When should iron supplementation be initiated in patients with documented iron deficiency or high risk for deficiency?

When to Start Iron Supplementation

Iron supplementation should be initiated immediately upon diagnosis of iron deficiency (ferritin <30 ng/mL without inflammation, or <100 ng/mL with inflammation) or iron deficiency anemia, without waiting for completion of diagnostic workup. 1

Diagnostic Thresholds for Starting Iron

In Patients Without Inflammation

• Start iron when ferritin <30 ng/mL regardless of hemoglobin level 2, 1
• Transferrin saturation <16-20% also indicates iron deficiency requiring treatment 2, 1
• Ferritin <15 ng/mL has 99% specificity for absolute iron deficiency 1

In Patients With Inflammation

• Start iron when ferritin <100 ng/mL AND transferrin saturation <20% 2
• Ferritin 30-100 ng/mL with low transferrin saturation suggests combined iron deficiency and anemia of chronic disease, which still requires iron supplementation 2, 1

Anemia Definitions

• Women: hemoglobin <12.0 g/dL 2, 1
• Men: hemoglobin <13.0 g/dL 2, 1
• Children 0.5-5 years: hemoglobin <11.0 g/dL 2
• Children 5-12 years: hemoglobin <11.5 g/dL 2
• Children 12-15 years: hemoglobin <12.0 g/dL 2

First-Line Oral Iron Regimen

Prescribe ferrous sulfate 200 mg (65 mg elemental iron) once daily on an empty stomach as first-line therapy. 1 This is the most cost-effective formulation with efficacy equal to all other oral iron preparations. 1

Optimizing Oral Absorption

• Add vitamin C 500 mg with each iron dose to enhance absorption, especially critical when transferrin saturation is severely low 1, 3
• Take on an empty stomach for maximal absorption; if gastrointestinal side effects occur, may take with food 1
• Avoid tea and coffee within 1 hour of the dose, as these inhibit absorption 1
• Once-daily dosing is superior to multiple daily doses because hepcidin remains elevated for ~48 hours after iron intake, blocking subsequent absorption and increasing side effects without improving efficacy 1, 3, 4
• If daily dosing is not tolerated, alternate-day dosing (giving twice the daily dose every other day) increases fractional absorption and improves tolerance 1, 3

Alternative Oral Formulations

• Ferrous fumarate (106 mg elemental iron) or ferrous gluconate (38 mg elemental iron) are equally effective if ferrous sulfate is not tolerated 1, 4
• These alternatives are typically more expensive with no therapeutic advantage 1

Expected Response and Monitoring

• Check hemoglobin at 4 weeks: expect a rise of approximately 2 g/dL (20 g/L) 1, 5, 6
• Failure to achieve ≥1 g/dL rise by 2-4 weeks predicts treatment failure and warrants reassessment 1, 5
• Continue oral iron for 3 months after hemoglobin normalizes to fully replenish iron stores; total treatment duration is typically 6-7 months 1, 6
• Monitor hemoglobin and red-cell indices every 3 months during the first year, then annually 1

When to Switch to Intravenous Iron

Absolute Indications (Use IV Iron as First-Line)

• Active inflammatory bowel disease with hemoglobin <10 g/dL because inflammation-induced hepcidin severely impairs oral absorption 2, 1
• Intolerance to at least two different oral iron preparations (e.g., ferrous sulfate and ferrous fumarate) 1, 7
• Post-bariatric surgery patients due to disrupted duodenal absorption mechanisms 2, 1
• Chronic kidney disease patients on hemodialysis 2

Relative Indications for IV Iron

• Ferritin fails to improve after 4 weeks of compliant oral therapy 1
• 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, 7
• Ongoing gastrointestinal blood loss exceeding oral replacement capacity 1
• Severe symptomatic anemia requiring rapid correction 1

Preferred Intravenous Iron Formulations

Choose IV iron preparations that can replace the iron deficit in 1-2 infusions to minimize risk and improve convenience. 1, 7

• Ferric carboxymaltose: 750-1000 mg per 15-minute infusion; two doses ≥7 days apart provide 1500 mg total 1, 7
• Ferric derisomaltose: 1000 mg as a single infusion 1
• Avoid iron dextran as first-line due to higher anaphylaxis risk (0.6-0.7%), though true anaphylaxis with any IV iron is rare 1, 8
• All IV iron must be administered in a setting with resuscitation equipment available 2, 7
• Monitor patients for at least 30 minutes after infusion 7

Special Population Considerations

Inflammatory Bowel Disease

• IV iron is first-line when hemoglobin <10 g/dL with active inflammation because oral iron is poorly absorbed and may worsen inflammation 2, 1
• For mild anemia (hemoglobin >10 g/dL) with quiescent disease, oral iron may be used 2, 1
• Treat active inflammation to enhance iron absorption 2, 1
• Re-treat when ferritin drops below 100 ng/mL or hemoglobin falls below 12 g/dL (women) or 13 g/dL (men) 2

Chronic Kidney Disease

• Non-dialysis CKD patients: Start iron when TSAT ≤30% and ferritin ≤500 ng/mL if not on ESA therapy 2
• Hemodialysis patients: IV iron is preferred route 2
• Peritoneal dialysis patients: Either oral or IV iron acceptable 2
• Maintain ferritin ≥100 ng/mL and TSAT ≥20% in patients with hemoglobin <11 g/dL 2

Pregnancy

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

Premenopausal Women

• Assess menstrual blood loss first, as menorrhagia accounts for iron deficiency in 5-10% of menstruating women 1
• Screen for celiac disease with tissue transglutaminase IgA antibodies 1
• Gastrointestinal endoscopy is not indicated in women <45 years without upper GI symptoms, alarm features, or family history of colon cancer 1

Adult Men and Postmenopausal Women

• Urgent bidirectional endoscopy (upper endoscopy + colonoscopy) is required because iron deficiency may be the sole manifestation of gastrointestinal malignancy 1
• Do not delay iron supplementation while awaiting endoscopy unless colonoscopy is scheduled within days (iron can impair visualization) 1

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, 3, 4
• Do not stop iron therapy when hemoglobin normalizes; continue for an additional 3 months to replenish stores 1, 6
• Do not persist with oral iron beyond 4 weeks without hemoglobin rise; reassess for malabsorption, ongoing loss, or need for IV iron 1, 5
• Do not overlook vitamin C supplementation when oral iron response is suboptimal 1, 3
• Do not fail to identify and treat the underlying cause of iron deficiency while providing supplementation 1, 5
• Do not use oral iron in active IBD patients with hemoglobin <10 g/dL; IV iron is the appropriate first-line option 2, 1
• Do not delay endoscopic evaluation in high-risk patients (men, postmenopausal women, age ≥50, alarm symptoms) as gastrointestinal malignancy may present solely with iron deficiency 1