Endocrine Diseases

Qiao Li, MD, PhD Dept of Pathology & Laboratory Medicine Faculty of Medicine University of Ottawa

qiaoli@uottawa.ca 613 562 5800 Ext. 8491

The Pathological Basis of Disease - Graduate Course CMM 5001

Q L

• Endocrine System • Adrenal Gland

– Anatomy Histology & Function – Steroid Hormones – Addison’s Disease – Cushing Syndrome – Clinical Case Presentation

Outline

Q L

• The Components • The Origin • The Microscopic Structure • Merocrine Secretion • Neuroendocrine System

Endocrine System

Q L

• Anatomy, Histology & Function • Steroid Hormones • Addison’s Disease • Cushing’s Syndrome • Clinical Case Presentation

Adrenal Gland

Q L

Adrenal Gland - Anatomy

Adrenal Gland – Male Abdomen

The Internet Pathology Laboratory

for Medical Education

Adrenal Gland - CT

Adrenal Gland - MRI

Adrenal Gland – in situ

The Internet Pathology Laboratory

for Medical Education

Adrenal Gland – Gross

The Internet Pathology Laboratory

for Medical Education

Adrenal Gland – Cut Surface

The Internet Pathology Laboratory

for Medical Education

Adrenal Gland – Cross Section

Capsule

Periadrenal fat Zona glomerulosa

Zona fasciculata

Zona reticularis

Medulla

Adrenal Gland – Low Power

The Internet Pathology Laboratory

for Medical Education

Adrenal Gland – Low & High Power

Q L

Adrenal Gland

Q L

• Anatomy, Histology & Function • Steroid Hormones • Addison’s Disease • Cushing’s Syndrome • Clinical Case Presentation

Adrenal Cortex Steroids

glomerulosa Mineralocorticoids Aldosterone salt and water homeostasis

fasiculata Glucocorticoids Cortisol carbohydrate metabolism

reticularis Sex Steroids Androgens minimal effects

Q L

O

O

CH2OH

O

O

Zone Class Representative Physiologic Effects

CH2OH

O

O O

CH

Adrenal Steroidogenesis

Adrenal Gland - Milestones

1552: Bartholomaeus Eustachius - adrenal glands on copper plates 1936: Edward Kendall and Tadeus Reichstein - isolation and synthesis of cortisone 1949: Edward Kendall and Philip Showalter Hench

- effects of cortisone and ACTH on arthritis 1950: Kendall, Reichstein & Hench - Nobel Prize “for their discoveries relating

to the hormones of the adrenal cortex, their structure and biological effects"

Q L

Glucocorticoids & the Receptor

• Cortisol (hydrocortisone) the majority of glucocorticoid activity in most mammals • 90% of circulating cortisol binds to corticol binding

globulin (CBG), limiting the rate of metabolic clearance and the concentration fluctuation

• Enter cells by passive diffusion

Histone acetylation

TAFII250

RNA Pol II

p300/CBP

TBP

Q L

Effects and Usage of Glucocorticoids

• Carbohydrate, proteins and fat metabolism increase gluconeogenesis muscle breakdown lipolysis

• Anti-inflammatory and immunosuppressive

• Medical Application: arthritis, dermatitis autoimmune diseases. fear phobic

Q L

Control of Cortisol Secretion

Dr. Gary Farr

Q L

Hypothalamus

ACTH

CRH

Cortisol

Pituitary

Adrenal Cortex

HPA Axis

Adrenal Gland

Q L

• Anatomy, Histology & Function • Steroid Hormones • Addison’s Disease • Cushing’s Syndrome • Clinical Case Presentation

* General languor and debility * Remarkable feebleness of the heart's action * Peculiar change in the color of the skin

Chronic adrenocortical insufficiency progressive destruction of 90%of cortex

Addison’s Disease

Q L

Extreme weakness and fatigue Unintentional weight loss Loss of appetite Darkening of the skin Low blood pressure, dizziness or fainting Craving for salt Nausea, diarrhea, vomiting Irritability, depression

• Primary acute Hypocortisolism - Stress crisis - Rapid Steroids withdraw - adrenal hemorrhage

• Primary chronic Hypocortisolism - Autoimmune adrenalitis 60-70% - Infections TB 90% - Metastatic neoplasms - Genetic disorder

Primary Adrenocortical Insufficiency

Q L

ACTH

CRH

Cortisol

• Secondary Hypocortisolism - Hypothalamic pituitary disease

- Hypothalamic pituitary suppression

Secondary Adrenocortical Insufficiency

Q L

ACTH

CRH

Cortisol

Glucocorticoid replacement

Mineralocorticoid replacement

Prevent adrenal crisis

Medic Alert bracelet

Management

Q L

ACTH

CRH

Cortisol

For people with Addison’s Disease

* prior to 1930, 90% died within 5 years

* from late 1930, much better prognosis

* since late 1950, normal life span

Prognosis

Q L

• Anatomy, Histology & Function • Steroid Hormones • Addison’s Disease • Cushing’s Syndrome • Clinical Case Presentation

Adrenal Gland

Q L

• Excessive Endogenous Cortisol - ACTH independent: cortical tumor - ACTH dependent:

* Pituitary adenoma * Small cell carcinoma

• Administration of Glucocorticoids - The most common cause

Cushing’s Syndrome

Q L

ACTH

CRH

Cortisol

Causes of Cushing’s Syndrome

• Excessive Endogenous Cortisol - ACTH independent: cortical tumor - ACTH dependent:

* Pituitary adenoma * Small cell carcinoma

• Administration of Glucocorticoids - The most common cause

Causes of Cushing’s Syndrome

Q L

ACTH

CRH

Cortisol

• Excessive Endogenous Cortisol - ACTH independent: cortical tumor - ACTH dependent:

* Pituitary adenoma * Small cell carcinoma

• Administration of Glucocorticoids - The most common cause

Causes of Cushing’s Syndrome

Q L

ACTH

CRH

Cortisol

• Excessive Endogenous Cortisol - ACTH independent: cortical tumor - ACTH dependent:

* Pituitary adenoma * Small cell carcinoma

• Administration of Glucocorticoids - The most common cause

Causes of Cushing’s Syndrome

Q L

ACTH

CRH

Cortisol

• Excessive Endogenous Cortisol - ACTH independent: cortical tumor - ACTH dependent:

* Pituitary adenoma * Small cell carcinoma

• Administration of Glucocorticoids - The most common cause

Causes of Cushing’s Syndrome

Q L

ACTH

CRH

Cortisol

• Central Obesity (trunk & upper back) 85-90% • Moon face 85% • Weakness and fatigability 85% • Hirsutism 75% • Hypertension 75% • Plethora 75% • Glucose intolerance / diabetes 70 / 20% • Osteoprosis 75% • Moodiness, irritability or depression 75-80% • Menstrual abnormalities 70% • Skin striae (sides of lower abdomen) 50%

Clinical Manifestations

24-hour urine free cortisol level am & pm cortisol * for loss of diurnal rhythm, Hall mark Low-dose Dex suppression * identify Cushing's Syndrome High-dose Dex suppression * identify Cushing’s Disease

Screening Tests

Q L

ACTH

CRH

Cortisol

Low-dose Dex suppression Day 1: 1 mg of Dex is given at 11 pm Day 2: 0.5 mg of Dex every 6 hrs for 48 hrs High-dose Dex suppression Day 1: a baseline cortisol measured at am 8 mg of Dex is given at 11 pm Day 2: 2 mg of Dex every 6 hrs for 48 hrs. blood cortisol at 8 am on day 2 urinary cortisol for 3 days

Dexamethasone Suppression Test

Q L

ACTH

CRH

Cortisol

• Is ACTH independent?

• If ACTH dependent * pituitary or ectopic

• Source of hormone overproduction * MRI pituitary * CT adrenals, chest, abdomen

Determining the Etiology

Q L

ACTH

CRH

Cortisol

Adrenal Gland - Adenoma

Adrenal Gland - Mass

Adrenal Gland - Adenoma

Surgical Therapy

Radiotherapy

Medical therapy adrenal enzyme blockers

The management

Q L

ACTH

CRH

Cortisol

Adrenal Gland

Q L

• Anatomy, Histology & Function • Steroid Hormones • Addison’s Disease • Cushing’s Syndrome • Clinical Case Presentation

Adrenal Gland – Gr / CS Nodular Cortical Hyperplasia

Confluent Nodules

Nodule

Adrenal Gland – Low Power Nodular Cortical Hyperplasia

Adrenal Gland – High Power Nodular Cortical Hyperplasia

Adrenal Gland, cortical adenoma in Cushing’s syndrome – Gr / CS

Adrenal Gland, cortical adenoma - LP

Adrenal Gland - Comparison

The Internet Pathology Laboratory

for Medical Education

Resources

• Pathologic Basis of Disease Robbins & Cotran 7th Edition

• Basic Pathology Robins 7th Edition

• Handbook of Clinical Pathology 2nd Edition

Q L