Process of hormonal regulation - aldosterone and its link to the endocrine system
Aldosterone and its action
- Mineralocorticoid from the adrenal zona glomerulosa - the final effector of the renin-angiotensin system
- Acts on the mineralocorticoid receptor in the principal cell of the distal nephron and collecting duct
- inc ENaC and inc Na-K ATPase -> Na+ and water reabsorption, K+ and H+ secretion
- Net: volume expansion, hypokalaemia, metabolic alkalosis, hypertension
- Also expressed in heart, vasculature, kidney and adipose tissue - where it drives inflammation and fibrosis independent of blood pressure
The three stimuli for aldosterone release
- 1. Angiotensin II (the main one)
- 2. Hyperkalaemia - a direct effect, independent of renin
- 3. ACTH (minor and transient)
Epidemiology
- Primary aldosteronism is the commonest secondary cause of hypertension: ~5-10% of all hypertension, and up to 20% of resistant hypertension
- *Massively under-diagnosed* - most guidelines now recommend far wider screening
- Adrenal insufficiency: ~5 per 100,000; aldosterone deficiency is what makes primary (Addison) disease hyperkalaemic and hypotensive, unlike secondary
Why cortisol does not act as a mineralocorticoid
- Cortisol binds the mineralocorticoid receptor with equal affinity to aldosterone, and circulates at ~1000x the concentration
- 11-beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) in the distal nephron converts cortisol -> cortisone, which does not bind the receptor
- *Anything that overwhelms or inhibits 11beta-HSD2 produces apparent mineralocorticoid excess*
- Liquorice (glycyrrhetinic acid), carbenoxolone
- Ectopic ACTH syndrome - cortisol swamps the enzyme; hence the profound hypokalaemic alkalosis
- Congenital 11beta-HSD2 deficiency (apparent mineralocorticoid excess syndrome)
States of aldosterone excess and deficiency
| Renin | Aldosterone | K+ | BP | |
|---|---|---|---|---|
| Primary aldosteronism | dec | inc | dec or normal | inc |
| Secondary hyperaldosteronism | inc | inc | dec | inc (RAS) or normal/low (Bartter, Gitelman, cirrhosis, HF) |
| Liddle syndrome (ENaC gain of function) | dec | dec | dec | inc |
| Apparent mineralocorticoid excess | dec | dec | dec | inc |
| Primary adrenal insufficiency | inc | dec | inc | dec |
| Type 4 RTA (hyporeninaemic hypoaldosteronism) | dec | dec | inc | normal/inc |
- Primary aldosteronism: bilateral adrenal hyperplasia (~60-70%), aldosterone-producing adenoma (Conn, ~30-35%), rare familial forms (GRA/familial hyperaldosteronism type 1 - dexamethasone-suppressible), adrenal carcinoma
- *Normokalaemia does NOT exclude primary aldosteronism* - only ~30% are hypokalaemic
Screen for primary aldosteronism in
Screen for primary aldosteronism in
- Resistant hypertension (uncontrolled on 3 agents including a diuretic)
- Hypertension with hypokalaemia (spontaneous or diuretic-induced)
- Hypertension with an adrenal incidentaloma
- Hypertension with sleep apnoea, AF, or a family history of early stroke or hypertension
- Hypertension before age 40, or any severe hypertension (>150/100)
Step 1 - Aldosterone-to-renin ratio (ARR)
- Morning sample, seated for 5-15 min after 2 h upright
- Correct hypokalaemia first - hypokalaemia suppresses aldosterone and causes false negatives
- Liberal salt intake before testing
Drug interference - the classic exam point
- FALSE POSITIVE: beta blockers (also clonidine, methyldopa, NSAIDs)
- They suppress renin more than aldosterone, so the ratio rises artificially
- FALSE NEGATIVE: ACE inhibitors, ARBs, diuretics (especially MRAs), dihydropyridine calcium channel blockers
- These raise renin
- Withdraw where clinically safe: MRAs and amiloride for 4-6 weeks, others for 2 weeks
- ARR-neutral substitutes: verapamil slow-release, prazosin, hydralazine, moxonidine
- An unequivocally suppressed renin with a high aldosterone on a beta blocker is still worth pursuing
Step 2 - Confirmatory testing
- Saline suppression test, fludrocortisone suppression test, oral salt loading, or captopril challenge
- May be omitted if: spontaneous hypokalaemia + undetectable renin + aldosterone >550 pmol/L
Step 3 - Subtype and lateralise
- Adrenal CT (thin-slice) - but CT misses small adenomas and finds non-functioning nodules
- Adrenal vein sampling is the gold standard for lateralisation - required before surgery in almost everyone over 35
- Under 35 with spontaneous hypokalaemia and a clear unilateral adenoma may proceed without it
- Genetic testing for familial forms if young or a strong family history
Primary aldosteronism - management
Primary aldosteronism
- Unilateral (adenoma, unilateral hyperplasia) -> laparoscopic adrenalectomy
- Cures hypertension in ~35-50%, improves it in most; corrects the hypokalaemia in nearly all
- Watch for post-operative hyperkalaemia - the contralateral gland is suppressed
- Bilateral hyperplasia -> mineralocorticoid receptor antagonist
- Spironolactone (gynaecomastia, breast tenderness, menstrual irregularity, erectile dysfunction - dose-related)
- Eplerenone if intolerant (more selective, shorter acting, twice daily, less potent)
- Amiloride as an alternative
- Titrate to normalise renin (not just BP) - unsuppressed renin indicates adequate blockade
- Glucocorticoid-remediable aldosteronism -> low-dose dexamethasone
- *Treating aldosterone excess reduces cardiovascular and renal events beyond the blood pressure effect* - AF, stroke, heart failure, LVH and CKD progression are all excess in untreated primary aldosteronism
Aldosterone blockade in other diseases
- Heart failure - MRA now Class I across the ejection fraction spectrum (ESC 2026)
- Diabetic CKD - finerenone added to a RASi and SGLT2i; less hyperkalaemia and no anti-androgenic effects
- Resistant hypertension - spironolactone is the best fourth-line agent (PATHWAY-2)
- Cirrhosis with ascites - spironolactone (+/- frusemide) is first-line, because the ascites is aldosterone-driven
Monitoring on an MRA
- K+ and creatinine at 1 and 4 weeks, then periodically; more often in CKD, diabetes or on a RASi
- Avoid or use with great care if eGFR <30
Aldosterone deficiency
- Primary adrenal insufficiency -> fludrocortisone in addition to hydrocortisone (not needed in secondary adrenal insufficiency - the RAS is intact)
- Type 4 RTA -> low-potassium diet, loop diuretic, sodium bicarbonate, potassium binder; fludrocortisone if truly hypoaldosteronic
Associations
- Resistant hypertension, hypokalaemia, metabolic alkalosis
- Atrial fibrillation, LVH, heart failure, stroke, CKD - excess in primary aldosteronism beyond the BP effect
- Obstructive sleep apnoea - bidirectional association
- Adrenal incidentaloma
- Liquorice ingestion, ectopic ACTH syndrome, Cushing syndrome - apparent mineralocorticoid excess
- Liddle syndrome, Bartter and Gitelman syndromes, congenital adrenal hyperplasia (11-beta and 17-alpha hydroxylase deficiency)
- Addison disease - aldosterone deficiency gives the hyperkalaemia, hyponatraemia and postural hypotension
- Heparin (inhibits aldosterone synthesis -> hyperkalaemia)
Consequences of untreated excess
- Untreated primary aldosteronism causes target organ damage disproportionate to the blood pressure - LVH, atrial fibrillation, stroke, heart failure, albuminuria and CKD
- Adrenalectomy for unilateral disease reverses much of this; medical therapy is effective if it achieves true mineralocorticoid receptor blockade (unsuppressed renin)
- *Under-treatment is common because clinicians use sub-therapeutic MRA doses and never check renin*
- Aldosterone escape - aldosterone rises back toward baseline after months on an ACEi/ARB, which is why MRAs add benefit
- Primary aldosteronism unmasks CKD after treatment: the hyperfiltration falls and eGFR drops - expected, not a complication
- Monitor: BP, K+, renin, eGFR, albuminuria; echocardiogram if LVH; screen for AF
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