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At a glance

It is a disorder characterized by renal tubular defects causing severe hypertension in children that is associated with low plasma level of renin activity, normal levels of aldosterone, metabolic alkalosis, hypokalemia, hypernatremia, and metabolic alkalosis. Adults are affected with severe hypokalemia, weakness, fatigue, heart palpitations, or muscle weakness.

Synonyms

Pseudohyperaldosteronism; Liddle’s Syndrome.

History

This medical condition was discovered in 1963 by Dr Grant Liddle (1921-1989), an American endocrinologist affiliated with Vanderbilt University.

Incidence

It is extremely rare and the exact incidence remains unknown. No more than 50 cases have been reported in the literature.

Genetic inheritance

Autosomal dominant trait with variable penetrance. It is due to mutations increasing the activity of the kidney epithelial sodium channel (ENaC). The variability is particularly evident with regard to serum potassium concentration. Complete linkage of the disorder localized to gene 16p13-p12.

Pathophysiology

Liddle Syndrome is the result of specific mutations that prevent the binding of a regulatory protein to a specific proline-rich region in the carboxyl terminal of the three subunits that compose the epithelial sodium channel SCNN1. This prevents normal degradation of the sodium channel so that the total number of channels is increased, giving rise to constitutive activation of the channel, which increases renal sodium absorption and excretes potassium despite the virtual absence of mineralocorticoids accounting for the clinical and biochemical abnormalities. It is classically associated with severe hypokalemia and suppression of renin and aldosterone functions. It responds to ENaC inhibitors but not to mineralocorticoid receptor inhibitors.

Diagnosis

Liddle Syndrome is characterized by hypertension, hypokalemia severe metabolic acidosis, decreased renin, and angiotensin. The hallmark is the finding of markedly suppressed serum aldosterone levels and the lack of response to administration of the mineralocorticoid receptor blocker spironolactone.

Clinical aspects

Clinically, patients resemble those with primary hyperaldosteronism. They may present with severe hypertension in their teenage years, and this is usually the presenting symptom. Amiloride and triamterene, but not spironolactone, are effective treatments for hypertension and hypokalemia in patients with this syndrome as long as dietary sodium intake is restricted. Hypokalemic metabolic alkalosis is present. Renal function is normal apart from the inability to conserve potassium. However, renal failure may occur secondary to hypertension. The metabolic defects are completely corrected with renal transplantation.

Precautions before anesthesia

Evaluate the extent and severity of end-organ damage secondary to long-standing hypertension in particular the cardiorespiratory and neurologic systems. Optimize antihypertensive therapy is recommended. The addition of triamterene or amiloride (both sparing potassium agents by reducing sodium resorption) may help reverse the biochemical abnormalities. Treatment of any volume deficit helps in the correction of a persistent metabolic alkalosis and hypokalemia. Investigations: urea, ...

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