Can PPIs Cause Iron Deficiency?
Yes, proton pump inhibitors (PPIs) can cause iron deficiency, particularly with long-term use (≥2 years) and higher doses, by reducing gastric acid production which impairs non-heme iron absorption from food. 1
Mechanism of Iron Deficiency
PPIs suppress gastric acid production, which is essential for:
- Releasing iron from food proteins 2
- Converting ferric iron (Fe³⁺) to the more absorbable ferrous form (Fe²⁺) 1
- Facilitating intestinal iron absorption 2
The resulting hypochlorhydria directly impairs non-heme iron absorption, leading to negative iron balance over time 1.
Quantified Risk Based on Duration and Dose
Duration-dependent risk:
- ≥2 years of PPI use: adjusted OR 2.49 (95% CI: 2.35-2.64) for iron deficiency 3
- ≥10 years at high doses (>1.5 pills/day): OR 4.27 (95% CI: 2.53-7.21) 3
- Risk decreases after medication discontinuation (P-trend <0.001) 3
Dose-dependent risk:
- Higher daily doses (>1.5 pills/day): adjusted OR 2.49 2
- Lower doses (<0.75 pills/day): OR 1.63 2
- Dose-response relationship confirmed (P-interaction = 0.004) 3
Clinical Evidence Quality
The British Society of Gastroenterology (2021) recognizes long-term PPI therapy as a contributor to iron deficiency risk 1. The FDA includes precautionary notices regarding anemia risk with PPI use 1, 2.
Important caveat: Some randomized controlled trials comparing PPIs to antireflux surgery found no significant differences in iron levels at 5 years 1. However, these trials were not specifically designed to detect iron deficiency, had limited follow-up, and did not consistently account for dietary intake or supplement use 1. The observational evidence from large case-control studies (77,046 cases) provides more compelling real-world data 3.
Clinical Recognition and Management
When to suspect PPI-induced iron deficiency:
- Duration of PPI use ≥2 years 2, 3
- Higher doses (>40mg daily or multiple daily doses) 2, 3
- Absence of other obvious causes of blood loss 1
- Multifactorial iron deficiency (PPIs may be one contributor) 1
Key clinical pitfall: Iron deficiency is often multifactorial, so PPI use should not deter appropriate gastrointestinal investigation, particularly in older patients 1. Always exclude other causes including occult GI bleeding, celiac disease, and renal tract pathology 1.
Practical Considerations
The American Gastroenterological Association does not recommend routine screening for iron deficiency in all PPI users 1, but individual risk assessment is warranted for patients with prolonged use, higher doses, or additional risk factors 2.
Therapeutic use of PPIs to reduce iron absorption: Conversely, in conditions with iron overload (e.g., hemochromatosis), PPIs can be used therapeutically to reduce iron absorption and decrease phlebotomy requirements during maintenance therapy 1. This demonstrates the clinically significant impact of PPIs on iron homeostasis.
H2-receptor antagonists: These also increase iron deficiency risk, though less potently than PPIs (≥2 years use: OR 1.58,95% CI: 1.46-1.71) 3.