Liddle Syndrome: Clinical Presentation
Classic Presentation
Liddle syndrome presents with early-onset hypertension, hypokalemia, metabolic alkalosis, and the pathognomonic finding of suppressed plasma renin activity with suppressed (not elevated) aldosterone levels—distinguishing it from primary aldosteronism. 1, 2, 3
Key Clinical Features
- Early-onset severe hypertension typically manifesting in childhood or adolescence, though diagnosis may be delayed into adulthood 1, 4, 5
- Hypokalemia with increased urinary potassium excretion (hyperkaliuria), though this is not universally present 1, 4, 3
- Metabolic alkalosis from excessive renal potassium loss 4, 3
- Suppressed plasma renin activity AND suppressed aldosterone levels—this dual suppression is the critical diagnostic clue that differentiates Liddle syndrome from primary aldosteronism 2, 3, 5
Important Diagnostic Pitfall
The most common misdiagnosis is primary aldosteronism, which occurs when clinicians fail to measure aldosterone levels and assume hyperaldosteronism based on the clinical picture of hypertension with hypokalemia. 2 In primary aldosteronism, aldosterone is elevated with suppressed renin (high aldosterone-to-renin ratio ≥30 with aldosterone ≥10 ng/dL) 6, whereas in Liddle syndrome, BOTH renin and aldosterone are suppressed 2, 3, 5.
Variable Phenotypic Expression
Age at Presentation
- First manifestations can occur as early as 6 months (presenting with dehydration and hypokalemia) 4
- More commonly presents between ages 2-17 years with hypertension discovery 1, 4
- Some cases remain undiagnosed until adulthood (reported case at age 48) 3
- Family members carrying the same mutation demonstrate marked heterogeneity in age of presentation and disease severity 1
Clinical Manifestations Beyond Hypertension
- Palpitations and cardiac arrhythmias from severe hypokalemia, particularly atrial fibrillation 4, 3
- Polydipsia with poor growth parameters in pediatric cases 4
- Muscle weakness and cramps from chronic hypokalemia 3
- Nephrocalcinosis and hypercalciuria reported in approximately 50% of cases 4
- Progressive renal failure can develop from chronic hypertensive nephropathy if diagnosis is delayed 4
Biochemical Findings
- Hypokalemia is NOT consistently present—the classical triad of hypertension, hypokalemia, and metabolic alkalosis may be incomplete 1
- Plasma renin activity is consistently suppressed 2, 3, 5
- Aldosterone levels are low or low-normal, NOT elevated 2, 3, 5
- 18-hydroxycorticosterone and deoxycortisol may be subnormal 5
Distinguishing from Other Causes of Hypertension with Hypokalemia
Critical Laboratory Pattern
When evaluating hypertension with hypokalemia, the aldosterone and renin pattern determines the diagnosis 6:
- Primary aldosteronism: High aldosterone (≥10 ng/dL), suppressed renin, ARR ≥30 6
- Liddle syndrome: Low aldosterone, suppressed renin 2, 3, 5
- Cushing syndrome: Low aldosterone and renin, with clinical features of hypercortisolism 6
- Congenital adrenal hyperplasia (11β-hydroxylase or 17α-hydroxylase deficiency): Low aldosterone and renin, elevated deoxycorticosterone 6
Response to Treatment
Failure to respond to aldosterone receptor antagonists (spironolactone) strongly suggests Liddle syndrome rather than primary aldosteronism. 2 This therapeutic failure should prompt genetic testing, as Liddle syndrome requires epithelial sodium channel blockers (amiloride or triamterene), not mineralocorticoid receptor antagonists 4, 2, 3.
Definitive Diagnosis
Genetic testing demonstrating mutations in SCNN1B (beta-subunit) or SCNN1G (gamma-subunit) of the epithelial sodium channel is the gold standard for diagnosis. 1, 2, 5 These mutations cause frameshift or missense changes in the carboxyl-terminus of the channel subunits, leading to constitutive sodium channel activation 5.
Treatment Response
Successful treatment requires amiloride or triamterene combined with sodium restriction—NOT spironolactone or other aldosterone antagonists 4, 2, 3. Blood pressure and potassium levels normalize within weeks of appropriate therapy 2. In one reported case, kidney transplantation completely resolved hypertension and hypokalemia, confirming the tubular origin of the disease 4.
Clinical Implications
Liddle syndrome should be suspected in any patient with early-onset hypertension resistant to conventional treatment, particularly with a strong family history, even in the absence of hypokalemia. 1 The autosomal dominant inheritance pattern means 50% of offspring are affected, making family screening essential once a diagnosis is established 5. Early diagnosis and precise treatment with epithelial sodium channel blockers prevent severe cardiovascular and renal complications of chronic uncontrolled hypertension 2.