Transcript Adrenal Diseases Causing Hypertension

Adrenal Physiology
David Feldman
Glucocorticoids
 Mineralocorticoids
 Catecholamines/Adrenal Medulla
 Adrenal Causes of Hypertension

◦ Cushings Syndrome
◦ Primary Aldosteronism (Conn’s Syndrome)
◦ Pheochromocytoma
Adrenal Steroidogenic Pathways
Regulation of Cortisol Secretion
Hypothalamic-Pituitary-Adrenal (HPA) Axis
Diurnal rhythm
Emotion
Trauma
Stress
Diurnal Pattern of Plasma Cortisol
ACTH Action on Fasiculata Cells to Stimulate Cortisol Secretion
Serum ACTH
Total serum cortisol
Urine free cortisol
Diagnostic test
Mechanism of Cortisol Action Via Nuclear GR
Actions
CBG
Glucocorticoids as Drugs
Used in pharmacological doses
 Many uses including immunosuppression and anti-inflammation

◦ Asthma, arthritis, COPD, cancer, transplants, etc.
Current drugs can separate GR from MR but NOT reduce other sideeffects
 Many side-effects

◦ Diabetes, osteoporosis, infection, adrenal suppression, etc
◦ Iatrogenic Cushings Syndrome

Future drugs (SGRMs) being designed to avoid side-effects by selective
activation of actions (like SERMs)
Etiology of Spontaneous Cushings Syndrome
Pituitary adenoma (Cushings Disease) 70%
 Adrenal disease 17%

◦ Adenoma 10%
◦ Carcinoma 7%

Ectopic ACTH Syndrome 12%
Cushings Disease
Findings
Cushings Disease Findings
Findings in Cushings Syndrome
Purple stretch
marks or striae
(singular stria)
Glucocorticoid Actions to Cause Osteoporosis
Adrenal Insufficiency
Pituitary Disease-Low ACTH
Addisons Disease Findings
Mineralocorticoid Actions in Kidney and Other Sites
Steroid Regulation and Synthesis in Glomerulosa vs. Fasiculata
Renal Regulation of
Blood Pressure: The
Renin-Angiotensin
System (RAS)
Actions of Renin and ACE to Generate ANG II
Hormonal
Regulation
of
Blood
Pressure
Regulation of
Aldosterone
Urine Na+,Renin and Aldosterone Levels
Regulation of Ang and Aldo
Secretion and Blood Pressure
Vasoconstriction
Blood pressure
Blood pressure
Salt-sensitivity is leading to hypertension in a large number of people
Blood pressure is controlled by the renin-angiotensin system (RAS). Polymorphisms in two
critical genes in the RAS have been identified thus far to cause salt-sensitivity.
1. A genetic variant of the angiotensinogen (AGT) gene leads to increased production of
angiotensinogen. People carrying this variant are salt-sensitive, meaning they keep more
sodium in the blood than non-carriers do. High sodium level increases blood volume, leading
to increased blood pressure. Therefore, carriers of this AGT variant have a higher risk for
hypertension.
2. The most common genetic variation related to the RAS system is in the ACE gene.
ACE I/D means insertion or deletion polymorphism of the angiotensin-converting enzyme
(ACE) gene. Carriers of the D variant of the ACE gene are more likely to develop
hypertension with a diet high in sodium and low in potassium. Over 50% of Africans and
Caucasians and about 40% of Asians carry this variant. Variant D carriers make more ACE
protein which results in a more active RAS system than that of variant I carriers.
The current trend to limit dietary salt intake will benefit these individuals
Mechanism of Aldosterone Action via MR
MR
MR/Aldo
Nucleus
ALDO
“Escape”
No Edema
No escape
“Escape”
Na+ retention
Na+ release
Mineralocorticoid Excess Causes Na+ Retention, K+ loss,
Hypertension, No Edema
Aldosteronoma Causes Na+ Retention, K+ Loss, Suppressed Renin
and Hypertension
Aldosteronoma
Clinical Clues to Primary Aldosteronism
Spontaneous hypokalemia
 Diuretic-induced hypokalemia
 Refractory hypertension
 Family history of primary aldosteronism

Differential Diagnosis of Hyperaldosteronism:
Adenoma vs Hyperplasia
John Luetscher
Co-discoverer
of aldosterone
Differential Diagnosis of Hyperaldosteronism:
Adenoma vs Hyperplasia
11-Beta Hydroxysteroid Dehydrogenase (11ß-HSD):
The “protector” of the mineralocorticoid receptor
11-hydroxy
Cortisol
active
11-keto
11ß-HSD-II
Cortisone
inactive
Cortisol is present in great excess in the circulation. CBG protects some from access to MR
but free cortisol is still high enough and could inappropriately bind to the MR and act as a
mineralocorticoid. 11ß-HSD-1 prevents this by converting cortisol to cortisone which can no
longer bind to the MR.
Hormone
Cortisone
cannot bind
the MR
MR
Defect in
11ß-HSD-No protection
Apparent
Mineralocorticod
Excess (AME)
Cortisol
drives
the MR
Or overwhelmed by very high cortisol
as in ectopic ACTH syndrome
Pheochromocytoma
MEN I (Wermer Syndrome)
3 P’s: parathyroid, pancreas & pituitary)
1. Parathyroid hyperplasia (Hyperparathyroidism (usually 4 gland hyperplasia)
2. Tumors of the pancreas
gastrinomas (Zollinger-Ellison Syndrome
pancreatic islets (insulinoma, glucagonoma);
3. Pituitary tumors
prolactinoma, Cushing disease, etc.
4. Other tumors including Carcinoid, lipomas and angiofibromas
Cause: Rare autosomal dominant mutations in the gene encoding menin, a
tumor suppressor.
MEN IIA (Sipple Syndrome)
1. Pheochromocytoma
2. Medullary thyroid carcinoma (C-cell hyperplasia to cancer)
3. Hyperparathyroidism
MEN IIB
1. Pheochromocytoma
2. Medullary thyroid carcinoma
3. Hyperparathyroidism
4. Multiple mucosal neuromas
5. Marfanoid habitus
Cause: MEN II is caused by mutations that constitutively activate the RET protooncogene.
Adrenal Diseases Causing Hypertension
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
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Hypercortisolism, Cushing’s syndrome
Hyperaldosteronism, Conn’s syndrome
Pheochromocytoma
Apparent Mineralocorticoid Excess (AME)
◦ 11ß-HSD defect
◦ Ectopic ACTH overwhelming 11ß-HSD
“Incidentaloma”
Beta blockers
ACE inhibitors
Angiotensin receptor
blockers (ARBs)
MR blocker