Thalassemia
Also known as: thalassemia syndromes, Mediterranean anemia
Thalassemia is an inherited anemia caused by reduced or absent production of the alpha or beta globin chains of hemoglobin. The imbalance in chain synthesis produces small, pale red blood cells and, in severe forms, chronic hemolysis requiring lifelong transfusion.
Thalassemia is a quantitative hemoglobin disorder: the globin chains that are produced are structurally normal, but too few of them are made. Adult hemoglobin (HbA) requires two alpha and two beta chains, so underproduction of either type leaves the other in excess. Those unpaired chains precipitate inside developing red cells, causing ineffective erythropoiesis in the marrow and hemolysis in the periphery. The result is a microcytic, hypochromic anemia.
Alpha-thalassemia results from deletion of one or more of the four alpha-globin genes and is most common in individuals of Southeast Asian and African ancestry. Losing one gene is clinically silent; two produces a mild trait; three causes hemoglobin H disease with moderate hemolytic anemia; and loss of all four causes hemoglobin Barts and hydrops fetalis, which is incompatible with life. Beta-thalassemia usually results from point mutations affecting beta-globin transcription or splicing and is most common around the Mediterranean, the Middle East, and South Asia. Beta-thalassemia minor causes mild anemia with a characteristically elevated HbA2, while beta-thalassemia major (Cooley anemia) presents at about six months of age, as fetal hemoglobin declines, with severe transfusion-dependent anemia.
Severe beta-thalassemia produces findings that follow directly from marrow expansion and chronic transfusion: frontal bossing and "crew cut" skull radiographs from expanded marrow, hepatosplenomegaly from extramedullary hematopoiesis, and iron overload with secondary hemochromatosis from repeated transfusions. On a peripheral smear, target cells are typical. A practical distinction from iron deficiency is that thalassemia trait produces microcytosis with a normal or elevated red cell count and normal iron studies, whereas iron deficiency lowers both. Hemoglobin electrophoresis confirms the beta-thalassemias, but it is typically normal in alpha-thalassemia trait, which requires genetic testing.
Thalassemia is a high-yield USMLE Step 1 topic in the hematology and oncology section. Focus on the genetics of each subtype, the microcytic anemia differential, the electrophoresis findings, and the complications of chronic transfusion therapy.
Key takeaways
- Thalassemia is a quantitative defect: normal globin chains are made in insufficient amounts, producing microcytic hypochromic anemia.
- Alpha-thalassemia is caused by alpha-globin gene deletions; severity scales with the number of genes lost, from silent carrier to hydrops fetalis.
- Beta-thalassemia arises from point mutations; the minor form shows elevated HbA2, while the major form is transfusion-dependent and presents around six months of age.
- Marrow expansion causes skeletal changes and extramedullary hematopoiesis; chronic transfusion causes iron overload.
- Thalassemia trait shows microcytosis with a normal or high red cell count and normal iron studies, distinguishing it from iron deficiency anemia.