How should I manage iron‑deficiency anemia in a patient taking a proton‑pump inhibitor?

Management of Iron-Deficiency Anemia in Patients Taking Proton Pump Inhibitors

Do not stop the PPI without addressing the underlying indication, but recognize that long-term PPI therapy impairs iron absorption through hypochlorhydria and should prompt consideration of intravenous iron if oral supplementation fails. 1

Understanding PPI-Related Iron Deficiency

• Long-term PPI therapy contributes to iron deficiency by reducing gastric acid secretion, which is essential for converting dietary non-heme iron into its absorbable ferrous form. 1, 2
• PPI-induced iron deficiency can develop even after 25 years of continuous use and should be considered in the differential diagnosis of unexplained iron deficiency anemia in chronic PPI users. 3, 4
• The presence of PPI therapy does not reduce the likelihood of gastrointestinal malignancy; complete investigation is still required before attributing iron deficiency solely to PPI use. 1

Initial Diagnostic Approach

• Perform complete gastrointestinal evaluation with upper endoscopy and colonoscopy in men and postmenopausal women to exclude occult bleeding sources, as PPI use does not eliminate the need for cancer screening. 1
• Screen for celiac disease with antiendomysial antibody and IgA measurement, as this is a common cause of malabsorption that may coexist with PPI use. 1
• Check for microscopic hematuria to exclude renal tract pathology as a source of chronic blood loss. 1
• Assess for other contributors to negative iron balance including menstrual blood loss, blood donation, inadequate dietary intake, chronic NSAID use, and previous gastrointestinal surgery. 1

First-Line Oral Iron Therapy

• Start ferrous sulfate 200 mg (65 mg elemental iron) once daily immediately upon diagnosis, without delaying treatment while awaiting diagnostic workup. 5
• Add vitamin C (ascorbic acid) 500 mg with each iron dose to enhance absorption, which is particularly critical when gastric acid is suppressed by PPIs. 5, 2
• Take iron on an empty stomach for optimal absorption; if gastrointestinal side effects occur, taking with food is acceptable. 5
• Avoid tea and coffee within 1 hour of iron dosing, as these inhibit absorption. 5
• Once-daily dosing is superior to multiple daily doses because hepcidin remains elevated for ~48 hours after a dose, blocking additional absorption. 5

Monitoring Response to Oral Iron

• Recheck hemoglobin at 4 weeks; expect a rise of approximately 2 g/dL (or ≥1 g/dL minimum). 5
• Failure to achieve ≥1 g/dL rise by 2–4 weeks predicts overall treatment failure and indicates the need to switch to intravenous iron. 5
• Continue oral iron for 3 months after hemoglobin normalizes to fully replenish iron stores; total treatment duration is typically 6–7 months. 5

When to Switch to Intravenous Iron

Intravenous iron should replace oral therapy in PPI users who meet any of the following criteria:

• Intolerance to at least two different oral iron preparations (ferrous sulfate, ferrous fumarate, ferrous gluconate). 5
• Lack of ferritin improvement after 4 weeks of adherent oral therapy despite vitamin C supplementation. 5, 2
• Failure of hemoglobin to rise by ≥1 g/dL after 4 weeks of compliant oral iron therapy. 5
• Presence of active inflammatory bowel disease or other inflammatory conditions that elevate hepcidin and block oral iron absorption. 5, 6
• Post-bariatric surgery anatomy that compromises duodenal iron absorption. 5
• Celiac disease with inadequate response to oral iron despite strict gluten-free diet adherence. 5

Evidence Supporting IV Iron in PPI-Related Iron Deficiency

• A prospective study of 43 iron-deficient patients taking PPIs found that 95% (41/43) responded to intravenous iron with hemoglobin increases ≥2 g/dL, whereas 41 of these patients had previously failed oral iron therapy. 7
• All 43 patients had elevated serum gastrin ≥100 pg/mL, confirming significant acid suppression. 7
• Intravenous iron corrects PPI-related iron deficiency reliably, with improvements in hemoglobin, mean corpuscular volume, ferritin, and transferrin saturation. 7

Preferred Intravenous Iron Formulations

• Choose IV iron preparations that can replace iron deficits in 1–2 infusions rather than multiple infusions to minimize infusion-related risk and improve convenience. 5, 6
• Ferric carboxymaltose: 750–1000 mg per 15-minute infusion; two doses ≥7 days apart provide a total of 1500 mg. 5, 6
• Ferric derisomaltose: 1000 mg given as a single infusion. 5
• Iron sucrose requires multiple visits with a maximum of 200 mg per infusion over 10–15 minutes. 6, 8
• Iron dextran can be given as a total dose infusion but carries a higher risk of anaphylaxis (0.6–0.7%) and requires a test dose. 5, 6
• Modern IV iron formulations have excellent safety profiles with serious adverse reactions occurring in <1% of patients. 6

PPI Management Considerations

• Do not discontinue the PPI without addressing the underlying indication (e.g., gastroesophageal reflux disease, peptic ulcer disease, Barrett's esophagus). 1
• If PPI therapy is not medically necessary (35% of chronic PPI users have no documented indication), consider discontinuation or dose reduction after consultation with the prescribing provider. 9
• Switching from a PPI to an H2-receptor antagonist (e.g., famotidine) may allow iron absorption to recover while maintaining some acid suppression for symptom control. 4
• One case report documented complete resolution of iron deficiency anemia within 3 months after switching from rabeprazole to famotidine. 4

Critical Pitfalls to Avoid

• Do not persist with oral iron beyond 4 weeks without a hemoglobin rise; reassess and switch to IV iron if response is absent. 5
• Do not overlook vitamin C supplementation when oral iron response is suboptimal in PPI users, as this significantly enhances absorption despite reduced gastric acidity. 5, 2
• Do not prescribe multiple daily oral doses; this increases side effects without improving efficacy due to hepcidin-mediated absorption blockade. 5
• Do not discontinue iron therapy when hemoglobin normalizes; continue for an additional 3 months to restore iron stores. 5
• Do not attribute iron deficiency solely to PPI use until complete gastrointestinal investigation excludes malignancy and other bleeding sources. 1
• Do not delay IV iron therapy in patients who have clearly failed oral iron; 95% of PPI users with oral iron failure respond to IV iron. 7

Algorithm for Non-Response to Oral Iron in PPI Users

1. Verify adherence to once-daily oral iron with vitamin C supplementation. 5
2. Evaluate for ongoing blood loss through repeat endoscopy or video capsule endoscopy if initial evaluation was negative. 1
3. Consider malabsorption syndromes including celiac disease, inflammatory bowel disease, or post-bariatric surgery anatomy. 1, 5
4. Check for concurrent vitamin B12 or folate deficiency, which may coexist with PPI-related malabsorption. 1
5. Assess gastrin levels (≥100 pg/mL confirms significant acid suppression). 7
6. Transition to intravenous iron if oral therapy failure is confirmed after 4 weeks. 5, 7

Long-Term Monitoring

• Monitor hemoglobin and red-cell indices every 3 months during the first year after correction, then again after the second year. 5
• Re-treat with intravenous iron when serum ferritin drops below 100 μg/L or hemoglobin falls below gender-specific thresholds. 6
• Reassess the ongoing need for PPI therapy annually, as prolonged use increases the risk of recurrent iron deficiency. 1, 9