Liddle Syndrome (Pseudoaldosteronism)
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- Autosomal dominant (AD) disorder characterized by early-onset hypertension associated with hypokalemia, metabolic alkalosis, suppressed plasma renin activity, and aldosterone levels
- Mutation of β- or γ-subunit of epithelial sodium channel (ENaC) located in the distal nephron results in gain of function mutation of ENaC and the following:
- Excess sodium reabsorption
- Increased urinary potassium excretion
- Suppressed renin and aldosterone levels
- Secondary hypertension
- Resistant to conventional treatment including mineralocorticoid receptor antagonist (spironolactone, eplerenone) but responsive to ENaC inhibitor (amiloride, triamterene)
- Unknown, rare
- May be underrecognized due to variable expressivity
- Described in populations worldwide
Etiology and Pathophysiology
- The ENaC is a cell membrane–bound ion channel that is permeable to sodium (Na+) ion. In the kidney, it is expressed in the apical membrane of principal cells and controls sodium reabsorption at the cortical collecting duct (CCD) and is regulated by aldosterone.
- ENaC is composed of three subunits: α, β, and γ.
- Under normal condition, ENaC is degraded by ubiquitin proteasome or NEDD4.
- Mutations in β- or γ-subunit make ENaC unrecognizable by NEDD4 and result in decreased degradation and removal of ENaC from the cell membrane, causing an overactivity of ENaC (gain of function mutation).
- Net result: excessive reabsorption of sodium, which leads to volume expanded hypertension and suppression of renin and aldosterone
- Mineralocorticoid antagonists are therefore ineffective.
- Hypokalemia and metabolic alkalosis develop in response to reabsorption of sodium in exchange for potassium and hydrogen ions secretion. These findings are, however, variable.
- Monogenic AD inheritance with high penetrance but variable expressivity
- Children of affected parents have a 50% chance of inheriting disease allele.
- Mutation in SCNN1B or SCNN1G genes encoding for β- or γ-subunit of ENaC located on chromosome 16p12
Family history of first-degree relative with onset of hypertension at young age. Sporadic cases have also been reported.