PATHOPHYSIOLOGY

T

he thalassemia syndromes were among the first genetic diseases to be understood at the molecular level. More than 200 β-globin and 30 α-globin mutation have been identified; these mutations result in decreased or absent productions of one globin chain (α or β) and a relative excess of the other. The resulting imbalance leads to unpaired globin chains which precipitate and cause premature death (apoptosis) of the red cell precursors within the marrow, termed ineffective erythropoiesis . Of the damaged but viable RBCs that are released from the bone marrow, many are removed by the spleen or hemolyzed directly in the circulation due to the hemoglobin precipitants. Combined RBCs destruction in the bone marrow, spleen and periphery causes anemia and, ultimately, an escalating cycle of pathology resulting in the clinical syndrome of severe thalassemia (Kearney et al., 2007).

Damaged erythrocytes enter the spleen and are trapped in this low pH and low oxygen environment; subsequent splenomegaly exacerbates the trapping of cells and worsens the anemia. Anemia and poor tissue oxygenation stimulate increased kidney erythropoietin production that further drives marrow erythropoiesis, resulting in increased ineffective marrow activity and the classic bony deformities associated with poorly managed TM and severe T1. Anemia in the severe thalassemia phenotypes necessitates multiple RBC transfusions and, over time, without proper chelation, results in transfusion-associated iron absorption and can result in iron overload, even in untransfused patients who have TI (Kearney et al., 2007).

It has long been recognized that the severity of ineffective erythropoiesis affects the degree of iron loading, but until the recent discovery of hepcidin and understanding, its role in iron metabolism the link was not understood. Hepcidin; an antimicrobial hormone, is recognized as playing a major role in iron deficiency and overload. Hepcidin initially was discovered due to its role in the etiology of anemia of chronic inflammation or chronic disease (Weinstein et al., 2002).

Figure (2):  Effect of excess production of free a globin chains
(Olivieri, 1999).