A patient taking iron polysaccharide 150 mg twice daily for three to four months has persistently low ferritin that has decreased; what could be causing this?

Failure of Oral Iron Therapy: Diagnostic Approach

Most Likely Explanation: Ongoing Blood Loss or Malabsorption

The most probable reason for declining ferritin (17→13 ng/mL) despite 3-4 months of iron polysaccharide 150mg BID is ongoing blood loss exceeding iron absorption, or a primary malabsorption disorder. 1

Iron polysaccharide is demonstrably inferior to ferrous sulfate for treating iron deficiency, with significantly lower hemoglobin increases (1.0 g/dL less) and ferritin restoration (10.2 ng/mL less improvement) at 12 weeks. 2 In one study, iron polysaccharide was associated with the smallest rise in mean hematocrit among four oral iron preparations tested in hemodialysis patients. 1

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Immediate Diagnostic Workup Required

1. Switch to Ferrous Sulfate Immediately

• Replace iron polysaccharide with ferrous sulfate 300 mg three times daily (providing ~200 mg elemental iron/day), as this is the evidence-based first-line oral iron preparation. 1, 2
• Iron polysaccharide provides no tolerability advantage over ionic iron salts despite being more expensive and less effective. 1
• Take ferrous sulfate on an empty stomach (at least 2 hours before or 1 hour after meals) to maximize absorption, as food reduces iron absorption by up to 50%. 1

2. Investigate for Occult Blood Loss

• Order fecal occult blood testing immediately and consider upper and lower endoscopy, particularly if the patient is >50 years old or has any gastrointestinal symptoms. 1
• A declining ferritin during iron supplementation strongly suggests ongoing iron loss exceeding absorption—blood losses can easily outpace even optimal oral iron therapy. 1
• Common sources include gastrointestinal bleeding (ulcers, gastritis, colon polyps/cancer, inflammatory bowel disease), menorrhagia in women, or chronic hematuria. 1

3. Evaluate for Malabsorption

• Check tissue transglutaminase (TTG) antibodies to screen for celiac disease, which impairs duodenal iron absorption. 1
• Consider inflammatory bowel disease if there are any gastrointestinal symptoms, as chronic inflammation both causes blood loss and impairs iron absorption. 1
• Assess medication history: proton pump inhibitors and H2-blockers reduce gastric acid needed for iron absorption; aluminum-based phosphate binders directly chelate iron. 1

4. Measure Inflammatory Markers

• Order C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) to detect occult inflammation. 1
• Ferritin is an acute-phase reactant that rises with inflammation independent of iron stores, but in this case the declining ferritin argues against pure inflammatory block. 1
• If CRP is elevated with low transferrin saturation (<20%), this suggests anemia of chronic inflammation where iron is sequestered and oral supplementation will fail. 1

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Critical Pitfalls to Avoid

• Do not continue iron polysaccharide—it is inferior to ferrous sulfate by every efficacy measure, with lower hemoglobin response, lower ferritin restoration, and no proven tolerability benefit. 1, 2
• Do not assume compliance failure alone—while adherence should be verified, a declining ferritin during treatment strongly indicates either inadequate absorption or ongoing loss exceeding intake. 1
• Do not overlook gastrointestinal malignancy—any adult with unexplained iron deficiency warrants endoscopic evaluation, especially when iron therapy fails. 1
• Do not check ferritin alone—always measure transferrin saturation simultaneously to distinguish true iron deficiency (TSAT <20%, ferritin <100 ng/mL) from inflammatory iron sequestration. 1

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When to Consider Intravenous Iron

• If ferritin remains <100 ng/mL after 3 months of optimal ferrous sulfate therapy (300 mg TID, taken correctly on empty stomach), switch to intravenous iron. 1
• IV iron is immediately indicated if the patient has inflammatory bowel disease, chronic kidney disease, or documented malabsorption where oral iron predictably fails. 1
• In hemodialysis patients, oral iron cannot meet the combined demands of erythropoietin-stimulated erythropoiesis plus dialysis-associated blood losses—IV iron is required. 1

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Monitoring Plan

• Recheck ferritin and transferrin saturation after 3 months of ferrous sulfate therapy to confirm iron store repletion (target ferritin >100 ng/mL, TSAT >20%). 1
• Continue supplementation for at least 3 months to fully replenish stores, not just until hemoglobin normalizes. 1
• If ferritin continues declining despite optimal ferrous sulfate and negative workup for blood loss/malabsorption, proceed to IV iron therapy. 1