When should iron replacement be initiated in patients with iron deficiency anemia?

When to Start Iron Replacement

Iron replacement should be initiated immediately upon diagnosis of iron deficiency, defined as ferritin <45 ng/mL in patients with anemia, or ferritin <30 μg/L in healthy individuals without inflammation. 1

Diagnostic Thresholds for Initiating Treatment

In Patients with Anemia

• Use ferritin <45 ng/mL as the diagnostic cut-off for iron deficiency in anemic patients, as this threshold optimizes sensitivity and specificity 1
• In patients with underlying inflammation or chronic kidney disease, ferritin up to 100 μg/L may still indicate iron deficiency despite the elevated acute phase reactant 1
• Confirm inflammation status by measuring C-reactive protein to avoid false-negative results 2
• Additional testing with transferrin saturation (<20%), soluble transferrin receptor, or reticulocyte hemoglobin may be needed when ferritin is 30-100 μg/L in inflammatory conditions 1

In Patients without Anemia

• For healthy adults >15 years: initiate treatment when ferritin <30 μg/L 2
• For adolescents 12-15 years: use ferritin <20 μg/L 2
• For children 6-12 years: use ferritin <15 μg/L 2
• Treatment of isolated iron deficiency without anemia remains somewhat controversial, but should be considered in symptomatic patients with fatigue, cognitive impairment, or reduced physical performance 2, 3

Route of Administration: Oral vs. Intravenous

Start with Oral Iron When:

• Disease is clinically inactive (particularly in inflammatory bowel disease) 1
• Anemia is mild (hemoglobin 10-12 g/dL in women, 10-13 g/dL in men) 1
• No prior intolerance to oral iron 1
• Patient can tolerate 8-10 weeks to achieve therapeutic goals 4

Oral iron dosing: 100-200 mg elemental iron daily, or as low as 28-50 mg daily to minimize gastrointestinal side effects 1, 2. Taking iron once daily or every other day improves tolerance without compromising efficacy, as hepcidin remains elevated for 48 hours after each dose 1

Start with Intravenous Iron When:

• Hemoglobin <10 g/dL (100 g/L) - this is severe anemia requiring rapid correction 1, 5
• Clinically active inflammatory bowel disease - oral iron may exacerbate mucosal inflammation and alter intestinal microbiota 1, 5
• Previous intolerance to oral iron (nausea, abdominal pain, constipation occur in 12-31% of patients) 1, 5
• Patients requiring erythropoiesis-stimulating agents - IV iron optimizes erythropoietic response 1, 5
• Hemodynamic instability or need for rapid correction (e.g., preoperatively, during pregnancy) 1, 5
• Malabsorption conditions (celiac disease, atrophic gastritis, bariatric surgery) 4, 5
• Oral iron fails to increase hemoglobin by ≥1 g/dL within 4-8 weeks 1, 5

IV iron dosing: Calculate based on hemoglobin and body weight using the Ganzoni formula, or give empiric 1000 mg total dose for mild anemia, 1500-2000 mg for moderate-severe anemia 1, 5

Special Populations Requiring Immediate Evaluation and Treatment

Mandatory Bidirectional Endoscopy Before or Concurrent with Treatment:

• All postmenopausal women and men with iron deficiency anemia - strong recommendation to detect gastrointestinal malignancy 1
• Premenopausal women with iron deficiency anemia - conditional recommendation, can defer if other plausible causes exist (heavy menstruation) and patient values avoiding endoscopy 1
• Test for Helicobacter pylori non-invasively and treat if positive 1
• Screen for celiac disease with transglutaminase antibody (IgA) and total IgA; perform small bowel biopsy only if serology positive 1

Inflammatory Bowel Disease:

• Monitor for recurrent iron deficiency every 3 months for at least one year after correction, then every 6-12 months 1
• Re-initiate IV iron when ferritin drops below 100 μg/L or hemoglobin falls below 12 g/dL (women) or 13 g/dL (men) 1, 5
• Target post-treatment ferritin levels of 400 μg/L to prevent rapid recurrence 1

Chronic Kidney Disease on Hemodialysis:

• FDA-approved indication for IV iron (ferric gluconate) in patients receiving supplemental epoetin therapy 6
• Adult dosing: 125 mg elemental iron per dialysis session 6
• Pediatric dosing (≥6 years): 1.5 mg/kg per dialysis session 6

Treatment Goals and Monitoring

Primary goals: Normalize hemoglobin levels AND replenish iron stores (ferritin within normal range) 1

Expected response:

• Hemoglobin increase of 1-2 g/dL within 4-8 weeks of IV iron 1, 5
• Oral iron requires 3-6 months to achieve therapeutic goals 4

Monitoring schedule:

• Recheck complete blood count and iron parameters 4-8 weeks after last infusion (for IV iron) 5
• For oral iron, reassess at 8-10 weeks 2
• Do not check iron parameters too early, as circulating iron interferes with assays 5

Critical Pitfalls to Avoid

• Never screen asymptomatic men or postmenopausal women for iron deficiency - but always evaluate them with gastrointestinal endoscopy if iron deficiency anemia is diagnosed 1, 7
• Do not administer iron during acute infection - withhold until infection resolves, though chronic inflammation is not a contraindication 5
• Avoid intramuscular iron - it is obsolete with no evidence of superiority over oral or IV routes 5
• Do not exceed 100 mg elemental iron daily in inflammatory bowel disease patients - higher doses increase side effects without improving absorption 1
• Do not give long-term iron supplementation when ferritin is normal or elevated - this is potentially harmful and may cause iron overload 2
• Do not mix IV iron with other medications or add to parenteral nutrition - administer only in 0.9% saline 6