Pathophysiology and Clinical Manifestations of the β-Thalassemias

Abstract

The β-thalassemia syndromes reflect deficient or absent β-globin synthesis usually owing to a mutation in the β-globin locus. The relative excess of α-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.

Figure 1.

Pathophysiology of β-thalassemia. Because of the imbalance in chain synthesis, an excess of freed α-globin chains accumulates within erythroid cells. Aggregation, denaturation, and degradation of these chains leads to the formation of insoluble precipitates as well as hemichromes, which damage cell membranes. Membrane damage leads to ineffective erythropoiesis within the bone marrow, hemolysis of red cells within the circulation, and binding of immunoglobulin and complement components to red cell membranes, triggering loss of red cells in the spleen. The resulting anemia leads to diminished tissue oxygenation, an increase in erythropoietin levels, and further stimulation of the bone marrow. Bone marrow expansion causes skeletal deformities and osteopenia. Substances released from degenerating red cells increase iron absorption, which contributes to iron overload.