Association Between Long-Term Proton Pump Inhibitor Therapy and Vitamin B12 Status: A Systematic Review and Meta-Analysis

Proton pump inhibitors (PPIs) are widely prescribed medications that have been linked to vitamin B12 deficiency. However, due to methodological differences between studies and the diagnostic inaccuracies of vitamin B12 assessment methods used, results are conflicting. This systematic review and meta-analysis investigated the association between chronic (>6 months) PPI use and vitamin B12 deficiency by assessing two biomarkers of vitamin B12 status: serum vitamin B12 and total homocysteine levels. A systematic search was conducted using PubMed, Cochrane Library, and Google Scholar. Data was extracted from each study and used to calculate standardised mean differences and 95% confidence intervals (95% CI) for serum vitamin B12 and total homocysteine levels between chronic PPI users and controls using a random effects model. Heterogeneity was tested via chi-squared, with p<0.05 indicating significant heterogeneity, and the degree of heterogeneity was quantified using the I² statistic. Six studies (1587 cases and 2272 controls), consisting of three cross-sectional studies, two cohort studies, and one randomised controlled trial, met the inclusion criteria. The standardised mean differences for serum total vitamin B12 (0.01, 95% CI -0.14-0.16, p=0.92) and total homocysteine levels (0.05, 95% CI -0.02-0.11, p=0.17) showed no difference between PPI users and controls. There was no association between chronic PPI use and vitamin B12 deficiency when assessing total serum vitamin B12 and total homocysteine levels. A lack of studies using multiple vitamin B12 biomarkers makes it difficult to recommend monitoring of vitamin B12 levels in low-risk patients prescribed chronic PPIs. Therefore, future studies should include at least two biomarkers of vitamin B12 status (serum vitamin B12, homocysteine, methylmalonic acid, and holotranscobalamin), in addition to serum folate, serum calcium, and dietary intake, across several age brackets and PPI dosages.