Clinical Pearls & Morning Reports
Published March 2, 2022
The combination of hypokalemia, hypomagnesemia, and hypochloremic metabolic alkalosis is consistent with Gitelman’s syndrome, an autosomal recessive disorder affecting the thiazide-sensitive transporter encoded by SLC12A3. Because multiple inherited tubulopathies manifest in similar ways, molecular genetic testing is necessary to confirm the diagnosis. Read the NEJM Clinical Problem-Solving Article here.
Q: Is Gitelman’s syndrome common?
A: The syndrome is considered to be the most frequently occurring form of tubulopathy, with an estimated carrier frequency of 1:100. The relatively high prevalence of heterozygous carriers may be attributable to a selective advantage of reduced cardiovascular risk associated with low baseline blood pressure.
Q: Describe some of the clinical and laboratory features of Gitelman’s syndrome.
A: The syndrome occurs primarily in adolescents and adults but may also occur in children as early as the neonatal period. Hallmark clinical features include salt craving, fatigue, muscle weakness, dizziness, nocturia, and palpitations. Typical laboratory manifestations include salt wasting, hypokalemic metabolic alkalosis, and hypocalciuria.
A: Hypokalemia, which can be severe, is primarily caused by hyperreninemic hyperaldosteronism, which occurs as a physiologic response to chronic salt wasting. Excessive salt loss increases delivery of sodium to the collecting duct and reabsorption by means of the aldosterone-sensitive epithelial sodium channel, which causes increased losses of urinary potassium and hydrogen as part of the body’s effort to maintain electroneutrality. The initiation of a pharmacologic blockade of the distal sodium–potassium exchange with potassium-sparing diuretics, such as amiloride, spironolactone, or eplerenone, may help to ameliorate the hypokalemia if supplements alone are inadequate in maintaining acceptable serum potassium levels. Direct effects of hypomagnesemia can also contribute to hypokalemia. Normomagnesemia supports normal sodium–potassium ATPase function, which promotes intracellular potassium intake and limits the excretion of distal tubular potassium by inhibiting the outer renal medullary potassium channel.
A: Successful diagnosis and treatment of Gitelman’s syndrome requires the provision of appropriate genetic counseling and the prevention of potentially life-threatening complications, such as ventricular tachycardia, seizures, and rhabdomyolysis. Education and support must be provided regarding the predictable challenges patients often face in maintaining adherence to the use of amiloride and electrolyte supplements, including cost, and adverse effects, particularly the diarrhea caused by magnesium.