Master Liddle Syndrome with Picmonic for Medicine

Liddle syndrome is inherited in an autosomal dominant manner, meaning one defective/mutated copy of the gene is required for the disease to manifest, and that the gene is not located on a sex chromosome.

Liddle syndrome is due to a dysfunction of the sodium channels in the renal collecting duct. The collecting duct is the final segment of the nephron, which is involved in electrolyte homeostasis. Major cell types of the collecting duct include alpha cells (for acid secretion), beta cells (for bicarbonate secretion), and principal cells (for water and sodium absorption and potassium secretion). Epithelial sodium channels (ENaC) are located on principal cells.

A gain of function (GOF) mutation in the genes encoding for beta and gamma subunits of the epithelial sodium channel is responsible for Liddle syndrome. This results in constitutive activation and decreased degradation of the sodium channels, causing excessive sodium reabsorption. The genes are SCNN1B and SCNN1G located on chromosome 16.

An inability to turnover ENaCs results in excessive sodium and water reabsorption in the collecting duct. The decreasing electropositivity in the tubular lumen causes passive diffusion of potassium (K+) and (H+) ions into the urine, which leads to a hypokalemic state with metabolic alkalosis.

The increased reabsorption of sodium inhibits juxtaglomerular release of renin and thus decreases activation of the renin-angiotensin-aldosterine system (RAAS). Renin and aldosterone levels will be decreased, although the effects of RAAS will be evident e.g. hypervolemia, hypertension, and hypokalemia.

The increased reabsorption of sodium inhibits juxtaglomerular release of renin and thus decreases activation of the renin-angiotensin-aldosterine system (RAAS). Renin and aldosterone levels will be decreased, although the effects of RAAS will be evident e.g. hypervolemia, hypertension, and hypokalemia.

Hypertension occurs because of excessive sodium and water reabsorption while hypokalemia results from passive potassium ion diffusion into the renal tubule to balance the electrochemical gradient.

In addition to potassium ions, hydrogen ions (H+) also diffuse into the renal tubule to balance the electrochemical gradient. This results in a serum metabolic alkalosis. Metabolic alkalosis is an elevated blood pH due to renal injury or disease (versus a respiratory cause).

Liddle syndrome mimics hyperaldosteronism in many ways, however it can be differentiated in that Liddle Syndrome, unlike hyperaldosteronism, has low plasma aldosterone. It is therefore sometimes referred to as causing pseudohyperaldosteronism. Pseudohyperaldosteronism is a condition that mimics hyperaldosteronism. Clinically, pseudohyperaldosteronism presents with hypertension, hypokalemia, and metabolic alkalosis.

Patients with Liddle syndrome require lifelong therapy with potassium-sparing diuretics that are not aldosterone antagonists (e.g. spironolactone) because aldosterone levels are already reduced. Specifically ENaC antagonists such as amiloride and triamterene are required.