Association of Long-Term Use of Proton Pump Inhibitors and Histamine-2 Receptor Antagonists with Vitamin B12 Deficiency

Abstract

Objective: To determine the association of long-term proton pump inhibitor, use and histamine 2 receptor antagonist with vitamin B12 deficiency.

Methodology: This Case-control Study was executed at the Department of General Medicine, Abbasi Shaheed Hospital, Karachi, from 15^th March 2025 to 14^th September 2025. The study included adult’s participants of both genders, aged between 20 to 70 years. The sample size of 100 vitamin B12-deficient cases and 100 controls were included through non-probability consecutive sampling. Long-term proton pump inhibitor or histamine-2 receptor antagonist use (≥ 2 years) served as the exposure. Data were analysed in SPSS 26 with Chi-square analyses and odds ratios, with p-value was taken to be below 5% as significant.

Results: The mean age of vitamin B₁₂-deficient patients was 61.6 ± 9.4 years, and 56% were females. Mean serum vitamin B₁₂ levels were significantly lower in deficient patients (148.9 ± 29.6 pg/ml) compared to controls (466.5 ± 129.2 pg/ml; p < 0.001). Long-term PPI use showed an adjusted odds ratio (OR) of 2.156 (95% CI: 0.826–5.626; p = 0.116), while H₂RA use had an adjusted OR of 1.264 (95% CI: 0.319–5.015; p = 0.739). Diabetes mellitus was significantly associated with vitamin B₁₂ deficiency (p = 0.038).

Conclusion: This investigation revealed an absence of statistically significant association between prolonged administration of PPI or H₂Ras and the incidence of vitamin B₁₂ deficiency within the cohort of assessed patients. Diabetes mellitus, however, was identified as an independent predictor of low vitamin B₁₂ levels. These findings emphasize careful and rational use of acid-suppressive medications and highlight the need for periodic vitamin B₁₂ monitoring in diabetic and vitamin B₁₂-deficient patients receiving prolonged acid suppression. This null finding is inconclusive rather than confirmation of safety, given the limited sample size and single time-point measurement.