Endocrine Diseases Endocrine Diseases Endocrine Diseases Endocrine Diseases Th P th l i l B i f Di Qiao Qiao Li MD PhD Li MD PhD The Pathological Basis of Disease - Graduate Course CMM5001 Graduate Course CMM5001 Qiao Qiao Li, MD, PhD Li, MD, PhD Faculty of Medicine Faculty of Medicine University of Ottawa University of Ottawa Qi Li@ Qi Li@ Qiao.Li@uottawa.ca Qiao.Li@uottawa.ca Q L
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Endocrine DiseasesEndocrine DiseasesEndocrine DiseasesEndocrine Diseases
Th P th l i l B i f Di
QiaoQiao Li MD PhDLi MD PhD
The Pathological Basis of Disease- Graduate Course CMM5001Graduate Course CMM5001
QiaoQiao Li, MD, PhDLi, MD, PhDFaculty of MedicineFaculty of MedicineUniversity of OttawaUniversity of Ottawa
Qi Li@Qi [email protected]@[email protected]
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Outline
Endocrine System Adrenal Gland Adrenal Gland
• Anatomy & Histology• Steroid HormonesSteroid Hormones• Addison’s Disease• Cushing Syndromeg y• Clinical Case Presentation
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Endocrine Glands
Pineal gland
Hypothalamus
Pituitary gland
Endocrine glands • Pineal
Pituitary gland
Thyroid gland
Parathyroid glands(on dorsal aspect of thyroid gland)
• Pituitary • Thyroid • Parathyroid
Thymus
Adrenal glands
• Adrenal Neuroendocrine organ
HypothalamusPancreas
Gonads
Hypothalamus Exocrine & endocrine
Pancreas, gonads, placenta Other Gonads
• Testis (male)• Ovary (female) Other
Thymus, heart, kidney etc.
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Endocrine Function
Controls & IntegratesG th d d l tGrowth and developmentMaintenance of electrolyte, water & nutrient balance of bloodRegulation of cellular metabolism & energy balanceMobilization of body defensesReproduction
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Homeostasis
Hypothalamus connectsi h d i i i inervous with endocrine via pituitary
Hypothalamic is controlled by neural connections negative feedback from hormones
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The Summary
Hypothalamic Hormone Anterior Pituitary Hormone Target Organ
Thyrotropin-ReleasingHormone (TRH)
Thyroid-StimulatingHormone (TSH) Thyroid GlandThyroid GlandHormone (TRH) Hormone (TSH) Thyroid GlandThyroid Gland
Corticotropin-ReleasingHormone (CRH)
AdrenocorticoidtropicHormone (ACTH) AdrenalAdrenal GlandsGlands
Gonadotropin-ReleasingHormone (GnRH)
Folicle-Stimulating Hormone (FSH)Lutenizing Hormone (LH) Ovaries / TestesOvaries / Testeso o e (G ) ute g o o e ( ) O a es / estesO a es / estes
Prolactin-Inhibiting Hormone (PIH, Dopamine) Prolactin (PRL) BreastBreast
Growth Hormone-Releasing Hormone (GHRH) Growth Hormone
GHIH (Somatostatin) (GH, Somatotropin) LiverLiver
Anterior lobe
HypothalamusHypothalamic neurons synthesizeGHRH, GHIH, TRH, CRH, GnRH, PIH
Hypophyseal portal system
• Primary capillary plexus• Hypophyseal portal veins• Secondary capillary plexus
Superiorhypophyseal
artery
Anterior lobeof pituitary
QLGH, TSH, ACTH, FSH, LH, PRL
Anterior lobe of pituitary
• Secondary capillary plexus
Homeostatic ImbalanceHomeostatic Imbalance
Increases risk of diseaseCauses changes associated with agingCauses changes associated with aging
control systems less efficient
most disease seen as a disturbance of homeostasis (homeostatic imbalance)
aging associated with progressiveaging associated with progressive decrease in our ability to maintain
homeostasis (greater risk for illness)
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Adrenal Gland
•• Anatomy & Histology Anatomy & Histology •• Steroid HormonesSteroid Hormones•• Addison’s DiseaseAddison’s Disease•• Cushing SyndromeCushing Syndrome•• Clinical Case PresentationsClinical Case Presentations
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Characteristics
Originll l d i f th ith li ( ll th l )all glands arise from the epithelium (all three germ layers)
Microscopic Structure d l h ll f lli l & b d t ill icords, clumps, hollow follicles & abundant capillaries
Merocrine Secretion
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Adrenal Gland (Suprarenal)
Adrenal Gland – in situ
Described as “accessory renal tissue”, “loose flesh” (left gland) by Claudius Galen (130-201) Depicted in 1552 by Bartholomeaus Eustachius on copper plateR d d b i i 1563
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Reproduced by prints in 1563
Adrenal Gland – Male Abdomen
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Adrenal Gland - CT
Adrenal Gland - MRI
Adrenal Gland – Gross
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Adrenal Gland – Cut Surface
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Adrenal Gland – Cut Surface
Adrenal Gland – Cross Section
Adrenal Gland – Medulla
Chromaffin cellsChromaffin cells
Catecholamines- epinephrine
i h i- norepinephrine
Ganglion cells
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Adrenal Gland
•• Anatomy & Histology Anatomy & Histology •• Steroid HormonesSteroid Hormones•• Addison’s DiseaseAddison’s Disease•• Cushing SyndromeCushing Syndrome•• Clinical Case PresentationsClinical Case Presentations
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Adrenal Gland – Low Power
Capsule
Periadrenal fatZona glomerulosa
Zona fasciculata
Zona reticularis
Medulla
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Adrenal Gland – Low & High Power
HP
sinusoid
HP-zrHP-zf
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Adrenal Cortex Steroids
Zone Class Representative Physiologic Effects
glomerulosa mineralocorticoids aldosterone salt and water homeostasis
fasiculata glucocorticoids cortisol carbohydrate metabolism
reticularis sex steroids androgens & estrogen minimal effects
O CH2OH O
CH2OH O
O CH
O O O
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Adrenal Steroidogenesis
Glucocorticoids & the Receptor
CortisolCortisol (hydrocortisone) (hydrocortisone) the majority of the majority of glucocorticoidglucocorticoid activity in most mammalsactivity in most mammals
90% f i l ti90% f i l ti ti lti l bi d tbi d t ti lti l bi dibi di 90% of circulating 90% of circulating cortisolcortisol binds to binds to cortisolcortisol binding binding globulin (CBG), for transportation, also limiting the rate globulin (CBG), for transportation, also limiting the rate of metabolic clearance & the concentration fluctuationof metabolic clearance & the concentration fluctuation
E t ll b i diff iE t ll b i diff i Enter cells by passive diffusionEnter cells by passive diffusion
Histone acetylationp300/CBP
TAFII250
RNA Pol IITBP
RNA Pol II
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Control of Cortisol Secretion
Hypothalamus
HPA Axis
y
ACTH
CRH
Anterior Pituitary
ACTH
Adrenal Cortex
Cortisol
Dr. Gary Farr
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Research Milestones
* 1552: * 1552: BartholomaeusBartholomaeus EustachiusEustachius- Depicted adrenal glands on copper plate
* 1656: * 1656: Thomas Wharton Thomas Wharton - Adrenals took something from the nerves and secreted it into the circulation
* 1936: * 1936: Edward Kendall and Edward Kendall and TadeusTadeus ReichsteinReichstein- Isolation and synthesis of cortisone
* 1949:* 1949: Edward Kendall and Philip HenchEdward Kendall and Philip Hench 1949: 1949: Edward Kendall and Philip HenchEdward Kendall and Philip Hench-- Effects of cortisone and ACTH on rheumatoid arthritisEffects of cortisone and ACTH on rheumatoid arthritis
* 1950: Nobel Prize to * 1950: Nobel Prize to Kendall, Reichstein & HenchKendall, Reichstein & Hench"for their discoveries relating to the hormones of the adrenal cortex, their structure and biological effects"
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Response to StressShort-term stress Prolonged stress
Nerve impulses
Stress
Hypothalamusp
Spinal cord
yp
CRH (corticotropin-releasing hormone)
Spinal cord
Preganglionicsympatheticfib
Corticotropic cellsof anterior pituitary
To target in blood
fibersAdrenal medulla(secretes amino acid–based hormones)
Catecholamines
Adrenal cortex(secretes steroidhormones)
Mineralocorticoids Glucocorticoids
ACTH
(epinephrine andnorepinephrine)
Short-term stress response
Mineralocorticoids Glucocorticoids
• Heart rate increasesLong-term stress response
• Kidneys retainsodium & water
• Proteins & fats convertedto glucose or broken downfor energyBlood gl cose increases
• Blood pressure increases• Bronchioles dilate• Liver converts glycogen to glucose and releases • Blood volume & • Blood glucose increases• Liver converts glycogen to glucose and releasesglucose to blood
• Blood flow changes, reducing digestive system activityand urine output
• Metabolic rate increases
Blood volume &blood pressure rise
• Immune syste supressed
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Adrenal Cortex Disorders
CRHCRH
ACTHACTH
CortisolCortisol
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Adrenal Gland
•• Anatomy & Histology Anatomy & Histology •• Steroid HormonesSteroid Hormones•• Addison’s DiseaseAddison’s Disease•• Cushing SyndromeCushing Syndrome•• Clinical Case PresentationsClinical Case Presentations
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Addison’s DiseaseAddison’s Disease
* General languor and debility* Remarkable feebleness of the heart's action* P li h i th l f th ki* Peculiar change in the color of the skinChronic adrenocortical insufficiency
progressive destruction of 90%of cortexprogressive destruction of 90%of cortex extreme weakness and fatigue extreme weakness and fatigue unintentional weight lossunintentional weight lossloss of appetiteloss of appetiteloss of appetite loss of appetite darkening of the skindarkening of the skinlow blood pressure, low blood pressure, dizziness or faintingdizziness or faintingcraving for saltcraving for salt
Thomas Addison 1855
craving for saltcraving for saltnausea, diarrhea, vomitingnausea, diarrhea, vomitingirritability, depression irritability, depression
Thomas Addison 1855
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Primary Adrenocortical Insufficiency
* Primary chronic * Primary chronic HypocortisolismHypocortisolism-- Autoimmune Autoimmune adrenalitisadrenalitis 6060--70%70% CRH-- Infections (TB, AIDS)Infections (TB, AIDS) TB 90%TB 90%-- Metastatic Metastatic neoplasmsneoplasms-- Genetic disorderGenetic disorder
(Addison’s disease)(Addison’s disease)ACTH
(Addison s disease)(Addison s disease)
* Primary acute * Primary acute HypocortisolismHypocortisolism-- Stress crisis Stress crisis (chronic AI)(chronic AI)-- Rapid Steroids withdrawRapid Steroids withdraw-- adrenal adrenal hemorrhagehemorrhage
Cortisol
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Secondary Adrenocortical Insufficiency
•• Secondary Secondary HypocortisolismHypocortisolism CRH
-- Hypothalamic pituitary diseaseHypothalamic pituitary disease
-- Hypothalamic pituitary suppressionHypothalamic pituitary suppression ACTHyp p y ppyp p y pp
Cortisol
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Managements
Glucocorticoid replacement CRHGlucocorticoid replacementMineralocorticoid replacementPrevent adrenal crisis
ACTH
Prevent adrenal crisisMedic Alert bracelet
Cortisol
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PrognosisPrognosis
For people with Addison’s Disease* i t 1930 90% di d ithi 5* prior to 1930, 90% died within 5 years* from 1930, much better prognosis* since 1950, normal life span
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Adrenal Atrophy
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Adrenal Gland
•• Anatomy & Histology Anatomy & Histology •• Steroid HormonesSteroid Hormones•• Addison’s DiseaseAddison’s Disease•• Cushing SyndromeCushing Syndrome•• Clinical Case PresentationsClinical Case Presentations
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Causes of Cushing Syndrome
Cushing’s Disease
•• Excessive Endogenous CortisolExcessive Endogenous Cortisol-- ACTH dependent:ACTH dependent: CRHACTH dependent: ACTH dependent:
* Pituitary adenoma * Pituitary adenoma (70(70--80%)80%)
** Small cell carcinomaSmall cell carcinoma ACTH
-- ACTH independent ACTH independent * Cortical tumor* Cortical tumor
•• Administration of GlucocorticoidsAdministration of Glucocorticoids-- The most common causeThe most common cause Cortisol
Cushing’s Disease
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Ectopic ACTH Secretion
•• Excessive Endogenous Excessive Endogenous CortisolCortisol-- ACTH dependent:ACTH dependent: CRHACTH dependent: ACTH dependent:
* Pituitary adenoma* Pituitary adenoma* Small cell carcinoma * Small cell carcinoma (10%)(10%)
ACTH
-- ACTH independent ACTH independent * Cortical tumor* Cortical tumor
•• Administration of Administration of GlucocorticoidsGlucocorticoids-- The most common causeThe most common cause Cortisol
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Adrenal Defects
•• Excessive Endogenous CortisolExcessive Endogenous Cortisol-- ACTH dependent:ACTH dependent: CRHACTH dependent: ACTH dependent:
* Pituitary adenoma* Pituitary adenoma* Small cell carcinoma* Small cell carcinoma ACTH
-- ACTH independent ACTH independent * Cortical tumor * Cortical tumor (10(10--20%)20%)
•• Administration of GlucocorticoidsAdministration of Glucocorticoids-- The most common causeThe most common cause Cortisol
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Exogenous CS
•• Excessive Endogenous CortisolExcessive Endogenous Cortisol-- ACTH dependent:ACTH dependent: CRHACTH dependent: ACTH dependent:
* Pituitary adenoma* Pituitary adenoma* Small cell carcinoma* Small cell carcinoma ACTH
CRH
-- ACTH independent ACTH independent * Cortical tumor* Cortical tumor
•• Administration of GlucocorticoidsAdministration of Glucocorticoids-- The most common causeThe most common cause Cortisol
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Cushing Syndrome
•• Excessive Endogenous CortisolExcessive Endogenous Cortisol-- ACTH dependent:ACTH dependent: CRHACTH dependent: ACTH dependent:
* Pituitary adenoma* Pituitary adenoma (Cushing’s Disease)(Cushing’s Disease)
* Small cell carcinoma* Small cell carcinoma ACTH
-- ACTH independent ACTH independent * Cortical tumor* Cortical tumor
•• Administration of GlucocorticoidsAdministration of Glucocorticoids-- The most common causeThe most common cause Cortisol
H C hi 1912Harvey Cushing 1912
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Adrenal Gland – Gr / CSN d l C ti l H l iNodular Cortical Hyperplasia
Confluent Nodules
Adrenal Gland – Low PowerN d l C ti l H l iNodular Cortical Hyperplasia
Nodule
Adrenal Gland – High PowerN d l C ti l H l iNodular Cortical Hyperplasia
Adrenal Gland, cortical adenoma i C hi S d G / CSin Cushing Syndrome – Gr / CS
Adrenal Gland, cortical adenoma - LP
Adrenal Gland - Tumor
CT
Adrenal Gland - Mass
MRI : in-phase sequence
Adrenal Gland - Adenoma
MRI : out-of-phase sequence
Clinical ManifestationsClinical Manifestations
•• Moodiness, depression 75Moodiness, depression 75--80%80%•• Moon face 85%Moon face 85%Moon face 85%Moon face 85%•• Facial plethora 75%Facial plethora 75%•• OsteoprosisOsteoprosis 75%75%•• TruncalTruncal obesityobesity (buffalo hump)(buffalo hump) 8585--90%90%• Skin Skin striaestriae (abdomen)(abdomen) 50%50%• Menstrual abnormalities 70%Menstrual abnormalities 70%•• Weakness and fatigability 85%Weakness and fatigability 85%
Hi iHi i %%•• HirsutismHirsutism 75%75%•• Hypertension 75%Hypertension 75%•• Glucose intolerance / diabetes 70 / 20%Glucose intolerance / diabetes 70 / 20%
Screening Tests
2424--hour urine free hour urine free cortisolcortisol levellevel
am & pm am & pm cortisolcortisol levellevel* * circadian circadian rhythmrhythm, a hall mark hall mark
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DST (Dex Suppression Test)
LowLow--dose dose DexDex suppressionsuppressionCRH
** identify Cushing Syndrome identify Cushing Syndrome
HighHigh--dose dose DexDex suppressionsuppression ACTHgg* identify Cushing’s Disease* identify Cushing’s Disease
Cortisol
QL
Low Dose DST
LowLow--dose DSTdose DSTDay 1:Day 1: 1 mg of 1 mg of DexDex at 11 pmat 11 pmDay 2:Day 2: bloodblood cortisolcortisol at 8 amat 8 am
CRHDay 2:Day 2: blood blood cortisolcortisol at 8 amat 8 am
0.5 mg of 0.5 mg of DexDex every 6 hrs for 48 hrsevery 6 hrs for 48 hrs2424--hr hr urinary urinary cortisolcortisol for 3 daysfor 3 days** identify Cushing Syndromeidentify Cushing Syndrome
ACTH
identify Cushing Syndrome identify Cushing Syndrome
HighHigh--dose DSTdose DSTDay 1:Day 1: a baseline a baseline cortisolcortisol at amat am
8 f8 f DD t 11t 118 mg of 8 mg of DexDex at 11 pm at 11 pm Day 2:Day 2: blood blood cortisolcortisol at 8 amat 8 am
2 mg of 2 mg of DexDex every 6 hrs for 48 hrs.every 6 hrs for 48 hrs.2424 hr urinaryhr urinary cortisolcortisol for 3 daysfor 3 days
Cortisol
2424--hr urinary hr urinary cortisolcortisol for 3 daysfor 3 days** identify Cushing's Diseaseidentify Cushing's Disease
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High Dose DST
LowLow--dose DSTdose DSTDay 1:Day 1: 1 mg of 1 mg of DexDex at 11 pmat 11 pmDay 2:Day 2: bloodblood cortisolcortisol at 8 amat 8 am
CRHDay 2:Day 2: blood blood cortisolcortisol at 8 amat 8 am
0.5 mg of 0.5 mg of DexDex every 6 hrs for 48 hrsevery 6 hrs for 48 hrs2424--hr hr urinary urinary cortisolcortisol for 3 daysfor 3 days** identify Cushing Syndromeidentify Cushing Syndrome
ACTH
identify Cushing Syndrome identify Cushing Syndrome
HighHigh--dose DSTdose DSTDay 1:Day 1: a baseline a baseline cortisolcortisol at amat am
8 f8 f DD t 11t 118 mg of 8 mg of DexDex at 11 pm at 11 pm Day 2:Day 2: blood blood cortisolcortisol at 8 amat 8 am
2 mg of 2 mg of DexDex every 6 hrs for 48 hrs.every 6 hrs for 48 hrs.2424--hr urinaryhr urinary cortisolcortisol for 3 daysfor 3 days
Cortisol
2424--hr urinary hr urinary cortisolcortisol for 3 daysfor 3 days** identify Cushing's Diseaseidentify Cushing's Disease
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Determining the Etiology
•• Is ACTH dependent?Is ACTH dependent?•• If ACTH dependentIf ACTH dependent CRHIf ACTH dependentIf ACTH dependent
* pituitary or ectopic* pituitary or ectopic
•• Source of overproductionSource of overproduction ACTH
* MRI pituitary* MRI pituitary* CT adrenals, chest, abdomen* CT adrenals, chest, abdomen
Cortisol
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Adrenal Gland - Comparison
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Managements
Surgical TreatmentSurgical Treatmentl il i d l td l t CRHlaparoscopic laparoscopic adrenalectomyadrenalectomy
Medical Treatment Medical Treatment d l bl kd l bl k
ACTH
adrenal enzyme blockersadrenal enzyme blockers
Cortisol
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Resources
•• Pathologic Basis of DiseasePathologic Basis of DiseaseR bbi &R bbi & C tC t 77thth EditiEditiRobbins & Robbins & CotranCotran 77thth EditionEdition
•• Basic Pathology Basic Pathology R b 7R b 7thth EdEdRobins 7Robins 7thth EditionEdition
•• Handbook of Clinical PathologyHandbook of Clinical Pathology22ndnd EditionEdition
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