What are the primary causes of microcytic anemia?

Causes of Microcytic Anemia

Primary Causes

Iron deficiency is the most common cause of microcytic anemia worldwide, accounting for approximately 80% of cases, followed by anemia of chronic disease, thalassemias, and sideroblastic anemia. 1, 2, 3

Iron Deficiency Anemia

• Nutritional deficiency, gastrointestinal blood loss, and malabsorption are the three main mechanisms leading to iron deficiency 1
• NSAID use is a particularly common cause of occult GI bleeding that clinicians should actively investigate 1
• Menstruation, pregnancy, and any source of chronic blood loss disrupt iron homeostasis, as the body's absorptive capacity cannot adequately compensate for significant losses 2
• Iron deficiency shows particularly high prevalence in infants, toddlers, premenopausal women, pregnant women, and elderly populations 3

Anemia of Chronic Disease

• This represents functional iron deficiency through iron sequestration rather than true depletion, characterized by elevated ferritin with low serum iron 1
• The mechanism involves blocking of iron absorption and release as a nonspecific defense mechanism during inflammation, which restricts iron availability for erythropoiesis 3
• This is particularly significant in hospitalized patients and elderly populations, where it can be easily confused with true iron deficiency 1, 4
• Associated conditions include cancer, chronic infections, and inflammatory diseases, with 50-70% presenting as normocytic but can be microcytic 5

Thalassemias and Hemoglobinopathies

• Should be considered when iron studies are normal, particularly in patients with very low MCV and elevated red cell count 1
• Beta thalassemia trait is a primary cause in pediatric populations 6
• These represent defects in globin gene synthesis rather than iron metabolism 6

Sideroblastic Anemia

• Rare inherited or acquired causes involving defects in heme synthesis 2, 6
• Can result from genetic disorders of iron metabolism or heme synthesis pathways 1, 6

Diagnostic Algorithm

Initial Laboratory Assessment

• Serum ferritin is the most powerful test for iron deficiency, with <12 μg/dL diagnostic of iron deficiency 1
• Mean cell volume (MCV) below 80 mcm³ in adults defines microcytic anemia (use age-specific parameters for patients under 17 years) 7
• A low MCV with exclusion of lead poisoning, infection, chronic inflammatory disease, and thalassemia minor serves as a specific index for iron-deficiency anemia 8

Differentiating Iron Deficiency from Other Causes

• Red blood cell distribution width (RDW) >14.0% with low MCV indicates iron-deficiency anemia, whereas RDW ≤14.0% with low MCV suggests thalassemia minor 8, 4
• Transferrin saturation <30% helps confirm iron deficiency diagnosis 1
• Erythrocyte sedimentation rate (ESR), zeta-sedimentation rate (ZSR), and C-reactive protein (CRP) are elevated in chronic disease but not in pure iron deficiency, helping differentiate these conditions 4
• Bone marrow examination showing absent iron stores remains the most definitive test, though serum markers can usually obviate this invasive procedure 2

When to Consider Genetic Disorders

• When ferritin is elevated and/or transferrin saturation is abnormal, or when anemia is refractory to iron supplementation, consider genetic disorders of iron metabolism or heme synthesis 1
• Iron-refractory iron-deficiency anemia (IRIDA) presents in childhood with microcytic anemia, remarkably low transferrin saturation, and low-to-normal ferritin, with failure to respond to oral iron 1
• DMT1 deficiency causes anemia with paradoxical systemic iron loading, presenting at birth with microcytic anemia and increased transferrin saturation 1

Common Pitfalls

Misdiagnosis in Special Populations

• In hospitalized and elderly patients, elevated inflammatory markers (ESR, CRP) should prompt consideration of anemia of chronic disease rather than assuming iron deficiency 4
• Ferritin can be falsely elevated in inflammatory conditions despite concurrent iron deficiency, potentially masking true iron deficiency 9

Overlooking Underlying Causes

• The cause of iron deficiency must always be sought - do not simply treat without investigating the source of blood loss or malabsorption 4
• In adults, particularly those over 50, iron deficiency should prompt evaluation for occult GI malignancy or other bleeding sources 1

Treatment Errors

• Therapeutic response to three weeks of oral iron or bone marrow aspiration are definitive for confirming iron deficiency when laboratory tests are equivocal 1
• The vast majority of patients respond to oral iron preparations; parenteral iron dextran is reserved for malabsorption, losses exceeding maximal oral replacement, or true intolerance 2
• Treatment must replete iron stores in addition to correcting the anemia, not just normalize hemoglobin 2