These result from either defective hemoglobin synthesis, leading to cytoplasmic maturation defects and small relatively empty red cells, or abnormally slow DNA replication, leading to nuclear maturation defects and large full red cells. Defects in hemoglobin synthesis usually result from insufficient iron supply (iron deficiency) or decreased globin production (thalassemia) or are idiopathic (sideroblastic anemia). Defects in DNA synthesis are usually due to nutritional problems (vitamin B₁₂ and folate deficiency), toxic (methotrexate or other cancer chemotherapeutic agent) exposure, or intrinsic marrow maturation defects (refractory anemia, myelodysplasia).

Laboratory tests useful in the differential diagnosis of the microcytic anemias are shown in Table 63-2. Mean corpuscular volume (MCV) is generally 60–80 fL. Increased lactate dehydrogenase (LDH) and indirect bilirubin levels suggest an increase in RBC destruction and favor a cause other than iron deficiency. Iron status is best assessed by measuring SI, TIBC, and ferritin levels. Macrocytic MCVs are >94 fL. Folate status is best assessed by measuring RBC folate levels. Vitamin B₁₂ status is best assessed by measuring serum B₁₂, homocysteine, and methylmalonic acid levels. Homocysteine and methylmalonic acid levels are elevated in the setting of B₁₂ deficiency.