Liddle Syndrome

Liddle syndrome is an autosomal dominant disorder of gain-of-function variants in SCNN1B or SCNN1G (rarely SCNN1A), encoding subunits of the epithelial sodium channel (ENaC) in the collecting duct, causing unregulated sodium reabsorption.

• Very rare; early-onset hypertension, hypokalaemia, metabolic alkalosis, and suppressed renin and aldosterone ("pseudohyperaldosteronism").
• Variants disrupt PY motifs in the C terminus, preventing Nedd4-2 ubiquitination and ENaC degradation.
• Onset in childhood or early adulthood; family history of early hypertension and strokes.
• Complications: severe hypertension, stroke, left ventricular hypertrophy, early cardiovascular death, kidney damage.

• Severe, early-onset, treatment-resistant hypertension (before age 35).
• Muscle weakness, fatigue, polyuria, cramps from hypokalaemia (may be normokalaemic in some).
• Family history of premature hypertension, stroke, early cardiovascular death.
• Normal or low renin; no oedema.

• Hypertension with hypokalaemia, metabolic alkalosis, low plasma renin activity, low aldosterone (separates from primary aldosteronism with high aldosterone).
• Urinary potassium wasting, low urinary aldosterone excretion.
• Exclude other forms: apparent mineralocorticoid excess (high cortisol:cortisone ratio, HSD11B2), glucocorticoid-remediable aldosteronism, congenital adrenal hyperplasia (11-beta hydroxylase, 17-alpha hydroxylase deficiency), Cushing syndrome, liquorice ingestion, exogenous mineralocorticoids.
• Genetic testing: SCNN1A, SCNN1B, SCNN1G.
• Spironolactone does not correct the abnormalities (differentiates from primary aldosteronism).
• Evaluate end-organ damage: ECG, echocardiography, fundoscopy, renal function.

• ENaC blockers are specific therapy: amiloride 5 to 20 mg daily (up to 40 mg) in divided doses or triamterene 100 to 300 mg daily; correct hypertension and hypokalaemia within days.
• Low sodium diet (under 2 g/day) enhances efficacy.
• Avoid spironolactone as monotherapy (ineffective), and avoid thiazides or loop diuretics (worsen hypokalaemia).
• Monitor potassium, creatinine (amiloride can cause hyperkalaemia, particularly with ACE inhibitors or renal impairment); target potassium 4.0 to 5.0 mmol/L.
• Add other antihypertensives if necessary (calcium channel blockers).
• Pregnancy: amiloride is used cautiously; labetalol and nifedipine alternatives.
• Family screening and genetic counselling; treat affected relatives early to prevent cardiovascular damage.
• Annual review of blood pressure, electrolytes, left ventricular mass.