What is Hypochromic Microcytic Anemia?
Hypochromic microcytic anemia is a type of anemia characterized by red blood cells that are smaller than normal (microcytic, MCV <80 fL in adults) and contain reduced hemoglobin content (hypochromic), resulting from defective hemoglobin synthesis most commonly due to disorders of iron metabolism or, less frequently, heme synthesis defects. 1, 2
Pathophysiology
The fundamental problem in hypochromic microcytic anemia is impaired hemoglobin production within developing red blood cells. 3, 4
When iron is lacking, both heme and globin synthesis slow, erythropoiesis becomes impaired, and reticulocytes emerging from bone marrow are few, poorly hemoglobinized, and small, eventually resulting in hypochromic microcytic anemia. 3
The reduced hemoglobin content per red cell reflects defective iron handling by erythroblasts during the critical iron-dependent period of red cell maturation. 4
In normal erythropoiesis, iron is essential for the hemoglobin-building steps that follow rapid cell division; without adequate iron, this process fails. 3
Primary Causes
Most Common Causes
Iron deficiency anemia is the most common cause of microcytic anemia worldwide, accounting for approximately 80% of cases. 1, 2
Nutritional iron deficiency, iron loss from gastrointestinal bleeding, and iron malabsorption are the primary mechanisms. 5
Anemia of chronic disease causes functional iron deficiency through iron sequestration rather than true depletion, characterized by elevated ferritin with low serum iron, and is particularly significant in hospitalized patients and elderly populations. 5, 1
Inflammatory cytokines stimulate hepatic release of hepcidin, which blocks iron absorption in the gut and iron release from macrophages, promoting iron-deficiency erythropoiesis even when total body iron stores are adequate. 3
Hemoglobinopathies
Thalassemia syndromes cause microcytic anemia due to defects in globin chain synthesis rather than iron deficiency. 1, 6
These should be considered in patients with particularly low MCV in the absence of systemic iron deficiency. 6
Genetic Disorders of Iron Metabolism and Heme Synthesis
When ferritin is elevated and/or transferrin saturation is abnormal, or when anemia is refractory to iron supplementation, consider genetic disorders such as iron refractory iron-deficiency anemia (IRIDA), hypotransferrinemia, DMT1 deficiency, and sideroblastic anemias. 5
DMT1 deficiency (SLC11A2 defects) causes microcytic anemia with paradoxical systemic iron loading, presenting at birth with increased transferrin saturation, and liver iron loading develops despite normal or mildly increased ferritin. 5, 3
SLC25A38 deficiency causes severe congenital sideroblastic anemia, presenting with transfusion-dependent microcytic hypochromic anemia in childhood, with bone marrow showing ring sideroblasts and elevated ferritin and transferrin saturation. 5, 3
Hypotransferrinemia due to transferrin gene defects presents with hypochromic microcytic anemia, low iron binding capacity (low serum transferrin), and increased ferritin concentrations. 3
STEAP3 defects cause hypochromic sideroblastic anemia with low or normal MCV, sometimes combined with gonadal dysfunction. 3
ABCB7 defects present in males with mild microcytic anemia and ataxia, with increased protoporphyrin IX in red blood cells. 3
Clinical Presentation
Patients typically present with symptoms of anemia including fatigue, weakness, pallor, and dyspnea on exertion. 1
The severity ranges from asymptomatic mild anemia detected on routine laboratory testing to severe transfusion-dependent anemia in genetic disorders. 3, 6
Family history of anemia refractory to iron supplementation, neurologic disease, or skin photosensitivity should raise suspicion for genetic disorders. 5
Critical Diagnostic Pitfalls
Do not start empiric oral iron therapy when ferritin is elevated, as this could worsen iron overload in sideroblastic anemia or genetic disorders. 5
Serum ferritin may be elevated in inflammatory conditions despite concurrent iron deficiency, potentially masking true iron depletion. 5, 7
Ferritin is an acute phase reactant and can be falsely elevated in inflammation, infection, malignancy, or liver disease. 7
Do not assume dietary insufficiency or ethnic background explains microcytosis without laboratory confirmation—hemoglobinopathies must be confirmed by laboratory testing, not presumed based on ethnicity alone. 7