Pathophysiology

The underlying pathophysiology of beta-thalassemia syndromes is ineffective erythropoiesis. Clinical manifestations

are usually seen only after the normal transition from fetal haemoglobin (tetramer of 2 alpha- and 2 gamma-globin
chains) to adult haemoglobin (2 alpha- and 2 beta-globin chains), due to the defect being in the beta-globin gene.
When the production of beta-globin chains is deficient or absent, the imbalance between alpha and beta chains leads
to precipitation of the excess alpha chains in erythroid precursors and maturing red cells, resulting in membrane
damage and cell destruction. The inability of these cells to survive is the cause of ineffective erythropoiesis, resulting
in anaemia and a compensatory erythroid hyperplasia. Bony changes in the skull (including the flat bones of the
cranium, the air spaces of the sinuses and the vertebral bodies) are due to the marked erythroid hyperplasia. The latter
may also lead to extramedullary haematopoiesis in the liver and spleen, resulting in enlargement of these organs.
In beta-thalassemia major there is a complete or near complete lack of beta-globin, leading to a transfusion-dependent
severe anaemia. When there is moderate reduction, some people may be less anaemic (beta-thalassemia intermedia),
and heterozygous individuals (beta-thalassemia minor or trait) have mild anaemia with compensatory overexpression
of the normal gene. Mutations of the alpha-, beta-, delta- and gamma-globin genes modify the severity, and usually
result in intermediate phenotypes. Ineffective erythropoiesis and, to a lesser degree, anaemia result in downregulation
of expression of hepcidin and enhanced absorption of iron from the intestine. This is more pronounced in beta-
thalassemia intermedia because regular transfusions mask ineffective erythropoiesis to some extent in beta-
thalassemia major. However, iron from transfused red cells accumulates in beta-thalassemia major and results in
tissue toxicity. Initially, excess iron is sequestered in the cells of the monocyte-macrophage system, but, with
continued accumulation, further excess is usually deposited in the liver, heart, pancreas and other endocrine organs,
leading to cellular damage. Without therapy, cirrhosis, heart disease, diabetes and other disorders develop; death is
usually the result of cardiac failure.