Beta-thalassemia is primarily found in South Asia, the Middle East, North Africa, and Southern Europe, but global migration patterns are changing the global distribution of the disease.5,6
Beta-thalassemia is inherited as an autosomal recessive disease; however, dominant mutations have also been reported in rare cases. The beta-globin gene (HBB gene) is located on the short arm of chromosome 11. Over 200 disease-causing HBB gene mutations have been identified, most of which are point mutations.4,10
Beta-thalassemia is caused by reduced or absent synthesis of the beta-globin chains of the adult hemoglobin tetramer (HbA), which is made up of two α-globin and two β-globin chains (α2β2).11 When beta-globin chains are absent, alpha-globin chains and their degradation products precipitate, causing ineffective erythropoiesis and hemolysis, which leads to anemia. Anemia, in turn, stimulates erythropoietin synthesis, resulting in intense proliferation of the bone marrow, skeletal deformities, and a variety of growth and metabolic abnormalities. Splenomegaly is typically seen in patients with beta-thalassemia as a result of extramedullary hematopoiesis or as a response to extravascular hemolysis.1
How Genetic Defects in
Beta-Thalassemia Lead to
Adapted from Rachmilewitz E, Giardina P. How I treat thalassemia. Blood. 2011;118(13):3479-88.
Range of Severity11
Historically, beta-thalassemia has been classified into three groups: minor (trait), intermedia, and major.
1. Beta-thalassemia minor (trait)
Clinically asymptomatic; patients are heterozygous for beta-thalassemia.
2. Beta-thalassemia intermedia
Clinically and genotypically heterogeneous disorders, ranging in severity from mild to the severe transfusion-dependent state.
3. Beta-thalassemia major
Severe, transfusion-dependent anemia.
These terms—major, intermedia and minor—continue to be used by patients and some clinicians today. However, current Thalassaemia International Federation (TIF) guidelines characterize the clinical severity of beta-thalassemia as:1
Beta-thalassemia major will usually present clinically between the ages of 6 and 24 months. Affected infants have severe microcytic anemia, fail to thrive, become progressively pale, develop hepatosplenomegaly that may distend the abdomen, have mild jaundice, and may also have feeding problems and recurrent fevers due to hypermetabolic state or inter-current infection.1
Beta-thalassemia intermedia usually presents at a later age with a milder form of these clinical findings. Those on the more severe end of the spectrum may show slow development and retarded growth, while those on the mild end may be completely asymptomatic, with just mild anemia. People with beta-thalassemia carrier state (heterozygous) show no important clinical effects since the activity of their normal beta-globin gene makes enough stable globin.1
Hemoglobin electrophoresis or high pressure liquid chromatography can reveal hemoglobin types and their amounts. In patients with TDT, HbF constitutes the majority of total hemoglobin. Additionally, mutations of the beta-globin gene can be detected by polymerase chain reaction (PCR) methods or gene sequencing.1
Until effective therapy for its management was developed, beta-thalassemia major was considered a pediatric condition: in the absence of a chronic transfusion regimen, children with the disease usually died within the first few years of life.1
Patients with transfusion-dependent beta-thalassemia typically require regular transfusions every two to five weeks, with the goal, according to TIF guidelines, of maintaining a pre-transfusion hemoglobin level above 9‑10.5 g/dL.1
Each unit of whole blood contains approximately 200 mg of iron, and receiving regular blood transfusions makes iron overload unavoidable since there is no dedicated iron excretion pathway that can increase the excretion of iron.16 While iron chelation treatment can help control iron overload, many patients experience iron overload-associated complications.16,17
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Consider Asking Your Patients:
"Can you describe any changes made to your life because of your symptoms or treatment?"
Actor portrayals throughout. Not real patients.
Take the Beta-Thalassemia Challenge
Which of the following might be seen in a patient with beta-thalassemia intermedia?
The clinical presentation of beta-thalassemia intermedia can vary widely, from asymptomatic to severe. At the mildest end of the clinical spectrum, patients are asymptomatic with only mild anemia until adulthood. At the severe end, patients present between age 2 and 6, and show growth retardation and slowed development. Clinical features may include deformities of the bones and face. In both beta-thalassemia major and intermedia, intestinal absorption of iron is increased. Chronic transfusions are the main source of iron overload in patients who are regularly transfused, but patients with beta-thalassemia can develop iron overload, even in the absence of transfusion, due to this increased intestinal absorption.1,11