A Novel Form of Apparent Hypokalemia

Introduction: In contrast to commonly observed rises in blood potassium levels when sample processing is delayed, pseudohypokalemia (an ex vivo fall in plasma potassium level) has previously been reported only rarely. Here we describe pseudohypokalemia as a novel clinical phenomenon in a group of patients with hereditary spherocytosis (HS) and SLC4A1 mutations. Case Description: Four patients were referred to our renal clinic for investigation of hypokalemia discovered in primary care. All were male and had HS with general malaise. All lived considerable distances from sites of sample processing. In vitro time-course experiments revealed marked falls from normal plasma K in patient samples during the first few hours after phlebotomy that were absent from unselected HS blood or a panel of normal controls. This ex vivo finding was most marked (up to 1 mEq/L drop) at 25oC, also observed at 18 and 37oC, but absent at 4oC. Three pseudohypokalemics carried mutations in SLC4A1 (gene encoding the chloride-bicarbonate exchanger AE1). There was no evidence of renal K wasting and acid-base balance was normal. K supplements were stopped without incident; freshly drawn K levels remained normal. The in vitro K falls were abolished by ouabain but not bumetanide, implicating the Na/K-ATPase and excluding NKCC1. Na/K-ATPase activity of patient erythrocyte membranes was increased, concomitant with increased Na/K-ATPase protein levels. In Xenopus oocytes, mutant AE1 proteins failed to reach and/or exchange chloride at the cell membrane. Discussion: Hypokalemia is frequently encountered in biochemistry laboratories and during routine patient management. The differential diagnosis is wide, including whole body K depletion and K redistribution into cells. The latter occurs temporarily with insulin treatment of diabetic ketoacidosis; in alkalosis; catecholamine excess; hypothermia; hypokalemic periodic paralysis and in various leukemias (where K is redistributed into the leukemic cells). An abnormally increased rate of K movement into the cells of whole blood in non-leukemic patients has not been previously documented. Here we have demonstrated this phenomenon in vitro in selected individuals with HS, associated with AE1 malfunction. Pseudohypokalemia should be considered in any patient with apparent hypokalemia where there has been a delay in sample processing, particularly in the summer, and a blood film examined, looking for red cell dysmorphology.