Mineralocorticoid Disorders & Endocrine Hypertension Flashcards
What is the StAR protein regulated by in the zona glomerulosa
A2 and potassium (reduces plasma sodium)
What is blood pressure?
Force pushing against blood vessel walls as blood is pumped out by the heart
What are the 3 main physiological factors regulating blood pressure?
** Cardiac output **
=volume of blood pumped out by the heart
=stroke volume x heart rate (beats/min)
** Vascular tone **
=‘stiffness’ or resistance of blood vessels
=balance between vasoconstrictor & vasodilator influences
** Extracellular fluid (ECF) volume
=Interstitial fluid in tissues
=intravascular fluid in the plasma
=increased by kidney water resorption**
What is Phaeochromocytoma?
- Catecholamine-producing tumour of the chromaffin cells, primarily affecting the cardiovascular system (vasoconstriction, episodes of rapid heart beat & hypertension, sweating & palpitations).
- Treated by receptor blockade & surgery
How is cardiac output regulated by hormones?
-increased by:
=catecholamines (SNS) (alpha adrenergic receptors)
=cortisol potentiation (HPA)= long term sustained
How is vascular tone/ vasoconstriction regulated by hormones?
increased by:
- angiotensin II (AII; RAS)
- aldosterone (RAS)
- catecholamines (SNS)
- cortisol potentiation (HPA)
How is extracellular fluid volume regulated by hormones?
increased by:
- aldosterone (RAS)
- cortisol (HPA)= affects water resorption, not seen in normal homeostasis (pathophysiologically altered)
What is endocrine hypertension?
-caused by excess:
=aldosterone from ZG
=cortisol or precursors from ZF
=catecholamines from medulla
When is renin released in response?
-JG cell baroreceptors
=reduced ECF & renal perfusion pressure in afferent arteriole
=directly activates renin release from granules
-Macula densa cell Na+ sensing
=decreased Na+ load to distal tubule (↓ECF/plasma Na+)
=activates sympathetic innervation of JG apparatus
-Carotid arch baroreceptors in periphery
=Low systemic arterial pressure (reduced ECF, cardiac output, vascular tone)
=activates sympathetic innervation of JG apparatus
What are the rapid effects of RAS and aldosterone?
-Vasculature rapid (secs)
=Increased vasoconstriction, postural regulation of BP
-Adrenal rapid (mins)
=Increased aldosterone synthesis (ZG), increased catecholamine synthesis
-Kidney 6-48hr
=Increased sodium and water reabsorption via RAAS
What are the physiological actions of aldosterone at the DCT?
- Aldosterone binding promotes AR (mineralocorticoid) receptor relocation from cytoplasm to nucleus
- Increased uptake of Na+ via apical ENaC protein and increased basolateral Na+/K+ exchange
What are the long term effects of RAS and aldosterone?
-Vasculature
=Smooth muscle, increased cell hyperplasia, increased cell hypertrophy, long-lasting change in vascular tone (stiffer)
-Adrenal
=Increased aldosterone synthase enzyme expression, increased glomerulosa cell proliferation
-CNS
=Increased thirst, increased salt appetite, increased ADH release
What are inhibitors of the adrenal gland?
- Low plasma K+
- High plasma Na+
- ANP
What are trophic factors of the adrenal gland?
- High plasma K+
- Low plasma Na+
- Angiotensin 2 (RAS)
What happens in long term exposure to aldosterone?
-Pathophysiological changes to adrenal, kidney, heart and peripheral vascular smooth muscle
=Vascular smooth muscle hyperplasia
=Cardiac fibrosis, left ventricular hypertrophy
=Increased blood pressure
Aldosterone direct damage to heart (hyperplasia, fibrosis) not consequence of hypertension
How is heart failure linked to aldosterone?
- Plasma aldosterone elevated in patients with heart failure
- Standard HF therapy: ACE inhibitor + loop diuretic + digoxin
What are the benefits of spironolactone in heart failure therapy?
-Mineralocorticoid receptor antagonist
-Spironolactone (MR antagonist) blocks aldosterone action in kidney AND other tissues (e.g. heart)
-Which otherwise leads to:
=myocardial remodelling,
=Na+ retention & vascular dysfunction
-Decreases all-cause mortality in heart failure patients
What are the causes of hypertension?
- ~30%= lifestyle/ environmental (poor diet, lack of exercise)
- ~70% major familial/genetic mono- or polygenic component
-85-90% classified as ‘Primary’ or ‘Essential’ hypertension
=all cases without any identifiable cause
-10-15% classified as ‘secondary’ hypertension
=neoplasia, vascular damage & endocrine causes (primary aldosteronism common cause of secondary hypertension)
What are causes of secondary hypertension?
- Renal: chronic renal failure, renal artery stenosis, renin-secreting tumour of the kidney (very rare)
- Vascular: atherosclerosis, co-arctation of the aorta
- Pregnancy: hormonal and heamodynamic changes
- Drugs: alcohol, glucocorticoids, oestrogen-containing oral contraceptives, non-steroidal anti-inflammatory drugs
- Endocrine: adrenal disorders, thyroid disease, pituitary disease (Cushings, acromegaly), primary hyperparathyroidism, diabetes mellitus (secondary to vascular damage)
What are the causes of primary hyperaldosteronism?
- Conn’s syndrome
- Bilateral adrenal hyperplasia
- Glucocorticoid-Remediable Aldosteronism (GRA)
Describe Conn’s Syndrome
=unilateral adrenal tumour ZG =aldosterone-producing adenoma -Phenotype: =high aldosterone, MR activation =high Na+, low K+, ECF expansion =hypertension, low renin (RAS) -Treatment – surgical (encapsulated, low chance of metastasis, slow growing): =venous sampling and/or CT scan =unilateral adrenalectomy
Describe Bilateral adrenal hyperplasia
=bilateral adrenal hyperplasia =most common form (60-70%) of PA -Phenotype: =high aldosterone, MR activation, =high Na+, low K+, ECF expansion, =hypertension, low renin (RAS) -Treatment – pharmacological: =anti-hypertensives, =e.g. MR anatgonists =spironolactone, eplerenone
Describe Glucocorticoid-Remediable Aldosteronism
=Autosomal dominant genetic disorder (human chromosome 8) =ACTH-driven hyperaldosteronism -Phenotype: =high aldosterone, MR activation, =high Na+, low K+, ECF expansion, =hypertension, low renin (RAS) -Treatment: =suppress pituitary ACTH secretion =synthetic glucocorticoid (Dex)
What genes are involved in GRA?
-Genes for Aldo synthase & 11β-OHase
=95% identity in protein-coding regions, sticky in hydridisation
-BUT gene promoters different:
=Aldo synthase regulated by AII & K+
=11β-OHase regulated by ACTH
-GRA hybrid gene :
=Unequal meiotic exchange
=11β-OHase promoter (ACTH-driven, more active)
=aldo synthase coding region
What are the causes of secondary hyperaldosteronism?
- Renin-secreting JG cell tumour
- Renal arterial stenosis
Describe renin-secreting JG cell tumour
=renin hyper-secretion, ↑RAAS =severe hypertension -Phenotype: =high plasma renin, high aldosterone =MR activation, high Na+, low K+ =ECF expansion, hypertension -Treatment: =surgical removal of tumour
Describe renal arterial stenosis
=low perfusion pressure, renin =secretion, ↑RAAS, hypertension -Phenotype: =high plasma renin, high aldosterone =MR activation, high Na+, low K+, =ECF expansion, hypertension -Treatment: =anti-hypertensive, e.g. MR blockers =statins, anti-platelet agents; =balloon angioplasty +/- stent
How does Cushing’s present?
- weight gain, stretch marks, easy bruising, proximal muscle weakness
- diabetes mellitus (high plasma glucose), menstrual irregularities, depression
Describe the Cushing’s phenotype
- hypertension due to multiple effects of elevated plasma cortisol - …
- high cortisol, high Na+, low K+ (=MR activation?), low renin & low aldosterone
How does elevated plasma cortisol cause hypertension?
- Glucocorticoids inhibit vascular nitric oxide production by eNOS
=increases vasoconstriction, resistance and blood pressure - Glucocorticoids potentiate catecholamine action in heart (B1) and vasculature (A1)
=increases adrenaline activation (increased PNMT), vasoconstriction and cardiac output - Glucocorticoids can inappropriately activate kidney MR (moderate affinity for MR, 11betaHSD2 enzyme usually protects)
What is eNOS involved in?
-Nitric Oxide Synthase converts arginine to NO which with citrulline leads to vasodilation which reduces blood pressure
Why is cortisol binding to MR receptors in excess?
- Increased plasma cortisol exceeds capacity of 11β-HSD2 to convert cortisol to cortisone
- Active cortisol inappropriately activates the kidney MR receptor, doesn’t bind when inactive
- Increases Na+ & water retention causing ECF expansion
What are the causes of glucocorticoid hyperactivity?
- Apparent mineralocorticoid excess
- Drugs and liquorice ingestion
Describe apparent mineralocorticoid excess
=Autosomal recessive ‘loss of function’ mutation in 11β-HSD2 (less active) =↓conversion of cortisol to cortisone -Phenotype: =high local kidney cortisol, low RAS =MR activation, high Na+, low K+ =ECF expansion, hypertension -Treatment – pharmacological: =MR antagonists (spironolactone, eplerenone) =low-Na+ diet & K+ supplements
Describe how drugs and liquorice ingestion leads to glucocorticoid hyperactivity
=carbenoxolone, glycyrrhizinic acid inhibitors of kidney 11β-HSD2 =↓conversion of cortisol to cortisone -Phenotype: =high local kidney cortisol, low RAS =MR activation, high Na+, low K+ =ECF expansion, hypertension -Treatment – environmental: =altered drug treatment =stop eating liquorice!
What are the actions of adrenaline released from the adrenal medulla?
- freeze, fight & flight response
- ↑ heart rate, vasoconstriction, peripheral resistance
- ↑ glucagon secretion, ↓ insulin secretion
- ↑ glycogen & lipid breakdown
What is pheochromocytoma?
- chromaffin cell tumour of adrenal medulla
- secrete catecholamines
- noradrenaline and/or adrenaline
What are the symptoms of pheochromocytoma?
-Palpitations, Headache, Episodic sweating
=racing heart, anxiety (~50%),
=hypertension – sustained/paroxysmal (~50%)
=diabetes mellitus (~40%)
*distinctive but variable symptoms
How is pheochromocytoma diagnosed and treated?
- 24 hour urinary metanephrines & catecholamines
- α-blockers, β-blockers, surgical resection
What recent advances have been made in primary/ essential hypertension?
-Monogenic endocrine hypertension accounts for 10-15% of hypertension
-Majority (85-90%) of hypertensive patients have ‘Essential’ hypertension,
=all cases lacking a single identifiable cause
-BUT: RAAS inhibitors can treat some ‘Essential’ Hypertension patients
=MR receptor antagonists
=Renin inhibitors
=A2 receptor antagonists
=ACE inhibitors
What are the ways to sub-classify primary/ essential hypertension?
- Low plasma renin status
- Aldosterone-Renin Ratio (ARR)
How do we sub-classify patients on low plasma renin status?
-< 20% of hypertensive patients display:
-low plasma renin (= expected feedback),
but inappropriately ‘normal’ or high aldo levels
- are low plasma renin due to high blood pressure? OR ‘excess’ mineralocorticoid feedback?
- suggests altered aldosterone levels may be involved in essential hypertension after all!
How do we sub-classify patients on Aldosterone-Renin Ratio (ARR)?
-<15% of hypertensive patients display:
=inappropriately normal or high plasma aldo & raised ARR
- both renin and aldosterone should be low in hypertension (= expected feedback)
- ARR = mass concentration of aldosterone divided by plasma renin activity (recommended screening tool for primary hyperaldosteronism)
- high ARR = evidence of undiagnosed aldosterone-secreting adenomas … ?
Describe the two-hit model for functional aldosterone-producing microadenomas
- Aldo-producing cell clusters (APCCs): somatic mutations in genes controlling, ZG:
=membrane depolarisation & intracellular Ca2+
=increased AS expression
=uncontrolled aldosterone production - Aldo-producing adenomas (APAs): somatic mutations in genes growth:
=membrane depolarisation & intracellular Ca2+
=increased AS expression
=uncontrolled aldosterone production
=+ cell proliferation & nodule formation
