How should I manage a patient with iron‑deficiency anemia (low serum iron, high total iron‑binding capacity, low transferrin saturation, borderline ferritin) who is already taking ferrous sulfate 325 mg daily?

Management of Iron Deficiency Anemia Despite Oral Ferrous Sulfate

Switch to intravenous iron therapy, as your patient has demonstrated an inadequate response to oral ferrous sulfate 325 mg daily. 1, 2

Confirming Inadequate Response to Oral Iron

Your patient's iron panel showing persistent low serum iron, high TIBC, low transferrin saturation, and borderline ferritin after taking ferrous sulfate 325 mg daily confirms treatment failure. 3 A therapeutic response to oral iron should produce a hemoglobin increase of 1-2 g/dL within 3-4 weeks. 4 If this has not occurred, oral iron has failed. 4

Why Oral Iron Failed

Three primary reasons explain oral iron failure: 1, 2

• Poor adherence due to gastrointestinal side effects (constipation, nausea, abdominal pain) - occurs in up to 70% of patients 2
• Malabsorption from conditions like atrophic gastritis, celiac disease, inflammatory bowel disease, or prior bariatric surgery 1, 5
• Ongoing blood loss exceeding the rate of oral iron replacement 6, 2

Immediate Next Steps

1. Identify the Underlying Cause

Investigate for sources of blood loss, particularly gastrointestinal: 4

• Upper endoscopy with small bowel biopsies (2-3% of IDA patients have celiac disease) 4
• Colonoscopy even if upper endoscopy reveals pathology, as dual pathology occurs in 10-15% of patients 4
• Review medications: NSAIDs, anticoagulants, aspirin 4
• In women of reproductive age: assess for heavy menstrual bleeding 1
• Consider less common causes: inflammatory bowel disease (13-90% have iron deficiency), chronic kidney disease, heart failure 4, 1

2. Switch to Intravenous Iron

Intravenous iron is superior to oral iron and should be your next step. 4, 2 Multiple randomized trials demonstrate IV iron produces significantly greater hemoglobin responses than oral iron (73% vs 45% response rates). 4

IV Iron Formulations and Dosing

Choose from these FDA-approved options: 7, 8

Ferric carboxymaltose (Injectafer): 7

• For patients ≥50 kg: 750 mg IV × 2 doses separated by ≥7 days (total 1,500 mg per course)
• Alternative single-dose regimen: 15 mg/kg up to maximum 1,000 mg IV as single dose
• For patients <50 kg: 15 mg/kg IV × 2 doses separated by ≥7 days
• Administer over 15 minutes minimum

Iron sucrose (Venofer): 8

• 200 mg IV given 5 times over 14 days, OR
• 500 mg IV on Day 1 and Day 14 (infused over 3.5-4 hours)

Safety Considerations for IV Iron

Modern IV iron formulations are very safe, with serious adverse events occurring in <1:250,000 administrations. 4 However: 7

• Monitor patients for hypersensitivity reactions for at least 30 minutes after infusion 7
• Serious anaphylactic reactions occur in only 0.1% of patients 7
• Check serum phosphate levels before repeat courses, especially if administered within 3 months, as hypophosphatemia can occur 7
• Avoid extravasation (causes prolonged brown skin discoloration) 7

Interpreting Iron Studies in Context

Your patient's borderline ferritin requires careful interpretation: 4

• Without inflammation: Ferritin <30 ng/mL confirms iron deficiency 4
• With inflammation present: Ferritin up to 100 ng/mL may still indicate iron deficiency 4
• Transferrin saturation <20% with ferritin 30-100 ng/mL suggests combined iron deficiency and anemia of chronic disease 4

If your patient has chronic kidney disease, inflammatory bowel disease, heart failure, or cancer, use these thresholds: 4

• Iron deficiency likely if: TSAT <20% and ferritin <100 ng/mL 4
• Anemia of chronic disease if: ferritin >100 ng/mL and TSAT <20% 4

Common Pitfalls to Avoid

Do not continue oral iron indefinitely without response. 2 If hemoglobin has not increased by 1-2 g/dL after 3-4 weeks of oral iron, the patient needs IV iron or has ongoing blood loss. 4, 3

Do not assume dietary insufficiency explains the anemia. Even with poor dietary intake, complete GI evaluation is still required. 4

Do not delay IV iron due to unfounded safety concerns. The safety profile of modern IV iron formulations (ferric carboxymaltose, iron sucrose, ferric gluconate) is excellent, far superior to older high-molecular-weight iron dextran. 4, 2

Do not use ferritin alone in inflammatory conditions. In patients with CKD, heart failure, IBD, or cancer, ferritin can be falsely elevated; use transferrin saturation <20% as the primary diagnostic criterion. 4

Monitoring Response to IV Iron

Recheck complete blood count and iron studies 8-10 weeks after IV iron administration, not earlier, as ferritin levels are falsely elevated immediately post-infusion. 4 Expect hemoglobin to increase by 1-2 g/dL and ferritin to normalize. 8

If anemia recurs, repeat IV iron courses are safe and appropriate. 7 For patients requiring repeat treatment within 3 months, check serum phosphate levels before the next course. 7