A Practical Approach to Genetic Hypokalemia

Mutations in genes encoding ion channels, transporters, exchangers, and pumps in human tissues have been increasingly reported to cause hypokalemia. Assessment of history and blood pressure as well as the K(+) excretion rate and blood acid-base status can help differentiate between acquired and inherited causes of hypokalemia. Familial periodic paralysis, Andersen's syndrome, congenital chloride-losing diarrhea, and cystic fibrosis are genetic causes of hypokalemia with low urine K(+) excretion. With respect to a high rate of K(+) excretion associated with faster Na(+) disorders (mineralocorticoid excess states), glucoricoid-remediable aldosteronism and congenital adrenal hyperplasia due to either 11β-hydroxylase and 17α-hydroxylase deficiencies in the adrenal gland, and Liddle's syndrome and apparent mineralocorticoid excess in the kidney form the genetic causes. Among slow Cl(-) disorders (normal blood pressure, low extracellular fluid volume), Bartter's and Gitelman's syndrome are most common with hypochloremic metabolic alkalosis. Renal tubular acidosis caused by mutations in the basolateral Na(+)/HCO(3)(-) cotransporter (NBC1) in the proximal tubules, apical H(+)-ATPase pump, and basolateral Cl(-)/HCO(3)(-) exchanger (anion exchanger 1, AE1) in the distal tubules and carbonic anhydroase II in both are genetic causes with hyperchloremic metabolic acidosis. Further work on genetic causes of hypokalemia will not only provide a much better understanding of the underlying mechanisms, but also set the stage for development of novel therapies in the future.