The major hemoglobin in adults is hemoglobin A, a tetramer consisting of one pair of alpha globin chains and one pair of beta globin chains. In normal subjects, globin chain synthesis is very tightly controlled, such that the ratio of production of alpha to non-alpha chains is 1.00 ± 0.05. Thalassemia refers to a spectrum of diseases characterized by reduced or absent production of one or more globin chains, thus disrupting this closely-regulated ratio. (See "Molecular pathology of the thalassemic syndromes".)
- The vast majority of adult patients with alpha or beta thalassemia minor are asymptomatic, and may be diagnosed because of the presence of microcytic, hypochromic red cells, with or without minor degrees of anemia.
- Thalassemias of intermediate degrees of severity are common throughout the world, and may be due to the presence of more than one hemoglobin mutation in the same patient (eg, sickle cell thalassemia, hemoglobin E/beta thalassemia) or to the presence of an abnormal hemoglobin with a reduced (ie, thalassemic) production rate (eg, hemoglobin Lepore, hemoglobin Constant Spring).
- Beta thalassemia and alpha thalassemia major are on the other end of this spectrum. The former is associated with life-long transfusion-dependent anemia, while the latter is incompatible with extra-uterine life.
The clinical manifestations and diagnosis of the thalassemias will be reviewed here. The management of beta thalassemia is discussed separately. (See "Treatment of beta thalassemia" and "Efficacy of hematopoietic cell transplantation in beta thalassemia major".)
BETA THALASSEMIA MAJOR
Overview — Beta thalassemia is due to impaired production of beta globin chains, leading to a relative excess of alpha globin chains. Excess alpha globin chains are unstable, incapable of forming soluble tetramers on their own, and precipitate within the cell, leading to a variety of clinical manifestations. The degree of alpha globin chain excess determines the severity of subsequent clinical manifestations, which are profound in patients homozygous for impaired beta globin synthesis (ie, beta thalassemia major) and much less pronounced in heterozygotes, who generally have minimal or mild anemia and no symptoms. (See "Pathophysiology of beta thalassemia".)
Infants with severe beta thalassemia major (BTM) are well at birth, because the production of beta globin is not essential during fetal life or the immediate perinatal period. The major non-alpha globin produced at the time of birth is gamma globin, such that the major hemoglobin in early postnatal life is fetal hemoglobin (Hb F, alpha2/gamma2).