What are the differential diagnoses for a low mean corpuscular volume (microcytic anemia)?

Differential Diagnosis for Low MCV (Microcytic Anemia)

Primary Causes

Iron deficiency anemia is the most common cause of microcytic anemia and should be your first diagnostic consideration. 1, 2, 3 The diagnosis is confirmed by serum ferritin <15 μg/L (99% specific) or <30 μg/L indicating depleted iron stores. 1 When ferritin is borderline (30–100 μg/L) or potentially elevated by inflammation, transferrin saturation <16–20% confirms iron deficiency. 1

Iron Deficiency Anemia

• Serum ferritin is the single most powerful test for diagnosing iron deficiency, with levels <15 μg/L providing 99% specificity and <30 μg/L indicating low body iron stores. 1
• A low MCV combined with RDW >14% strongly indicates iron deficiency anemia, whereas RDW ≤14% suggests thalassemia minor. 1
• Transferrin saturation <16% confirms iron deficiency even when ferritin appears falsely normal due to inflammation. 1
• In inflammatory states, ferritin up to 100 μg/L may still represent iron deficiency; add C-reactive protein to assess for inflammation. 1

Thalassemia Trait

• Thalassemia minor typically presents with MCV disproportionately low relative to the degree of anemia, normal or near-normal RDW (≤14%), and normal iron studies. 1
• Hemoglobin electrophoresis should be ordered when microcytosis persists despite normal iron studies, when MCV is markedly low relative to anemia severity, or in patients of African, Mediterranean, or Southeast Asian ancestry. 1
• Elevated hemoglobin A2 levels confirm beta-thalassemia trait. 3

Anemia of Chronic Disease

• Anemia of chronic disease is characterized by low serum iron, low total iron-binding capacity (TIBC), ferritin >100 μg/L, and transferrin saturation <20%. 1
• The MCV rarely falls below 70 fL in anemia of chronic disease; severe microcytosis (MCV <70 fL) strongly favors iron deficiency or thalassemia. 4
• Elevated inflammatory markers (CRP, ESR) support this diagnosis. 1

Sideroblastic Anemia

• X-linked sideroblastic anemia (ALAS2 defects) should be considered when there is microcytosis with elevated ferritin and/or transferrin saturation. 1
• Initial treatment is pyridoxine (vitamin B6) 50–200 mg daily, with lifelong supplementation at 10–100 mg daily if responsive. 1
• Ring sideroblasts on bone marrow examination with iron staining confirm the diagnosis. 1

Rare Genetic Causes

Iron-Refractory Iron Deficiency Anemia (IRIDA)

• IRIDA presents with remarkably low transferrin saturation, low-to-normal ferritin, and failure to respond to oral iron but may respond to intravenous iron. 1
• Caused by autosomal recessive TMPRSS6 mutations affecting hepcidin regulation. 1
• Requires repeated intravenous iron (iron sucrose or iron gluconate) rather than oral supplementation. 1

Other Genetic Disorders

• SLC11A2, STEAP3, SLC25A38, and ABCB7 defects should be considered with extreme microcytosis (MCV <70 fL), family history of refractory anemia, or elevated ferritin with microcytosis. 1
• Genetic testing is indicated when standard treatments fail or family history suggests inherited disorders. 1

Diagnostic Algorithm

1. Initial Testing:

• Order serum ferritin, complete blood count with RDW, and C-reactive protein simultaneously. 1
• Calculate transferrin saturation (serum iron ÷ TIBC). 1

2. Interpretation:

• Ferritin <30 μg/L + RDW >14% → Iron deficiency anemia; investigate bleeding sources. 1
• Ferritin >30 μg/L + RDW ≤14% → Thalassemia trait; proceed to hemoglobin electrophoresis. 1
• Low iron + low TIBC + ferritin >100 μg/L → Anemia of chronic disease. 1
• Elevated ferritin + microcytosis → Consider sideroblastic anemia or genetic iron metabolism disorders. 1

3. Equivocal Ferritin (30–100 μg/L):

• Add transferrin saturation; <16–20% confirms iron deficiency. 1
• Measure CRP to identify inflammation that may falsely elevate ferritin. 1

4. Normal Iron Studies:

• Order hemoglobin electrophoresis to evaluate for thalassemia or hemoglobinopathy. 1
• Consider genetic testing if extreme microcytosis or family history present. 1

Critical Pitfalls to Avoid

• Do not rely on serum iron alone—it shows significant day-to-day variability and overlaps between different causes of microcytic anemia. 1
• Do not assume all microcytic anemia is iron deficiency—anemia of chronic disease, thalassemia, and sideroblastic anemia require different management. 1
• Do not use hemoglobin electrophoresis as a first-line test—it is costly and unnecessary when iron studies are abnormal. 1
• Do not give iron therapy when ferritin is markedly elevated without clearly establishing true iron deficiency, as this may cause iron overload. 4
• Recognize that approximately 50% of thalassemia cases can show elevated RDW, so RDW alone cannot definitively exclude thalassemia. 1