Treatment and Causes of Microcytic Anemia
Primary Causes
The most common cause of microcytic anemia is iron deficiency, followed by thalassemia trait, anemia of chronic disease, and hereditary disorders of iron metabolism or heme synthesis. 1, 2, 3
Major Etiologies:
- Iron deficiency anemia – Most frequent cause, resulting from blood loss (GI bleeding, menstruation), inadequate dietary intake, or malabsorption 1, 4, 5
- Thalassemia trait – Hereditary hemoglobinopathy, suggested when MCV is disproportionately low relative to anemia severity with normal iron studies 1, 4
- Anemia of chronic disease – Low iron with decreased total iron-binding capacity in inflammatory conditions 4, 5
- Hereditary sideroblastic anemia – X-linked (ALAS2 defects) or autosomal recessive (SLC25A38, STEAP3, SLC11A2 defects) 1, 6
- Iron-refractory iron deficiency anemia (IRIDA) – TMPRSS6 gene defects causing resistance to oral iron 1, 4
Diagnostic Algorithm
Initial Laboratory Assessment:
- Serum ferritin is the single most useful test: <15 μg/L indicates absent iron stores, <30 μg/L indicates low stores, and 45 μg/L provides optimal sensitivity/specificity for iron deficiency 1, 4
- RDW helps differentiate causes: RDW >14.0% with low MCV suggests iron deficiency; RDW ≤14.0% suggests thalassemia minor 1, 4
- Transferrin saturation should be added if ferritin is falsely elevated due to inflammation (ferritin up to 100 μg/L may still indicate iron deficiency in inflammatory states) 4
When Iron Studies Are Normal or Equivocal:
- Hemoglobin electrophoresis – Order if microcytosis persists with normal iron parameters, appropriate ethnic background, or MCV disproportionately low 4
- Genetic testing – Consider for extreme microcytosis (MCV <70), family history, or failure to respond to iron therapy 6, 4
Treatment Based on Etiology
Iron Deficiency Anemia (First-Line):
Oral ferrous sulfate 200 mg three times daily (providing 65 mg elemental iron per dose) is the standard treatment, continued for at least three months after anemia correction to replenish iron stores. 1, 4, 7
- Alternative oral formulations: Ferrous gluconate or ferrous fumarate if ferrous sulfate not tolerated 4
- Ascorbic acid can be added to enhance iron absorption 1
- Expected response: Hemoglobin should rise ≥10 g/L within 2 weeks, confirming iron deficiency 1, 4
- Avoid taking within 2 hours of tetracycline antibiotics due to absorption interference 7
When Oral Iron Fails:
Intravenous iron is indicated for malabsorption, intolerance to oral iron, or losses exceeding oral replacement capacity, with expected hemoglobin increase of at least 2 g/dL within 4 weeks. 4, 2
Hereditary Sideroblastic Anemia:
- X-linked sideroblastic anemia (ALAS2 defects): Initial pyridoxine 50-200 mg daily; if responsive, continue lifelong supplementation at 10-100 mg daily with regular monitoring for iron overload 1, 6
- SLC25A38 defects: Hematopoietic stem cell transplantation is the only curative option; symptomatic treatment includes transfusions and iron chelation 6, 4
- STEAP3 defects: Erythrocyte transfusions combined with erythropoietin, plus chelation therapy for systemic iron loading 6, 4
- SLC11A2 defects: Oral iron supplementation, erythropoietin, and/or transfusions based on individual needs; monitor with liver MRI as normal ferritin doesn't exclude liver iron loading 6, 4
Iron-Refractory Iron Deficiency Anemia (IRIDA):
Initial treatment with oral iron combined with ascorbic acid; if ineffective, intravenous iron (iron sucrose or iron gluconate) is required, with monitoring to keep serum ferritin below 500 μg/L to avoid toxicity. 1, 4
Myelodysplastic Syndrome with Ring Sideroblasts (MDS-RS):
Luspatercept has shown promising results, especially in patients with SF3B1 mutation. 1, 6
Management of Iron Overload
Phlebotomy is the preferred method for managing iron overload when tolerated; iron chelation therapy is recommended when phlebotomies are not tolerated. 1, 6
- Regular monitoring of ferritin, transferrin saturation, and liver enzymes is essential 1, 6
- Consider liver MRI to assess iron loading, particularly in genetic disorders 6, 4
Critical Pitfalls to Avoid
- Always investigate the source of iron loss in adults: Men with Hb <110 g/L or non-menstruating women with Hb <100 g/L warrant fast-track GI referral to exclude malignancy 4, 5
- Don't assume all microcytic anemia is iron deficiency: Differentiate from thalassemia, anemia of chronic disease, and sideroblastic anemia to avoid unnecessary iron therapy 4, 2
- Screen for combined deficiencies: Iron deficiency can coexist with B12 or folate deficiency 1
- Family screening and genetic counseling are important for hereditary forms 1, 6