Association Between Long-Term Proton Pump Inhibitor Use and Deficiency of Vitamin B12 and Magnesium in Gharbia, Egypt: a Retrospective Study
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Abstract
Proton pump inhibitors (PPIs) are widely prescribed for acid-related disorders, but prolonged use has been implicated in nutrient malabsorption. Therefore, this study aimed to evaluate the association between long-term PPI use and deficiency of vitamin B12 and magnesium. Medical records for 312 adult patients with documented PPI use between January 2020 and January 2025 were reviewed. These patients were recruited from Tanta University Hospital and its affiliated centers in Gharbia Governorate, Egypt. Participants were stratified by PPI duration: <3 months, 3–6 months, 6–12 months, and >1 year. Serum vitamin B12 and magnesium were compared across groups. Multivariate regression was performed, adjusting for age, gender, comorbidities, and concomitant medications. Statistical significance was set at p<0.05. The results demonstrate that mean age was 58.7±12.4 years; 55% were male. Mean vitamin B12 levels significantly declined with longer PPI use (421.3 pg/mL in <3 months vs. 271.9 pg/mL in >1 year, p<0.001), as did magnesium levels (2.03 mg/dL vs. 1.69 mg/dL, p<0.001). Regression analysis confirmed that age, duration of PPI use, certain concomitant medications, and comorbidities were independent predictors of deficiency. Participants using PPIs for over 1 year had 11.6 times higher odds of B12 deficiency and 12.8 times higher odds of magnesium deficiency, with corresponding 95% CI, after adjustment. Altogether, long-term use of PPIs is significantly associated with deficiencies in both vitamin B12 and magnesium levels among patients in Gharbia Governorate, Egypt. The risk of deficiency increased with age and length of use, regardless of PPI type or sex of user.
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References
Mössner J. The indications, applications, and risks of proton pump inhibitors: A review after 25 years. Dtsch Arztebl Int. 2016; 113(27-28):477.
Perry IE, Sonu I, Scarpignato C, Akiyama J, Hongo M, Vega KJ. Potential proton pump inhibitor–related adverse effects. Ann N Y Acad Sci. 2020;1481(1):43-58.
Festen HP. Intrinsic factor secretion and cobalamin absorption: physiology and pathophysiology in the gastrointestinal tract. Scand J Gastroenterol. 1991;26(188):1-7.
Hirschowitz BI, Worthington J, Mohnen J. Vitamin B12 deficiency in hypersecretors during long‐term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther. 2008;27(11):1110-1121.
Krishnan M, Fernando H, Mohammed HH, Vithanage N. Proton pump inhibitor induced hypomagnesemia causing seizures: a rare adverse effect of a commonly used medication. Cureus. 2024;16(7):e64044. doi:10.7759/cureus.64044
Florentin M, Elisaf MS. Proton pump inhibitor-induced hypomagnesemia: a new challenge. World J Nephrol. 2012;1(6):151.
Ortiz-Guerrero G, Amador-Muñoz D, Calderón-Ospina CA, López-Fuentes D, Nava Mesa MO. Proton pump inhibitors and dementia: physiopathological mechanisms and clinical consequences. Neural Plast. 2018;2018:5257285
Novotny M, Klimova B, Valis M. PPI long term use: risk of neurological adverse events?. Front Neurol. 2019;9:1142.
Dries LS, Haefliger R, Seibert BS, de Lima AG, Cardoso CD, Perassolo MS. Cognition, oxidative stress and vitamin B12 levels evaluation on patients under long-term omeprazole use. J Pharm Pharmacol. 2022;74 (4):547-555.
Koyyada A. Long-term use of proton pump inhibitors as a risk factor for various adverse manifestations. Therapies. 2021;76(1):13-21.
Ito T, Jensen RT. Association of long-term proton pump inhibitor therapy with bone fractures and effects on absorption of calcium, vitamin B12, iron, and magnesium. Curr Gastroenterol Rep. 2010;12(6):448-457.
Kowalewski J, Bęben D, Pyc G, Kowalewski Ł. Proton pump inhibitors-possible side effects of long-term therapy: a review. Qual Sport. 2024;36:56387.
Savarino E, Marabotto E, Zentilin P, Furnari M, Bodini G, Pellegatta G, et al. A safety review of proton pump inhibitors to treat acid-related digestive diseases. Expert Opin Drug Saf. 2018;17(8):785-794.
Kristanto A, Adiwinata R, Rasidi J, Phang BB, Adiwinata S, Richard T, et al. Long term risks of proton pump inhibitor administration: a literature review. Indones J Gastroenterol Hepatol Dig Endosc. 2020;18(3):169-176.
Rahamn MR, Ahmed QM, Rahim MA, Sami CA, Ahmad HI, Hasan MN. Correlation of long term proton pump inhibitors (PPI) use with iron and vitamin b12 deficiency anaemia. Bangladesh Med J. 2021;50(1):27-32.
Den Elzen WP, Groeneveld Y, De Ruijter W, Souverijn JH, Le Cessie S, Assendelft WJ, et al. Long‐term use of proton pump inhibitors and vitamin B12 status in elderly individuals. Aliment Pharmacol Ther. 2008;27(6):491-497.
Kusano M, Kuribayashi S, Kawamura O, Shimoyama Y, Hosaka H, Nagoshi A, et al. A review of the management of gastric acid-related diseases: focus on rabeprazole. Clinical Medicine. Gastroenterol. 2011;4:CGast-S5133.
Mumtaz H, Ghafoor B, Saghir H, Tariq M, Dahar K, Ali SH, et al. Association of Vitamin B12 deficiency with long-term PPIs use: a cohort study. Ann Med Surg (Lond). 2022;1:82.
Swarnakari KM, Bai M, Manoharan MP, Raja R, Jamil A, Csendes D, et al. The effects of proton pump inhibitors in acid hypersecretion-induced vitamin B12 deficiency: a systematic review. Cureus. 2022;14(11):e31672. doi:10.7759/cureus.31672
Khan A, Hussain M, Ahmed A, Nazir N, Malik MK, Saeed N. Effects of long-term proton pump inhibitor use on serum electrolytes and vitamin levels: a Quasi-experimental study in Pakistan. Cureus. 2025;17(4):e82102. doi:10.7759/cureus.82102
Dharmarajan TS, Kanagala MR, Murakonda P, Lebelt AS, Norkus EP. Do acid-lowering agents affect vitamin B12 status in older adults?. J Am Med Dir Assoc. 2008;9(3):162-167.
Buendgens L, Bruensing J, Matthes M, Dückers H, Luedde T, Trautwein C, et al. Administration of proton pump inhibitors in critically ill medical patients is associated with increased risk of developing Clostridium difficile–associated diarrhea. J Crit Care. 2014;29(4):696-e11.
Qorraj-Bytyqi H, Hoxha R, Sadiku S, Bajraktari IH, Sopjani M, Thaçi K, et al. Proton pump inhibitors intake and iron and vitamin B12 status: a prospective comparative study with a follow up of 12 months. Open Access Maced J Med Sci. 2018;6(3):442.
Brisebois S, Merati A, Giliberto JP. Proton pump inhibitors: review of reported risks and controversies. Laryngoscope Investig Otolaryngol. 2018;3(6):457-462. doi:10.1002/lio2.187
Carabotti M, Annibale B, Lahner E. Common pitfalls in the management of patients with micronutrient deficiency: keep in mind the stomach. Nutrients. 2021;13(1):208. doi:10.3390/nu13010208
Miller JW. Proton pump inhibitors, H2-receptor antagonists, metformin, and vitamin B-12 deficiency: clinical implications. Adv Nutr. 2018;9(4):511S-518S. doi:10.1093/advances/nmy023
Damodharan S, Raj GM, Sakthibalan M, Dakshinamoorthy K, Muraliswaran P. Effect of long-term acid suppression therapy with proton pump inhibitors or H2 receptor blockers on serum vitamin B12 levels in elderly population. Ir J Med Sci. 2021;190(3):1213-1237.
Srinutta T, Chewcharat A, Takkavatakarn K, Praditpornsilpa K, Eiam-Ong S, Jaber BL, et al. Proton pump inhibitors and hypomagnesemia: a meta-analysis of observational studies. Medicine (Baltimore). 2019;98(44):e17788.
Park CH, Kim EH, Roh YH, Kim HY, Lee SK. The association between the use of proton pump inhibitors and the risk of hypomagnesemia: a systematic review and meta-analysis. PLoS One. 2014;9:e112558.
Cheungpasitporn W, Thongprayoon C, Kittanamongkolchai W, Srivali N, Edmonds PJ, Ungprasert P, et al. Proton pump inhibitors linked to hypomagnesemia: a systematic review and meta-analysis of observational studies. Ren Fail. 2015;37(7):1237-1241.
Bai JP, Hausman E, Lionberger R, Zhang X. Modeling and simulation of the effect of proton pump inhibitors on magnesium homeostasis. 1. Oral absorption of magnesium. Mol Pharm. 2012;9(12):3495-3505.
Gommers LM, Hoenderop JG, de Baaij JH. Mechanisms of proton pump inhibitor‐induced hypomagnesemia. Acta Physiologica. 2022;235(4):e13846.
Bahtiri E, Islami H, Hoxha R, Gashi A, Thaçi K, Karakulak Ç, et al. Proton pump inhibitor use for 12 months is not associated with changes in serum magnesium levels: a prospective open label comparative study. Turk J Gastroenterol. 2017;28(2):104-109.
Chowdhry M, Shah K, Kemper S, Zekan D, Carter W, McJunkin B. Proton pump inhibitors not associated with hypomagnesemia, regardless of dose or concomitant diuretic use. J Gastroenterol Hepatol. 2018;33(10): 1717-1721.
Liao S, Gan L, Mei Z. Does the use of proton pump inhibitors increase the risk of hypomagnesemia: an updated systematic review and meta-analysis. Medicine (Baltimore). 2019;98(13):e15011.
Gau JT, Yang YX, Chen R, Kao TC. Uses of proton pump inhibitors and hypomagnesemia. Pharmacoepidemiol Drug Saf. 2012;21(5):553-559.
Putri WD, Andrajati R, Supardi S. Relationship between proton-pump inhibitor use and lower blood magnesium levels. Int J Appl Pharm. 2018;10(1):367. doi:10.22159/ijap.2018.v10s1.81
Luk CP, Parsons R, Lee YP, Hughes JD. Proton pump inhibitor–associated hypomag-nesemia: what do FDA data tell us?. Ann Pharmacother. 2013;47(6):773-780.
Aydın Yoldemir Ş, Zeren Ozturk G, Akarsu M, Ozcan M. Is there a correlation between hypomagnesemia linked to long-term proton pump inhibitor use and the active agent?. Wien Klin Wochenschr. 2022;134(3):104-109.
Heidelbaugh JJ. Proton pump inhibitors and risk of vitamin and mineral deficiency: evidence and clinical implications. Ther Adv Drug Saf. 2013;4(3):125-133.
Lane A, Lau L, Alhannat C, Arya M, Bokor M, Cheney C, et al. Risk factors and comorbidities associated with vitamin B12 deficiency in an adult population. J Prim Care Community Health. 2025;16:21501319251360498. doi:10.1177/21501319251360498
Bioletto F, Pusterla A, Fraire F, Sauro L, Presti M, Arvat E, et al. Sex-specific association of chronic proton pump inhibitor use with reduced bone density and quality. J Clin Endocrinol Metab. 2025;110(6):e2071-e2079. doi:10.1210/clinem/dgae598
Infante M, Leoni M, Caprio M, Fabbri A. Long-term metformin therapy and vitamin B12 deficiency: an association to bear in mind. World J Diabetes. 2021;12(7):916.
Bouras H, Roig SR, Kurstjens S, Tack CJ, Kebieche M, de Baaij JH, et al. Metformin regulates TRPM6, a potential explanation for magnesium imbalance in type 2 diabetes patients. Can J Physiol Pharmacol. 2020;98(6):400-411.