Can Proton Pump Inhibitors (PPIs) cause iron deficiency?

Proton Pump Inhibitors and Iron Deficiency

Yes, proton pump inhibitors (PPIs) can cause iron deficiency, with long-term use (≥2 years) being associated with a 2.5-fold increased risk of iron deficiency. 1

Mechanism and Evidence

PPIs reduce gastric acid production, which impairs the absorption of non-heme iron in the following ways:

• Gastric acid is essential for converting dietary iron from its ferric (Fe³⁺) to ferrous (Fe²⁺) form, which is more readily absorbed in the duodenum
• The reduced acidity in the stomach decreases iron solubility and bioavailability
• Higher doses and longer duration of PPI use correlate with greater risk of iron deficiency

Multiple guidelines and studies confirm this association:

• The British Society of Gastroenterology recognizes long-term PPI therapy as a contributor to iron deficiency, noting that impaired absorption is likely due to hypochlorhydria 2
• A large case-control study found that ≥2 years of PPI use was strongly associated with iron deficiency, with higher doses (≥1.5 PPI pills/day) showing an even stronger association (adjusted OR: 2.49; 95% CI: 2.35-2.64) 2, 1
• The risk increases with higher daily doses and longer duration of use, with patients taking >1.5 pills per day for at least 10 years having over 4 times the risk (OR: 4.27; 95% CI: 2.53-7.21) 1

Risk Factors and Monitoring

Certain factors increase the risk of PPI-induced iron deficiency:

• Duration of use: Risk significantly increases after 2+ years of continuous use 1
• Dosage: Higher doses (>1.5 pills/day) carry greater risk than lower doses (<0.75 pills/day) 2
• Concurrent conditions: Patients with other risk factors for iron deficiency are at higher risk

Clinical Implications

• A retrospective cohort study showed that patients on chronic PPI therapy had significant decreases in hemoglobin (-0.19 g/dL, P=0.03) and hematocrit (-0.63%, P=0.02) compared to matched controls 3
• After adjusting for confounders, the odds ratio of decreasing hemoglobin by 1.0 g/dL while on chronic PPI therapy was 5.03 (95% CI, 1.71-14.78) 3
• Even patients taking multivitamins with 100% daily value of B12 showed an inverse correlation between PPI duration and iron levels 4

Management Recommendations

For patients requiring long-term PPI therapy:

1. Use the lowest effective dose for the shortest duration necessary 4
2. Monitor iron status in patients on long-term PPI therapy, especially those on higher doses
3. Consider iron supplementation for patients with declining iron parameters or those at high risk
4. The risk of iron deficiency decreases after PPI discontinuation, suggesting a reversible effect 1

Other Nutrient Deficiencies Associated with PPIs

PPIs are also associated with other nutrient deficiencies:

• Vitamin B12: Long-term use (>2 years) increases risk, with higher doses showing stronger association (OR: 1.95 for >1.5 pills/day vs OR: 1.63 for <0.75 pills/day) 2, 4
• Magnesium: PPIs can reduce magnesium status, though this relationship is complicated by genetic factors 2

Conclusion

The evidence clearly demonstrates that long-term PPI use increases the risk of iron deficiency through reduced gastric acid production and impaired iron absorption. This risk is dose-dependent and increases with duration of use. Clinicians should be aware of this association and monitor iron status in patients on long-term PPI therapy.