Secondary hypertensive disorders - primary hyperaldosteronism
Description
- Autonomous aldosterone production independent of renin and angiotensin II
- Triad: hypertension + suppressed renin + inappropriately high aldosterone
- *Hypokalaemia is present in only ~30% - a normal potassium does not exclude it*
- The commonest surgically curable cause of hypertension, and the commonest secondary cause overall
Clinical
- Hypertension - often resistant, often early-onset
- Symptoms of hypokalaemia when present: polyuria, nocturia, polydipsia (hypokalaemic nephrogenic DI), cramps, weakness, tetany, arrhythmia
- Metabolic alkalosis; oedema is characteristically absent (aldosterone escape)
- *Aldosterone excess causes cardiovascular and renal damage out of proportion to the blood pressure* - LVH, AF, stroke, MI, albuminuria
Epidemiology
- 5-10% of all hypertension; ~20% of resistant hypertension
- Vastly under-diagnosed - <1-2% of eligible patients are ever screened
- Subtypes
- Bilateral idiopathic adrenal hyperplasia ~60% (not surgically curable)
- Aldosterone-producing adenoma (Conn) ~30% (curable)
- Unilateral hyperplasia ~2%; adrenocortical carcinoma and familial forms rare
- Adenoma: F>M, younger, higher aldosterone, more hypokalaemia. Hyperplasia: older, milder
Aetiopathogenesis
- Somatic mutations in the aldosterone-producing adenoma alter zona glomerulosa membrane potential -> inc intracellular calcium -> CYP11B2 transcription
- KCNJ5 (~40%, commoner in young women and in East Asian populations), CACNA1D, ATP1A1, ATP2B3
- Aldosterone-producing cell clusters are found in normal adrenals and increase with age - the likely substrate for the milder phenotypes now being recognised
Familial forms
| Gene | Feature | |
|---|---|---|
| FH-I (glucocorticoid-remediable) | CYP11B1/CYP11B2 chimeric gene | ACTH-driven aldosterone; early stroke/haemorrhage; *suppressed by dexamethasone* |
| FH-II | CLCN2 | Commonest familial form; indistinguishable clinically |
| FH-III | KCNJ5 germline | Severe, childhood onset, massive hyperplasia |
| FH-IV | CACNA1H | Early onset |
- Test for FH-I if onset <20y, or a family history of primary aldosteronism or haemorrhagic stroke <40y
Physiology
- Aldosterone -> mineralocorticoid receptor in the distal nephron -> inc ENaC and Na/K ATPase
- -> Na retention -> hypertension
- -> K and H secretion -> hypokalaemia + metabolic alkalosis
- Direct, non-epithelial effects on heart, vessels and kidney -> fibrosis, inflammation, remodelling
- *Aldosterone escape: after a few days, natriuretic peptides and pressure natriuresis restore sodium balance - hence hypertension without oedema*
Diagnosis
Who to screen - the 2025 guideline widened this substantially
- *2025 Endocrine Society: offer biochemical screening to all patients with hypertension***
- A major change from the old restricted list. In practice, prioritise
- Resistant hypertension (uncontrolled on 3 agents including a diuretic)
- Hypertension + spontaneous or diuretic-induced hypokalaemia
- Hypertension + adrenal incidentaloma
- Hypertension + OSA, or AF, or LVH out of proportion
- Hypertension <40y, or family history of early hypertension or stroke <40y
- First-degree relative of a patient with primary aldosteronism
- A major change from the old restricted list. In practice, prioritise
Screening test
- Aldosterone:renin ratio (ARR), morning, seated for 15 min after 2h upright
- Suspicious: ARR raised with a suppressed renin AND an aldosterone that is not low
- An elevated ratio driven entirely by a very low renin, with a low aldosterone, is not primary aldosteronism
- Correct hypokalaemia first - hypokalaemia suppresses aldosterone and causes false negatives
- Do not sodium-restrict
- Suspicious: ARR raised with a suppressed renin AND an aldosterone that is not low
Drug interference - the practical trap
| Cause false negatives (dec ratio) | Cause false positives (inc ratio) |
|---|---|
| MRA (spironolactone, eplerenone), amiloride | Beta blockers |
| ACEi, ARB, direct renin inhibitor | Clonidine, methyldopa (central alpha-2 agonists) |
| Diuretics (K-wasting and K-sparing) | NSAIDs |
| Dihydropyridine CCB | High sodium intake, renal impairment, older age |
| Hypokalaemia, sodium restriction, pregnancy, renovascular/malignant hypertension |
- Safe agents for BP control during workup: verapamil SR, hydralazine, prazosin/doxazosin, moxonidine
- Cease MRAs for 4-6 weeks; other agents for ~2 weeks where safe
- If the patient cannot come off drugs, an ARR that is positive despite an ACEi/ARB is still meaningful; a negative one on those drugs is not
Confirmation
- *2025 guideline: confirmatory testing is no longer mandatory*
- Diagnosis can rest on the biochemical triad - suppressed renin + elevated aldosterone + elevated ARR
- Rationale: the saline infusion test has a high false-negative rate, and the confirmed-negative group still had disease
- Where confirmation is still used (equivocal results, before committing to surgery)
- Seated saline infusion test - 2 L 0.9% saline over 4h; failure of aldosterone to suppress confirms autonomy
- Oral sodium loading (~200 mmol/day x3 days with 24h urine aldosterone and sodium), fludrocortisone suppression, captopril challenge
Subtyping - only if the patient would accept surgery
- Adrenal CT first (also excludes carcinoma), then
- *Adrenal vein sampling is the reference standard for lateralisation*
- CT alone misleads: non-functioning incidentalomas are common, and micro-adenomas are invisible
- Exception: age <35 with marked hypokalaemia, florid biochemistry and a clear unilateral adenoma on CT - may proceed straight to surgery
- 11C-metomidate or 68Ga-pentixafor PET as an emerging non-invasive alternative
- The 2025 broadened criteria detect milder phenotypes with intermediate lateralisation - these are less likely to benefit from AVS and surgery
Management
Unilateral disease (adenoma or unilateral hyperplasia)
- Laparoscopic unilateral adrenalectomy
- Hypokalaemia corrected in ~100%; hypertension cured in ~35-50%, improved in nearly all
- Predictors of cure: young, female, short duration, few antihypertensives, no family history
- Post-operative: stop the MRA, stop potassium supplements, monitor for hyperkalaemia (the contralateral zona glomerulosa is suppressed - transient hypoaldosteronism)
Bilateral disease, or unfit/unwilling for surgery
- Mineralocorticoid receptor antagonist
- Spironolactone first line - 12.5-25 mg starting, up to 100 mg daily
- Gynaecomastia, breast tenderness, erectile dysfunction, menstrual irregularity - dose-dependent, the main reason for switching
- Eplerenone if intolerant - more selective, fewer antiandrogenic effects, shorter half-life so twice daily and less potent
- Amiloride as an alternative (blocks ENaC directly)
- Monitor potassium and creatinine at 1 week, 1 month, then regularly
- Spironolactone first line - 12.5-25 mg starting, up to 100 mg daily
- *Titrate to a renin that is no longer suppressed - not just to blood pressure. An unsuppressed renin indicates the mineralocorticoid receptor is adequately blocked and the cardiovascular risk is being addressed*
- Add other antihypertensives as needed; salt restriction
Familial hyperaldosteronism type I
- *Low-dose dexamethasone or prednisolone* - suppresses the ACTH drive
- MRA if incompletely controlled
Associations
- Obstructive sleep apnoea - bidirectional; aldosterone-driven fluid shift worsens upper airway collapse
- Atrial fibrillation - independent of blood pressure
- Left ventricular hypertrophy, diastolic dysfunction, heart failure
- CKD and albuminuria - may worsen apparently after treatment, unmasking the loss of hyperfiltration
- Metabolic syndrome, osteoporosis, anxiety and reduced quality of life
- Adrenal incidentaloma
- Differential of hypertension with hypokalaemia: Cushing syndrome, 11beta- and 17alpha-hydroxylase CAH, apparent mineralocorticoid excess (11beta-HSD2 deficiency; liquorice), Liddle syndrome (ENaC, low aldosterone AND low renin), renin-secreting tumour, renovascular disease
Natural history & complications
- Untreated -> excess cardiovascular events over and above matched essential hypertension: stroke ~2-4x, MI, AF, heart failure, CKD
- This is the argument for finding it - the blood pressure alone understates the harm
- Targeted treatment (surgery or MRA titrated to renin) reduces that excess to that of essential hypertension
- MRA at a token dose with a still-suppressed renin does not**
- Long-standing disease -> irreversible nephrosclerosis and vascular remodelling -> hypertension persists after cure
- Adrenocortical carcinoma as a cause is rare but should be suspected with a large mass and mixed steroid secretion
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