The thalassemias are hereditary disorders characterized by reduction in the synthesis of globin chains (alpha or beta).
Reduced globin chain synthesis causes reduced hemoglobin synthesis and a hypochromic microcytic anemia because of defective hemoglobinization of red blood cells. Thalassemias can be considered among the hyperproliferative hemolytic anemias, the anemias related to abnormal hemoglobin, and the hypoproliferative anemias, since all of these factors play a role in pathogenesis.
Normal adult hemoglobin is primarily hemoglobin A, which represents approximately 98% of circulating hemoglobin. Hemoglobin A is formed from a tetramer of two alpha chains and two beta globin chains—and is designated alpha2beta2. Two copies of the alpha-globin gene are located on each chromosome 16, and there is no substitute for alpha-globin in the formation of adult hemoglobin.
One copy of the beta-globin gene resides on each chromosome 11 adjacent to genes encoding the beta-like globins delta and gamma (the so-called beta-globin gene cluster region). The tetramer of alpha2delta2 forms hemoglobin A2, which normally comprises 1–3% of adult hemoglobin. The tetramer alpha2gamma2 forms hemoglobin F, which is the major hemoglobin of fetal life but which comprises less than 1% of normal adult hemoglobin.
The thalassemias are described as “trait” when there are laboratory features without significant clinical impact, “intermedia” when there is an occasional red blood cell transfusion requirement or other moderate clinical impact, and “major” when the disorder is life-threatening and the patient is transfusion-dependent. Most patients with thalassemia major die of the consequences of iron overload from RBC transfusions.
Mild forms of thalassemia must be differentiated from iron deficiency. Compared to iron deficiency anemia, patients with thalassemia have a lower MCV, a normal or elevated red blood cell count (rather than low), a more abnormal peripheral blood smear at modest levels of anemia, and usually a reticulocytosis. Iron studies are normal or the transferrin saturation or ferritin (or both) are elevated.
Severe forms of thalassemia may be confused with other hemoglobinopathies. The diagnosis of beta-thalassemia is made by the above findings and hemoglobin electrophoresis showing elevated levels of hemoglobins A2 and F (provided the patient is replete in iron).
The diagnosis of alpha-thalassemia is made by exclusion since there is no change in the proportion of the normal adult hemoglobin species or confirmed by alpha gene deletion studies. The only other microcytic anemia with a normal or elevated red blood cell count is iron deficiency in a patient with polycythemia vera.
Patients with mild thalassemia (alpha-thalassemia trait or beta-thalassemia minor) require no treatment and should be identified so that they will not be subjected to repeated evaluations and treatment for iron deficiency. Patients with hemoglobin H disease should take folic acid supplementation (1 mg/day orally) and avoid medicinal iron and oxidative drugs such as sulfonamides.
Patients with severe thalassemia are maintained on a regular transfusion schedule (in part to suppress endogenous erythropoiesis and therefore bone marrow expansion) and receive folic acid supplementation.
Splenectomy is performed if hypersplenism causes a marked increase in the transfusion requirement or refractory symptoms. Patients with regular transfusion requirements should be treated with iron chelation (oral or parenteral) in order to prevent or delay life-limiting organ damage from iron overload.
Allogeneic stem cell transplantation is the treatment of choice for beta-thalassemia major and the only available cure. Children who have not yet experienced organ damage from iron overload do well, with long-term survival in more than 80% of cases.