Familial Hyperaldosteronism

Familial hyperaldosteronism is an inherited form of primary aldosteronism with autonomous aldosterone production, suppressed renin, hypertension and often hypokalaemia.

Four types are described. Type I (glucocorticoid remediable) is a chimeric CYP11B1/CYP11B2 gene. Type II is linked to CLCN2 variants and to the CYP11B2 locus. Type III is due to KCNJ5 variants. Type IV is due to CACNA1H variants. CACNA1D variants cause a related syndrome with neurological features.

Familial forms are under 5% of primary aldosteronism, and type I under 1%. Early onset hypertension (under 20 years), a family history of primary aldosteronism or stroke at a young age should raise suspicion.

Pathophysiology.

In type I the chimeric gene puts aldosterone synthase under ACTH control, so aldosterone is driven by ACTH rather than angiotensin II and is suppressed by glucocorticoid.

In the other types, altered ion channel function depolarises zona glomerulosa cells and raises intracellular calcium, driving aldosterone synthesis and cell proliferation (hyperplasia, severe in type III).

• Hypertension, often severe and early, with or without hypokalaemia, weakness, polyuria and cramps.
• Type I: haemorrhagic stroke or cerebral aneurysm rupture at a young age.
• Type III: massive bilateral adrenal hyperplasia with severe hypokalaemia in childhood.

Red flags.

• Severe hypertension in a child or young adult.
• Cerebral aneurysm, subarachnoid haemorrhage or stroke in a family member.

• Screen with plasma aldosterone to renin ratio (aldosterone raised, renin suppressed) while normokalaemic and off interfering drugs. Confirm with an aldosterone suppression test (saline infusion or captopril test) in adults.
• Type I: genetic testing for the chimeric gene (long range PCR). Urinary 18-hydroxycortisol and 18-oxocortisol are raised. Dexamethasone suppression test lowers aldosterone.
• Types II to IV: sequencing of CLCN2, KCNJ5 and CACNA1H. Adrenal vein sampling is not diagnostic in familial disease, and type III hyperplasia is bilateral.
• Cross-sectional adrenal imaging. MR angiography of the head in type I.
• Screen first degree relatives.

Differential diagnosis.

• Sporadic aldosterone producing adenoma and bilateral adrenal hyperplasia.
• Liddle syndrome, apparent mineralocorticoid excess and congenital adrenal hyperplasia (11-beta hydroxylase and 17-alpha hydroxylase deficiency).
• Renovascular hypertension and Cushing syndrome.

• Type I: the lowest dose of glucocorticoid that normalises blood pressure and renin: dexamethasone 0.125 to 0.25 mg at night, or prednisolone 2.5 to 5 mg daily (children: hydrocortisone 12 to 15 mg/m2 daily). Add a mineralocorticoid receptor antagonist if blood pressure is not controlled.
• Mineralocorticoid receptor antagonists (types II to IV): spironolactone 12.5 to 25 mg daily, titrated every 4 weeks to 100 mg daily (up to 400 mg in resistant disease), or eplerenone 25 to 50 mg twice daily. Amiloride 5 to 20 mg daily is an alternative. Monitor potassium and eGFR.
• Spironolactone causes gynaecomastia, menstrual disturbance and hyperkalaemia. Avoid with other potassium sparing drugs in kidney impairment.
• Type III with massive hyperplasia and uncontrolled disease: bilateral adrenalectomy with lifelong hydrocortisone and fludrocortisone.
• Add other antihypertensive drugs as needed, and treat other vascular risks.

Special groups. Pregnancy: spironolactone is avoided; use labetalol, nifedipine or methyldopa and take specialist advice. Children: manage in a paediatric endocrine team.

Monitoring. Blood pressure, potassium, renin and eGFR every 3 to 6 months. Intracranial imaging in type I every 5 years from 10 years, or as directed by earlier findings.

Referral and escalation. Endocrinology and clinical genetics for all patients; hypertension specialist for resistant disease.