Do PPIs Cause Vitamin B12 or Vitamin D Deficiency?
PPIs are associated with vitamin B12 deficiency, particularly with long-term use (≥2 years) and higher doses, though the evidence remains inconsistent; there is no established association between PPIs and vitamin D deficiency in the current evidence.
Vitamin B12 Deficiency Risk
Mechanism of Action
- PPIs reduce gastric acid production, which impairs vitamin B12 absorption by limiting the release of B12 from food proteins and reducing intestinal absorption 1
- Genetic variations in CYP2C19 may alter individual susceptibility to PPI-induced B12 deficiency 1
Evidence for Association
- Duration matters most: Risk increases significantly after ≥2 years of continuous PPI use 2, 3
- Dose-dependent effect: Higher doses (>1.5 pills/day) show stronger associations (OR: 1.95) compared to lower doses (<0.75 pills/day, OR: 1.63) 2, 3
- A large Kaiser Permanente case-control study found that ≥2 years of PPI use was associated with increased B12 deficiency risk (OR: 1.65) 3
- One cohort study found B12 deficiency 0.5 times more likely in PPI users, particularly in men aged 18-40 4
Conflicting Evidence Creates Diagnostic Challenges
- Some cross-sectional studies in older adults found no significant differences in mean serum B12 levels between PPI users and non-users, despite inverse correlation between duration and B12 levels 1, 5
- Randomized controlled trials comparing PPIs to antireflux surgery showed no significant differences in serum B12 levels after 5 years 1
- Critical caveat: Measuring serum B12 alone underestimates true deficiency prevalence 1, 6
- When additional markers (methylmalonic acid and homocysteine) were measured, B12 deficiency was detected in 31% of PPI users despite normal serum B12 6
- A 2025 meta-analysis found no association when assessing only total serum B12 and homocysteine, highlighting the inadequacy of single-marker testing 7
FDA Warning and Clinical Guidance
- FDA drug labels include precautionary notices regarding vitamin B12 deficiency risk with long-term PPI use 1, 2
- The American Gastroenterological Association does not recommend routine screening for all PPI users due to lack of causal evidence 1, 2
- However, individual risk assessment is warranted for high-risk patients 5
Who Requires Monitoring
High-risk patients include those with:
- Duration of PPI use ≥2 years 2, 3
- Higher doses (>40mg daily or multiple daily doses) 2, 3
- Pre-existing risk factors for B12 deficiency 2
- Known genetic variations in CYP2C19 (if available) 2
Supplementation Limitations
- Standard multivitamin supplementation containing 100% daily value of B12 may not fully prevent PPI-induced malabsorption 1, 5, 2
- Crystalline B12 from fortified foods does not require gastric acid for absorption and shows better bioavailability in PPI users, though may be inadequate to restore normal status in those with atrophic gastritis 8
Vitamin D Deficiency
No evidence in the provided guidelines or research establishes an association between PPI use and vitamin D deficiency. The evidence focuses on vitamin B12, iron, calcium, magnesium, and bone fracture risks, but does not address vitamin D status 1, 2.
Other Nutritional Concerns with PPIs
Iron Deficiency
- ≥2 years of PPI use strongly associates with iron deficiency, especially at higher doses (≥1.5 pills/day, adjusted OR: 2.49) 2
Hypomagnesemia
- Meta-analysis showed PPI use associated with hypomagnesemia (adjusted OR: 1.71), with TRPM6 genetic variations altering individual susceptibility 2