Liddle Syndrome

A 16 year old male presents to the cardiology clinic with persistent hypertension noted during a school health checkup. He has no significant past medical history. He reports muscle cramps and weakness. Vital signs show blood pressure of 160/100 mm Hg. Laboratory studies show normal serum sodium, hypokalemia, low plasma renin activity, and low plasma aldosterone. Genetic testing reveals a mutation in the beta subunit of the epithelial sodium channel. Diagnosis?

Diagnosis is Liddle syndrome.

1. Definition

Liddle syndrome is a rare autosomal dominant disorder caused by a gain of function mutation in ENaC, leading to pseudohyperaldosteronism and early onset hypertension.

2. Pathophysiology

1. Mutation in alpha, beta, or gamma subunits of ENaC
2. Impaired binding of Nedd4-2 ubiquitin ligase
3. Reduced ENaC degradation
4. Increased ENaC expression at the apical membrane
5. Increased sodium reabsorption leading to extracellular volume expansion
6. Suppression of renin and aldosterone
7. Increased potassium and hydrogen ion excretion
8. Results in hypokalemia and metabolic alkalosis

3. Clinical Features

1. Early onset or resistant hypertension
2. Hypokalemia causing muscle weakness and cramps
3. Metabolic alkalosis
4. Usually no edema despite volume expansion
5. May be asymptomatic or incidentally detected

4. Diagnosis

1. Hypertension with hypokalemia
2. Low renin and low aldosterone
3. Normal adrenal imaging
4. Genetic confirmation of ENaC mutation

5. Differential Diagnosis

1. Primary hyperaldosteronism
2. Apparent mineralocorticoid excess
3. Congenital adrenal hyperplasia
4. Gordon syndrome, which presents with hyperkalemia

6. Management

1. Amiloride or triamterene are first line therapies
2. Low sodium diet enhances treatment response
3. Spironolactone is ineffective due to low aldosterone
4. Additional antihypertensives may be used if needed

7. Complications

1. Arrhythmias due to hypokalemia
2. Cardiovascular complications such as left ventricular hypertrophy, stroke, and heart failure
3. Chronic kidney disease if untreated

8. Key Clinical Insight

Young patient with hypertension, hypokalemia, low renin, and low aldosterone strongly suggests Liddle syndrome, a form of pseudohyperaldosteronism due to ENaC overactivity

9. Exam Level Pearls

1. Low renin and low aldosterone is the key distinguishing feature
2. Mimics hyperaldosteronism but aldosterone is suppressed
3. ENaC gain of function causes sodium retention independent of aldosterone
4. Amiloride is the treatment of choice
5. Spironolactone does not work in Liddle syndrome