What is microcytic hypochromic anemia?

What is Microcytic Hypochromic Anemia

Microcytic hypochromic anemia is a condition characterized by red blood cells that are smaller than normal (microcytic) and contain reduced hemoglobin concentration (hypochromic), resulting from defective iron handling by erythroblasts that decreases hemoglobin content per red cell. 1

Definition and Laboratory Characteristics

Microcytic anemia is defined by the presence of small red blood cells with a mean corpuscular volume (MCV) less than 80-83 fL. 2 The condition is characterized by several key laboratory findings:

• Low MCV (<80 fL) indicates red blood cells are smaller than normal 3
• Low mean corpuscular hemoglobin (MCH) confirms reduced hemoglobin content per red cell 3
• Low mean corpuscular hemoglobin concentration (MCHC) demonstrates hypochromia, indicating decreased hemoglobin concentration within red cells 3
• Red cells appear small and pale (hypochromic) on peripheral blood smear due to reduced hemoglobin content 2

Pathophysiology

The fundamental defect in microcytic hypochromic anemia involves impaired hemoglobin synthesis, which can result from defects in globin chains (hemoglobinopathies or thalassemias), heme synthesis, or iron availability/acquisition by erythroid precursors. 4

In iron deficiency specifically, the absence of adequate iron leads to decreased hemoglobin (hypochromic) in the red cell and a shape change from a biconcave disk to a rigid microsphere approximately 8 μm in diameter. 5 These microcytic hypochromic iron-deficient red cells have decreased oxygen-carrying capacity due to reduced mean hemoglobin levels and reduced deformability in capillaries. 5

Major Etiologic Categories

Microcytic hypochromic anemia represents a heterogeneous group of acquired and inherited disorders that can be classified into four main categories:

1. Defects of intestinal iron absorption (e.g., iron deficiency anemia, IRIDA) 1
2. Disorders of the transferrin receptor cycle that impair erythroblast iron uptake 1
3. Defects of mitochondrial iron utilization for heme or iron-sulfur cluster synthesis (e.g., sideroblastic anemias due to SLC25A38, ALAS2, or ABCB7 defects) 5, 1
4. Defects of iron recycling 1

Common Causes

Iron deficiency is the most common cause of microcytic anemia. 2 Other frequent etiologies include:

• Anemia of chronic disease 6, 2
• Thalassemias (alpha and beta) 6, 2
• Sideroblastic anemias 2
• Lead toxicity 6
• Hemoglobin E disorders 6

Genetic Causes

Recent advances have identified novel inherited microcytic anemias that must be distinguished from common iron deficiency:

• SLC25A38 defects cause severe congenital sideroblastic anemia with microcytic hypochromic erythrocytes, often transfusion-dependent, clinically similar to thalassemia major 5
• ALAS2 defects (X-linked sideroblastic anemia) result in mild hypochromic, microcytic sideroblastic anemia with systemic iron overload 5
• ABCB7 defects cause mild, slightly microcytic sideroblastic anemia with cerebellar ataxia 5
• STEAP3 defects result in severe microcytic anemia 5
• Alpha-thalassemia must be considered as a differential diagnosis, with an overall frequency of -alpha3.7 deletion of approximately 20% in some populations 7

Diagnostic Approach

When the underlying cause is obscure, serum ferritin should be measured first, as it is the most specific test for iron deficiency. 6, 2

If ferritin is normal or increased, serum iron and free erythrocyte protoporphyrin levels can be determined to distinguish between different causes:

• Serum iron is low in iron deficiency and anemia of chronic disease but normal or elevated in thalassemias, hemoglobin E disorders, and lead toxicity 6
• Free erythrocyte protoporphyrin is elevated with iron deficiency, anemia of chronic disease, and lead toxicity but normal with thalassemias and hemoglobin E disorders 6

The absence of iron stores in bone marrow remains the most definitive test for differentiating iron deficiency from other microcytic states (anemia of chronic disease, thalassemia, sideroblastic anemia), though measurement of serum ferritin, iron concentration, transferrin saturation, and serum transferrin receptors may obviate bone marrow evaluation. 2

Clinical Significance

Diagnosis of microcytic anemia is particularly important in children and adolescents to establish a treatment plan based on etiology and pathogenesis. 4 Molecular genotyping provides a rapid and reliable method for identification of common, rare, and unknown alpha- and beta-gene mutations, helping to diagnose unexplained microcytosis and prevent unnecessary iron supplementation. 7

In cyanotic congenital heart disease, iron deficiency can exacerbate hyperviscosity, as microcytic red cells are relatively rigid and less deformable in the microcirculation, further decreasing tissue oxygenation. 5