Liddle's syndrome

Overview

Liddle's syndrome is a rare, inherited form of hypertension (high blood pressure) characterized by early-onset, often severe, high blood pressure and low levels of potassium in the blood (hypokalemia). It mimics hyperaldosteronism (increased aldosterone activity) but occurs in the absence of elevated aldosterone levels, leading to its classification as a pseudohyperaldosteronism. The condition usually becomes apparent in childhood or early adulthood and can lead to complications such as heart disease or stroke if left untreated.

Causes

Liddle's syndrome is caused by mutations in the SCNN1A, SCNN1B, or SCNN1G genes, which encode the subunits of the epithelial sodium channel (ENaC) in the kidney. These mutations lead to increased activity of ENaC, causing the kidneys to retain excessive sodium and water while excreting more potassium. This results in volume expansion and high blood pressure. Liddle's syndrome is inherited in an autosomal dominant pattern, meaning only one copy of the mutated gene from either parent can cause the disorder.

Symptoms

Symptoms of Liddle’s syndrome may vary, but the most common clinical features include:

• Hypertension – high blood pressure, often beginning in adolescence or early adulthood

• Hypokalemia – low potassium levels leading to symptoms such as:

  • Muscle weakness or cramps

  • Fatigue

  • Constipation

  • Heart palpitations or arrhythmias

• Metabolic alkalosis – elevated blood pH due to loss of hydrogen ions

• Absence of edema – despite fluid retention, swelling is typically not present

Some individuals may be asymptomatic and diagnosed only through routine screening for hypertension or low potassium.

Diagnosis

Diagnosis of Liddle’s syndrome involves a combination of clinical findings, laboratory testing, and genetic analysis. Key diagnostic steps include:

• Blood pressure measurement – persistent hypertension, especially in young patients

• Serum electrolyte tests – showing low potassium and metabolic alkalosis

• Renin and aldosterone levels – both are low or suppressed, which helps distinguish Liddle's syndrome from other forms of hyperaldosteronism

• Genetic testing – confirmation by identifying mutations in ENaC subunit genes (SCNN1A, SCNN1B, SCNN1G)

Early diagnosis is crucial to prevent long-term cardiovascular complications.

Treatment

The treatment of Liddle’s syndrome focuses on controlling blood pressure and correcting electrolyte imbalances. Effective management strategies include:

• Potassium-sparing diuretics – such as amiloride or triamterene, which directly block ENaC and reduce sodium reabsorption

• Low-sodium diet – to reduce fluid retention and help control blood pressure

• Potassium supplementation – in some cases, to manage hypokalemia

• Avoidance of mineralocorticoid receptor antagonists – such as spironolactone, which are ineffective because aldosterone is not elevated

• Regular monitoring – of blood pressure, electrolytes, and kidney function

Prognosis

With early diagnosis and appropriate treatment, the prognosis for individuals with Liddle’s syndrome is generally excellent. Blood pressure and electrolyte levels can often be well-controlled, preventing complications such as stroke, heart failure, or kidney damage. Lifelong therapy and monitoring are typically required, but affected individuals can lead normal, healthy lives with proper medical care. Undiagnosed or untreated cases, however, carry a higher risk of severe cardiovascular events.