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

i li@i li@qiaoli@uottawa.caqiaoli@uottawa.ca

QL

Outline

Endocrine System Adrenal Gland Adrenal Gland

• Anatomy & Histology• Steroid HormonesSteroid Hormones• Addison’s Disease• Cushing Syndromeg y• Clinical Case Presentation

QL

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.

QL

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

QL

Adrenal Gland

•• Anatomy & Histology Anatomy & Histology •• Steroid HormonesSteroid Hormones•• Addison’s DiseaseAddison’s Disease•• Cushing SyndromeCushing Syndrome•• Clinical Case PresentationsClinical Case Presentations

QL

Adrenal Gland (Suprarenal)

Adrenal Gland – in situ

Described as loose flesh for the left gland by Claudius Galen (130-201)Depicted in 1552 by Bartholomeaus Eustachius (1520-1574) on copper plateR d d b i i 1563

The Internet Pathology Laboratory

for Medical Education

Reproduced by prints in 1563

Adrenal Gland – Male Abdomen

The Internet Pathology Laboratory

for Medical Education

Adrenal Gland - CT

Adrenal Gland - MRI

Adrenal Gland – Gross

The Internet Pathology Laboratory

for Medical Education

Adrenal Gland – Cut Surface

The Internet Pathology Laboratory

for Medical Education

Adrenal Gland – Cut Surface

Adrenal Gland – Cross Section

Adrenal Gland – Medulla

Chromaffin cellsChromaffin cells

Catecholamines- epinephrine

i h i- norepinephrine

Ganglion cells

QL

Adrenal Medulla

Medullary chromaffin cells synthesizeepinephrine (80%) & norepinephrine (20%)epinephrine (80%) & norepinephrine (20%)

Effects– Vasoconstriction– Increased heart rate– Increased blood glucose levels– Blood diverted to brain, heart, & skeletal muscleBlood diverted to brain, heart, & skeletal muscle

Hypersecretion– Hyperglycemia, increased metabolic rate, rapid heartbeat &

l it ti h t i i t tipalpitations, hypertension, intense nervousness, sweating

Hyposecretion– Not problematic (adrenal catecholamines not essential to life)p ( )

QL

Adrenal Gland

•• Anatomy & Histology Anatomy & Histology •• Steroid HormonesSteroid Hormones•• Addison’s DiseaseAddison’s Disease•• Cushing SyndromeCushing Syndrome•• Clinical Case PresentationsClinical Case Presentations

QL

Adrenal Cortex

Three layers of cortex produce three corticosteroids Zona glomerulosa - mineralocorticoids Zona glomerulosa mineralocorticoids Zona fasciculata - glucocorticoids Zona reticularis - gonadocorticoids

CapsuleZona

glomerulosa

Hormonessecreted

Aldosterone

g

Cor

tex

Zonafasciculata

Adrenal gland• Medulla• Cortex

Kid

Cortisolandandrogens

Med

ulla

Zonareticularis

Adrenalmedulla

Kidneyandrogens

Epinephrineandnorepinephrine

Photomicrograph (115x)Drawing of the histology of theadrenal cortex and a portion ofthe adrenal medulla

QL

Adrenal Gland – Low Power

Capsule

Periadrenal fatZona glomerulosa

Zona fasciculata

Zona reticularis

Medulla

The Internet Pathology Laboratory

for Medical Education

Adrenal Gland – Low & High Power

HP

sinusoid

HP-zrHP-zf

QL

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

QL

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

QL

Effects & Usage of Effects & Usage of Glucocorticoids

Carbohydrate, proteins and fat metabolismCarbohydrate, proteins and fat metabolismgluconeogenesisgluconeogenesismuscle breakdownmuscle breakdownlipolysislipolysis

A tiA ti i fl t d i ii fl t d i i AntiAnti--inflammatory and immunosuppressive inflammatory and immunosuppressive

Medical Application:Medical Application:th iti d titith iti d titiarthritis, dermatitisarthritis, dermatitis

autoimmune diseases autoimmune diseases fear phobicfear phobic

QL

Homeostasis

Hypothalamus connectsi h d i i i inervous with endocrine via pituitary

Hypothalamic is controlled by neural connections negative feedback from hormones

QL

Control of Cortisol Secretion

Hypothalamus

HPA Axis

y

ACTH

CRH

Anterior PituitaryACTH

Adrenal Cortex Cortisol

Dr. Gary Farr

QL

The StressShort-term stress Prolonged stress

Nerve impulses

Stress

Hypothalamusp

Spinal cord

yp

CRH (corticotropin-releasing hormone)

Spinal cord

Preganglionicsympatheticfibers

Corticotropic cellsof anterior pituitary

To target in blood

Adrenal cortexfibersAdrenal medulla(secretes amino acid–based hormones)

Catecholamines(epinephrine and

Adrenal cortex(secretes steroidhormones)

Mineralocorticoids Glucocorticoids

ACTH

(epinephrine andnorepinephrine)

Short-term stress response• Heart rate increases

Long-term stress response• Kidneys retainsodium and water

• Proteins and fats convertedto glucose or broken downfor energy

• Blood glucose increases

• Blood pressure increases• Bronchioles dilate• Liver converts glycogen to glucose and releasesglucose to blood

• Blood volume andblood pressurerise • Immune systemglucose to blood

• Blood flow changes, reducing digestive system activityand urine output

• Metabolic rate increases

rise Immune systemsupressed

QL

Adrenal Cortex Disorders

CRHCRH

ACTHACTH

CortisolCortisol

QL

Adrenal Gland

•• Anatomy & Histology Anatomy & Histology •• Steroid HormonesSteroid Hormones•• Addison’s DiseaseAddison’s Disease•• Cushing SyndromeCushing Syndrome•• Clinical Case PresentationsClinical Case Presentations

QL

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

QL

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

QL

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

QL

Managements

Glucocorticoid replacement CRHGlucocorticoid replacementMineralocorticoid replacementPrevent adrenal crisis

ACTH

Prevent adrenal crisisMedic Alert bracelet

Cortisol

QL

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

QL

Adrenal Atrophy

The Internet Pathology Laboratory

for Medical Education

Adrenal Gland

•• Anatomy & Histology Anatomy & Histology •• Steroid HormonesSteroid Hormones•• Addison’s DiseaseAddison’s Disease•• Cushing SyndromeCushing Syndrome•• Clinical Case PresentationsClinical Case Presentations

QL

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

Cushing’s Disease

Cortisol

QL

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

QL

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

QL

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

QL

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

QL

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

QL

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

ACTHidentify 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

QL

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

ACTHidentify 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

QL

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

QL

Adrenal Gland - Comparison

The Internet Pathology Laboratory

for Medical Education

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

QL

Adrenal Gland

•• Anatomy & Histology Anatomy & Histology •• Steroid HormonesSteroid Hormones•• Addison’s DiseaseAddison’s Disease•• Cushing SyndromeCushing Syndrome•• Clinical Case PresentationsClinical Case Presentations

QL

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

QL