Endocrine 2016 posting - med.uottawa.ca · * Cortical tumor • Administration of ... Adrenal Gland, cortical adenoma - LP. Adrenal Gland - Tumor CT. Adrenal Gland - Mass MRI : in-phase

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 Li@Qiao.Li@uottawa.caQiao.Li@uottawa.ca

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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

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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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