What does microcytic anemia indicate?

What Microcytic Anemia Indicates

Microcytic anemia most commonly indicates iron deficiency, but also signals the need to investigate for gastrointestinal blood loss, anemia of chronic disease, thalassemia, or rare genetic disorders of iron metabolism and heme synthesis. 1, 2

Primary Diagnostic Considerations

Iron Deficiency (Most Common Cause)

• Iron deficiency is the most common cause of microcytic anemia, resulting from nutritional deficiency, gastrointestinal blood loss, menstrual losses, or malabsorption. 2, 3, 4
• In adults, iron deficiency anemia is presumed to be caused by blood loss until proven otherwise, with the gastrointestinal tract being the most common source. 5
• The possibility of gastrointestinal malignancy must be considered in all adults with confirmed iron deficiency, particularly in men with hemoglobin <110 g/L and non-menstruating women with hemoglobin <100 g/L. 1, 5

Anemia of Chronic Disease (Second Most Common)

• Anemia of chronic disease causes functional iron deficiency through iron sequestration mediated by hepcidin upregulation in response to inflammatory cytokines, rather than true iron depletion. 2
• This condition is particularly significant in hospitalized patients, elderly populations, and those with cancer, infections, chronic inflammatory conditions, or kidney disease. 2
• Laboratory findings show elevated ferritin (>100 μg/L) with low serum iron and transferrin saturation <20%, distinguishing it from true iron deficiency. 1, 2

Thalassemia and Hemoglobinopathies

• Thalassemias should be considered when iron studies are normal, particularly with very low MCV and elevated red cell count. 2, 5
• A low MCV with RDW ≤14.0% suggests thalassemia minor, whereas RDW >14.0% indicates iron deficiency. 1, 2
• Hemoglobin electrophoresis should be ordered if microcytosis persists with normal iron studies, appropriate ethnic background, or MCV disproportionately low relative to degree of anemia. 1

Rare but Important Causes

Genetic Disorders of Iron Metabolism

• Iron-refractory iron deficiency anemia (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, 2
• DMT1 deficiency causes anemia with paradoxical systemic iron loading, presenting at birth with microcytic anemia and increased transferrin saturation. 2
• Congenital atransferrinemia shows transferrin markedly low or undetectable, serum iron low, ferritin elevated, and transferrin saturation essentially 100%. 1

Sideroblastic Anemias

• Sideroblastic anemias present with elevated ferritin and transferrin saturation even before transfusions, requiring bone marrow examination showing ring sideroblasts. 6, 2
• X-linked sideroblastic anemia (ALAS2 defects) may respond to pyridoxine (vitamin B6) 50-200 mg daily initially, then 10-100 mg daily lifelong if responsive. 1
• Unrecognized tissue iron loading in sideroblastic anemias leads to severe morbidity and mortality if not identified early. 2

Critical Clinical Implications

Mandatory Investigation of Underlying Cause

• Do not treat microcytic anemia with iron supplementation alone without investigating the source of iron loss. 1
• Adult males with hemoglobin <110 g/L and non-menstruating women with hemoglobin <100 g/L warrant fast-track gastrointestinal referral for both upper endoscopy and colonoscopy. 1
• Upper endoscopy with duodenal biopsies is mandatory to exclude celiac disease, which accounts for 2-3% of iron deficiency anemia cases. 1

Common Pitfalls to Avoid

• Do not assume all microcytic anemia is iron deficiency—anemia of chronic disease, thalassemia, and sideroblastic anemia require different management. 1, 2
• Do not rely on ferritin alone when inflammation is present; ferritin is an acute-phase reactant that can be falsely elevated by inflammation, infection, malignancy, or hepatic disease. 1, 6
• Do not overlook combined deficiencies—iron deficiency can coexist with vitamin B12 or folate deficiency, recognizable by elevated RDW. 1
• Do not attribute iron deficiency in adults solely to inadequate dietary intake; occult gastrointestinal blood loss, especially from malignancy, must be excluded. 1

Special Populations

• In elderly patients on antiplatelet therapy (e.g., clopidogrel), occult gastrointestinal blood loss is the most common cause of severe iron deficiency anemia, requiring immediate GI investigation even when overt bleeding is absent. 1
• NSAID use is a common cause of occult gastrointestinal blood loss leading to iron deficiency and should be specifically evaluated. 2
• In premenopausal women, heavy menstrual bleeding is the most common cause, but gastrointestinal evaluation is still required unless menstrual loss fully accounts for the anemia. 1