What is the appropriate iron supplementation regimen for a patient with iron‑deficiency anemia who has a peptic ulcer being treated with a proton‑pump inhibitor or H2‑blocker?

Iron Supplementation in Peptic Ulcer Disease

Critical First Principle: Treat the Ulcer First, Then Address Iron Deficiency

In patients with peptic ulcer disease and iron-deficiency anemia, oral iron supplementation should be initiated immediately alongside ulcer treatment with PPIs or H2-blockers, but clinicians must recognize that acid suppression significantly impairs oral iron absorption and plan accordingly. 1

Understanding the PPI/H2-Blocker Problem

Proton pump inhibitors and H2-blockers create a challenging paradox: they are essential for healing peptic ulcers but simultaneously impair iron absorption by reducing gastric acid needed to convert dietary non-heme iron to absorbable ferrous iron. 2, 3, 4

Evidence of Impaired Absorption

• In iron-deficient patients taking omeprazole, only 16% achieved a normal hemoglobin response (rise >2 g/dL) and only 40% achieved a normal ferritin response (rise >20 μg/dL) after 3 months of oral ferrous sulfate. 2
• Patients on PPIs with iron deficiency who failed oral iron therapy showed 95% response rates when switched to intravenous iron, confirming that malabsorption—not ongoing blood loss—was the primary issue. 3
• One case report documented complete resolution of iron-deficiency anemia within 3 months simply by switching from rabeprazole to famotidine, demonstrating the direct causal relationship. 4

First-Line Oral Iron Regimen (Despite Acid Suppression)

Start with ferrous sulfate 200 mg (65 mg elemental iron) once daily on an empty stomach, taken in the morning. 1

Critical Optimization Strategies

• Add vitamin C 500 mg with each iron dose—this is non-negotiable in PPI users, as ascorbic acid provides an alternative pathway for iron reduction that bypasses the need for gastric acid. 1, 5
• Use alternate-day dosing if daily dosing is not tolerated—fractional iron absorption actually increases with alternate-day schedules because hepcidin elevation from the first dose blocks absorption for 24-48 hours. 5
• Take iron at least 1 hour away from tea or coffee, which strongly inhibit absorption. 1
• Morning dosing is superior to afternoon/evening dosing because the circadian increase in hepcidin is augmented by morning iron doses. 5

Alternative Oral Formulations

If ferrous sulfate causes intolerable gastrointestinal side effects (which are common and may worsen peptic ulcer symptoms), switch to ferrous gluconate or ferrous fumarate—these are equally effective but typically more expensive. 1

Monitoring and Expected Response

Check hemoglobin at 4 weeks; expect a rise of approximately 2 g/dL. 1

Red Flags for Treatment Failure

• Hemoglobin rise <1 g/dL after 2-4 weeks predicts overall treatment failure with 90.1% sensitivity and 79.3% specificity. 1
• Failure to achieve this response in a PPI user strongly suggests that acid suppression has rendered oral iron ineffective. 2, 3

When to Switch to Intravenous Iron

Do not persist with oral iron beyond 4 weeks without a hemoglobin response in patients on PPIs or H2-blockers. 1

Absolute Indications for IV Iron in This Population

• Failure of ferritin to improve after 4 weeks of adherent oral therapy despite vitamin C co-administration. 1
• Hemoglobin <10 g/dL with active peptic ulcer disease, where rapid correction is needed. 6
• Documented intolerance to at least two different oral iron preparations. 1
• Ongoing occult bleeding from the ulcer that exceeds oral replacement capacity. 1

Preferred IV Iron Formulations

Choose IV iron preparations that can replace iron deficits in 1-2 infusions rather than multiple infusions. 1

• Ferric carboxymaltose: 750-1000 mg per 15-minute infusion; two doses ≥7 days apart provide 1500 mg total. 1
• Ferric derisomaltose: 1000 mg as a single infusion. 1
• Avoid iron dextran as first-line due to higher anaphylaxis risk (though true anaphylaxis with any IV iron is rare at 0.6-0.7%). 6, 1

Critical Pitfall: Do Not Attribute Iron Deficiency Solely to PPI Use

A complete gastrointestinal investigation must exclude malignancy and other bleeding sources before attributing iron deficiency solely to PPI-induced malabsorption. 1

Required Diagnostic Work-Up

• Upper endoscopy and colonoscopy are mandatory in adult men and post-menopausal women to exclude occult bleeding sources; PPI use does not eliminate the need for cancer screening. 1
• Celiac disease screening with anti-endomysial antibodies and IgA measurement, as this common malabsorption cause may coexist with PPI therapy. 1
• Assess for microscopic hematuria to rule out renal tract pathology. 1
• Evaluate additional contributors: menstrual blood loss, blood donation, inadequate dietary intake, chronic NSAID use, prior gastrointestinal surgery. 1

Duration of Iron Therapy

Continue iron supplementation for 3 months after hemoglobin normalizes to fully replenish iron stores—total treatment duration is typically 6-7 months. 1

Long-Term Monitoring

• Monitor hemoglobin and red-cell indices every 3 months during the first year, then again after the second year. 1
• Review the necessity of ongoing PPI therapy at least annually, because prolonged use increases the risk of recurrent iron deficiency. 1

Management of PPI/H2-Blocker Therapy

Do not discontinue the PPI or H2-blocker without first addressing its underlying indication (gastro-esophageal reflux disease, peptic ulcer disease, Barrett's esophagus). 1

• Once the peptic ulcer has healed (typically 4-8 weeks), consider stepping down to the lowest effective dose of acid suppression or switching to an H2-blocker if appropriate. 1
• If iron deficiency recurs after stopping acid suppression, this suggests the PPI was indeed the primary cause. 4

Special Consideration: Rare Gastric Ulceration from Oral Iron

While extremely rare, prolonged oral iron therapy itself can cause gastric ulceration through direct mucosal injury and iron deposition. 7 This creates a vicious cycle in patients with pre-existing peptic ulcer disease. If symptoms worsen on oral iron despite adequate ulcer treatment, consider endoscopic re-evaluation and switch to IV iron. 7

Algorithm for Iron Supplementation in Peptic Ulcer Disease

1. Start PPI/H2-blocker for ulcer healing + ferrous sulfate 200 mg once daily in the morning + vitamin C 500 mg. 1
2. Check hemoglobin at 4 weeks—expect ≥2 g/dL rise. 1
3. If hemoglobin rise <1 g/dL: verify adherence, then switch to IV iron (ferric carboxymaltose or ferric derisomaltose). 1, 2, 3
4. Continue iron for 3 months after hemoglobin normalizes. 1
5. Once ulcer healed, consider stepping down acid suppression to lowest effective dose. 1
6. Monitor hemoglobin every 3 months for first year. 1

Common Pitfalls to Avoid

• Do not use multiple daily doses of oral iron—this increases side effects without improving efficacy due to hepcidin-mediated absorption blockade. 1, 5
• Do not continue oral iron beyond 4 weeks without response in PPI users—switch to IV iron promptly. 1, 2
• Do not stop iron therapy when hemoglobin normalizes—continue for 3 months to replenish stores. 1
• Do not overlook vitamin C supplementation—this is critical when gastric acid is suppressed. 1, 5
• Do not attribute iron deficiency solely to PPI use until malignancy is excluded. 1
• Do not discontinue PPI/H2-blocker abruptly—address the underlying indication first. 1