BackgroundThalassemia was first described in peoples of the Mediterranean region and Southeast Asia. In fact, in Greek, the word thalassemia means sea. The most severe form of beta thalassemia is thalassemia major, or Cooley anemia. The syndrome of Cooley anemia, first described in 1925, is caused by the complete absence of beta-globin gene production. Milder forms of thalassemia have also been recognized and include beta thalassemia intermedia, beta thalassemia minor, and alpha thalassemia. This article focuses only on beta thalassemia major.
Normal hemoglobin, hemoglobin A, is composed of 2 beta and 2 alpha subunits. In beta thalassemia major, more than 200 mutations have been described in the beta-globin genes, cause loss of both beta-globin subunits. This leaves the normally paired alpha subunits unpaired. Unpaired subunits are cytotoxic. Normally, compensatory mechanisms are present to protect the cell from the small amounts of unpaired alpha subunits, which may regularly be present; however, in beta thalassemia major, these mechanisms are overwhelmed and more that 95% of red cell precursors undergo cytolysis in the intramedullary space. Mechanisms for this hemolysis include increased apoptosis as well as cell membrane fragility through the action of oxidation of alpha chains into hemochromes, which bind to various red cell membrane proteins making the membrane rigid and fragile.
This ineffective erythropoiesis and profound hemolysis result is a severe anemia that is usually manifest in affected individuals by age 6 months. The physiologic response is to attempt to increase red cell production by expanding the bone marrow space up to 30-fold and/or increase production of non-beta hemoglobin chains such as A2 (delta) and fetal (gamma) hemoglobin. However, despite these mechanisms, erythropoiesis remains ineffective and these patients become transfusion-dependent early in life. In fact, the presence or absence of adequate transfusions significantly impacts the appearance of these patients and the course of the disease.
The classic phenotype of patients with Cooley anemia includes the effects of marrow expansion such as frontal bossing of the skull and abnormalities of sinuses and facial bones producing an appearance described as mongoloid. Growth is retarded, which causes very short stature, and marrow expansion causes thinning of long bones and an increased risk for fractures. Folate deficiency is the result of increased utilization of folic acid in the expanded marrow space. Hepatomegaly and splenomegaly are common due to extramedullary hematopoiesis, which can lead to thrombocytopenia and leukopenia. The high red cell turnover causes increased GI absorption of iron to try to compensate for the ineffective erythropoiesis, which leads to hemochromatosis and accompanying endocrinopathies. Adequate transfusion regimens accelerate the development of hemochromatosis as well as the risk for transfusion-transmitted infections.
This ineffective erythropoiesis and profound hemolysis result is a severe anemia that is usually manifest in affected individuals by age 6 months. The physiologic response is to attempt to increase red cell production by expanding the bone marrow space up to 30-fold and/or increase production of non-beta hemoglobin chains such as A2 (delta) and fetal (gamma) hemoglobin. However, despite these mechanisms, erythropoiesis remains ineffective and these patients become transfusion-dependent early in life. In fact, the presence or absence of adequate transfusions significantly impacts the appearance of these patients and the course of the disease.
The classic phenotype of patients with Cooley anemia includes the effects of marrow expansion such as frontal bossing of the skull and abnormalities of sinuses and facial bones producing an appearance described as mongoloid. Growth is retarded, which causes very short stature, and marrow expansion causes thinning of long bones and an increased risk for fractures. Folate deficiency is the result of increased utilization of folic acid in the expanded marrow space. Hepatomegaly and splenomegaly are common due to extramedullary hematopoiesis, which can lead to thrombocytopenia and leukopenia. The high red cell turnover causes increased GI absorption of iron to try to compensate for the ineffective erythropoiesis, which leads to hemochromatosis and accompanying endocrinopathies. Adequate transfusion regimens accelerate the development of hemochromatosis as well as the risk for transfusion-transmitted infections.
Frequency
United States
Cooley anemia occurs in the offspring of 2 heterozygote beta thalassemia parents. Incidence of thalassemia major in the black population of the United States is approximately 20 cases per 100,000 persons.
Cooley anemia occurs in the offspring of 2 heterozygote beta thalassemia parents. Incidence of thalassemia major in the black population of the United States is approximately 20 cases per 100,000 persons.
International
Estimates of incidence rates of heterozygote beta thalassemia are 10% in Italian, Sicilian, and Greek populations; 5% in Southeast Asian populations; and 1.5% in African and American black populations
Estimates of incidence rates of heterozygote beta thalassemia are 10% in Italian, Sicilian, and Greek populations; 5% in Southeast Asian populations; and 1.5% in African and American black populations
With modern treatment, life expectancy has increased. However, the development of certain complications is inevitable. Untreated patients usually do not survive past the second decade of life. With transfusion therapy, patients can survive to the fifth decade of life.
-Hemosiderosis is a major cause of morbidity and mortality and can occur independently of transfusion therapy; however, it occurs at a younger age with transfusion therapy
*Cardiac siderosis resulting from iron overload and long-term transfusion therapy is the most common cause of death when it occurs in patients early in their third decade of life. Cardiac hypertrophy and dilatation, myocarditis, right ventricular hypertrophy, and pulmonary hypertension and restrictive lung disease can occur in children younger than 10 years.
*Liver dysfunction can be due to hepatitis B or C and hemosiderosis is associated with an elevated prothrombin time and vitamin K malabsorption.
*Cirrhosis and liver dysfunction due to iron overload usually occurs in elderly patients.
*Endocrine abnormalities such as diabetes mellitus, thyroid and adrenal dysfunction, and delayed sexual maturation with secondary amenorrhea due to infiltration of the pituitary with iron are known complications of hemosiderosis. Endocrine problems are usually recognized in older children and elderly individuals.
-Overwhelming infection is a common cause of death in children younger than 6 years, especially those who had early splenectomies; immunosuppression and increased susceptibility to infection also occurs as a result of the leukopenia related to hepatosplenomegaly.
-Thalassemia is associated with hypercoagulability (Eldor, 2002).
-Neglected anemia can cause death when standard transfusion protocols are not readily available
-Beta thalassemia is found in peoples of African and Southeast Asian descent as well as in descendants of Mediterranean countries. Beta thalassemia may be protective against malaria.
-No predilection is recognized
-Thalassemia major is evident by 6 months to 1 year after Hgb switching has occurred.
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