Unmasking of a Heterozygous SLC12A3 Variant

Three months after starting 25 mg chlorthalidone, a patient was admitted to the medical intensive care unit to manage hypokalemia, metabolic alkalosis, hypo-osmolar hyponatremia, hyperglycemia, and 30 lb weight loss. The patient received ∼936 mEq potassium over 8 days, of which 456 mEq was administered during the first 2 days of admission. In the first 24 hours, the individual received intravenous fluids that delivered 406 mEq sodium chloride. By day 2, serum potassium level increased from 2.5 to 3.0 mEq/L, bicarbonate fell from 40 to 35 mEq/L, serum sodium improved from 121 to 134 mEq/L, and serum glucose levels improved from the 400s to the 200s (mg/dL). On day 4, serum chemistries normalized. Twenty-four hours after admission, serum aldosterone level and renin activity were unremarkable, and brain natriuretic peptide concentration was <10 pg/mL. The primary therapeutic interventions were potassium chloride replacement, modest sodium chloride replacement, and subcutaneous insulin administration. Natera Renasight genetic testing identified a pathologic missense variant (p.Glu121Asp) in a single allele of the thiazide-sensitive Na⁺/Cl^- cotransporter, solute carrier family 12 member 3 (SLC12A3). We speculate that chlorthalidone unmasked a Gitelman syndrome-like phenotype in a patient with a single functional SLC12A3 allele. Moreover, this case informs us of the interrelationships of total body potassium depletion and glucose metabolism and systemic blood pressure.