptors aggregate to form signaling complexes which aggregate to form signaling complexes which through adapter proteins bring about high local through adapter proteins bring about high local concentrations of procaspase-8 iii) association concentrations of procaspase-8 iii) association with a regulatory subunit eg caspase-9 and with a regulatory subunit eg caspase-9 and Apaf-1Apaf-1
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
DNA damage can initiate apoptosis DNA damage can initiate apoptosis Dual function of p53 If damage Dual function of p53 If damage detected cell cycle arrest If detected cell cycle arrest If damage not repaired iniates damage not repaired iniates apoptosis How is damage sensed apoptosis How is damage sensed Proteins of the ATM (ataxia Proteins of the ATM (ataxia telangiectasia-mutated) and DNA-telangiectasia-mutated) and DNA-PK contain DNA binding domains PK contain DNA binding domains and protein and protein
kinase activity Both phosphorylate kinase activity Both phosphorylate p53 p53
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Signals for ingestion i) altered Signals for ingestion i) altered sugars recognized by lectins on sugars recognized by lectins on macrophages ii) Thrombospondin macrophages ii) Thrombospondin ndash secreted by macrophages ndash secreted by macrophages binds to apoptotic cells binds to apoptotic cells (mechanism not known) then (mechanism not known) then macrophage macrophage
integrins bind to integrins bind to thrombospondin iii) thrombospondin iii) phosphatidyl serine (annexin V) phosphatidyl serine (annexin V)
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Apoptosis can be suppressedApoptosis can be suppressed bullbullat the level of caspasesat the level of caspases bullbullat the level of the mitochondriaat the level of the mitochondria bullbullby ionic controlby ionic control
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Intracellular AccumulationsIntracellular Accumulations Manifestation of Manifestation of ldquoldquometabolic derangementsrdquometabolic derangementsrdquo
intracellular accumulation of abnormal intracellular accumulation of abnormal amounts of various substancesamounts of various substances
FatFat
ProteinProtein
GlycogenGlycogen
PigmentsPigments
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Mechanisms of Mechanisms of intracellular intracellular
accumulationsaccumulations
(1)(1)abnormal metabolism abnormal metabolism
(2)(2)alterations in protein alterations in protein folding and transportfolding and transport
(3)(3)deficiency of critical deficiency of critical enzymesenzymes
(4)(4)inability to degrade inability to degrade phagocytosed phagocytosed particlesparticles
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Intracellular Accumulations of Intracellular Accumulations of LipidsLipids
Accumulation of LipidsAccumulation of Lipids - Triglycerides- Triglycerides - Cholesterol- Cholesterol
SteatosisSteatosis (fatty change)(fatty change) abnormal accumulation of abnormal accumulation of
triglyceridestriglycerides within parenchymal cells within parenchymal cells
ndash ndash fatty liver in chronic alcoholismfatty liver in chronic alcoholism
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Lipid circulation
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Fatty liverFatty liver
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Intracellular Accumulations Intracellular Accumulations of of LipidsLipids
Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters AtherosclerosisAtherosclerosis - accumulation of cholesterol-- accumulation of cholesterol-
laden laden macrophage macrophage ((foam cellfoam cell) and ) and smooth musclesmooth muscle cells in the cells in the intimaintima of of aortaaorta and and arteriesarteries
CholesterolosisCholesterolosis - accumulation of - accumulation of foam cellsfoam cells in in
the lamina propria of the lamina propria of gallbladdergallbladder
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Accumulation of protein droplets in Accumulation of protein droplets in proximal renal tubuleproximal renal tubule
- renal disease with - renal disease with heavy heavy protein leakageprotein leakage across the across the glomerular filterglomerular filter
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Protein reabsorption droplets in the renal tubular epithelium
Downloaded from Robbins amp Cotran Pathologic Basis of Disease (on 19 October 2005 0551 PM)
copy 2005 Elsevier
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Intracellular Accumulations of Intracellular Accumulations of ProteinsProteins
Defects in protein foldingDefects in protein folding
Defective intracellular transport Defective intracellular transport and secretionand secretion
ER stress induced by unfolded and ER stress induced by unfolded and misfolded protein ndash cell deathmisfolded protein ndash cell death
Aggregation of abnormal folded Aggregation of abnormal folded protein - amyloidosis protein - amyloidosis
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
ldquoldquoPatients with abnormal metabolism of Patients with abnormal metabolism of glucose or glycogenrdquoglucose or glycogenrdquo
Diabetes mellitusDiabetes mellitus disorder of glucose metabolismdisorder of glucose metabolism - glycogen accumulate in - glycogen accumulate in
epithelial cells of renal tubulesepithelial cells of renal tubules liver liver cellscells beta-cells of the islets of beta-cells of the islets of LangerhansLangerhans and and heart muscle cellsheart muscle cells
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Glycogen storage disease Glycogen storage disease (Glycogenosis)(Glycogenosis)
- genetic diseases- genetic diseases
- defect of enzymes in the - defect of enzymes in the synthesis or breakdown of glycogensynthesis or breakdown of glycogen
accumulation cell injury deathaccumulation cell injury death
Intracellular Accumulations of Intracellular Accumulations of GlycogenGlycogen
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Accumulation of PigmentsAccumulation of Pigments
Exogenous pigmentsExogenous pigments Carbon ( anthracosis)Carbon ( anthracosis) Coal dust ( pneumoconiosis)Coal dust ( pneumoconiosis) Lung pick up by alveolar Lung pick up by alveolar
macrophages regional lymph nodsmacrophages regional lymph nods
blackening the tissues of the lungs blackening the tissues of the lungs ((anthracosisanthracosis))
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Endogenous pigmentEndogenous pigment
LipofuscinLipofuscin ndash aging pigment ndash aging pigment
lipid phospholipid-protein complex lipid phospholipid-protein complex (lipid peroxidation)(lipid peroxidation)
MelaninMelanin ndash in melanocyte ndash in melanocyte
HemosiderinHemosiderin ndash aggregates of ferritin ndash aggregates of ferritin micelles (iron + apoferritin = ferritin)micelles (iron + apoferritin = ferritin)
Accumulation of PigmentsAccumulation of Pigments
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Pathologic CalcificationPathologic Calcification
Abnormal tissue deposition of Abnormal tissue deposition of Calcium SaltsCalcium Salts
Two formsTwo forms
1 1 Dystrophic calcificationDystrophic calcification
2 2 Metastatic calcificationMetastatic calcification
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Pathologic CalcificationPathologic Calcification
Dystrophic CalcificationDystrophic Calcification
- Area of tissue necrosis- Area of tissue necrosis
- Aging or damage heart valve- Aging or damage heart valve
- Atherosclerosis- Atherosclerosis
- Single necrotic cell- Single necrotic cell
ldquo ldquopsammoma bodyrdquopsammoma bodyrdquo
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Metastatic CalcificationMetastatic Calcification
- Occur in normal tissue in - Occur in normal tissue in ldquoldquohypercalcemiahypercalcemiardquordquo
Pathologic CalcificationPathologic Calcification
HypercalcemiaHypercalcemia
bull Hyperparathyroidism
bull Destruction of bone tissue
bull Renal failure
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Cellular Response to InjuryNature amp Severity of Injurious Stimuli Cellular Response
Altered physiologic stimuli1 Increased demand increased trophic
stimulation (growth factors hormones work load etc)
2 Decreased nutrients stimulation3 Chronic irritation (chemical or
physical)
Cellular Adaptation1 Hyperplasia hypertrophy2 Atrophy3 Metaplasia
Reduced O2 supply chemical injury
infection1 Acute self limited2 Progressive an severe (including DNA
damage3 Mild chronic injury
Cell Injury1 Acute reversible injury2 Irreversible injuryrarr cell death
a Necrosisb Apoptosis
3 Subcellular alterations in particular organelles
Metabolic alterations acquired or genetic Intercellular accumulations1proteins2lipids3carbohydrates4minerals
Prolonged lifespan with cumulative sublethal injury
Cellular aging
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
Different cells showdifferent sensitivitiesthresholds Examples bullBrain cells heart cells susceptible to hypoxiaand ischemia liver cells susceptible to chemical injury bullCalf muscletolerates 2-3h of ischemia cardiacmuscle diesin20-30 min bullHighly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia bullNutritional status ndash glycogen-replete hepatocyte moreresistant to ischemiathan depleted one
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
bull Hypoxia - Oxygen deficiency bull Ischemia - Impaired blood supply (arterial or venous occlusion) bull Infarction - Area of necrosis due to ischemia
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
bullSimplendashSimple squamous(endothelium)ndashSimple cuboidal(renal tubule)ndashSimple columnar (small intestine)bullStratified squamousndashLow keratin (esophagus)ndashKeratinized (epidermis)bullPseudostratifiedndashColumnar ciliated (trachea epididymis)ndashTransitional (bladder)
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
FOUR VULNERABLE SYSTEMS 1048576bull Cell membrane integrity 1048576bull ATP generation mitochondrial function 1048576bull Protein synthesis enzyme function 1048576bull Genetic integrity
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
SIX GENERAL MECHANISMS 1048576bull ATP depletion (oxphos or glycolysis) 1048576bull Oxygen (i) ndash ischemiahypoxia 1048576bull Oxygen (ii) ndash ROS 1048576bull Loss of Ca2+ homeostasis 1048576bull Plasma membrane integrity 1048576bull Mitochondrial damage
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