Pathology - Week 1

7/30/2019 Pathology - Week 1

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Lecture 1 Pathology Introduction Mon. 08/16/10

Myocardial Infarction at 1 hour; H&E slide is normal Clot-busters or angioplasty can prevent infarction of the ventricular muscle

Myocardial Infarction first 72 hours Coagulation necrosis of heart muscle and arrhythmias are generated Coronary Care Unit- monitor and prevent and/or treat arrhythmiasTest q: When is a patient who has suffered an acute MI at greatest risk for fatal arrhythmias? Days 1-3.

Test q: When is a MI patient at greatest risk for fatal arrhythmias? Days 1-3.

Test q: A patient suffers an MI and dies 30hr later in the coronary care unit. At autopsy, the infarcted area of the myocardium would most likely show:Coagulation necrosis w/neutrophil infiltration.

Test q: A 76y/o woman suffers a massive MI and dies in cardiogenic shock 20hr after its onset. Microscopic exam of her infarcted myocardium wouldbe expected to demonstrate which of the following? Coagulative necrosis w/few neutrophils.Test q:A 76y/o man presents to the ER w/progressive substernal chest pain over the past 4 hr. He is short of breath and reports pain in his left jaw and

shoulder area. An initial ECG demonstrates ST elevation changes and a baseline troponin I level of 2.8ng/mL. Which of the following complications areyou most concerned about occurring in this patient within the next 24hr? Ventricular arrhythmia.

Myocardial Infarction at 7 days: macrophages and fibroblasts on the H&E slide 1. Myocardium is destroyed 2. Scar formation is incomplete 3. Aneurisms develop or ventricular wall may rupture 4. Patient must avoid strenuous exercise and heavy liftingTest q:A 49y/o male suffers an acute MI. He is treated w/angioplasty. Serum troponin I becomes elevated, but his recovery is otherwise uneventful.He is discharged 5 days after onset of chest pain. At day 9 post-MI, what would be the appearance of the infarcted area of the myocardium?

Neutrophils, macrophages, and fibroblasts.Test q: A patient is found dead at home. The patient has a history of angina. At autopsy the CK-MB was normal and the cardiac Troponin I waselevated. The heart shows an area of coagulative necrosis with mixed inflammatory cells and evidence of new capillary growth and increasedfibroblastic activity. The age of the infarct is approximately: 5 days 1 week old. (Question was repeated with this answer: 3 days 1 week old)

Test q: (slightly diff from one above)A patient is found dead at home. Patient has a history of angina. At autopsy, the CK-MB was normal and thecardiac troponin I was elevated. The heart shows an area of coagulative necrosis with monocytes and evidence of new capillary growth and increasedfibroblastic activity. The age of the infarct is approximately: 6-10 days old.

GROSS OBSERVATIONS Size Consistency/texture Color Shape Location

SIZE Increased- HYPERTROPHY (increased cell size e.g. muscle) orHYPERPLASIA (increased cell # - e.g. glands) Decreased- ATROPHY (once normal, now smaller) orHYPOPLASIA (never normal in size)

Accumulations of material may also increase the overall size of the organ; example: AMYLOIDOSISTest q: A 45 y/o woman is investigated for hypertension and is found to have a small right kidney. Contrast studies reveal stenosis of the right renalartery. The size change in the right kidney is an example of which of the following adaptive changes? Atrophy.

Test q: A 45y/o man is evaluated for hypertension. Arteriography shows marked stenosis of the left renal artery. Unfortunately, he has an acute MI anddies shortly after the procedure. At autopsy, the left kidney weighs only 30g and has a smooth capsule. The right kidney weighs 120g (normal is 150)with a pitted surface. The left kidney is best described as: Atrophic.

Test q: A 50y/o female w/a history of hypertension develops acute chest pain, arrest and cannot be resuscitated. At autopsy the free wall of the leftventricle is noted to be 4.0cm in thickness. The best description of this change is: Hypertrophy. QUESTION REPEATED TWICE.Test q: On a routine visit to the physician, an otherwise healthy 51y/o man has a BP of 150/95mmHg. If the patients hypertension remains untreated

for years, which of the following cellular alterations will most likely be seen in the myocardium? Hypertrophy.Test q: A 60y/o male has been treated for hypertension for over 20 years. He has become increasingly short of breath over the past 2 years. An EKGis normal. The left ventricle would most likely show: Hypertrophy.

Test q: A 60y/o male dies after a massive MI. He was known to be hypertensive. At autopsy the left renal artery is completely stenosed. The rightkidney is almost normal in size but shows many surface pits and scars, and on cut section shows very little cortex remaining. The left kidney would moslikely show: Atrophy.

Test q: Following injury, which of the following restores functional capacity by hypertrophy? Cardiac muscle.

Hypertrophy of LV,probably due to hypertension.


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AMYLOIDOSIS causes heart and renal failure Pink, fluffy extracellular(protein) material in tissue stained with H&E Congo Red Stain- orange on light microscopy and Apple-green birefringence when polarized Beta-Pleated Sheet by x-ray diffraction or EMTest q: What is a diagnostic test for amyloid? Congo Red w/polarizationTest q: A 62y/o man dies following a 6-yr history of progressively worsening heart failure. At autopsy, the heart is found to have extensive infiltration of

the myocardium by an acellular, eosinophilic material. This extracellular material most likely represents:Amyloid.

Examples of Amyloid:Disease Type of Amyloid Multiple myeloma Lambda or kappa(^ malignancy of plasma cells)

Dialysis patients B-2 microglobulin Inflammation SAA Medullary CA Procalcitonin(^ thyroid cancer makes huge amounts of procalcitonin)

Lardaceous spleen: greasy appearance. Liver w/amyloid. Most hepatocytes replaced by this abnormal protein.

Test q:A 52y/o female on hemodialysis develops left heart failure and elevatedliver transaminases. A biopsy of liver shows acellular pink deposits which stain

positively w/Congo red. The deposits contain: -2 macroglobulin. (typo?should be microglobulin?)

Normal (right)and hyperplastic(left) adrenalglands. Could becaused by pituitarytumor.

Normal (left) andatrophic (right) kidneys.The normal kidney has asmooth, capsular surface.The atrophic kidney has arough, pitted surface due todestruction of glomeruli andscars pulling inward.

Amyloid here, isprocalcitonin.


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SHAPE Shape of lesions may indicate the pathologic process Infarcts (tissue death, secondary to a thrombus) are wedge-shaped; arterial bloodvessels distribute in an inverted tree-like fashion

Spleen Infarction

COLOR Organs may acquire color or lose their natural color When liver accumulates FAT (as in alcoholism) it becomes enlarged and pale toyellow-orange in color Also, when a SCAR forms in the myocardium of the heart (post MI), the colorchanges from red/tan to gray/white

LIVER COLORS (Gross) FAT Yellow/orange IRON Red (brick red) BILE Green

MELANIN Black/brown

HEMOCHROMATOSIS 1. Genetic

2. Secondary (as opposed togenetic/primary)A. Iron overload due to

transfusions for anemiasB. Increased oral intake (rare)

Above: can see brownish/red granules (iron).

Below: bile stains greenin liver. Caused byobstruction of bile ducts.Gross green.Microscopic brown.

Above: nodules of malignant melanoma(black/brown).

thrombusstarted here,everythingdistal = infarct.

Infarct along IV septum.Takes weeks to develop thiskind of scar. Remote infarcthere, not acute infarct.

Below: too much iron.Brick red/brownish


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Example of color change in melanoma (brown/black).

CONSISTENCYOrgans become stiff, hard, soft, waxy or greasy in diseaseAlcoholism and hepatitis cause extensive fibrosis (cirrhosis/scar tissue) in the liver and the liver is pale, shrunken andfirm with round NODULES (firm, circumscribed areas)

Cirrhosis/fibrosis of liver scar tissue. Icteric sclera. Ascites. Esophageal varices.

LOCATIONSome pathologic processes occur in specific locations (organ specific, tissue specific)For example, FAT NECROSIS occurs in the pancreas (enzymic fat necrosis) and breast (traumatic fat necrosis)Also, tumors in the cortex of the kidney are usually glandular in origin (adenocarcinoma)

Above: Fat necrosis in pancreas.Above: Tumor growing out of kidney cortex. Above: cysts fluid-filled sacs.

Almost always is renal cell carcinoma.

CYST- fluid-filled sac; Ovary orKidney cysts are OK BULLA- fluid-filled sac in the lung or skin Uterus- LEIOMYOMAS in the myometrium;ADENOCARCINOMAS in the endometrium METASTASES- multiple nodules of tumor

Leiomyoma in the uterus.If in cervix, would be Liver metastasessquamous cell carcinoma.

Test q: A 35y/o male alcoholic develops portal hypertension and esophageal varices.You would expect the histopathology to show: hepatocytes surrounded by scar.

Test q: A 30y/o alcoholic male presents to the ER w/acute abdominal pain and vomitingw/dehydration. Serum lipase is elevated. Phys exam shows esophageal varices. HisEKG is normal.

-H&E stained slides of a liver biopsy would show: fibrosis and fatty change.-H&E stained slides of a pancreas biopsy would show: fat necrosis.

Fluid inperitonealcavity.Distinguishw/wave sign.

Bullae. Fluid-filled sacs in thelung. Spaces in lungbut no capillaries forgas exchange.


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TYPES OF NECROSISCOAGULATIVE InfarctsLIQUIFACTIVE AbscessCASEATION TB GranulomaFAT (ENZYMIC) Pancreas and breast

^ release lipase (pancreas), destroy tissue.

Old MI Living heart MI and acuteinflammation

(weeks, months old)

Abscess (pus pocket)Brain abscess

Caseous

necrosis in TBgranuloma

(cottage cheeseappearance)

Granuloma w/central necrosis

Enzymic fat necrosis

Fat necrosis

of pancreas tissuetotally destroyed butno neutrophils

Viable pancreas


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Lecture 2 Adaptation, Injury, and Death of Cells (Part 1) Tues. 08/17/10

Pathology: the Study of Disease Etiology or cause: infection, genetic etc. and often mutifactoral Pathogenesis: progression of the disease from start to finish (Molecular and Morphologic Changes) Clinical Manifestations: signs and symptoms

At least two ways for cells to die necrosis and apoptosis. Another isautophagy (will discuss later).

If membrane or organelles rupture, or if thenucleus is destroyed, these changes areirreversible. In necrosis, almost always haveneutrophils cleaning up the mess.

Cell Proliferation Varies Labile cells continuously dividing/mitosing (epithelium, bone marrow) Stable cells quiescent but can reenter cell cycle (in G0 stage; hepatocytes, smooth muscle, lymphocytes) Permanent cells nondividing (neurons, skeletal and cardiac muscle)

Test q: A 50y/o woman tests positive for HepA antibody. Theserum AST level is 275 U/L and ALT is 310 U/L. One monthlater, these enzyme levels have returned to normal. Whichphase of the cell cycle describes the hepatocytes one monthafter infection? G0.

Test q: Examples of stable of quiescent cells (G0) are:Hepatocytes and smooth muscle. QUESTION REPEATEDTWICE.Test q: All of the following are labile cells EXCEPT:

fibroblasts. (Other choices were: epidermal keratinocytes,endometrial glandular cells, bone marrow stem cells, andgastric mucosal cells.)Test q:A 25y/o med student embarks on a drinking bingeafter block exams and is hospitalized for acute alcohol toxicity.The serum AST level is 275U/L, and ALT is 310 U/L. One

month later, these enzyme levels have returned to normal.Which phase of the cell cycle best describes the hepatocytes

1 month after the drinking episode? G0.

CELLULAR ADAPTATIONS:STIMULUS CELL RESPONSE

Increased demand (ex: left ventricle) Hyperplasia, hypertrophy Decreased nutrients Atrophy Chronic irritation (cigarette smoke) Metaplasia one adult cell replaces another Hypoxia- acute, limited Reversible changes Hypoxia- severe Death: necrosis or apoptosis


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Cardiac musclehypertrophy andinfarction: Hypertrophyof left ventricle inhypertension. If MIcauses myocardialmuscle to becomehypoxic, you will getnecrosis.

Hypertrophy Increase in cell size with subsequent increase in organ

size Hypertrophy can be physiologic or pathologic

Causes of hypertrophy:1. Increased functional demand (body builders; HT)2. Hormonal stimulation

Physiologic reasons for hypertrophy, ex: pregnant uterus. Smooth muscle in uterine wall hypertrophies.

No evidence this is true (did not explain at all)


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Hyperplasia: Increase in the number of cells in an organ, which may then increase organ size. Physiologic or Pathologic

PHYSIOLOGIC HYPERPLASIA1. Hormonal hyperplasia- female breast at puberty and in pregnancy2. Compensatory hyperplasia- liver regeneration after partial resection

Test q: A 16y/o boy sustained blunt trauma to the abdomen when the vehicle he was driving struck a bridge abutment at high speed. Peritoneal lavage

shows a hemoperitoneum, and at laprotomy, a small portion of the left lobe of the liver is removed because of the injury. Several weeks later, a CT scanof the abdomen shows that the liver has nearly regained the size it was prior to injury. Which of the following processes best explains this CT scan

finding? Hyperplasia.

Female Breast Tissue after Puberty: Lactating Breast during Pregnancy:

A few breast ducts present, arranged in lobules. Physiologic hyperplasia many more glands to make milk (due

to hormonal stimulation)Causes of Pathologic Hyperplasia:1. Excess hormone- endometrial hyperplasia due to estrogens2. Growth factors- Warts (HPV 6, 11)

Hyperplasia is NOT a neoplastic process (tumor/cancer), but it may be fertliesoil for malignancy.Atypical Hyperplasia (increased cells that look abnormal) in the endometriumcarries an increased risk for development of endometrial adenocarcinoma.

Normal uterus: relatively flat glandular lining Hyperplasia: much thicker

Test q: Which of the features of fibrocystic change is most associated with predisposition todevelopment of adenocarcinoma? Atypical hyperplasia.

Test q: A 69y/o man has had difficulty w/urination for the past 5 years. A digital rectal exam reveals thatthe prostate gland is palpably enlarged to about twice normal size. A transurethral resection of theprostate is performed, and the microscopic appearance of the prostate chips obtained is that of largeglands lined by 2 cell layers and with intervening stroma. Which of the following pathologic processes

has most likely occurred in the prostate? Hyperplasia.

Endometrial hyperplasia

Normal proliferative endometrium: Endometrial hyperplasia: Endometrial adenocarcinoma:

Many more glands; cells. Atypical hyperplasia in endometrium:great risk for developing cancer. Seesimilar changes in breast, prostate.


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Atrophy:Decrease in the size of a cell or organ by loss of cell substanceCauses (many more than just these):

1. Decreased workload2. Loss of innervation3. Decreased blood supply4. Inadequate nutrition5. Loss of endocrine stimulation6. Pressure

Figure: Central skeletal muscle bundle is atrophic Patient who had damage to skeletal muscle. Normal bundles ontop and bottom of figure; abnormal in the middle. In themechanical injury to this muscle, the innervation of this musclebundle was severed undergoes atrophy. Very prominent after trauma.

Atrophic brain: Normal brain:

As you get older, the sulci get bigger and the gyri get smaller.

Protein degradation is important in atrophyA. Lysosomes with hydrolytic enzymes - or -B. The ubiquitin-proteasome pathway

HypoplasiaIncomplete development of an organ so that it fails to reach adultsize; most common example: hypoplastic left ventricleOrgan was never normal in size.

Hypoplastic left heart syndrome: Only a remnant of the LV(vestigial) is there. Must have surgery very early on, may needheart transplant.

MetaplasiaA reversible change in which one ADULT cell type is replaced byanother ADULT cell type. Reversible if stimulus is removed.

Causes of Metaplasia (USUALLY columnar epithelium changes to squamous) Chronic irritation (cigarette smoke) Calculi (stones) in ducts Vitamin A deficiency

Test q: A 40y/o male has been smoking since college. Biopsy of a suspicious area of the right upper lobe found on chest x-ray shows a squamous

epithelium lining the bronchial tree. There is no cytologic atypia. These changes are consistent with: Metaplasia.A 67y/o smoker has shortness of breath and a chronic cough. His pulmonary function tests are abnormal and a bronchial biopsy is taken. The finding ostratified squamous epithelial cells lining the bronchus is indicative of which of the following? Metaplasia.

Test q:An experiment is conducted in which cells intissue culture are submitted to high levels of UV radiant

energy. EM shows cellular damage in the form ofincreased cytosolic aggregates of denatured proteins.In situ hybridization reveals that protein components in

these aggregates are also found in proteasomes.Which of the following substances is most likely to bind

to the denatured proteins, targeting them for catabolismby cytosolic proteasomes? Ubiquitin.


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Cervix- squamous epithelium of the endocervix replaces columnar (dysplasia and squamous CA may develop). Samething happens in lung

Barrett esophagus- gastric reflux results in columnar epithelium (glandular) replacing squamous epithelium in theesophagus (dysplasia and adenocarcinoma may occur)

Test q: After several years of gastric reflux, a 30y/o male develops Barretts Esophagus (syndrome). Histologically, the distal esophageal mucosashows: Columnar epithelium.Test q: Secondary to gastric reflux, the distal esophagus exhibits replacement of squamous epithelium by columnar epithelium. This change is termed

Metaplasia.Test q: A 32y/o has heartburn and gastric reflux. Endoscopy reveals columnar epithelial metaplasia w/goblet cells in the lower esophagus. This patientis at risk for: Adenocarcinoma.

Squamous cells replace columnar cells: Glandular metaplasia:

Adenocarcinoma of the esophagus:

Esophagus: glandular epithelium (R) is metaplastic(HIGH risk of adenocarcinoma)

Dysplasia:Atypical proliferative changes due to chronic irritation or inflammation;Premalignant change: unless there is some intervention, cells that undergo this change will become malignant

Metaplasia vs. Dysplasia: In metaplasia if you take away stimulus, it goes away. Dysplasia molecular change. (ex:HPV becomes incorporated into the host genome not reversible change)

Figure (dysplasia in the cervix): 1st pic (left) = normalsquamous epithelium (originally was columnar but underwent

metaplasia to become squamous). If squamous epitheliumgets infected by HPV, it will undergo dysplastic change.Nuclei get bigger and darker. Mild picture only goes up alittle. Moderate goes up 2/3 of the picture. In markeddysplasia picture, could also be called carcinoma in situ its already malignant but hasnt punched through the BM yet.

If you have just the metaplasia, its reversible. Dysplasia,however, will go on to malignancy unless its treated.

Test q: A transbronchial biopsy of lung shows a squamous epithelium withincreased nucleus:cytoplasm ratio, increased mitoses, and an overall disordered maturation. The basement membrane is intact. The epithelial changesare best described as: Dysplasia.

Test q: Loss of orderly maturation of epithelium is by definition: Dysplasia.


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Causes of cell injury: Oxygen deprivation Physical agents Chemical agents and drugs Infectious agents Immunologic reactions Genetic derangements Nutritional imbalances

Cellular Changes Secondary to Injury:Reversible Irreversible

Cellular swelling Lysosomes ruptureCell membrane blebs Dense bodies in mitochondriaDetached ribosomes Cell membrane ruptureChromatin clumping Karyolysis, karyorrhexis, pyknosis

Karyolysis = the complete dissolution of the chromatinmatter of a dying cell due to the activity of DNAase.

Karyorrhexis = the destructive fragmentation of thenucleus of a dying cell whereby its chromatin is distributed irregularly throughout the cytoplasm.

Pyknosis = the irreversible condensation of chromatin in the nucleus of a cell undergoing necrosis or apoptosis.

Listed above: Microscopic changes. If membranes are ruptured or if nucleus is significantly damaged, it is irreversible.

Test q: A 50 yo farmer is exposed to a pesticide that exhibits potent hepatotoxicity. Which is a reversible change in the hepatocytes? Cellularswelling. (NOT plasma membrane rupture, mitochondrial permeability, nuclear karyorrhexis, calcium influx into mitochondria)

Test q: A 17y/o boy w/HepA experiences mild nausea for about 1 week and develops very mild scleral icterus. On physical exam, he has minimal rightupper quadrant tenderness. Lab findings include a serum AST of 168U/L, ALT 175U/L, and total bilirubin 5.1mg/dL. The increase in this patients serumenzyme levels most likely results from which of the following changes in the hepatocytes? Cell membrane rupture.

Test q: A 55y/o male present to the ER w/crushing chest pain and EKG consistent with acute MI. Both troponin I and CKMB are markedly elevated at24hr post-admission. What is the cellular change responsible for the elevated serum values? Cell membrane rupture.

Ruptured membranes or marked destruction of the nucleus = irreversible change. Others pictured above are reversible.

NECROSIS vs APOPTOSIS Necrosis- death of GROUPS of cells after injury; usually with inflammation (neutrophils). Accidental death. Apoptosis- genetically controlled, ATP and enzyme-dependent death of individual cells; usually no inflammation.

Programmed cell death are genetically programmed to die at a certain time or secondary to a certain stimulus.

Figure: NECROSIS vs APOPTOSIS Necrosis cell swells. Cell membrane ruptures, nucleusdisintegrates, organelles rupture. Neutrophils present.Apoptosis shrinks (cell and nucleus). Cell membraneremains intact, gets compartmentalized into smaller bodiesw/membranes and intact organelles. Theoretically is a wayfor a cell to preserve material. Finally, macrophages engulfthe small bodies. No neutrophils around.

Cell Injury Principles1. The cellular response to injurious stimuli depends on

the type of injury, its duration and its severity.2. The consequences of cell injury depend on the type,

state, and adaptability of the injured cell.

Susceptibility of Cells to Ischemic NecrosisHigh: Neurons (3-4 min) Must start CPRimmediately.Test q: A 25 yo man is electrocuted in a thunderstorm. He is successfullyresuscitated after being unresponsive for 6 minutes. Cells most likely to die during this event are:neurons.

Test q: Which of the following tissue types are most susceptible to ischemic necrosis? Neurons.

Intermediate: Myocardium, hepatocytes, renal epithelium (30 min-2hr) the reason you can do angioplasty or clotbusters and still preserve part of the myocardium

Low: Fibroblasts, epidermis, skeletal muscle (many hours) mesenchymal tissues.

Ischemia = not enough blood flow (so not enough oxygen). Can have hypoxia without ischemia (ex: CO poisoning), but ifyou have ischemia, you always have hypoxia. Test q: Total loss of blood supply to an organ or region of an organ is called: Ischemia.


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Cell Injury Principles (contd from above)3. The morphologic changes of cell injury become apparent only after some critical biochemical system within the

cell has been deranged: Manifestations of lethal damage take more time to develop than those of reversible damage. Ultrastructural alterations are visible earlier than light

microscopic changes.Figure: A & B may not see anything too abnormal until necrosis (C).Reversible Injury

Cellular swelling mainly seen in kidney Fatty change mainly seen in liver

Test q: Cloudy swelling, hydropic change, and fatty change are all examples of:Reversible cell injury.

Above: Normal kidney histology Above: normal tubules

Above: renal tubules exhibit cloudy swelling. Cell Above: tubules accumulate water.membranes lose functional integrity. Take in too muchfluid or lose too much fluid, and the electrolytes get outof balance. However, this is reversible.

Basically anything that increases triglycerides causes fatty change (if you make too many TGs, if you cant transport them out of the liver,

etc. chronic alcoholism is most common reason). In fatty changeand cloudy swelling, if the damage persists long enough, irreversiblechange will happen. Fatty changeliver is yellow/orange. If fatty changelasts long enough, the hepatocyteswill die (get cirrhosis).

Fatty change Hepatocytes filled with fat(triglyceride).


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Figure: Hepatocytes filled with triglyceride. Nuclei pushed to the sides. See big globules of fat. Fatty change is reversible if the person stops drinking if you drink a 6-pack on Saturday night, your liver will undergo fatty changebut it will reverse itself. Test q: Which of the following is an example of reversible cellularchange? Fatty change (NOT karyolysis, karyorrhexis, cell membrane rupture, or dense bodies inmitochondria) QUESTION REPEATED TWICE.

Rupture of cell membrane, organellemembranes, significant change in the nucleus =irreversible damage. Everything else isdebatable.

Myocardial Infarction Markers

Cardiac specific enzymes and proteins leak out of cells in 2 hours (CK, isoenzymes, LDH. troponin I and troponinT are most common) Morphologic (light microscopic) changes in 4-12 hours

Figure:A = normal myocardiumB = coagulation necrosis (Muscle has lost its nuclei andinflammatory cells are infiltrating. necrosisneutrophils)

NECROSIS Morphologic changes in GROUPS of cells that follow the death of living tissue; cells and PMNs leak lytic enzymes CYTOPLASM: eosinophilia, vacuoles, calcification, myelin figures NUCLEUS: pyknosis, karyorrhexis, karyolysis

Patterns of Necrosis Coagulative - hypoxic death (except brain) usually due to a

thrombus. All tissue distal to the artery dies. Can still tell what thetissue is can see its still heart muscle but a lot of the nuclei aregone (eventually all will disappear all cells die at the same timebecause of blood supply cut off). Test q: A 56y/o male has left chest pain thatradiates to his left arm. Troponin I levels are elevated at 3hr; cardiac catheterizationshows occlusion of the LAD artery. What is the diagnosis? Coagulation necrosis.Test q: Coagulative necrosis usually results from: ischemia.

Liquefactive - bacterial infections (influx of neutrophils and theenzymes they release); *also hypoxic death in brain tissue (infarction).Everything destroyed by neutrophils. Will only see neutrophils, ifanything. Test q: A 70y/o female loses consciousness and later cannot speak ormove her right arm. The pattern of necrosis seen in the brain is:Liquefactive.

Test q: A 70y/o woman suffered an MI followed by a stroke due to focal cerebralischemia. Expected findings include: Coagulative necrosis in heart; liquefactivenecrosis in CNS. REPEATED x3!!

Caseous - tuberculosis; will see macrophages Fat - enzymic or traumatic damage to fatty tissue; eg. Pancreatitis (enzymic) If pancreas damaged, enzymes leak

and they will break down all the lipids in the pancreas, and that will combine w/calcium to produce calcium soaps.Saponification = fat changed into soap. Test q: Digestion of tissue w/soap formation and calcification is characteristic of: Enzymicfat necrosis

Fibrinoid - immune complexes (Antigens and Igs) in the walls of arteries

A B


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Coagulation necrosis in the kidney.See the roughly triangular-shaped infarct.Thrombus was at the bottom point of it allthe distal tissue died.

Test q: A well-demarcated lesion w/increasedcytoplasmic eosinophilia, karyolysis, and intact tissuearchitecture is characteristic of: Coagulative necrosis

Brain abscess with liquefactive necrosis.Test q:An abscess is best defined as: a localizedcollection of pus.

Coagulative necrosis (A) cantell a glomerulus and tubules arepresent, but all the nuclei are gone(pale ghost of itself) all tissue lostoxygen supply at the same time andtherefore died at the same time.

Liquefactive necrosis (B) in thekidney lots of neutrophils. Tissue in

the middle totally destroyed.

Above: abscess; liquefactive necrosis. Above: caseous necrosis of lungSee neutrophils. Cottage cheese appearance.

Above: Granulomatous Inflammation with Central Necrosis. Above: Fat necrosis in pancreas. When the materialNecrotic in the middle, has lots of multinucleated turns to soap, it calcifies and can be seen on a CT.giant cells around the periphery (bottom left).

Test q: A chest radiograph of an

asymptomatic, 37y/o man showed a 3-cmnodule in the middle lobe of the right lung. Thenodule was excised with a pulmonary wedge

resection, and sectioning showed the nodule tobe sharply circumscribed with a soft, whitecenter. Culture of tissue from the nodule grew

Mycobacterium tuberculosis. Which of thefollowing pathologic processes has most likelyoccurred in this nodule? Caseous necrosis.

Test q: A chest radiograph of an asymptomatic37y/o man showed a 3cm nodule in the middle

lobe of the right lung. The nodule was excised

w/a pulmonary wedge resection, andsectioning showed the nodule to be sharply

circumscribed w/a soft, white center. Cultureof tissue from the nodule grew Mycobacteriumtuberculosis. Which of the following pathologic

processes has most likely occurred in thisnodule? Necrotizing granuloma (otherchoices were abscess, coag. necrosis, fatnecrosis, and liquefactive necrosis.)

Test q:A 45y/o Gulf war veteran and lifelong resident of Indy develops a positive skin test for

tuberculosis. Chest x-ray shows a 3cm diameter nodule in the left lower lobe. Histopathology willmost likely show: macropahges, lymphocytes, and fibroblasts.


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Above: Fat necrosis (L) and normal pancreas (R). Above: Fibrinoid necrosis seen in certain rheumatoid

and autoimmune diseases. See pink material depositedin the wall of the artery.

Mechanisms of Cell Injury Oxidative

phosphorylation

Mitochondrial damage (Ifyou lose ATP, you losemembrane function andmitochondrial function.)

Influx of Ca++ (too muchwill kill cells)

Free radical formation Membrane damage DNA and Protein

damageEverything pictured above can result in necrosis.

Depletion of ATP Na+ pump fails- Na+ and water enter and K+ is lost; glycolysis

depletes glycogen and lowers pH (loss of enzymic activity andfluid exchange messed up)

Ca++ pump fails- Ca++ into cells (toxic turns on enzymes thatbreak down the cell)

Decreased protein synthesis (ribosomes detach) Unfolded protein response

Figure: Ischemic event (loss of blood supply due to a thrombosis) tissue becomes anoxic because you dont have oxygen as the terminalelectron acceptor (so no ATP) lose Na pump, etc.

Mitochondrial Damage Increased cytosolic Ca++ Decreased ATP (Hypoxia) Mitochondrial permeability transition (MPT)- pore that allows

cytochrome C to escape; apoptosis is triggered and cell deathoccurs (sort of combo of necrosis/apoptosis destroying the cell)

Test q: A tissue preparation is experimentally subjected to a hypoxic environment. The cellsin this tissue begin to swell, and chromatin begins to clump in the nucleus. ATPases are

activated, and ATP production decreases. Which of the following ions released frommitochondria leads to these findings and to eventual cell death? Ca

2+

Test q: The cell membranes are ruptured and leaking. Water and calcium enter the cell. Calcium binds to mitochondria. At this point:the cell is

irreversibly damaged.


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Loss of Ca++ Homeostasis Extracellular Ca++ is 15X higher than

cytosolic Ca++ Loss of ATP increases intracellular

Ca++ Increased Ca++ activates many

enzymes phospholipases.proteases, endonucleases andATPases

Increased Ca++ also increasesmitochondrial permeability triggeringapoptosis

Figure (far right):Enzymes chew up proteins, nucleus, etc.Also will disrupt mitochondria (decreasingATP, leading to problems). All of theseare interrelated.

Free Radical Formation

Single unpaired electron; highly reactive destroy chemical compounds

Normal metabolism produces superoxideanion, hydrogen peroxide and hydroxylion; superoxide is produced in neutrophils

Lipid peroxidation of cell membranes Protein fragmentation Breaks in DNA

Body has a lot of preventative mechanismsagainst ROS: superoxide dismutase, catalase,peroxidase, etc. Books say vitamins do the samething, but this has been proven to be somewhat

untrue (may have some related function but notprimary function).

Major Antioxidants: Antioxidant Enzymes: superoxide dismutase,

catalase, glutathione peroxidase Vitamins: A, E, ascorbic acid, glutathione. (Vitamins

can be considered antioxidants but do not play majorrole.)

Membrane Permeability Defects: Plasma membrane Mitochondrial membrane Lysosomal membrane- release of RNases, DNases

and proteases


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Anoxia is most common mechanism of membrane damage if

you cant generate ATP, the Na and Ca pumps are disrupted. ROS isless common cause.

Hypoxia and Ischemia Hypoxia- deficiency of oxygen; causes: cardiorespiratory

failure, anemia, CO poisoning; cell injury and death Ischemia- loss of blood supply (oxygen and nutrients); more

rapidly and severely injures tissues than does hypoxia alone AGAIN: Ischemia involves hypoxia, but you can have hypoxia

without ischemia.

Lecture 3 Adaptation, Injury, and Death of Cells (Part 2) Fri. 08/20/10

Mechanisms of Cell Death:Necrosis- groups of cells are killed by injurious agents Apoptosis- individual cells are induced to commit suicide

Apoptosis (predetermined) NecrosisATP-dependent ATP not requiredCell membrane intact Cell membrane ruptureOrganelles intact Organelles ruptureNo inflammation Inflammation

Test q: Which of the following is characteristic of apoptosis? Energy dependence. (NOT cell membrane rupture, lysosome rupture, karyolysis, acute

inflammation)Test q: Apoptosis is associated with all of the following EXCEPT: Local tissue inflammation. (the other choices were cleavage of chromatin by

endonucleases, activation of caspases, phagocytosis of apoptotic bodies, and chromatin condensation beneath the nuclear membrane)

NECROSIS: APOPTOSIS:

Rupture of cell/organelle membrane or rupture/lysis of Apoptosis membrane recompartmentalizes, thennucleus = dead cell. compartments are engulfed by macrophages

Apoptosis Morphology Cell shrinkage Chromatic condensation/reorganization of the nucleus Plasma membrane wrinkles/blebs Fragmentation into apoptotic bodies Phagocytosis of apoptotic cells/bodies

Test q: A 30y/o female w/metastatic breast carcinoma hasreceived several courses of chemotherapy. A post treatment

biopsy shows individual neoplastic cells that exhibit nuclearfragmentation and cytoplasmic budding in cell that exhibit anoverall decrease in size. The neoplastic cells responding tochemotherapy are exhibiting changes consistent with: apoptosis

Test q:A 54y/o man experienced onset of severe substernal chest pain over 3hr.An ECG showed changes consistent w/an acute MI. After thrombolytic therapy

w/t-PA, his serum creatine kinase (CK) level increased. Which of the followingevents most likely occurred after t-PA therapy? Free radical injury. (Robbinsexplanation: The reperfusion of damaged cells results in generation of oxygen-

derived free radicals, however, causing a reperfusion injury. The elevation in theCK level is indicative of myocardial cell necrosis because this intracellular enzymedoes not leak in large quantities from intact cells.)


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Apoptotic Cells in H & E Sections Oval mass of intensely eosinophilic

cytoplasm with dense chromatinfragments; occurs rapidly; noinflammation

There is not tremendous shrinkage may be hard to tell.

Tend to be individual cells

Figure: Civatte Bodies Civatte body = two cells undergoing apoptosis. Can dospecial stains for caspases, other intermediates, also (tovisualize apoptosis).

PHYSIOLOGIC APOPTOSIS: Embryology- fingers and toes/maleness

Hormone-dependent- endometrial cells shed on estrogen withdrawal; breast ductregression after weaning.

When the hormone is taken away (dont need the cells anymore),those cells undergo apoptosis. Breasts undergo hyperplasia, whichwould be dangerous if it didnt go away. But it does disappear viaapoptosis.

Neutrophils (PMNs) disappear in acute inflammation Neutrophils only live 4 hr after they go into tissues good thing bc

they destroy everything w/enzymes. If they lived longer, we would beautodigested away.

Figure: Apoptosis of Neutrophils Cytotoxic T cells eliminate virus-infected cells by inducing apoptosis

PATHOLOGIC APOPTOSIS: Radiation and anticancer drugs damage DNA and apoptosis follows (role of p53) Hypoxia- apoptosis (if mild) or necrosis if the hypoxia is severe Decreased cell death in lymphomas (Bcl-2) APOPTOSIS IS BLOCKED BY BCL-2. Misfolded proteins

Test q: A 40y/o man notices an increasing number of lumps in his groin and armpits. On physical exam, he has a generalized lymph node enlargemen

and hepatosplenomegaly. An inguinal node biopsy shows a malignant tumor of lymphoid cells. Immunoperoxidase staining of the tumor cellsw/antibody to BCL2 is positive. Which of the following mechanisms has most likely produced the lymphoma? Lack of apoptosis.Test q: Which of the following results in increased apoptosis? Decreased of defective Bcl-2.

Test q: Prior to the start of a womans menstrual cycle, which protein decreases in mitochondrial cell membranes to allow for menses to proceed?Bcl2Test q:An experiment introduces a knockout gene mutation into a cell line. The frequency of shrunken cells w/chromatin clumping and cytoplasmicblebbing is increased, compared w/a cell line w/o the mutation. Overall survival of the mutant cell line is reduced. Which of the following genes is most

likely to be affected by this mutation? Bcl-2. (other choices were Bax, C-myc, Fas, and p53)


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Pathologic Apoptosis in Viral Infections APOPTOSIS AFTER RADIATION: HPV- E6 protein inactivates p53

If p53 inactivated, you dont get apoptosis (cells dont die).Test q: A 30y/o woman who has had multiple sexual partners sees her physician because she has hadvaginal bleeding and discharge for the past 5 days. Pelvic examination shows an ulcerated lesionarising from the squamocolumnar junction of the uterine cervix. A cervical biopsy is performed.

Microscopic examination reveals an invasive tumor containing areas of squamous epithelium, withpearls of keratin. In situ hybridization shows the presence of HPV type 16 (HPV-16) DNA within thetumor cells. Which of the following molecular abnormalities in this tumor is most likely related to

infection w/HPV-16? Decrease in p53 protein. EBV- makes Bcl-2-like substance (blocks apoptosis)

HIV- infected cells make high levels of FasL which induce apoptosis inHIV-uninfected Tcells

Biochemical Events in Apoptosis Caspases (cysteine proteases) cleave the cytoskeleton and activate

DNAses DNA breaks into 50- to 300-kilobase pieces; further broken into multiples of 200 base pairs by endonucleases

(Ca++ and Mg++)- demonstrated as a ladder pattern on agarose gel; also proteases. Phosphatidylserine is exposed and attracts macrophages with little collateral damage

Figure: apoptosis. Caspases activate othercaspases, those activate proteases and nucleases

= cell broken down. Red tags on bottom right phosphotidyl serine tags allow them to bephagocitized more easily.

The intrinsic Pathway of Apoptosis: Majormechanism. Increased mitochondrial permeability and

release of pro-apoptotic molecules(cytochrome c)

Pro:1. membrane- Bim, Bid, Bad and Bax, Bak2. cytoplasm- Smac/DIABLO

Anti: Bcl-2, Bcl-x

Figure 1-25: The intrinsic (mitochondrial) pathway of apoptosis. A. Cell viability is maintained by the induction of anti-apoptotic proteins such asBcl-2 by survival signals. These proteins maintain the integrity of mitochondrialmembranes and prevent leakage of mitochondrial proteins. B. Loss of survivalsignals, DNA damage, and other insults activate sensors that antagonize the anti-apoptotic proteins and activate the pro-apoptotic proteins Bax and Bak, whichform channels in the mitochondrial membrane. The subsequent leakage ofcytochrome C (and other proteins, not shown) leads to caspase activation and

apoptosis.

Certain hormones in the environment can trigger apoptosis involves themitochondrial release of cytochrome c.

Test q: A 40 y/o man had undifferentiated carcinoma of the lung. Despite chemotherapy, the man died

of widespread metastases. At autopsy, tumors were found in many organs. Histologic examinationshowed many foci in which individual tumor cells appeared shrunken and deeply eosinophilic. Their nuclei exhibited condensed aggregates ofchromatin under the nuclear membrane. The process affecting these shrunken tumor cells was most likely triggered by the release of which of the

following substances from mitochondria (into the cytosol)? Cytochrome c. QUESTION REPEATED x4!!


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Figure: Intrinsicpathway.

Figure: Extrinsic pathway.

Extrinsic Pathway: Activation of plasma membrane death receptors TNFR1 and Fas

Activation begins at cell membrane. Does not directlyinvolve mitochondria. (Some stimuli do both. Maystart as a ligand, then activate the mitochondrial

pathway.) Fas ligand (FasL in figure above, right) attaches to

Fas receptor, then eventually activates caspase-8. Caspase-9 is usually first in the intrinsic pathway

(above, left).

Control and Integration Stage: Specific proteins connect the death signals to proteolytic

enzymes in the capase family responsible for theexecution phase. Can see in figure below that there are some intermediaries.

The Execution Stage:

Caspases cleave cytoskeletal and nuclearmatrix proteins and result in DNA cleavageinto fragments giving DNA Ladder patternby agarose gel electrophoresis. Can see ladder pattern in apoptosis

(nuclear material specific cleavage ofnuclear components)

Necrosis = smudge

Removal of Apoptotic Bodies: Apoptotic cells are coated by

Phosphatidyl serine (which flipsout) orC1q leading to early recognition andremoval by macrophages (makes thecell more attractive to macrophages).Thrombospondin isan adhesiveglycoprotein may also coat.


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DNA-damage and Apoptosis Radiation or chemotherapy damages

DNA p53 accumulates Cell cycle arrested at G1 (allows repair) If repair fails, p53 triggers apoptosis

p53 = guardian of the genome. Ifthere is damage to DNA, p53 shutsdown cell cycle so cells cant mitose.Then it induces DNA repair.

Figure: If you have active p53 and there is alteration to theDNA, you can have potential repair. IF successful, go back tohaving normal cell. If not successful, apoptosis triggered.

Tumor Necrosis Factor and Cytotoxic Lymphocytes in

Apoptosis Fas (CD95) FasL induces apoptosis in lymphocytes

that recognize self; Fas/FasL mutations may causeautoimmune disease

TNF/TNFR1-TRADD-FADD causes caspaseactivation and APOPTOSIS; TNF activates NF-kBwhich aids cell SURVIVAL and is antiapoptotic

Foreign Ag-CTLs- lymphocytes produce PERFORMINwhich allows entry ofGRANZYME which activatescaspases; CTLs kill target cells If you could therapeutically trigger T lymphocytes

to attack certain cells and send them intoapoptosis, could be therapeutic tool.

Dysregulated Apoptosis Too little: activity diminished in certain cancers Too much: neurodegenerative diseases, ischemic

injury, virus-induced lymphocyte depletion

Defective Apoptosis 50% of human cancers have p53 mutations Hormone-dependent tumors (breast, prostate) Follicular lymphomas and colon cancers express high levels of

Bcl-2 (translocation of bcl-2 gene) HPV- protein E6 binds and inactivates p53 EBV- proteins that mimic or increase production of Bbcl-2 Autoimmune disorders

Test q: A 55y/o man visits the physician because of hemoptysis and worsening cough.On physical examination, wheezes are auscultated over the right lung posteriorly. A chestradiograph shows a 6cm perihilar mass on the right. A fine-needle aspiration biopsy yields

cells consistent with non-small cell bronchogenic carcinoma. Molecular analysis of theneoplastic cells show a p53 gene mutation. Which of the following mechanisms has mostlikely produced the neoplastic transformation? Loss of cell cycle arrest. REPEAT x2.

Test q: In a clinical trial, a chemotherapeutic agent is given to patients w/breast cancermetastases. Samples of the cancer cells are obtained and assessed for the presence ofdeath of tumor cells by apoptosis. Mutational inactivation of which of the following

products is most likely to render tumor cells resistant to the effects of such an agent? p53.REPEAT x2.

Figure: Hasimotos thyroiditis can involve (A) A Bcl-2 decrease inthyroid cells with a Bcl-2 increase in T-cells. (B) Bcl-2 decrease in thyroid cells. (C) Graves disease involves a Bcl-2increase in thyroid cells with a Bcl-2 decrease in T-cells.


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Increased Apoptosis Neurodegenerative diseases Ischemic injury Death of virus-infected cells

(hepatitis) AIDS (death of uninfected CD4 cells) FasL+ tumors are MORE aggressive Microorganisms induce apoptosis

Most CD4 helper cells are not infected byvirus. Only 1 in 1000 are infected. But theyall end up dying, as seen in this figure.

Pneumocystis pneumonia Pneumocystis causes pneumonia in

AIDS (most common atypicalpneumonia in AIDS patients)

Human macrophages are killedbefore they can engulf the organisms

Apoptosis is triggered inmacrophages by polyamines Can see cluster of organisms in

the alveolar space.

Never see them inside themacrophages. Never getphagocytosed, just kill themacrophages.

Apoptosis Summary Normal part of the cellular machinery Pathology results when it is increased or decreased Future Study of Apoptosis: inflammation and repair (cell signaling); immune system; neoplasia; infectious

diseases Future targets for new chemotherapeutic and antimicrobial

agents

Clinical Applications Velcade (bortezomid)- blocks proteasomes in multiple myeloma;

proteins accumulate which are toxic to myeloma cells Genasense (oblimersen)- blocks production of Bcl-2 in

lymphomas rendering them more susceptible to other anticancerdrugs

Subcellular response to Injury Primary lysosome- hydrolytic enzymes Lysosome/vacuole fusion- secondary

lysosome or phagolysosome Heterophagy Autophagy - smaller components of the cell

are destroyed if they become aberrant Others- lipids, proteins, filaments, Ca++


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Cytoskeletal Abnormalities Microtubules- 25 nm Actin filaments (thin)- 8 nm Myosin filaments (thick)- 15 nm Intermediate- 10 nm

Abnormal Microtubules Sperm motility deficiency YBCS syndrome (microtubules in sperm become defective = cant swim) Immotile cilia syndrome (Kartageners Syndrome) Colchicine- disrupt microtubule formation and inhibit PMN migration; gout therapy Vinca alkaloids- antitumor; disrupt the mitotic spindle

Intermediate Filaments (IM) Mallory bodies (alcoholic hyalin)- keratin IM Neurofibrillary tangles- neurofilament IM seen in

Alzheimers Disease (below)

Intracellular Accumulations1. Normal substance that cannot be metabolized- fatty liver

(triglyceride)

2. Genetic defect in metabolism of a substance (alpha-1-antitrypsindeficiency and storage diseases like Gauchers)

3. No normal enzymes to degrade an abnormal substance (silica-silicosis)

Figure: 1. Fatty change. Cell will die necrosis/cirrhosis of the liver.2. Protein abnormality like amyloid buildup can be toxic to cells3. Enzyme deficiency (Gauchers, Tay-Sachs) may get buildup of

cerebroside, etc.4. Emphysema can take up carbon (not toxic) but if exposed to

silica will getsilicosis, toxic to cell

Fatty Change (Steatosis) Triglycerides

accumulates inparenchymal cells

Alcoholism, proteinmalnutrition, anoxia

1

2

3

4


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Figure: Pale liver = fatty liver (just has been plasticized so color is not brilliant anymore)

Below: Oil Red O Stain Below: Cerebroside in Gauchers Disease (spleen)

Gauchers cerebroside isdeposited in macrophages. Haveproblems w/reticulo-endothelialsystem. In Tay-Sachs,ganglioside deposits in neurons.

Test q: The adult form of Gauchers disease: has marked splenomegaly due to glucocerebroside accumulation (QUESTION REPEATED TWICE)

Test q:Accumulations of gangliosides in lysosomes is seen with: Tay Sachs disease.

Cholesterol Accumulation Atherosclerosis- smooth

muscle cells andmacrophages (foam cells)

We saw infarcts that mayhave been due to cholesterolaccumulation andatherosclerosis

Above: Silica in silicosis (polarized view) Above: Foam Cells in Atherosclerosis

Protein Accumulation Renal failure- reabsorption of filtered protein in the

proximal tubule accelerates Vesicles of protein fuse with lysosomes and appear as

pink hyalin droplets in the tubules (=increased protein in

tubules) Figure: Protein in renal tubules

Protein Folding Errors (failure of chaperones) Alpha-1-antitrypsin deficiency Cystic fibrosis Familial hypercholesterolemia Unfolded Protein Response-

caspase-12 is activated withapoptosis induction; Alzheimers,Huntingtons, Parkinsons

Amyloidosis- amyloid noteliminated

Hyaline change Homogenous, glassy, pink

appearance Eg. Mallory alcoholic hyaline

#1 pink substance intissue = protein.

Fibrin fibrinousperitinitis comes fromall the protein in theblood


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Hyaline change in hypertension (increased pink material in vessels)

Pigments some pathologic, some not. Carbon (exogenous) Lipofuscin- lipid and phospholipid polymers complexed with protein;

wear-and-tear pigment- liver and heart of aging patients Melanin- dihydroxyphenylalanine (from Tyr) Hemosiderin- iron-ferritin forms hemosiderin granules; hemosiderosis

(in macrophages); hemochromatosis (in parenchymal cells)Test q: A 25y/o male sickle cell patient has had several transfusions. He appears slightly

jaundiced and hepatitis is suspected. An aggressive resident performs a liver biopsy which is unremarkable except for hemosiderin in Kupffer cells.Hepatocytes do not exhibit necrosis and do not contain brown pigment. The best description is: Hemosiderosis.

Below: Lipofuscin. (slightly brownish, no path associated Wear and tear pigment)

Pathologic Calcification Dystrophic- calcification on necrotic tissue; serum Ca++

normal; atheromas, heart valves; psammoma body/asbestosbody. if tissue dies and patient is still alive, it will probablycalcify.

Metastatic- calcification on living tissue. Hypercalcemia; parathyroid, skeletal metastases, vitamin D, renal failure;lungs, arteries

Test q: A 50y/o man from Guatemala recently immigrated to the US. He undergoes a routine physical as part of an employment requirement. A chest

X-ray shows a coin lesion (small nodule) in the right lower lobe. The radiologist notes focal calcifications in the nodule and a biopsy shows caseousnecrosis w/focal calcification. These changes represent: dystrophic calcification.Test q: A 70y/o man died suddenly and unexpectedly. At autopsy, multiple tissue sites were sample for microscopic analysis. Exam of the tissuesshowed amorphous deposits of calcium salts in gastric mucosa, renal interstitium, and alveolar walls of lungs. Which of the following conditions is most

likely to explain these findings? Chronic glomerulonephritis. (From Robbins. Explanation: The findings suggest metastatic calcification. Chronicrenal disease reduced phosphate excretion increase in serum phosphate PTH increases Ca level Ca deposition.) Other choices were:Bacterial endocarditis, Disseminated TB, Generalized atherosclerosis, and Normal aging process.

Above: calcified heart valve. Above: dystrophic calcification.

Dystrophic calcification after endocarditis. Tends to be bluish color.

Above: Asbestos bodies (aka ferruginous Above: metastatic calcification in lung.bodies seen in mesothelioma)

Above: Iron/hemosiderin. Prussian blue stain.Iron is usually granular and brown. If inside cells, istoxic. In hemachromatosis, see liver cells andpancreatic islet cells destroyed by iron.

Above: Psamomma body = dystrophiccalcification. Seen in meningiomas of thebrain. Also in papillary adenocarcinoma(ex: thyroid).


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Cellular Aging Genetic Cellular damage over time

We know that cells are programmed to die at a certain point. Telomerase is associated. You can potentially live forever if you

have extra telomerase (see figures below).

Test q: Which of the following cells is most likely tohave highest telomerase activity? Stem cells. (Otherchoices were endothelial cells, smooth muscle cells,

neutrophils, and erythrocytes.)Test q: In human cells, telomerase activity is highestin: stem cells. (Other choices were epithelial cells,

mesenchymal cells, WBCs, and neurons)

Lecture 4: Week 1 in Review 08/20/10

The Grandmother Rules1. You must see the pathology/disease and be shown it several times before you can recognize it.2. Grandma (disease) does not always look the same

Q-1 Most of the inflammatory cellspresent in the lesions pictured areexpected to be?A. EosinophilsB. LymphocytesC. MacrophagesD. Neutrophils

E. Plasma cells

Answer: D, neutrophils The CT and gross represent brain abscess and the microscopic shows sheets of neutrophils. Some cells show 3 lobes while others show 1 or 2. Remember, you are looking at a 2-dimensional image, so you

cannot identify every cell.

Q 1A. Which microorganism most likely caused this lesion?A. Mycobacterium tuberculosisB. Streptococcus mitisC. Histoplasma capsulatumD. Mycoplasma pneumoniaeE. H1N1 Influenza A


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Answer: B, Streptococcus mitis Bacteria- neutrophils (abscess) Fungi- macrophages (granuloma) TB- macrophages (granuloma) Virus/mycoplasma- lymphocytes

TYPES OF NECROSIS:COAGULATIVE InfarctsLIQUIFACTIVE AbscessCASEATION TB GranulomaFAT (ENZYMIC) PancreasFAT (TRAUMATIC) Breast

Q-2 20-y.o female with nausea, vomiting, and right lower quadrant pain. No occultblood in stool and rebound tenderness. What lab test best predicts appendicitis?A. Increased amylaseB. Increased amylase and lipaseC. Increased alkaline phosphataseD. LeukocytosisE. Leukocytosis with left shift

Answer: E, left shift Neutrophils are increased and immature forms (bands, metamyelocytes) are present

Test q: A 25y/o female presents w/abdominal pain, nausea, and vomiting. Appendicitis is suspected. Which of the following lab tests are consistentwith appendicitis? WBCs in the urine.

Q-3 The microscopic appearance (photo) of this lungbiopsy is consistent with activation of:A. Complement C5aB. Interferon-gammaC. BradykininD. Nitric OxideE. Prostaglandin

Answer: B, interferon gamma

Q-4 A 38-y.o. female presented

with abdominal pain and shock,dying after 36 hours. The imagesare consistent with:A. Hepatitis B infectionB. Infarction of the small intestineC. TuberculosisD. Gangrenous cholecystitisE. Acute pancreatitis

Answer E, acute pancreatitis Fat necrosis with saponification and perhaps calcification with chronic enzymic fat necrosis

Caseous necrosis of Lung

This was a test q REPEATED TWICE!


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Q-5 What lab tests might have been useful in the diagnosis of acute pancreatitis? (THIS WAS A TEST Q)A. TroponinsB. Alkaline phosphataseC. Transaminases (ALT, AST)D. BilirubinE. Amylase and lipase

Ans. ESerum amylase is more sensitive (fewer false negatives); serum lipase is more specific (fewer false positives).

RR-1-1 Hepatitis A patient shows a bilirubin of 5.1 mg/dL and elevated AST (150) and ALT (180). Serum enzymechanges are due to?A. AutophagyB. Clumping of chromatinC. Cell membrane ruptureD. Dispersion of ribosomesE. Swollen mitochondria

Ans. CTransaminases are produced by hepatocytes. If serum levels are increased then the cells have been destroyed (cellmembrane rupture)

RR-1-2. 16 y.o. in auto accident has resection of his liver. CT scan 8 weeks later shows normal liver size.

Explain?A. ApoptosisB. DysplasiaC. HyperplasiaD. HypertrophyE. Metaplasia

Ans. CHepatocytes can re-enter the cell cycle and divide (hyperplasia).

The pattern of necrosis pictured in the spleen is? A. Coagulation necrosisB. Liquefactive necrosis

C. Caseous necrosisD. Enzymic fat necrosisE. Traumatic fat necrosis

Answer A, coagulation necrosisWedge-shaped pale infact; loss of nuclei histologically.

RR-1-9. 68 y.o. suddenly loses consciousness and later cannot speak. CT of the L parietal lobe is abnormal.Type of necrosis?A. Enzymic FatB. Traumatic fatC. CoagulativeD. LiquefactiveE. Apoptosis

Ans. D, liquefactiveException to the rule- ischemic events in the brain lead toliquefactive necrosis with a pocket of neutrophils anddebris

Q-6 How old is this myocardial infarction? A. 30 minutesB. 1 hourC. 2 hoursD. A few daysE. Several months

Test q: A 51y/o alcoholic man is admitted to the ER w/a 6hr history of severe epigastric painthat radiates to his back. EKG is normal. Phys exam reveals tachycardia, hypotension, and

low-grade fever consistent w/the early stage of shock. Which of the following serummeasurements would be most useful in providing a diagnosis of his condition? Amylase.(Other choices: Aspartate aminotransferase, Myoglobin, Calcium, and Troponin I.

Test q:A 52y/o male presents to the ER w/a pathologic fracture of his femur. Additional x-rays show small, punched-out defects in his skull. You would exprect the following lab testabnormality: Increased serum calcium,


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Answer D, a few daysIt usually takes 4-6 hours to see anything microscopically and probably longer to see gross changes; scars take severalweeks to develop.

Contraction bands (above) are early changes. Above: 12-24 hr post-MI

Fibrous vs Fibrinous:

Fibrosis/fibrous FibrinousFibroblasts/collagen Fibrin/liquid proteinScar, desmoplasia, sclerosis Pericarditis and peritonitisPermanent Reversible, but may become fibrosis

Q-7 A 56-y.o. male has left chest pain that radiates to his left arm. Troponin Ilevels are elevated at 3 hours; cardiac cath. shows occlusion of the LAD artery.Etiology?A. Enzymic fat necrosisB. Gall stonesC. Herpes zosterD. Esophageal spasmE. Coagulation necrosis(This was Test q on p13)

Answer E , coagulation necrosisAlthough any of these can cause 6

thdermatome pain, the radiating pain and elevated

troponin level points to MI.

Fatal event

The plaque that initially ruptured continued to evolve while the patient was in the ER and lead to a completely obstructedLAD, which is fatal.

Myocardial Infarction MarkersCardiac specific enzymes and proteins in 2-3 hoursMorphologic (light microscopic) changes in 4-12 hours


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Laboratory testsABGs BNPCBC CoagsSerial Troponin I, Myoglobin, CK-MB CXRElectrolytes, glucose, Hgb A1c EKGCreatinine/BUN

ST elevation in the anterior leads V1 - 6, I and aVL.Reciprocal ST depression in the inferior leads

Lab Results: Myoglobin markedly elevated, Troponin I and CK-MB elevated. BNP is 400 Mild leukocytosis Ph 7.51, PaCO2 26, Pao2 90, Bicarb 21 Patient was taken to cath lab, but unfortunately went into cardiogenic shock and died on the table.

More on Markers:Troponin I

Is a specific indicator of MI Appears 4-6 hours post infarction, maybe not until 12 hours Peaks at 16 hours and decrease in 9-10 days.

CK-MB

MB fraction is specific for cardiac muscle, esp when there is no skeletal muscle damage in patient'shistory

Appears to rise 4-6 hours post MI Not elevated in all patients until 12 hours post MI Level returns to baseline in 36-48 hours

Myoglobin Elevates within 1-4 hours, most sensitive during early time period Lacks specificity; any skeletal muscle injury

Other markers C-reactive protein (CRP), an acute phase reactant made in the liver, has been suggested as a predictor of risk of

coronary heart disease. But, no better predictor than lipid levels, family history, physical exam Brain Natriuetic Peptide (BNP)- measure of heart failure, esp LV

Q-8 What drug therapy should the patient receive in the ER?A. t-PAB. AspirinC. HeparinD. Nitric oxideE. Vitamin K

Answer A, tPA Tissue plasminogen activator (clot buster). Give

within 3 hours of stroke or within 12 hours of MI(some positive change in 75%).

Q-9 Which of the following features ofinflammation is affected by aspirin?A. VasodilationB. ChemotaxisC. PhagocytosisD. Leukocyte migrationE. Leukocyte release from the bone marrow

Answer A, vasodilitation


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Q-10 On day 3 the MI patient developed CHFand died later that day. The lungs wouldshow:A. Fibrin and neutrophils in alveoliB. Congested capillaries and transudate inalveoliC. Heart failure cells in alveoli and fibrosis ofalveolar wallsD. Subpleural hemorrhagic necrosisE. Purulent exudate in the pleural space

Answer: B

BNP Beta natriuretic peptide is the active product of a split prohormone in response to atrial or ventricular wall stretch. In this case it is a response to the acute congestive heart failure secondary to acute myocardial infarction. 400 CHF likely

Q-11 What is the diagnosis in a 60-y.o. male with pitting edema in hislegs, elevated AST and ALT and the following gross changes A. Thrombocytopenia

B. Portal vein thrombosisC. Renal failureD. Bile duct obstructionE. Congestive heart failure

Answer B, congestive heart failure

Nutmeg (congested central veins) liverElevated transaminases indicate death of hepatocytesRight-sided failure is usually associated with left-sided failure-pulmonary congestion also present with heart-failure cells (brown)

Q-12 When is the patient at greatest risk for fatal arrhythmias?A. Days 1-3B. Days 5-7C. After 2 weeksD. After 4 weeksE. After 1 year

Answer A, 1st

72 hoursMyocardial cells are dying and conduction pathways disruptedCCU, monitor, anti-arrhythmics

4-12 hours: beginning coagulation necrosis; edema; hemorrhage The wavy part is the necrosis with edema between the remains of the muscle fibers.

Coagulative necrosis (PERLjam)


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Q-13 When is the patient at greatest risk for perforation (rupture) of the left ventricle?A. Days 1-3B. Days 5-10C. 2 weeksD. 4 weeksE. 1 year

Answer B, 5-10 (average 7) daysHeart muscle undergoes coagulation necrosisNeutrophils enter to clear debris- enter at 12- 24 hours and persist 5 daysAt 5-7-10 days, the muscle is gone and fibroblasts have not made collagen (noscar); maximal weakness

Q-14 Six weeks post-MI, a 56-y.o. male has chest pain, SOB, precordial friction rub.He dies within days of heart failure. This late complication of infarction (photo) is?A. Granulomatous inflammationB. Dresslers syndrome This was a test q!C. Metastatic carcinomaD. Ruptured LVE. Viral infection

Answer B, fibrinous pericarditis can see shaggy material on surface of pericardium.Dresslers syndrome is an autoimmune disorder that may occur months after MI.

Q-15 57-y.o. male with hx of MI presents 1 year later with abdominal painand no bowel sounds. WBC is normal as is lipase and amylase. ??A. Acute appendicitis with perforationB. Acute pancreatitisC. Small intestine infarctionD. Acute cholecystitisE. Pseudomembranous enterocolitis

Answer C , infarctionIt is likely the patient sufferd a mesenteric artery thrombosis. Or, another MI(abdominal pain may be seen in MI) with decreased cardiac output and infarction

Necrosis:

Cell membraneruptures; organellesrupture; enzymaticdigestion of the cell;inflammation


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Q-16 The epidermalchanges in thephotographs arecaused by:A. Activation of caspasesB. Reduced ATPsynthesisC. TraumaD. Activation of lipasesE. Lipid peroxidation

Answer A, caspasesApoptosis: Cells activate enzymes that degrade DNA and proteins (ATP/energy-dependent); cell membrane remainsintact; organelles are intact; NO INFLAMMATION

Defective Apoptosis: Tumors with p53 mutations

Follicular lymphomas express high levels of bcl-2 (translocation of bcl-2 gene) HPV- protein E6 binds and inactivates p53; E7 blocks Rb inhibition EBV- proteins that mimic or increase production of bcl-2 Autoimmune disorders

Q-17 Given the next 2 photos, what enzymeabnormality would you expect?A. Increased alkaline phosphataseB. Decreased alkaline phosphataseC. Decreased gamma GTD. Markedly increased AST and ALTE. Decreased direct bilirubin

Answer A, increased AP The photos show a gallbladder with stones

and a large stone in the common bile duct. AP is made by the cells lining the bile canaliculi. During obstruction bile enters the lining cells and damages cell

membranes, releasing AP. The yellow area represents galbladder adenocarcinoma

Test q:A 53y/o female has multiple gallstone. What enzyme abnormality would you expect? Increased alkaline phosphatase.

Test q: Which of the following tests is elevated in damage to the cells lining the canaliculi in the liver: Alkaline phosphatase


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Q-18 The PAP smear labeled B in the photo suggests:A. Herpes virus infectionB. Human papillomavirus infectionC. CMV infectionD. Carcinoma insituE. Invasive cervical cancer

Answer B, HPV infectionKoilocytes are present c/w a low grade dysplasia (LGSIL)

Q-19 These endocervical biopsies show: A. Glandular metaplasiaB. Squamous metaplasiaC. CISD. Invasive squamous cell carcinomaE. Invasive adenocarcinoma

Answer B, squamous metaplasiaThe endocervical glands have columnar epithelium. At earlyages the female endocervix also has a columnar surface.With age, sexual activity, childbirth etc a mature squamousepithelium replaces the glandular epithelium.

Metaplasia:A REVERSIBLE change in which one ADULTcell type is replaced by another ADULT cell type Dysplasia: Atypical proliferative changes due to chronicirritation or inflammation; PREMALIGNANT CHANGE.

Q-20 A 32-y.o. has heartburn andgastric reflux. What change hasoccurred in this esophagealbiopsy (photo)?

A. Squamous metaplasiaB. Mucosal hypertrophyC. Columnar epithelial metaplasiaD. Atrophy of lamina propriaE. Goblet cell hyperplasia

(No answer listed in the ppt wouldit be A or C? Google says either oneworks for Barretts esophagus)


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Q-21 This patient is at increased risk for:A. Squamous carcinomaB. AdenocarcinomaC. A sarcomaD. A lymphomaE. HPV infection

Answer B, adenocarcinomaBarretts esophagus (Syndrome) must be screened regularly for malignant change.

Q-22 This cut-section of liver is c/w: A. CongestionB. CirrhosisC. HepatitisD. Metastasis

Answer D, metastasesThe tumor nodules are diffuse (not a primary) and are too big to be cirrhoticnodules- there is also an absence of white connective tissue.

Fatty change:

Above: Oil Red O Stain

RR-1-16. A 22 y.o. SS patient has had manytransfusions. Her serum albumin is low but PE is

normal. What would a liver biopsy show?A. SteatosisB. Bile stasisC. Glycogen in hepatocytesD. AmyloidosisE. Hemosiderin in hepatocytes

Ans. E hemosiderin in hepatocytesRed cell breakdown from transfusions results inhemosiderin which is trapped by kuppfer cells(macrophages) in the liver. If the macrophages areoverwlelmed, hemosiderin enters hepatocytes with celldeath (hemochromatosis).

Test q: A 45y/o male dies in an automobile accident. At autopsy, the liveris shrunken and nodular. Focally, the liver is markedly green. The liver

exhibits no traumatic injury. The patients sclerae are markedly yellow.

-If serum were drawn on this patient at the time of death, which test result

pattern best matches the gross findings? Elevated transaminases,alkaline phosphatase, and total bilirubin.

-Based on the gross findings, what microscopic features would beexpected? Bile stasis and fibrosis.

Test q: All of the following serum tests would be used in the initialevaluation of a jaundiced patient EXCEPT:

A. Lipase

B. Alkaline phosphataseC. Bilirubin fractionsD. ALTE. AST


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Bile plugs. Metastatic melanoma in liver and bone marrow. Cirrhosis of liver.

CONSISTENCYOrgans become stiff, hard, soft, waxy or greasy in disease. Alcoholism or hepatitis cause extensive fibrosis (scar tissue)in the liver and the liver is pale, shrunken and firm with round NODULES (firm, circumscribed areas)

Q-23 What is a diagnostic test for amyloid?A. Prussian blue with polarizationB. Oil Red O with polarizationC. Sudan blackD. Congo redE. Congo red with polarization

Answer E, congo red and polarizationApple-green birefringence

Amyloid 15 types- 3 major

AL (light chain); Ig light chains AA (amyloid associated); liver product A-beta (amyloid in Alzheimer) And beta-2-microglobulin (dialysis) All are beta-pleated sheet proteins and all stain with

Congo Red

Pathology - Week 1

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