What are the diagnostic criteria for iron deficiency and the first-line treatment?

Diagnostic Criteria for Iron Deficiency

Iron deficiency is diagnosed by serum ferritin <30 µg/L or transferrin saturation <16% in patients without inflammation; in the presence of inflammation, ferritin <100 µg/L with transferrin saturation <20% indicates iron deficiency. 1

Diagnostic Thresholds Without Inflammation

• Serum ferritin <30 µg/L defines iron deficiency in patients without biochemical or clinical evidence of inflammation 1
• Transferrin saturation <16% is a sensitive marker of iron deficiency, though it has low specificity 1
• Ferritin <15 µg/L indicates absolute iron deficiency with 99% specificity 1
• Ferritin <45 µg/L provides optimal balance between sensitivity and specificity for clinical practice 2

Diagnostic Thresholds With Inflammation

The presence of inflammation fundamentally changes ferritin interpretation because ferritin is an acute-phase reactant. 1

• Ferritin <100 µg/L is the appropriate lower limit consistent with normal iron stores when inflammation is present 1
• Ferritin 30-100 µg/L with transferrin saturation <16% indicates a combination of true iron deficiency and anemia of chronic disease 1
• Ferritin >100 µg/L with transferrin saturation <16% defines anemia of chronic disease (also called anemia of inflammation) 1
• Measure C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) to assess for inflammation when ferritin is 30-100 µg/L 3

First-Line Treatment

Oral ferrous sulfate 200 mg once daily is the preferred first-line treatment for iron deficiency anemia due to its effectiveness and low cost. 2

Oral Iron Therapy Protocol

• Prescribe ferrous sulfate 200 mg (containing 65 mg elemental iron) once daily, not multiple times per day 2
• Once-daily dosing improves tolerance while maintaining equal or better iron absorption compared to multiple daily doses due to hepcidin regulation 2
• Add vitamin C (ascorbic acid) 500 mg with each iron dose to enhance absorption, especially when transferrin saturation is severely low 2
• Take on an empty stomach for optimal absorption; taking with food is acceptable if gastrointestinal side effects occur 2
• Alternative formulations (ferrous fumarate or ferrous gluconate) are equally effective if ferrous sulfate is not tolerated 2

Expected Response and Monitoring

• Check hemoglobin at 4 weeks, expecting a rise of approximately 2 g/dL 2
• Continue oral iron for 3 months after hemoglobin normalizes to fully replenish iron stores; total treatment duration is typically 6-7 months 2
• Monitor hemoglobin and red cell indices every 3 months for the first year, then again after another year 2

When to Switch to Intravenous Iron

Intravenous iron should replace oral therapy when specific clinical criteria are met. 2

Absolute Indications for IV Iron

• Intolerance to at least two different oral iron preparations (ferrous sulfate, ferrous fumarate, and ferrous gluconate) 2
• Active inflammatory bowel disease with hemoglobin <10 g/dL, because inflammation-induced hepcidin elevation severely impairs oral iron absorption 2
• Failure of ferritin levels to improve after 4 weeks of compliant oral therapy 2
• Post-bariatric surgery patients due to disrupted duodenal absorption mechanisms 2
• Ongoing gastrointestinal blood loss exceeding oral replacement capacity 2

Relative Indications for IV Iron

• Celiac disease with inadequate response to oral iron despite strict gluten-free diet adherence 2
• Chronic kidney disease with functional iron deficiency (ferritin 100-300 ng/mL with transferrin saturation <20%) 2
• Chronic heart failure with iron deficiency (ferritin <100 ng/mL or 100-300 ng/mL with transferrin saturation <20%) 2

Preferred IV Iron Formulations

• Choose IV iron preparations that replace iron deficits in 1-2 infusions rather than multiple infusions to minimize risk 2
• Ferric carboxymaltose (500-1000 mg single doses delivered within 15 minutes) is a preferred formulation 2
• Iron dextran can be given as a total dose infusion but carries a higher risk of anaphylaxis (0.6-0.7%) 2
• All IV iron formulations have similar overall safety profiles; most reactions are complement activation-related pseudo-allergy (infusion reactions) rather than true anaphylaxis 2

Special Population Considerations

Inflammatory Bowel Disease

• In IBD patients with active inflammation and hemoglobin <10 g/dL, use IV iron as first-line treatment 2
• IV iron is more effective (odds ratio 1.57 for achieving 2.0 g/dL hemoglobin increase) and better tolerated than oral iron in IBD patients 2
• For mild anemia (hemoglobin >10 g/dL) with clinically inactive disease, oral iron may be appropriate 2
• Treat active inflammation effectively to enhance iron absorption or reduce iron depletion 2

Pregnant Women

• Start oral low-dose iron 30 mg/day at first prenatal visit for prevention 2
• Treat anemia with 60-120 mg/day elemental iron 2
• Refer pregnant women with hemoglobin <9.0 g/dL for further medical evaluation 2
• IV iron is indicated during second and third trimesters if oral iron fails 2, 4

Chronic Kidney Disease

• Functional iron deficiency is common and defined by ferritin 100-300 ng/mL with transferrin saturation <20% 2
• IV iron is preferred for dialysis patients; either IV or oral iron for non-dialysis CKD stages 3-5 2

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 2
• Do not stop iron therapy when hemoglobin normalizes—continue for 3 months to replenish stores 2
• Do not continue oral iron beyond 4 weeks without hemoglobin rise—reassess for non-adherence, malabsorption, or ongoing blood loss and switch to IV iron 2
• Do not overlook vitamin C supplementation when oral iron response is suboptimal 2
• Do not fail to identify and treat the underlying cause of iron deficiency while supplementing 2
• Do not use oral iron in active IBD patients with hemoglobin <10 g/dL—IV iron is the appropriate first-line option 2

Algorithm for Non-Response to Oral Iron

If hemoglobin fails to rise by 2 g/dL after 4 weeks of oral iron: 2

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