Does acid-suppressing therapy impair non-heme iron absorption and cause iron deficiency?

Prolonged acid suppression is a well-documented contributor to impaired iron homeostasis, particularly through its effects on the bioavailability of non-heme iron. For individuals on chronic therapy, the physiological shift in gastric pH directly interferes with the early stages of iron processing in the digestive tract.

Mechanistic pathways

The absorption of non-heme iron is highly pH-dependent and relies on two critical chemical transformations:

• Solubilization and reduction: Gastric acid (HCl) is essential for releasing ferric iron (Fe³⁺) from food matrices and preventing it from forming insoluble ferric hydroxides. Acidic conditions (pH < 3) also facilitate the reduction of Fe³⁺ to the absorbable ferrous (Fe²⁺) state.
• Transporter efficiency: The Divalent Metal Transporter 1 (DMT1), the primary gatekeeper for iron entry into duodenal enterocytes, functions as a proton-coupled symporter. By increasing gastric pH, acid-suppressing therapies diminish the proton gradient required to drive iron across the intestinal membrane.

Clinical and effectiveness evidence

Large-scale clinical data confirms the impact of chronic suppression:

• Increased risk: Meta-analyses and cohort studies indicate that long-term proton pump inhibitor (PPI) use is associated with a 2- to 3-fold increased risk of iron deficiency anemia (IDA). For example, a large case-control study (n > 25,000) found that PPI use for more than two years was significantly associated with a 1.65-fold increased risk of IDA (95% CI: 1.59–1.71).
• Therapeutic validation: The potency of this effect is further evidenced by the clinical use of PPIs as a targeted intervention to reduce the frequency of phlebotomy in patients with hereditary hemochromatosis, where acid suppression successfully limits excessive iron absorption.

Bottom line

Acid-suppressing therapies, particularly PPIs, impair non-heme iron absorption by raising gastric pH, which reduces iron solubility and disrupts proton-coupled transport. Long-term use is a significant risk factor for iron deficiency, and monitoring of iron stores (serum ferritin) is warranted for patients on chronic therapy.