Monogenic Forms of Low-Renin Hypertension

Vesna D Garovic; Anthony A Hilliard; Stephen T Turner

Disclosures

Nat Clin Pract Nephrol. 2006;2(11):624-630. 

In This Article

Liddle Syndrome

Liddle syndrome is an autosomal dominant disorder caused by hyperactivity of the amiloride-sensitive sodium channel (ENaC) of the principal cell of the cortical collecting tubule. In 1963, Liddle described a family in which multiple siblings developed early-onset severe hypertension and hypokalemia. Genetic studies have revealed mutations in the genes coding the beta or gamma subunits of ENaC (chromosome 16p) that cause deletions of proline-rich regions.[19,20] These regions are important to regulation of ENaC activity as they facilitate binding of Nedd4, a regulatory repressor that promotes channel degradation. The inability of beta and gamma subunits to bind Nedd4 results in constitutive expression of sodium channels at the apical surface of principal cells, leading to increased rates of sodium reabsorption, volume expansion and hypertension (Figure 3C).

The typical presentation of patients with Liddle syndrome includes early-onset severe hypertension, hypokalemia, metabolic alkalosis in the setting of low plasma renin and aldosterone, low rates of urinary aldosterone excretion, and a family history of hypertension.[21] Hypokalemia and metabolic alkalosis develop in response to reabsorption of cationic sodium in the absence of an anion. This creates a lumen-negative electrical gradient, which promotes secretion of potassium and hydrogen ions into the collecting tubule. In untreated patients, cardiovascular complications are common.

Treatment of Liddle syndrome with amiloride or triamterene lowers blood pressure and corrects the hypokalemia and acidosis. These agents effectively block the constitutively active ENaC in the collecting tubule. Spironolactone is not an effective treatment as the increased activity of the ENaC is not mediated by aldosterone (as reflected by the low plasma and urinary aldosterone levels).

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