Workup for Liddle Syndrome
The diagnostic workup for Liddle syndrome should include biochemical testing for hypokalemia, metabolic alkalosis, and suppressed renin and aldosterone levels, followed by genetic testing for mutations in the epithelial sodium channel (ENaC) genes SCNN1B and SCNN1G. 1, 2
Initial Clinical Assessment
- Clinical suspicion should arise in patients with:
- Early-onset hypertension (before age 30)
- Family history of early-onset hypertension
- Resistant hypertension
- Hypokalemia
- Metabolic alkalosis
- Poor response to standard antihypertensive medications 2
Laboratory Investigations
First-line Testing
- Serum electrolytes (looking for hypokalemia)
- Arterial blood gas (to detect metabolic alkalosis)
- Plasma renin activity (typically suppressed)
- Plasma aldosterone concentration (typically suppressed)
- Urinary potassium (elevated, indicating renal potassium wasting) 1, 2
Key Diagnostic Pattern
- Hypokalemia with metabolic alkalosis
- Low plasma renin activity
- Low plasma aldosterone levels
- Elevated urinary potassium excretion despite hypokalemia 3
Genetic Testing
- Genetic testing is the definitive diagnostic method and should be performed when biochemical findings suggest Liddle syndrome 2
- Testing should focus on:
- Specific mutations to look for include those affecting the PY motif in the C-terminus of these subunits, which lead to increased ENaC activity 4
Differential Diagnosis Considerations
- Primary aldosteronism
- Apparent mineralocorticoid excess (AME)
- Glucocorticoid-remediable aldosteronism
- Congenital adrenal hyperplasia
- Exogenous mineralocorticoid intake 1
Therapeutic Trial as Diagnostic Tool
- Response to specific treatment can support diagnosis:
- Marked improvement with potassium-sparing diuretics that directly block ENaC (amiloride, triamterene)
- Poor response to spironolactone (which acts via the mineralocorticoid receptor) 5
Family Screening
- Once a genetic diagnosis is confirmed, screening of first-degree relatives is recommended, even if they are normotensive 2, 6
- Family screening should include:
- Blood pressure measurement
- Serum potassium
- Plasma renin and aldosterone levels
- Genetic testing for the identified mutation 6
Important Clinical Pearls
- Hypoaldosteronism appears to be the most sensitive marker for Liddle syndrome in Caucasian populations, with reported sensitivity of up to 96% 3
- The phenotypic expression can be variable, with some mutation carriers showing only mild hypertension without hypokalemia 6
- Early diagnosis is critical to prevent end-organ damage from prolonged hypertension 7
- Liddle syndrome is likely underdiagnosed due to variable clinical presentation and lack of routine genetic testing in hypertensive patients 3
By following this systematic approach to diagnosis, clinicians can identify this rare but treatable cause of secondary hypertension and provide targeted therapy to affected individuals.