Pathophysiology and Clinical Manifestations of the b-Thalassemias

The b-thalassemia syndromes reflect deficient or absent b-globin synthesis usually owing to a mutation in theb-globin locus. The relative excess ofa-globin results in the formation of insoluble aggregates leading to ineffective erythropoiesis and shortened red cell survival. A relatively high capacity for fetal hemoglobin synthesis is a major genetic modifier of disease severity, with polymorphisms in other genes also having a significant role. Iron overload secondary to enhanced absorption and red cell transfusions causes an increase in liver iron and in various other tissues, leading to endocrine and cardiac dysfunction. Modern chelation regimens are effective in removing iron and preserving or restoring organ function.