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Endocrine Diseases
Qiao Li, MD, PhD Faculty of Medicine University of Ottawa
The Pathological Basis of Disease - Graduate Course CMM5001
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• Endocrine System • Adrenal Gland
– Anatomy & Histology – Steroid Hormones – Addison’s Disease – Cushing Syndrome – Clinical Case Presentation
Outline
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Pineal gland
Hypothalamus
Pituitary gland
Thyroid gland
Parathyroid glands (on dorsal aspect of thyroid gland)
Thymus
Adrenal glands
Pancreas
Gonads
• Testis (male)
• Ovary (female)
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Endocrine Glands
Endocrine glands • Pineal • pituitary • thyroid • parathyroid • adrenal
Hypothalamus Neuroendocrine organ
Exocrine & endocrine Pancreas, gonads, placenta
Other Thymus, heart, kidney etc.
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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
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Hypothalamus connects: nervous with endocrine via pituitary
Hypothalamic is controlled by: neural connections negative feedback from hormones
Neuroendocrine - Homeostasis
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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
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The Summary
Hypothalamic Hormone
Anterior Pituitary Hormone
Target Organ
Thyrotropin-Releasing Hormone (TRH)
Thyroid-Stimulating Hormone (TSH) Thyroid Gland
Corticotropin-Releasing Hormone (CRH)
Adrenocorticoidtropic Hormone (ACTH) 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
GH, TSH, ACTH, FSH, LH, PRL
Anterior lobe of pituitary
Hypophyseal portal system
• Primary capillary plexus • Hypophyseal portal veins • Secondary capillary plexus
Superior hypophyseal
artery
Anterior lobe of pituitary
Hypothalamus Hypothalamic neurons synthesize GHRH, GHIH, TRH, CRH, GnRH, PIH
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Increases risk of disease Produces changes associated with aging Control systems less efficient
Overwhelmed negative feedbacks Destructive positive feedback takes over
(heart failure)
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Homeostatic Imbalance
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)
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• Anatomy & Histology • Steroid Hormones • Addison’s Disease • Cushing Syndrome • Clinical Case Presentation
Adrenal Gland
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Adrenal Gland (Suprarenal)
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Adrenal Gland – in situ
The Internet Pathology Laboratory
for Medical Education
Described as loose flesh for the left gland by Claudius Galen (130-201) Depicted in 1552 by Bartholomeaus Eustachius (1520-1574) on copper plate Reproduced by prints in 1563
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Adrenal Gland – Male Abdomen
The Internet Pathology Laboratory
for Medical Education
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Adrenal Gland - CT
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Adrenal Gland - MRI
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Adrenal Gland – Gross
The Internet Pathology Laboratory
for Medical Education
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Adrenal Gland – Cut Surface
The Internet Pathology Laboratory
for Medical Education
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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
Kidney
Adrenal gland
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Adrenal Gland – Cross Section
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Chromaffin cells
Catecholamines epinephrine norepinephrine
Ganglion cells
Adrenal Gland – Medulla
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The Stress Short-term stress Prolonged stress
Nerve impulses
Spinal cord
Preganglionic sympathetic fibers
Adrenal medulla (secretes amino acid– based hormones)
Catecholamines (epinephrine and norepinephrine)
Short-term stress response
Stress
Hypothalamus
Corticotropic cells of anterior pituitary
To target in blood
CRH (corticotropin- releasing hormone)
Adrenal cortex (secretes steroid hormones)
Mineralocorticoids Glucocorticoids
ACTH
• Heart rate increases Long-term stress response
• Kidneys retain sodium and water
• Proteins and fats converted to glucose or broken down for energy • Blood glucose 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
• Blood volume and blood pressure rise • Immune system
supressed
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Med
ulla
C
orte
x
Capsule Zona
glomerulosa
Zona fasciculata
Zona reticularis
Adrenal medulla
Adrenal gland • Medulla • Cortex
Kidney
Hormones secreted
Aldosterone
Cortisol and androgens
Epinephrine and norepinephrine
Photomicrograph (115x) Drawing of the histology of the adrenal cortex and a portion of the adrenal medulla Q L
Adrenal Cortex
Three layers of cortex produce three corticosteroids Zona glomerulosa - mineralocorticoids Zona fasciculata - glucocorticoids Zona reticularis - gonadocorticoids
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Capsule
Periadrenal fat Zona glomerulosa
Zona fasciculata
Zona reticularis
Medulla
Adrenal Gland – Low Power
The Internet Pathology Laboratory
for Medical Education
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Adrenal Gland – Low & High Power
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sinusoid
HP-zr HP-zf
HP
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Adrenal Gland
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• Anatomy & Histology • Steroid Hormones • Addison’s Disease • Cushing Syndrome • Clinical Case Presentation
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Adrenal Cortex Steroids
glomerulosa mineralocorticoids aldosterone salt and water homeostasis
fasiculata glucocorticoids cortisol carbohydrate metabolism
reticularis sex steroids androgens & estrogen minimal effects
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O
O
CH2OH
O
O
Zone Class Representative Physiologic Effects
CH2OH
O
O O
CH
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Adrenal Steroidogenesis
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Histone acetylation
TAFII250
RNA Pol II
p300/CBP
TBP
GR, a Transcription Factor
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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
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Control of Cortisol Secretion
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Hypothalamus
Anterior Pituitary
Adrenal Cortex
HPA Axis
ACTH
Cortisol
CRH
Dr. Gary Farr
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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"
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Adrenal Gland
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• Anatomy & Histology • Steroid Hormones • Addison’s Disease • Cushing Syndrome • Clinical Case Presentation
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* 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
Thomas Addison 1855 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
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* 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
Primary Adrenocortical Insufficiency
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ACTH
Cortisol
CRH
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• Secondary Hypocortisolism - Hypothalamic pituitary disease
- Hypothalamic pituitary suppression
Secondary Adrenocortical Insufficiency
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ACTH
Cortisol
CRH
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Glucocorticoid replacement
Mineralocorticoid replacement
Prevent adrenal crisis
Medic Alert bracelet
Managements
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ACTH
Cortisol
CRH
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For people with Addison’s Disease
* prior to 1930, 90% died within 5 years
* from 1930, much better prognosis
* since 1950, normal life span
Prognosis
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Adrenal Gland - Comparison
The Internet Pathology Laboratory
for Medical Education
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• Anatomy & Histology • Steroid Hormones • Addison’s Disease • Cushing Syndrome • Clinical Case Presentation
Adrenal Gland
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Causes of Cushing Syndrome
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Cushing’s Disease
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• Excessive Endogenous Cortisol - ACTH dependent:
* Pituitary adenoma (70-80%)
* Small cell carcinoma - ACTH independent * Cortical tumor • Administration of Glucocorticoids
- The most common cause Cushing’s Disease
ACTH
Cortisol
CRH
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Ectopic ACTH Secretion
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• 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
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Adrenal Defects
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• 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
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Exogenous CS
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• Excessive Endogenous Cortisol - ACTH dependent:
* Pituitary adenoma * Small cell carcinoma
- ACTH independent * Cortical tumor • Administration of Glucocorticoids
- The most common cause
ACTH
Cortisol
CRH
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• Excessive Endogenous Cortisol - ACTH dependent:
* Pituitary adenoma (Cushing’s Disease)
* Small cell carcinoma - ACTH independent * Cortical tumor • Administration of Glucocorticoids
- The most common cause
Cushing Syndrome
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ACTH
Cortisol
CRH
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Adrenal Gland – Gr / CS Nodular Cortical Hyperplasia
Confluent Nodules
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Nodule
Adrenal Gland – Low Power Nodular Cortical Hyperplasia
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Adrenal Gland – High Power Nodular Cortical Hyperplasia
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Adrenal Gland, cortical adenoma in Cushing Syndrome – Gr / CS
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Adrenal Gland, cortical adenoma - LP
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Adrenal Gland - Tumor
CT
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Adrenal Gland - Mass
MRI : in-phase sequence
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Adrenal Gland - Adenoma
MRI : out-of-phase sequence
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• 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%
Clinical Manifestations
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Screening Tests
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24-hour urine free cortisol level
am & pm cortisol level * circadian rhythm, a hall mark
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Low-dose Dex suppression
* identify Cushing Syndrome High-dose Dex suppression
* identify Cushing’s Disease
DST (Dexamethasone Suppression Test)
ACTH
Cortisol
CRH
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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
Low Dose DST
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ACTH
Cortisol
CRH
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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
High Dose DST
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ACTH
Cortisol
CRH
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• Is ACTH dependent?
• If ACTH dependent * pituitary or ectopic
• Source of overproduction * MRI pituitary * CT adrenals, chest, abdomen
Determining the Etiology
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ACTH
Cortisol
CRH
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Surgical Treatment laparoscopic adrenalectomy
Medical Treatment adrenal enzyme blockers
Managements
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ACTH
Cortisol
CRH
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Adrenal Gland
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• Anatomy & Histology • Steroid Hormones • Addison’s Disease • Cushing Syndrome • Clinical Case Presentation
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Resources
• Pathologic Basis of Disease Robbins & Cotran 7th Edition
• Basic Pathology Robins 7th Edition
• Handbook of Clinical Pathology 2nd Edition
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