What is the recommended iron replacement regimen for iron deficiency anemia, including when to use oral ferrous salts versus intravenous iron, appropriate dosing, duration of therapy, and monitoring parameters?

Iron Deficiency Replacement

First-Line Oral Iron Therapy

Ferrous sulfate 200 mg (65 mg elemental iron) taken once daily on an empty stomach is the gold-standard first-line treatment for iron deficiency anemia. 1

• Ferrous sulfate is the most cost-effective formulation, costing approximately £1.00 per 28-day supply compared to £47.60 for alternative preparations like ferric maltol 2
• No oral iron formulation has demonstrated superiority in efficacy or tolerability over ferrous sulfate 1, 2
• Alternative ferrous salts (ferrous fumarate 106 mg elemental iron or ferrous gluconate 37–38 mg elemental iron) may be substituted if ferrous sulfate is not tolerated, though evidence does not support improved tolerability 1, 2

Optimal Dosing Strategy

Once-daily dosing is superior to multiple daily doses because iron intake triggers hepcidin elevation that persists for 48 hours, blocking subsequent absorption by 35–45% and increasing gastrointestinal side effects without improving efficacy. 1, 2

• Alternate-day dosing (every other day) with 100–200 mg elemental iron markedly increases fractional iron absorption compared to daily dosing and reduces side effects while maintaining efficacy 1, 2
• Take iron on an empty stomach 1–2 hours before or after meals for maximal absorption 1, 2
• Co-administer vitamin C 500 mg with each iron dose to enhance absorption, especially when transferrin saturation is severely low 1
• Avoid tea and coffee within 1 hour of iron intake, as they inhibit absorption 1

Formulations to Avoid

• Do not prescribe modified-release iron preparations—they release iron beyond the duodenum (the primary absorption site) and are classified as "less suitable for prescribing" by the British National Formulary 2
• Do not rely on multivitamin products containing ≤14 mg elemental iron, as they are insufficient for treating iron deficiency anemia 1, 2

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Expected Response and Monitoring

Hemoglobin should rise by approximately 2 g/dL (20 g/L) after 3–4 weeks of treatment. 1

• Re-check hemoglobin at 2 weeks; an increase of ≥10 g/L predicts treatment success with 90% sensitivity and 79% specificity 2
• If hemoglobin fails to rise by ≥10 g/L at 2 weeks, this strongly predicts treatment failure—investigate for non-adherence, ongoing blood loss, malabsorption, or concurrent vitamin B12/folate deficiency 2
• Continue oral iron for 3 months after hemoglobin normalizes to fully replenish iron stores, resulting in a total treatment duration of 6–7 months 1
• Monitor hemoglobin and red-cell indices every 3 months during the first year, then again after another year 1

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Indications for Intravenous Iron

Switch to intravenous iron when oral therapy fails or is contraindicated—do not persist with ineffective oral iron beyond 4 weeks. 1

Absolute Indications

• Active inflammatory bowel disease with hemoglobin <10 g/dL: inflammation-driven hepcidin elevation markedly impairs oral absorption, and oral iron may exacerbate intestinal inflammation 3, 1
• Intolerance to at least two different oral iron formulations (e.g., ferrous sulfate and ferrous fumarate or gluconate) 1
• Ferritin fails to improve after 4 weeks of compliant oral therapy 1
• Post-bariatric surgery patients: duodenal absorption is disrupted by anatomic changes 1

Relative Indications

• Celiac disease with inadequate response to oral iron despite strict gluten-free diet adherence 1
• Chronic heart failure with iron deficiency (ferritin <100 ng/mL or 100–300 ng/mL with transferrin saturation <20%), where IV iron improves symptoms and quality of life 1
• Ongoing gastrointestinal blood loss exceeding the replacement capacity of oral iron 1
• Chronic kidney disease with functional iron deficiency (ferritin 100–300 ng/mL with transferrin saturation <20%); IV iron is preferred for dialysis patients 1

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Preferred Intravenous Iron Formulations

Choose IV iron products that can replenish the iron deficit in 1–2 infusions to minimize infusion-related risk and improve convenience. 1

• Ferric carboxymaltose: 750–1000 mg per 15-minute infusion; two doses given ≥7 days apart provide a total of 1500 mg 1
• Ferric derisomaltose: 1000 mg can be delivered as a single infusion 1
• Avoid iron dextran as first-line due to higher anaphylaxis risk (0.6–0.7%); most infusion reactions are complement-activation pseudo-allergies (CARPA) that respond to slower infusion rates 1, 4
• All IV iron formulations share a comparable overall safety profile; true anaphylaxis is very rare 1, 4
• Administer IV iron in a setting equipped with resuscitation equipment 1

Safety Considerations

• Most adverse events are infusion-related pseudo-allergic reactions rather than true anaphylaxis; manage with antihistamines and corticosteroids, not epinephrine 2
• Hypophosphatemia (the 6H syndrome: hyperphosphaturic hypophosphatemia triggered by high FGF23 causing hypovitaminosis D, hypocalcemia, and secondary hyperparathyroidism) affects 50–74% of patients treated with ferric carboxymaltose and can cause bone pain, osteomalacia, and fractures 4
• Check serum phosphate before retreatment in patients at risk or when repeat dosing is planned within 3 months 2

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Special Population Considerations

Inflammatory Bowel Disease

• IV iron is first-line when hemoglobin <10 g/dL with active inflammation, as oral iron is poorly absorbed and may worsen disease activity 3, 1
• For mild anemia (hemoglobin >10 g/dL) with clinically inactive disease, oral iron may be used if disease is truly quiescent 3
• Do not exceed 100 mg elemental iron per day in patients with IBD, as higher doses may trigger inflammation 3, 2
• After successful IV iron treatment, re-treat when serum ferritin drops below 100 µg/L or hemoglobin falls below 12 g/dL (women) or 13 g/dL (men) 3
• Monitor for recurrent iron deficiency every 3 months for at least 1 year after correction, then every 6–12 months thereafter 3, 2

Pregnant Women

• Start oral low-dose iron 30 mg/day at the first prenatal visit for prevention 1
• Treat anemia with 60–120 mg/day elemental iron 1
• Refer pregnant women with hemoglobin <9.0 g/dL for further medical evaluation 1
• IV iron is safe and effective during the second and third trimesters when oral iron fails 1

Chronic Kidney Disease

• Functional iron deficiency is defined by ferritin 100–300 ng/mL with transferrin saturation <20% 1
• IV iron is preferred for dialysis patients; either IV or oral iron for non-dialysis CKD stages 3–5 1
• Once GFR is <45 mL/min, IV iron becomes the preferred route for anemia treatment 2

Post-Bariatric Surgery

• IV iron is preferred due to disrupted duodenal absorption mechanisms 1
• Patients require 45–60 mg elemental iron daily from dedicated supplements, not multivitamins alone 2

Celiac Disease

• Ensure strict adherence to a gluten-free diet to improve iron absorption 1
• Screen with tissue transglutaminase IgA antibodies; celiac disease is present in 3–5% of iron-deficiency cases 1
• Progress to IV iron if iron stores do not improve despite dietary compliance 1

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Diagnostic Workup for Iron Deficiency Anemia

All adult males and post-menopausal females with confirmed iron deficiency anemia require gastrointestinal investigation (bidirectional endoscopy) to exclude malignancy. 1

• Upper endoscopy with small-bowel biopsies is advised because 2–3% of such patients have celiac disease 1
• Test for Helicobacter pylori and eradicate when positive in patients with recurrent iron deficiency anemia 1
• In premenopausal women, assess menstrual blood loss first; menorrhagia, pregnancy, and breastfeeding account for iron deficiency in 5–10% of menstruating women 1
• Reserve gastrointestinal investigation for premenopausal women with upper-GI symptoms, alarm features, or family history of colorectal cancer 1

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Critical Pitfalls to Avoid

• Do not prescribe multiple daily doses of oral iron—this increases side effects without improving efficacy due to hepcidin-mediated absorption blockade 1, 2
• Do not discontinue iron therapy when hemoglobin normalizes—continue for 3 months to replenish stores 1
• Do not persist with oral iron beyond 4 weeks without a hemoglobin rise—reassess for malabsorption, ongoing loss, or need for IV iron 1
• Do not use oral iron in active IBD patients with hemoglobin <10 g/dL—IV iron is the appropriate first-line option 3, 1
• Do not overlook vitamin C supplementation when oral iron response is suboptimal 1
• Do not fail to identify and treat the underlying cause of iron deficiency while providing supplementation 1
• Do not administer oral iron during active bleeding or immediately before scheduled endoscopy, as it can impair endoscopic visualization 1

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Algorithm for Non-Response to Oral Iron

1. Verify adherence to oral therapy 1
2. Evaluate for ongoing blood loss (e.g., occult GI bleeding) 1
3. Consider malabsorption syndromes (celiac disease, IBD, post-bariatric surgery) 1
4. Check for concurrent vitamin B12 or folate deficiency 1
5. Assess for systemic disease, bone-marrow pathology, or hemolysis 1
6. Transition to intravenous iron if oral therapy failure is confirmed 1