From the Guidelines
Liddle syndrome causes hypertension through excessive sodium reabsorption in the distal nephron of the kidneys, leading to volume expansion, potassium wasting, and hypertension. This rare genetic disorder results from mutations in the epithelial sodium channel (ENaC) genes, which encode the subunits of the channel, as noted in the context of monogenic forms of hypertension 1. The condition is characterized by suppressed plasma renin activity (PRA) and increased sodium absorption in the distal tubule, with variable clinical presentations that may include serum potassium abnormalities and metabolic acid-base disturbances 1.
Key features of Liddle syndrome include:
- Excessive sodium reabsorption in the distal tubule and collecting duct
- Volume expansion and potassium wasting
- Hypertension with low aldosterone levels (pseudohyperaldosteronism)
- Suppressed plasma renin activity (PRA)
Treatment of Liddle syndrome involves:
- Sodium restriction
- Potassium-sparing diuretics that directly block ENaC, such as amiloride or triamterene
- Avoidance of spironolactone and eplerenone, which are ineffective in this condition due to the lack of involvement of aldosterone. Early diagnosis and treatment are crucial to prevent complications of chronic hypertension, such as cardiovascular disease and stroke, as highlighted in the management of high blood pressure in children and adolescents 1.
From the Research
Mechanism of Hypertension in Liddle Syndrome
- Liddle syndrome is a rare genetic disorder characterized by hypertension, hypokalemia, and metabolic alkalosis, resulting from excessive sodium reabsorption in the distal nephron 2, 3, 4, 5.
- The syndrome is caused by mutations in the genes encoding the α, β, and γ-subunits of the epithelial sodium channel (ENaC), leading to increased expression and activity of the channel 3, 4.
- These mutations typically prevent ubiquitination of the ENaC subunits, slowing their internalization from the membrane and resulting in elevated channel activity 4.
- The increased sodium reabsorption leads to volume expansion, resulting in arterial hypertension 5.
Clinical Presentation and Diagnosis
- The clinical presentation of Liddle syndrome typically includes early-onset hypertension, hypokalemia, metabolic alkalosis, suppressed plasma renin activity, and low plasma aldosterone 3, 6.
- Diagnosis can be confirmed through genetic testing, which identifies mutations in the ENaC genes 3, 4, 6.
- Phenotypic variability can make diagnosis challenging, often resulting in misdiagnosis and severe complications at an early age 5.
Treatment and Management
- Treatment of Liddle syndrome is based on the administration of ENaC blockers, such as amiloride and triamterene, which reduce sodium reabsorption and restore normotension and electrolyte balance 2, 3, 4, 5, 6.
- A reduced sodium diet can also help restore normotension and electrolyte balance in patients with Liddle syndrome 4.