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Endocrine Diseases
Th P
The
Pathological
th l i l Basis
B i of
f Disease
Di
-
Graduate Course CMM5001
Qiao Li,
Li MD,
MD PhD
Faculty of Medicine
University of Ottawa
Qi Li@
[email protected]
QL
Outline
 Endocrine System
 Adrenal Gland
•
•
•
•
•
Anatomy & Histology
Steroid Hormones
Addison’s Disease
Cushingg Syndrome
y
Clinical Case Presentation
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Endocrine Glands
 Endocrine glands
•
•
•
•
•
Pineal
Pituitary
Thyroid
Parathyroid
Adrenal
Pineal gland
Hypothalamus
Pituitary gland
Thyroid gland
Parathyroid glands
(on dorsal aspect
of thyroid gland)
Thymus
 Neuroendocrine organ
Hypothalamus
 Exocrine & endocrine
Adrenal glands
Pancreas
Pancreas, gonads, placenta
 Other
Thymus, heart, kidney etc.
Gonads
• Ovary (female)
• Testis (male)
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Endocrine Function
 Controls & Integrates
Growth
G
th and
d development
d
l
t
Maintenance of electrolyte, water & nutrient balance of blood
Regulation of cellular metabolism & energy balance
Mobilization of body defenses
Reproduction
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Homeostasis
Hypothalamus connects
nervous with
i h endocrine
d i via
i pituitary
i i
Hypothalamic is controlled by
 neural connections
 negative feedback from hormones
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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
o
o e (G
(GnRH))
Folicle-Stimulating Hormone (FSH)
Lutenizing
ute
g Hormone
o
o e (LH)
(
)
Ovaries
O
a es / Testes
estes
Prolactin-Inhibiting
Hormone (PIH, Dopamine)
Prolactin (PRL)
Breast
Growth Hormone-Releasing
Hormone (GHRH)
GHIH (Somatostatin)
Growth Hormone
(GH, Somatotropin)
Liver
Hypothalamus
Hypothalamic neurons synthesize
GHRH, GHIH, TRH, CRH, GnRH, PIH
Anterior lobe
of pituitary
Superior
hypophyseal
artery
Hypophyseal portal system
• Primary capillary plexus
• Hypophyseal portal veins
• Secondary capillary plexus
GH, TSH, ACTH, FSH, LH, PRL
Anterior lobe of pituitary
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Homeostatic Imbalance
 Increases risk of disease
 Causes changes associated with aging
control systems less efficient
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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Adrenal Gland
•
•
•
•
•
Anatomy & Histology
Steroid Hormones
Addison’s Disease
Cushing Syndrome
Clinical Case Presentations
QL
Characteristics
 Origin
all
ll glands
l d arise
i from
f
the
th epithelium
ith li
(all
( ll three
th
germ layers)
l
)
 Microscopic Structure
cords,
d clumps,
l
h ll follicles
hollow
f lli l & abundant
b d t capillaries
ill i
 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 plate
R
Reproduced
d d by
b prints
i in
i 1563
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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 cells
Catecholamines
- epinephrine
- norepinephrine
i
hi
Ganglion cells
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Adrenal Gland
•
•
•
•
•
Anatomy & Histology
Steroid Hormones
Addison’s Disease
Cushing Syndrome
Clinical Case Presentations
QL
Adrenal Gland – Low Power
Medulla
Zona fasciculata
Zona reticularis
Capsule
Zona glomerulosa
Periadrenal fat
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Adrenal Gland – Low & High Power
HP
sinusoid
HP-zf
HP-zr
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Adrenal Cortex Steroids
Zone
Class
Representative
glomerulosa
mineralocorticoids
aldosterone
fasiculata
glucocorticoids
reticularis
sex steroids
cortisol
salt and water homeostasis
carbohydrate metabolism
androgens & estrogen
O
O
Physiologic Effects
CH2OH
CH
O
O
minimal effects
CH2OH
O
O
O
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Adrenal Steroidogenesis
Glucocorticoids & the Receptor
 Cortisol (hydrocortisone)
the majority of glucocorticoid activity in most mammals
 90% off circulating
i
l ti cortisol
ti l binds
bi d to
t cortisol
ti l binding
bi di
globulin (CBG), for transportation, also limiting the rate
of metabolic clearance & the concentration fluctuation
 Enter
E t cells
ll by
b passive
i diffusion
diff i
Histone acetylation
p300/CBP
TAFII250
TBP
RNA Pol II
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Control of Cortisol Secretion
HPA Axis
y
Hypothalamus
CRH
ACTH
Anterior Pituitary
Adrenal Cortex
Cortisol
Dr. Gary Farr
QL
Research Milestones
* 1552: Bartholomaeus Eustachius
- Depicted adrenal glands on copper plate
* 1656: 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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Response to Stress
Short-term stress
Prolonged stress
Stress
Nerve impulses
p
Hypothalamus
yp
CRH (corticotropinreleasing hormone)
Spinal cord
Corticotropic cells
of anterior pituitary
Preganglionic
sympathetic
fib
fibers
To target in blood
Adrenal medulla
(secretes amino acid–
based 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
Adrenal cortex
(secretes steroid
hormones)
ACTH
Mineralocorticoids
Glucocorticoids
Long-term stress response
• Kidneys retain
sodium & water
• Blood volume &
blood pressure rise
• Proteins & fats converted
to glucose or broken down
for energy
• Blood gl
glucose
cose increases
• Immune syste supressed
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Adrenal Cortex Disorders
CRH
ACTH
Cortisol
CRH
ACTH
Cortisol
QL
Adrenal Gland
•
•
•
•
•
Anatomy & Histology
Steroid Hormones
Addison’s Disease
Cushing Syndrome
Clinical Case Presentations
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Addison’s Disease
* General languor and debility
* Remarkable feebleness of the heart's action
*P
Peculiar
li change
h
in
i the
th color
l off the
th skin
ki
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
QL
Primary Adrenocortical Insufficiency
* Primary chronic Hypocortisolism
- Autoimmune adrenalitis
- Infections (TB, AIDS)
- Metastatic neoplasms
- Genetic disorder
60
60--70%
TB 90%
CRH
ACTH
(Addison
(Addison’s
s disease)
* Primary acute Hypocortisolism
- Stress crisis (chronic AI)
- Rapid Steroids withdraw
- adrenal hemorrhage
Cortisol
QL
Secondary Adrenocortical Insufficiency
• Secondary Hypocortisolism
CRH
- Hypothalamic pituitary disease
- Hypothalamic
yp
p
pituitary
y suppression
pp
ACTH
Cortisol
QL
Managements
CRH
Glucocorticoid replacement
Mineralocorticoid replacement
ACTH
Prevent adrenal crisis
Medic Alert bracelet
Cortisol
QL
Prognosis
For people with Addison’s Disease
* prior
i to
t 1930,
1930 90% di
died
d within
ithi 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
Steroid Hormones
Addison’s Disease
Cushing Syndrome
Clinical Case Presentations
QL
Causes of Cushing Syndrome
Cushing’s Disease
• Excessive Endogenous Cortisol
- ACTH dependent:
* Pituitary adenoma (70
(70--80%)
* Small cell carcinoma
- ACTH independent
* Cortical tumor
• Administration of Glucocorticoids
- The most common cause
CRH
ACTH
Cortisol
Cushing’s Disease
QL
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
CRH
ACTH
Cortisol
QL
Adrenal Defects
• Excessive Endogenous Cortisol
- ACTH dependent:
* Pituitary adenoma
* Small cell carcinoma
- ACTH independent
* Cortical tumor (10
(10--20%)
• Administration of Glucocorticoids
- The most common cause
CRH
ACTH
Cortisol
QL
Exogenous CS
• Excessive Endogenous Cortisol
- ACTH dependent:
* Pituitary adenoma
* Small cell carcinoma
- ACTH independent
* Cortical tumor
• Administration of Glucocorticoids
- The most common cause
CRH
ACTH
Cortisol
QL
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
CRH
ACTH
Cortisol
H
Harvey
C
Cushing
hi
1912
QL
Adrenal Gland – Gr / CS
N d l C
Nodular
Cortical
ti l H
Hyperplasia
l i
Confluent Nodules
Adrenal Gland – Low Power
N d l C
Nodular
Cortical
ti l H
Hyperplasia
l i
Nodule
Adrenal Gland – High Power
N d l C
Nodular
Cortical
ti l H
Hyperplasia
l i
Adrenal Gland, cortical adenoma
i C
in
Cushing
hi Syndrome
S d
– Gr
G / 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 Manifestations
• Moodiness, depression
• Moon face
• Facial plethora
• Osteoprosis
• Truncal obesity (buffalo hump)
• Skin striae (abdomen)
• Menstrual abnormalities
• Weakness and fatigability
• Hirsutism
Hi
i
• Hypertension
• Glucose intolerance / diabetes
7575-80%
85%
75%
75%
85--90%
85
50%
70%
85%
75%
%
75%
70 / 20%
Screening Tests
24--hour urine free cortisol level
24
am & pm cortisol level
* circadian rhythm
rhythm, a hall mark
QL
DST (Dex Suppression Test)
Low--dose Dex suppression
Low
CRH
* identify Cushing Syndrome
g -dose Dex suppression
High
High-
ACTH
* identify Cushing’s Disease
Cortisol
QL
Low Dose DST
Low--dose DST
Low
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
24
CRH
ACTH
* identify Cushing Syndrome
High--dose DST
High
Day 1: a baseline cortisol at am
8 mg off Dex
D att 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
24
Cortisol
* identify Cushing's Disease
QL
High Dose DST
Low--dose DST
Low
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
24
CRH
ACTH
* identify Cushing Syndrome
High--dose DST
High
Day 1: a baseline cortisol at am
8 mg off Dex
D att 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
24
Cortisol
* identify Cushing's Disease
QL
Determining the Etiology
• Is ACTH dependent?
• If ACTH dependent
CRH
* pituitary or ectopic
• Source of overproduction
ACTH
* MRI pituitary
* CT adrenals, chest, abdomen
Cortisol
QL
Adrenal Gland - Comparison
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Managements
Surgical Treatment
CRH
l
laparoscopic
i adrenalectomy
d
l t
Medical Treatment
ACTH
adrenal
d
l enzyme blockers
bl k
Cortisol
QL
Resources
• Pathologic Basis of Disease
R bbi & Cotran
Robbins
C t
7th Edition
Editi
• Basic Pathology
Robins
R b 7th Edition
Ed
• Handbook of Clinical Pathology
2nd Edition
QL