The Perilous PPI: Proton Pump Inhibitor as a Cause of Clinically Significant Hypomagnesaemia
DOI:
https://doi.org/10.15605/jafes.035.01.18Keywords:
Proton pump inhibitors, hypomagnesaemia, hypocalcaemia, hypokalemiaAbstract
Proton pump inhibitors (PPIs) are the mainstay of therapy for all gastric acid related diseases and are commonly used in current clinical practice. Although widely regarded as safe, PPIs have been associated with a variety of adverse effects, including hypomagnesaemia. The postulated mechanism of PPI-related hypomagnesaemia involves inhibition of intestinal magnesium absorption via transient receptor potential melastin (TRPM) 6 and 7 cation channels. PPI-induced hypomagnesaemia (PPIH) has become a well recognized phenomenon since it was first reported in 2006. Clinical concerns arise from growing number of case reports presenting PPIH as a consequence of long-term PPI use, with more than 30 cases published to date.
In this article, we report 2 cases of PPIH associated with the use of pantoprazole. Both patients presented with severe hypomagnesaemia and hypocalcaemia. One of them had associated hypokalemia and cardiac arrhythmia. A casual relation with PPIs postulated and supported by resolution of electrolyte abnormalities after discontinuation of PPIs.
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Kinoshita Y, Ishimura N, Ishihara S. Advantages and disadvantages of long-term proton pump inhibitor use. J Neurogastroenterol Motil. 2018;24(2):182–96. https://www.ncbi.nlm.nih.gov/pubmed/29605975. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885718. https://doi.org/10.5056/jnm18001.
Famularo G, Gasbarrone L, Minisola G. Hypomagnesaemia and proton-pump inhibitors. Expert Opin Drug Saf. 2013;12(5):709-16. https://www.ncbi.nlm.nih.gov/pubmed/23808631. https://doi.org/10.1517/14740338.2013.809062.
Schlingmann KP, Waldegger S, Konrad M, Chubanov V, Gudermann T. TRPM6 and TRPM7–Gatekeepers of human magnesium metabolism. Biochim Biophys Acta. 2007;1772(8): 813–21. https://www.ncbi.nlm.nih.gov/pubmed/17481860. https://doi.org/10.1016/j.bbadis.2007.03.009.
William JH, Danziger J. Proton-pump inhibitor-induced hypomagnesaemia: Current research and proposed mechanisms. World J Nephrol. 2016;5(2): 152-7. https://www.ncbi.nlm.nih.gov/pubmed/26981439. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4777786. https://doi.org/10.5527/wjn.v5.i2.152.
Weisinger JR, Bellorin-Font E. Magnesium and phosphorus. Lancet. 1998;352(9125):391–6. https://www.ncbi.nlm.nih.gov/pubmed/9717944. https://doi.org/10.1016/S0140-6736(97)10535-9.
Epstein M, McGrath S, Law F. Proton-pump inhibitors and hypomagnesemic hypoparathyroidism. N Engl J Med. 2006;355(17):1834-6. https://www.ncbi.nlm.nih.gov/pubmed/17065651. https://doi.org/10.1056/NEJMc066308.
Hess MW, Hoenderop JG, Bindels RJ, Drenth JP. Systematic review: Hypomagnesaemia induced by proton pump inhibition. Aliment Pharmacol Ther. 2012;36(5):405–13. https://www.ncbi.nlm.nih.gov/pubmed/22762246. https://doi.org/10.1111/j.1365-2036.2012.05201.x.
Cundy T, Dissanayake A. Severe hypomagnesaemia in long-term users of proton-pump inhibitors. Clin Endocrinol (Oxf). 2008;69(2):338–41. https://www.ncbi.nlm.nih.gov/pubmed/18221401. https://doi.org/10.1111/j.1365-2265.2008.03194.x.
Hoorn EJ, van der Hoek J, de Man RA, Kuipers EJ, Bolwerk C, Zietse R. A case series of proton pump inhibitor-induced hypomagnesaemia. Am J Kidney Dis. 2010;56(1):112-6. https://www.ncbi.nlm.nih.gov/pubmed/20189276. https://doi.org/10.1053/j.ajkd.2009.11.019.
Fernández-Fernández FJ, Sesma P, Caínzos-Romero T, Ferreira-González L. Intermittent use of pantoprazole and famotidine in severe hypomagnesaemia due to omeprazole. Neth J Med.2010;68(10):329–30. https://www.ncbi.nlm.nih.gov/pubmed/ 21071783.
Shabajee N, Lamb EJ, Sturgess I, Sumathipala RW. Omeprazole and refractory hypomagnesaemia. BMJ. 2008;337:a425. https://www.ncbi.nlm.nih.gov/pubmed/18617497. https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC2483862. https://doi.org/10.1136/bmj.39505.738981.BE.
Arulanantham N, Anderson M, Gittoes N, Ferner RE. A 63-year-old man with hypomagnesaemia and seizures. Clin Med (Lond). 2011;11(6):591–3. https://www.ncbi.nlm.nih.gov/pubmed/22268316. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4952343. https://doi.org/10.7861/clinmedicine.11-6-591.
Famularo G, Minisola G, Bravi MC, Colucci P, Gasbarrone L. Tetany, hypomagnesaemia, and proton-pump inhibitors. Am J Med. 2012; 125(10):e7–8. https://www.ncbi.nlm.nih.gov/pubmed/22800870. https://doi.org/10.1016/j.amjmed.2012.04.027.
Broeren M, Geerdink E, Vader HL, van den Wall Bake AW. Hypomagnesaemia induced by several proton-pump inhibitors. Ann Intern. 2009; 151(10): 755–6. https://www.ncbi.nlm.nih.gov/pubmed/19920278. https://doi.org/10.7326/0003-4819-151-10-200911170-00016.
Mackay JD, Bladon PT. Hypomagnesaemia due to proton-pump inhibitor therapy: A clinical case series. QJM. 2010;103(6): 387–95. https://www.ncbi.nlm.nih.gov/pubmed/20378675. https://doi.org/10.1093/qjmed/hcq021.
Kuipers MT, Thang HD, Arntzenius AB. Hypomagnesaemia due to use of proton pump inhibitors-A review. Neth J Med 2009; 67:169-72. https://www.ncbi.nlm.nih.gov/pubmed/19581665.
Furlanetto TW, Faulhaber GAM. Hypomagnesaemia and proton pump inhibitors: Below the tip of the iceberg. Arch Intern Med. 2011; 171(15): 1391–2. https://www.ncbi.nlm.nih.gov/pubmed/21555654. https://doi.org/10.1001/archinternmed.2011.199.
Matsuyama J, Tsuji K, Doyama H, Kim F, Takeda Y, et al. Hypomagnesaemia associated with a Proton Pump Inhibitor. Intern Med. 2012; 51(16): 2231–4. https://www.ncbi.nlm.nih.gov/pubmed/22892510. https://doi.org/10.2169/internalmedicine.51.7748.
Gandhi NY, Sharif WK, Chadha S, Shakher J. A patient on long term proton pump inhibitors develops sudden seizures and encephalopathy: An unusual presentation of hypomagnesaemia. Case Rep Gastrointest Med. 2012; 2012:632721. https://www.ncbi.nlm.nih.gov/pubmed/23213582. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3506867. https://doi.org/10.1155/2012/632721.
Egshatyan LV. Functional hypoparathyroidism secondary to magnesium deficiency in long-term users of proton pump inhibitor: Case report. Osteopo Bone Dis. 2017; 20(3):102-7. https://doi.org/10.14341/osteo20173102-107.
François M, Lévy‐Bohbot N, Caron J, Durlach V. Chronic use of proton-pump inhibitors associated with giardiasis: A rare cause of hypomagnesemic hypoparathyroidism? Ann Endocrinol (Paris). 2008;69(5):446–8. https://www.ncbi.nlm.nih.gov/pubmed/18614153. https://doi.org/10.1016/j.ando.2008.03.003.
Regolisti G, Cabassi A, Parenti E, Maggiore U, Fiaccadori E. Severe hypomagnesaemia during long-term treatment with a proton pump inhibitor. Am J Kidney Dis. 2010;56(1):168–74. https://www.ncbi.nlm.nih.gov/pubmed/20493607. https://doi.org/10.1053/j.ajkd.2010.03.013.
FDA Drug Safety Communication: Low magnesium levels can be associated with long-term use of proton pump inhibitor drugs (PPIs). Available from: URL: https://www.fda.gov/drugs/drugsafety/ucm245011.htm. Accessed on December 18m 2018.
Voets T, Nilius B, Hoefs S, et al. TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption. J Biol Chem. 2004;279(1):19-25. https://www.ncbi.nlm.nih.gov/pubmed/14576148. https://doi.org/10.1074/jbc.M311201200.
Thébault S, Cao G, Venselaar H, Xi Q, Bindels RJ, Hoenderop JG. Role of the alpha-kinase domain in transient receptor potential melastatin 6 channel and regulation by intracellular ATP. J Biol Chem. 2008;283(29):19999-20007. https://www.ncbi.nlm.nih.gov/pubmed/18490453. https://doi.org/10.1074/jbc.M800167200.
Lameris AL, Hess MW, van Kruijsbergen I, Hoenderop JG, Bindels RJ. Omeprazole enhances the colonic expression of the Mg(2+) transporter TRPM6. Pflugers Arch. 2013;465(11):1613-20. https://www.ncbi.nlm.nih.gov/pubmed/23756852. https://doi.org/10.1007/s00424-013-1306-0.
Li M, Du J, Jiang J, Ratzan W, Su LT, Runnels LW, Yue L. Molecular determinants of Mg2+ and Ca2+ permeability and pH sensitivity in TRPM6 and TRPM7. J Biol Chem. 2007;282(35): 25817-30.
https://www.ncbi.nlm.nih.gov/pubmed/17599911. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3239414. https://doi.org/10.1074/jbc.M608972200.
Groenestege WM, Hoenderop JG, van den Heuvel L, Knoers N, Bindels RJ. The epithelial Mg2+ channel transient receptor potential melastatin 6 is regulated by dietary Mg2+ content and estrogens. J Am Soc Nephrol 2006;17(4):1035-43. https://www.ncbi.nlm.nih.gov/pubmed/16524949. https://doi.org/10.1681/ASN.2005070700.
Agus ZS. Hypomagnesemia. J Am Soc Nephrol. 1999;10(7):1616-22.
https://www.ncbi.nlm.nih.gov/pubmed/10405219.
Deng X, Song Y, Manson JE, et al. Magnesium, vitamin D status and mortality: Results from US National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 and NHANES III. BMC Med. 2013;11:187. https://www.ncbi.nlm.nih.gov/pubmed/23981518. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765911.
https://doi.org/10.1186/1741-7015-11-187.
Litosch I. G protein regulation of phospholipase C activity in a membrane-solubilized system occurs through a Mg2(+)- and time dependent mechanism. J Biol Chem. 1991; 266(8):4764-71.
https://www.ncbi.nlm.nih.gov/pubmed/2002026.
Northup JK, Smigel MD, Gilman AG. The guanine nucleotide activating site of the regulatory component of adenylate cyclase. Identification by ligand binding. J. Biol. Chem. 1982;257(19): 11416-23. https://www.ncbi.nlm.nih.gov/pubmed/6288684.
Volpe P, Alderson-Lang BH, Nickols GA. Regulation of inositol 1,4,5-trisphosphate-induced Ca2+ release. I. Effect of Mg2+. Am J Physiol. 1990;258(6 Pt 1): C1077-85. https://doi.org/10.1152/ajpcell.1990.258.6.C1077.
Rude RK, Oldham SB, Sharp CF Jr., Singer FR. Parathyroid hormone secretion in magnesium deficiency. J Clin Endocrinol Metab. 1978;47(4):800-6. https://www.ncbi.nlm.nih.gov/pubmed/263326. https://doi.org/10.1210/jcem-47-4-800.
Freitag JJ, Martin KJ, Conrades MB, et al. Evidence for skeletal resistance to parathyroid hormone in magnesium deficiency. J Clin Invest.1979;64(5):1238-44. https://www.ncbi.nlm.nih.gov/pubmed/227929. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC371269. https://doi.org/10.1172/JCI109578.
Rude RK, Oldham SB, Singer FR. Functional hypoparathyroidism and parathyroid hormone end-organ resistance in human magnesium deficiency. Clin Endocrinol (Oxf). 1976;5(3):209–24.
https://www.ncbi.nlm.nih.gov/pubmed/182417. https://doi.org/10.1111/j.13652265.1976.tb01947.x.
Fatemi S, Ryzen E, Flores J, Endres DB, Rude RK. Effect of experimental human magnesium depletion on parathyroid hormone secretion and 1,25-dihydroxyvitamin D metabolism. J Clin Endocrinol Metabol. 1991;73(5):1067–72. https://www.ncbi.nlm.nih.gov/pubmed/1939521. https://doi.org/10.1210/jcem-73-5-1067.
Rahman SA, Chee WS, Yassin Z, Chan SP. Vitamin D status among postmenopausal Malaysian women. Asia Pac J Clin Nutr. 2004;13(3):255-60. https://www.ncbi.nlm.nih.gov/pubmed/15331337.
Whang R, Ryder KW. Frequency of hypomagnesaemia and hypermagnesemia. Requested vs routine. JAMA. 1990; 263(22): 3063-4. https://www.ncbi.nlm.nih.gov/pubmed/2342219.
Huang CL, Kuo E. Mechanism of hypokalemia in magnesium deficiency. J Am Soc Nephrol. 2007; 18(10): 2649-52. https://www.ncbi.nlm.nih.gov/pubmed/17804670. https://doi.org/10.1681/ASN.2007070792.
Nichols CG, Ho K, Hebert S. Mg(2+)-dependent inward rectification of ROMK1 potassium channels expressed in Xenopus oocytes. J Physiol. 1994 May; 476(3): 399-409. https://www.ncbi.nlm.nih.gov/pubmed/8057249. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1160454. https://doi.org/10.1113/jphysiol.1994.sp02014.
Yang L, Frindt G, Palmer LG. Magnesium modulates ROMK channel-mediated potassium secretion. J Am Soc Nephrol. 2010;21(12):2109-16. https://www.ncbi.nlm.nih.gov/pubmed/21030597. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3014024. https://doi.org/10.1681/ASN.2010060617.
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