What are microcytes?

What Are Microcytes

Microcytes are abnormally small red blood cells with a mean corpuscular volume (MCV) less than 80 fL in adults, typically appearing hypochromic (pale) on peripheral blood smear due to reduced hemoglobin content. 1, 2

Definition and Laboratory Criteria

• Microcytosis is defined by MCV < 80 fL in adults, though age-specific parameters should be applied for patients younger than 17 years 2, 3
• The small cell size reflects defective hemoglobin synthesis in erythroid precursors, most commonly from inadequate iron availability, impaired heme production, or defective globin chain synthesis 1, 4
• Microcytes often appear hypochromic (pale) on blood smear because the reduced hemoglobin content creates increased central pallor 1

Common Causes of Microcytosis

The differential diagnosis follows a clear hierarchy based on prevalence:

Iron Deficiency (Most Common)

• Iron deficiency anemia accounts for 35–40% of microcytosis cases, making it the single most frequent etiology even in populations pre-selected for hemoglobinopathy evaluation 5, 3
• Characterized by depleted iron stores (ferritin < 30 µg/L), low serum iron, elevated total iron-binding capacity, and transferrin saturation < 16% 6, 3
• RDW > 14% combined with low MCV strongly indicates iron deficiency rather than thalassemia, because the mixed population of older normocytic and newer microcytic cells creates size variability 6, 7

Thalassemia Trait (Second Most Common)

• α-thalassemia represents approximately 31% of microcytosis cases, followed by β-thalassemia trait at 19% 5
• Distinguished by RDW ≤ 14% with marked microcytosis, reflecting uniformly small red cells 6, 7
• Normal or elevated ferritin with disproportionately low MCV relative to anemia severity suggests thalassemia over iron deficiency 6, 3
• β-thalassemia trait shows elevated hemoglobin A2 levels on electrophoresis 3

Anemia of Chronic Disease

• Presents with elevated ferritin (> 100 µg/L), low transferrin saturation (< 20%), and low serum iron due to inflammatory cytokine-mediated iron sequestration 6, 3
• Microcytosis is less pronounced than in iron deficiency 3

Less Common Causes

• Sideroblastic anemia (inherited or acquired) 6, 2
• Lead toxicity 3
• Hemoglobinopathies (HbC, HbE, HbS/C) account for approximately 1.3% of cases 5

Diagnostic Approach to Microcytosis

The initial test should be serum ferritin, as it provides the highest specificity for distinguishing iron deficiency from other causes 6, 3:

1. Ferritin < 15 µg/L → 99% specific for absent iron stores; confirms iron deficiency 6
2. Ferritin < 30 µg/L → indicates depleted iron stores consistent with iron deficiency 6, 7
3. Ferritin 30–100 µg/L with inflammation → may still represent iron deficiency; add transferrin saturation (< 16–20% confirms deficiency) 6
4. Ferritin > 100 µg/L → iron deficiency unlikely; consider thalassemia, anemia of chronic disease, or sideroblastic anemia 6

Secondary Testing When Ferritin Is Equivocal

• Add transferrin saturation, total iron-binding capacity, and C-reactive protein if ferritin is borderline or inflammation is suspected 6, 3
• Order hemoglobin electrophoresis when iron studies are normal, MCV is disproportionately low, or patient has Mediterranean, African, or Southeast Asian ancestry 6, 7
• Measure serum iron and TIBC together: low iron with high TIBC confirms iron deficiency; low iron with low TIBC suggests anemia of chronic disease 3

Key Diagnostic Pitfalls

• Do not assume all microcytosis is iron deficiency—thalassemia trait is nearly as common and requires no iron therapy 6, 5
• Ferritin can be falsely elevated by inflammation, infection, malignancy, or liver disease; in these contexts, transferrin saturation < 20% helps confirm true iron deficiency 6, 3
• Combined deficiencies (iron plus B12/folate) can produce a normal MCV because macrocytic and microcytic effects cancel out; an elevated RDW may be the only clue 6, 7
• Approximately 50% of thalassemia cases can show elevated RDW, so RDW alone cannot definitively exclude thalassemia 6
• Do not order hemoglobin electrophoresis as a first-line test—it is costly and unnecessary when iron studies are abnormal 6