Multiple electrolyte disorders triggered by proton pump inhibitor-induced hypomagnesemia: Case reports with a mini-review of the literature.

Drug-induced hypomagnesemia is an adverse effect with the potential for serious and fatal outcomes. Although rare, chronic use of proton pump inhibitors (PPIs) can cause hypomagnesemia due to impaired intestinal absorption, mainly attributed to reduced transcellular transport of magnesium via transient receptor potential melastatin 6 (TRPM6) and 7 (TRPM7) channels. However, a reduction of magnesium paracellular absorption due to the downregulation of intestinal claudins has also been reported. PPI-induced hypomagnesemia can trigger other concomitant electrolyte derangements, including hypokalemia, hypocalcemia, hypophosphatemia, and hyponatremia. Here we report two cases of multiple electrolyte disorders associated with PPI-induced hypomagnesemia, the clinical manifestations of which were cardiac arrhythmia, cognitive changes, and seizure crisis. These cases illustrate the need to monitor serum magnesium levels in patients on long-term PPI use, especially in the elderly and those with malabsorptive bowel syndromes or taking loop diuretics and thiazides.
Competing Interests: The authors declare no potential conflicts of interest concerning this article’s research, authorship, and/or publication. Table 1.Summary of the patients’ blood and urine test results. Patient 1Patient 2Reference values HospitalizationAfter hospital dischargeHospitalizationAfter hospital dischargeD1D2D3Omeprazole restartingOmeprazole interruptionD1D3D4D9D151° Outpatient consultationMagnesium0.82.52.31.5120.61.41.70.72.121.8 – 2.4 mg/dLIonized calcium3.24.14.14.64.153.1–––4.95.24.4 – 5.4 mg/dLSodium138135135136142137144141137–135140135 – 145 mEq/LPotassium2.63.13.843.24.62.73.45554.73.5 – 5 mEq/LPhosphate2.92.93.23.74.5–2.2––4.34.12.5 – 4.5 mg/dLPTH35407*185895953––6430–3415 – 68 pg/mLCreatinine0.620.80.660.840.90.920.980.810.851.41.10.990.7 – 1.2 mg/dLUrea19211726263522192648353019 – 44 mg/dLFEMg2+0.25%––0.17%0.23%2.5%–12%**–0.5%***–5.4%2 – 4%FEK+15%––––4.4%––––––4 – 16%TRP82%–––––––––––86 – 99%TmP/TGF2.3–––––––––––2.6 – 3.8 mg/dL*Patient 1: 24 hours after intravenous infusion of magnesium sulfate; **Patient 2: elevation of FEMg2+ during intravenous supplementation (inducing a false interpretation of renal loss); ***Patient 2: Without intravenous supplementation, characterizing extrarenal loss; TRP = (1 – phosphorus excretion fraction) × 100; TmP/GFR = [(0.3 × TRP) / (1 – (0.8 × TRP)] × serum phosphorus; FEK+ = (UK × PCr) / (PK × UCr)] × 100; FEMg2+ = (UMg × PCr) / (PMg × UCr × 0.7)] × 100. D = day; FEK+ = fractional excretion of potassium; FEMg+2 = fractional excretion of magnesium; PTH = parathyroid hormone; TRP = tubular reabsorption of phosphate; TmP/GFR = transport maximum for phosphate reabsorption/glomerular filtration rate. Figure 1.Influence of proton pump inhibitors (PPIs) on intestinal absorption of Mg2+. A: Mg2+ is absorbed into the enterocytes via the paracellular (solid red lines) and the transcellular route (through TRPM6/7) (solid black lines). After absorption, it enters the interstitial space via CNNM4 and, finally, the bloodstream via the portal vein. B: PPIs inhibit Mg2+ absorption by increasing the intestinal lumen pH, both by gastric and colonic (non-gastric) H+/K+ATPase antagonism. In this condition, the affinity of TRPM6/7 for Mg2+ decreases, resulting in lower intestinal absorption, despite the compensatory increase in TRPM6 channel expression (dotted black curved line). Additionally, paracellular transport through claudins (orange hexagons) is compromised with increased intestinal pH (dotted red lines). TRPM = transient receptor potential channel of melastatin; CNNM4 = cyclin M4.Figure 2.Multiple electrolyte disorders due to hypomagnesemia induced by proton pump inhibitors. Hypomagnesemia caused by the reduction of intestinal absorption provokes a series of other concomitant electrolyte disturbances, highlighted by hypokalemia and hypocalcemia and, less frequently, hypophosphatemia and hyponatremia. Hypokalemia itself can aggravate phosphaturia (black dotted arrow). ROMK = medullary renal outer potassium channel; NaPi = sodium-phosphorus cotransport present in the kidney; PTH = parathyroid hormone; SIADH = syndrome of inappropriate antidiuretic hormone secretion; AIN = acute interstitial nephritis; RSW = renal salt wasting.
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