Hypoaldosteronism

Hypoaldosteronism is deficient production or action of aldosterone. It causes salt wasting, hyperkalaemia and a normal anion gap metabolic acidosis (type 4 renal tubular acidosis). It is common in people over 60 years with diabetes and chronic kidney disease, and primary adrenal insufficiency affects about 1 in 10 000 people.

Aldosterone from the zona glomerulosa acts on the principal cells of the distal nephron. It increases sodium reabsorption through the epithelial sodium channel and drives potassium and hydrogen ion secretion.

Causes are:

• Low renin states (diabetic nephropathy, chronic tubulointerstitial disease, NSAIDs, calcineurin inhibitors).
• Drugs that block the renin angiotensin system or aldosterone (ACE inhibitors, angiotensin receptor blockers, spironolactone, eplerenone, finerenone).
• Heparin, which suppresses aldosterone synthesis within days.
• Trimethoprim and pentamidine, which block the sodium channel.
• Adrenal destruction (autoimmune adrenalitis, tuberculosis, haemorrhage, metastases, HIV related infections).
• Congenital enzyme defects (21-hydroxylase deficiency in salt wasting form, aldosterone synthase deficiency from CYP11B2 variants).
• Critical illness.

Pathophysiology. Reduced aldosterone effect lowers sodium reabsorption and potassium and hydrogen ion secretion. This causes volume depletion, hyperkalaemia and acidosis. Hyperkalaemia further suppresses ammonium excretion, and aldosterone effect is lost in a cycle.

• Often asymptomatic and found on blood tests: potassium 5.5 to 7.0 mmol/L, bicarbonate 15 to 20 mmol/L, mild to moderate reduction in eGFR.
• Muscle weakness, palpitations, paralysis, bradycardia, conduction block.
• Postural hypotension, salt craving, weight loss, dehydration.
• Adrenal insufficiency: fatigue, anorexia, hyperpigmentation (primary), hypoglycaemia, abdominal pain, vomiting, hyponatraemia, shock in adrenal crisis.
• Neonates with enzyme defects: vomiting, failure to thrive, dehydration, ambiguous genitalia (21-hydroxylase deficiency in girls).

Red flags

• Potassium over 6.5 mmol/L or ECG changes (peaked T waves, wide QRS, loss of P waves).
• Hypotension with hyponatraemia, hypoglycaemia or hyperpigmentation (adrenal crisis).
• Newly started ACE inhibitor, angiotensin receptor blocker, trimethoprim, heparin or potassium sparing diuretic with hyperkalaemia.
• Neonatal vomiting and dehydration.

• Potassium (repeat on a non-haemolysed sample), sodium, bicarbonate, chloride, urea, creatinine, eGFR, glucose, venous blood gas, ECG.
• Plasma renin and aldosterone (seated, after 2 hours upright; withhold interfering drugs where safe).
• High renin with low aldosterone suggests adrenal disease or enzyme defect. Low renin with low aldosterone suggests hyporeninaemic hypoaldosteronism or drugs. High renin with high aldosterone suggests aldosterone resistance.
• Early morning cortisol: under 100 nmol/L suggests adrenal insufficiency; over 400 nmol/L excludes it.
• Short synacthen test: cortisol under 420 to 500 nmol/L at 30 minutes with 250 microg tetracosactide confirms failure. Also check ACTH and 21-hydroxylase antibodies.
• Urine potassium, sodium and chloride.
• Transtubular potassium gradient: under 6 to 7 with hyperkalaemia suggests aldosterone deficiency or resistance.
• Urine pH (under 5.5 despite acidosis); urine anion gap.
• Imaging of adrenals (CT) when adrenal disease is suspected; genetic testing (CYP21A2, CYP11B2) in infants.

Differential diagnosis

• Other causes of hyperkalaemia with acidosis: acute kidney injury and advanced chronic kidney disease, pseudohypoaldosteronism, Gordon syndrome, drug effects, tubulointerstitial disease, rhabdomyolysis, tumour lysis, redistribution (insulin deficiency), pseudohyperkalaemia.

Emergency: hyperkalaemia with ECG changes or potassium over 6.5 mmol/L

• Calcium gluconate 10% 10 mL intravenously over 10 minutes (repeat after 10 minutes if ECG changes persist).
• Insulin 10 units with glucose 25 g intravenously (check glucose hourly for 6 hours).
• Salbutamol 10 to 20 mg nebulised.
• Sodium zirconium cyclosilicate 10 g three times daily for up to 48 hours, then 5 to 10 g daily (maximum 15 g).
• Dialysis when potassium remains over 6.5 mmol/L despite these measures, or with oliguria or acidosis (pH under 7.15).

Adrenal crisis

• Hydrocortisone 100 mg intravenously at once, then 200 mg over 24 hours by continuous infusion (or 50 mg intravenously every 6 hours).
• 0.9% sodium chloride 1 litre over 1 hour then as needed, with 10% glucose when hypoglycaemic.
• Treat the precipitant (infection).

Long term replacement

• Primary adrenal insufficiency: hydrocortisone 15 to 25 mg daily in 2 or 3 divided doses (largest dose on waking).
• Add fludrocortisone 0.05 to 0.2 mg once daily. Adjust to blood pressure (no postural drop), potassium (under 5.0 mmol/L), sodium and plasma renin in the upper normal range. Stop if hypertension or oedema develops.
• Sick day rules: double the hydrocortisone dose for fever over 38 degrees Celsius and treble for fever over 39 degrees Celsius; hydrocortisone 100 mg intramuscularly for vomiting; steroid alert card.
• Isolated hypoaldosteronism without adrenal disease: fludrocortisone 0.05 to 0.1 mg daily (increase to 0.2 mg), and sodium chloride 6 to 10 g daily if not hypertensive.
• Add a loop diuretic (furosemide 40 to 80 mg once or twice daily) for hyperkalaemia and oedema. Add sodium bicarbonate 500 mg to 1 g two to three times daily to bicarbonate at least 22 mmol/L.
• Dietary potassium 50 to 70 mmol (2 to 2.7 g) daily when potassium is over 5.5 mmol/L.
• Stop or reduce ACE inhibitors, angiotensin receptor blockers, mineralocorticoid antagonists, trimethoprim, NSAIDs and heparin where possible.
• Chronic hyperkalaemia: sodium zirconium cyclosilicate 5 to 10 g daily (maximum 15 g), allowing continuation of renoprotective drugs; ramipril 2.5 to 10 mg daily with potassium checked at 1 to 2 weeks.

Monitoring. Potassium, sodium, bicarbonate and creatinine every 1 to 2 weeks until stable, then every 3 months. Blood pressure sitting and standing. Annual renin and plasma glucose in adrenal insufficiency. Bone density.

Referral and escalation. Endocrinology for adrenal disease; nephrology for kidney disease; paediatric endocrinology for enzyme defects. Refer urgently for potassium over 6.5 mmol/L, ECG changes or adrenal crisis.

Special groups

• Pregnancy: continue hydrocortisone with increased dose in the third trimester (add 5 to 10 mg) and fludrocortisone; avoid mineralocorticoid antagonists.
• Children: salt wasting congenital adrenal hyperplasia needs hydrocortisone 10 to 15 mg/m² daily in 3 divided doses, fludrocortisone 0.05 to 0.2 mg daily and sodium chloride 1 to 2 g daily in infancy.
• Older adults: low renin states with diabetes and chronic kidney disease are common; review drugs before adding fludrocortisone.