Endocrine Diseases. The Pathological Basis of Disease
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1 Endocrine Diseases The Pathological Basis of Disease - Graduate Course CMM5001 Qiao Li, MD, PhD Faculty of Medicine University of Ottawa qiaoli@uottawa.ca
2 Outline Endocrine System Adrenal Gland Anatomy & Histology Steroid Hormones Addison s Disease Cushing Syndrome Clinical Case Presentation
3 Endocrine Glands Endocrine glands Pineal pituitary thyroid parathyroid adrenal Hypothalamus Neuroendocrine organ Exocrine & endocrine Pancreas, gonads, placenta Other Thymus, heart, kidney etc. Pineal gland Hypothalamus Pituitary gland Thyroid gland Parathyroid glands (on dorsal aspect of thyroid gland) Thymus Adrenal glands Pancreas Gonads Ovary (female) Testis (male)
4 Endocrine Function Controls & integrates Reproduction Growth and development Maintenance of electrolyte, water & nutrient balance of blood Regulation of cellular metabolism & energy balance Mobilization of body defenses
5 Neuroendocrine - Homeostasis Hypothalamus connects: nervous with endocrine via pituitary Hypothalamic is controlled by: neural connections negative feedback from hormones The nervous and endocrine systems (integrating) In response to external & internal stimuli, send signals to various parts of the body to adjust to the changes Both are homeostatic mechanisms that help maintain a steady state in different physiologic systems of the body
6 The Summary Hypothalamic Hormone Anterior Pituitary Hormone Target Organ Thyrotropin-Releasing Hormone (TRH) Corticotropin-Releasing Hormone (CRH) Thyroid-Stimulating Hormone (TSH) Adrenocorticoidtropic Hormone (ACTH) Thyroid Gland Adrenal Glands Gonadotropin-Releasing Hormone (GnRH) Folicle-Stimulating Hormone (FSH) Lutenizing Hormone (LH) Ovaries / Testes Prolactin-Inhibiting Hormone (PIH, Dopamine) Prolactin (PRL) Breast Growth Hormone-Releasing Hormone (GHRH) GHIH (Somatostatin) Growth Hormone (GH, Somatotropin) Liver Anterior lobe of pituitary Superior hypophyseal artery Hypothalamus Hypothalamic neurons synthesize GHRH, GHIH, TRH, CRH, GnRH, PIH Hypophyseal portal system Primary capillary plexus Hypophyseal portal veins Secondary capillary plexus GH, TSH, ACTH, FSH, LH, PRL Anterior lobe of pituitary
7 Homeostatic Imbalance Increases risk of disease Produces changes associated with aging Control systems less efficient Overwhelmed negative feedbacks Destructive positive feedback takes over (heart failure) most disease seen as a disturbance of homeostasis (homeostatic imbalance) aging associated with progressive decrease in our ability to maintain homeostasis (greater risk for illness)
8 Adrenal Gland Anatomy & Histology Steroid Hormones Addison s Disease Cushing Syndrome Clinical Case Presentation
9 Adrenal Gland (Suprarenal)
10 Adrenal Gland in situ Described as loose flesh for the left gland by Claudius Galen ( ) Depicted in 1552 by Bartholomeaus Eustachius ( ) on copper plate Reproduced by prints in 1563 The Internet Pathology Laboratory for Medical Education
11 Adrenal Gland Male Abdomen The Internet Pathology Laboratory for Medical Education
12 Adrenal Gland - CT
13 Adrenal Gland - MRI
14 Adrenal Gland Gross The Internet Pathology Laboratory for Medical Education
15 Adrenal Gland Cut Surface The Internet Pathology Laboratory for Medical Education
16 Medulla & Cortex Paired, pyramid-shaped organs atop kidneys Structurally and functionally are two glands in one Adrenal medulla (nervous tissue) part of sympathetic nervous system Adrenal cortex three layers of glandular tissue that synthesize and secrete corticosteroids Adrenal gland Kidney
17 Adrenal Gland Cross Section
18 Adrenal Gland Medulla Chromaffin cells Catecholamines epinephrine norepinephrine Ganglion cells
19 The Stress Short-term stress Stress Prolonged stress Nerve impulses Hypothalamus CRH (corticotropinreleasing hormone) Spinal cord Preganglionic sympathetic fibers Adrenal medulla (secretes amino acid based hormones) ACTH Corticotropic cells of anterior pituitary To target in blood Adrenal cortex (secretes steroid hormones) Catecholamines (epinephrine and norepinephrine) Short-term stress response Heart rate increases Blood pressure increases Bronchioles dilate Liver converts glycogen to glucose and releases glucose to blood Blood flow changes, reducing digestive system activity and urine output Metabolic rate increases Mineralocorticoids Long-term stress response Kidneys retain sodium and water Blood volume and blood pressure rise Glucocorticoids Proteins and fats converted to glucose or broken down for energy Blood glucose increases Immune system supressed
20 Adrenal Cortex Three layers of cortex produce three corticosteroids Zona glomerulosa - mineralocorticoids Zona fasciculata - glucocorticoids Zona reticularis - gonadocorticoids Capsule Zona glomerulosa Hormones secreted Aldosterone Adrenal gland Medulla Cortex Kidney Medulla Cortex Zona fasciculata Zona reticularis Adrenal medulla Cortisol and androgens Epinephrine and norepinephrine Drawing of the histology of the adrenal cortex and a portion of the adrenal medulla Photomicrograph (115x)
21 Adrenal Gland Low Power Medulla Zona fasciculata Capsule Zona reticularis Zona glomerulosa Periadrenal fat The Internet Pathology Laboratory for Medical Education
22 Adrenal Gland Low & High Power HP sinusoid HP-zf HP-zr
23 Adrenal Gland Anatomy & Histology Steroid Hormones Addison s Disease Cushing Syndrome Clinical Case Presentation
24 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 CH 2 OH CH O CH 2 OH O O O O O
25 Adrenal Steroidogenesis
26 GR, a Transcription Factor Histone acetylation p300/cbp TAFII250 TBP RNA Pol II QL
27 Effects & Usage of Glucocorticoids Carbohydrate, proteins and fat metabolism gluconeogenesis muscle breakdown lipolysis Anti-inflammatory and immunosuppressive Medical Application: arthritis, dermatitis autoimmune diseases fear phobic
28 Control of Cortisol Secretion HPA Axis Hypothalamus CRH Anterior Pituitary ACTH Adrenal Cortex Cortisol Dr. Gary Farr
29 Research Milestones * 1552: Bartholomaeus Eustachius - Depicted adrenal glands on copper plate * 1556: Thomas Wharton - Adrenals took something from the nerves and secreted it into the circulation * 1936: Edward Kendall and Tadeus Reichstein - Isolation and synthesis of cortisone * 1949: Edward Kendall and Philip Hench - Effects of cortisone and ACTH on rheumatoid arthritis * 1950: Nobel Prize to Kendall, Reichstein & Hench "for their discoveries relating to the hormones of the adrenal cortex, their structure and biological effects"
30 Adrenal Gland Anatomy & Histology Steroid Hormones Addison s Disease Cushing Syndrome Clinical Case Presentation
31 Addison s Disease * 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 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 Thomas Addison 1855
32 Primary Adrenocortical Insufficiency * Primary chronic Hypocortisolism - Autoimmune adrenalitis 60-70% - Infections (TB, AIDS) TB 90% - Metastatic neoplasms - Genetic disorder (Addison s disease) * Primary acute Hypocortisolism - Stress crisis (chronic AI) - Rapid Steroids withdraw - adrenal hemorrhage ACTH Cortisol CRH
33 Secondary Adrenocortical Insufficiency Secondary Hypocortisolism CRH - Hypothalamic pituitary disease - Hypothalamic pituitary suppression ACTH Cortisol
34 Managements Glucocorticoid replacement Mineralocorticoid replacement Prevent adrenal crisis Medic Alert bracelet ACTH CRH Cortisol
35 Prognosis For people with Addison s Disease * prior to 1930, 90% died within 5 years * from 1930, much better prognosis * since 1950, normal life span
36 Adrenal Gland - Comparison The Internet Pathology Laboratory for Medical Education
37 Adrenal Gland Anatomy & Histology Steroid Hormones Addison s Disease Cushing Syndrome Clinical Case Presentation
38 Causes of Cushing Syndrome
39 Cushing s Disease Excessive Endogenous Cortisol - ACTH dependent: * Pituitary adenoma (70-80%) * Small cell carcinoma - ACTH independent * Cortical tumor Administration of Glucocorticoids ACTH Cortisol CRH - The most common cause Cushing s Disease
40 Ectopic ACTH Secretion Excessive Endogenous Cortisol - ACTH dependent: * Pituitary adenoma * Small cell carcinoma (10%) - ACTH independent * Cortical tumor Administration of Glucocorticoids - The most common cause ACTH Cortisol CRH
41 Adrenal Defects Excessive Endogenous Cortisol - ACTH dependent: * Pituitary adenoma * Small cell carcinoma - ACTH independent * Cortical tumor (10-20%) Administration of Glucocorticoids - The most common cause ACTH Cortisol CRH
42 Exogenous CS Excessive Endogenous Cortisol - ACTH dependent: * Pituitary adenoma * Small cell carcinoma - ACTH independent * Cortical tumor Administration of Glucocorticoids - The most common cause ACTH Cortisol CRH
43 Cushing Syndrome Excessive Endogenous Cortisol - ACTH dependent: * Pituitary adenoma (Cushing s Disease) * Small cell carcinoma - ACTH independent * Cortical tumor Administration of Glucocorticoids - The most common cause ACTH Cortisol CRH Harvey Cushing 1912
44 Adrenal Gland Gr / CS Nodular Cortical Hyperplasia Confluent Nodules
45 Adrenal Gland Low Power Nodular Cortical Hyperplasia Nodule
46 Adrenal Gland High Power Nodular Cortical Hyperplasia
47 Adrenal Gland, cortical adenoma in Cushing Syndrome Gr / CS
48 Adrenal Gland, cortical adenoma - LP
49 Adrenal Gland - Tumor CT
50 Adrenal Gland - Mass MRI : in-phase sequence
51 Adrenal Gland - Adenoma MRI : out-of-phase sequence
52 Clinical Manifestations Moodiness, depression 75-80% Moon face 85% Facial plethora 75% Osteoprosis 75% Truncal obesity (buffalo hump) 85-90% Skin striae (abdomen) 50% Menstrual abnormalities 70% Weakness and fatigability 85% Hirsutism 75% Hypertension 75% Glucose intolerance / diabetes 70 / 20%
53 Screening Tests 24-hour urine free cortisol level am & pm cortisol level * circadian rhythm, a hall mark
54 DST (Dexamethasone Suppression Test) Low-dose Dex suppression * identify Cushing Syndrome CRH High-dose Dex suppression * identify Cushing s Disease ACTH Cortisol
55 Low Dose DST Low-dose DST Day 1: 1 mg of Dex at 11 pm Day 2: blood cortisol at 8 am 0.5 mg of Dex every 6 hrs for 48 hrs 24-hr urinary cortisol for 3 days * identify Cushing Syndrome High-dose DST Day 1: a baseline cortisol at am 8 mg of Dex at 11 pm Day 2: blood cortisol at 8 am 2 mg of Dex every 6 hrs for 48 hrs. 24-hr urinary cortisol for 3 days * identify Cushing's Disease ACTH Cortisol CRH
56 High Dose DST Low-dose DST Day 1: 1 mg of Dex at 11 pm Day 2: blood cortisol at 8 am 0.5 mg of Dex every 6 hrs for 48 hrs 24-hr urinary cortisol for 3 days * identify Cushing Syndrome High-dose DST Day 1: a baseline cortisol at am 8 mg of Dex at 11 pm Day 2: blood cortisol at 8 am 2 mg of Dex every 6 hrs for 48 hrs. 24-hr urinary cortisol for 3 days * identify Cushing's Disease ACTH Cortisol CRH
57 Determining the Etiology Is ACTH dependent? If ACTH dependent * pituitary or ectopic Source of overproduction * MRI pituitary * CT adrenals, chest, abdomen ACTH CRH Cortisol
58 Managements Surgical Treatment laparoscopic adrenalectomy CRH Medical Treatment adrenal enzyme blockers ACTH Cortisol
59 Adrenal Gland Anatomy & Histology Steroid Hormones Addison s Disease Cushing Syndrome Clinical Case Presentation
60 Resources Pathologic Basis of Disease Robbins & Cotran 7 th Edition Basic Pathology Robins 7 th Edition Handbook of Clinical Pathology 2 nd Edition
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