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Iron Deficiency Anemia

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Iron Metabolism - Normal Physiology

• Daily dietary iron in the US: 10-20 mg; daily losses: 1-2 mg (shed epithelial/mucosal cells)
• Heme iron (animal products): ~20% absorbed. Non-heme iron (vegetables): only 1-2% absorbed
• Average daily requirement: 7-10 mg (males), 7-20 mg (females)
• Absorption is enhanced by ascorbic acid, citric acid, amino acids; inhibited by tannins (tea), carbonates, oxalates, phosphates

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Hepcidin - The Master Regulator

• Non-heme iron is reduced from Fe³⁺ to Fe²⁺ by ferrireductases (duodenal cytochrome B), then transported into enterocytes by DMT1
• Fe²⁺ exits the enterocyte via ferroportin, is oxidized by hephaestin/ceruloplasmin to Fe³⁺, and binds transferrin
• Hepcidin (hepatic peptide) binds ferroportin → endocytosis and degradation → traps iron in enterocytes → iron lost as cells slough
• In iron deficiency: hepcidin falls → increased absorption
• In chronic inflammation: hepcidin rises → iron sequestration in macrophages → anemia of chronic disease

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Etiology

Chronic blood loss is the most common cause in adult males and postmenopausal women in high-resource countries - GI malignancy must be excluded.

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Stages of Iron Deficiency

1. Storage depletion - serum ferritin falls, bone marrow iron disappears (Prussian blue stain negative)
2. Transport depletion - serum iron falls, TIBC rises, transferrin saturation falls (<15%)
3. Functional deficiency - hemoglobin synthesis impaired → microcytic, hypochromic anemia

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Morphology

• Small cells (microcytic)
• Pale/central pallor enlarged (normally 1/3 diameter; in IDA, hemoglobin seen only at rim)
• "Pencil cells" (elongated red cells) - characteristic
• Poikilocytosis

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Clinical Features

• Fatigue, pallor, weakness, dyspnea on exertion, palpitations

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Laboratory Diagnosis

Ferritin is the most sensitive and specific early marker. In pregnancy, a ferritin cutoff of 30 ng/mL gives 92% sensitivity and 98% specificity.

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Treatment

• Ferrous sulfate 325 mg (65 mg elemental iron) 1-3×/day
• Non-enteric-coated preparations preferred for absorption
• Take on empty stomach or with vitamin C to enhance absorption; avoid with tea/dairy/antacids
• Single daily dosing is as effective as multiple doses and has fewer GI side effects (important in pregnancy)
• Reticulocytosis appears in 5-7 days; hemoglobin rises over 6-8 weeks; continue therapy for 3-6 months after normalization to replenish stores

• Oral intolerance or malabsorption
• Severe anemia (Hgb <9 g/dL)
• Ongoing rapid blood loss
• Pregnancy: IV iron is the treatment of choice in the third trimester and for severe IDA (Hgb <9 g/dL) in the second trimester
• Formulations: ferric carboxymaltose, iron sucrose, low-molecular-weight iron dextran
• Note: A 2025 systematic review (PMID 39935027) identified hypophosphatemia as a significant adverse effect of ferric carboxymaltose (FCM)

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GI Work-up

• All adult males (any age)
• All postmenopausal women

1. Colonoscopy first
2. Upper endoscopy + push enteroscopy if colonoscopy negative
3. Duodenal biopsy for celiac disease
4. Test and treat H. pylori if found
5. Capsule endoscopy if all above are negative
6. Pursue non-GI causes if capsule study is also negative

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Special Populations

• Iron deficiency occurs in ~18% of US pregnancies; IDA in ~5%
• Severe anemia (<6-7 g/dL) associated with preterm birth, fetal mortality, PROM, gestational hypertension
• ACOG/WHO recommend at least 30 mg elemental iron daily; intermittent dosing (2-3×/week) reduces GI side effects while maintaining efficacy
• A 2024 USPSTF systematic review (PMID 39163033) examined screening and supplementation in pregnancy - supports universal supplementation recommendations

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Key Differentials (Microcytic Anemia)

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