Microcytic Anemias

Microcytic anemia is defined by a mean corpuscular volume (MCV) < 80 fL. The final act of erythropoiesis is packing each red cell with hemoglobin; when a building block runs short, precursors keep dividing to reach a threshold hemoglobin concentration, yielding small (microcytic), pale (hypochromic) cells. Hemoglobin has two parts — heme (iron + a protoporphyrin ring) and four globin chains — so every microcytic anemia is a failure of one of three things: iron supply (iron-deficiency anemia, anemia of chronic disease), protoporphyrin/heme synthesis (sideroblastic anemia, lead poisoning), or globin synthesis (the thalassemias).

Thalassemias are inherited defects in the rate of globin-chain synthesis; the resulting chain imbalance precipitates and damages RBCs (ineffective erythropoiesis + hemolysis). α-thalassemia arises from deletions of α-globin genes (4 total, chromosome 16), and severity tracks the number lost. β-thalassemia arises from point mutations (promoter/splice-site) in the β-globin gene (chromosome 11).

Because β-chains are needed for adult HbA (α2β2), β-thalassemia major only becomes symptomatic around 6 months of age, as protective fetal HbF (α2γ2) declines. Chronic ineffective erythropoiesis expands the marrow — 'crew-cut' skull on X-ray and chipmunk facies — and drives extramedullary hematopoiesis with hepatosplenomegaly. Lifelong transfusions then cause secondary iron overload (hemochromatosis), managed with iron chelation. Smear shows target cells. One α-thal genetics pearl: Asian carriers tend to have both deletions on the same chromosome (cis), risking severe (HbH / Hb Barts) offspring, whereas African carriers usually carry them in trans.

Sideroblastic anemia is defective heme synthesis: iron enters erythroblast mitochondria but can't be incorporated into heme (protoporphyrin synthesis is impaired), so it accumulates as ringed sideroblasts. Iron studies therefore mimic overload (↑ iron, ↑ ferritin, ↑ transferrin saturation). Causes are hereditary (X-linked δ-ALA synthase / ALAS2 defect) or acquired — reversible causes include alcohol (most common overall), lead, isoniazid (depletes vitamin B6 / pyridoxine, the ALA-synthase cofactor), and copper deficiency; the key clonal (irreversible) cause is myelodysplastic syndrome. Pyridoxine-responsive (often hereditary) forms improve with B6.

Lead poisoning inhibits ferrochelatase and ALA dehydratase, blocking heme synthesis (effectively an acquired sideroblastic anemia). Boards clues: a child with pica in an old building (paint/dust) with abdominal pain, constipation, and encephalopathy, plus basophilic stippling on smear; adults get peripheral neuropathy (wrist/foot drop) and gingival Burton (lead) lines. Treat with succimer (oral, children) or EDTA + dimercaprol (BAL) for severe or symptomatic poisoning.