Beta-thalassemia
Beta-thalassemia is an inherited hemoglobinopathy caused by point mutations that reduce or abolish beta-globin chain synthesis, producing a spectrum from asymptomatic trait to transfusion-dependent thalassemia major (Cooley anemia) with ineffective erythropoiesis, marrow expansion, and hepatosplenomegaly. Diagnosis rests on hemoglobin electrophoresis showing elevated HbA2 and HbF, and management of major disease centers on chronic transfusion paired with iron chelation, since transfusional iron overload is the leading cause of death.
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What this article covers
- Overview
Definition: an inherited hemoglobinopathy caused by point mutations in the beta-globin gene on chromosome 11 that reduce (beta+) or abolish (beta0) beta chain synthesis, unbalancing the normal 1:1 alpha-to-beta ratio.
- Epidemiology
Geographic distribution: most prevalent in populations of Mediterranean, Middle Eastern, and Southeast Asian ancestry, mirroring historical malaria endemicity.
- Risk factors
Family history and ancestry: Mediterranean, Middle Eastern, or Southeast Asian ancestry with a family history of thalassemia or unexplained microcytic anemia.
- Pathophysiology
Globin chain imbalance: point mutations in the beta-globin gene reduce or abolish beta chain synthesis while alpha chain production continues normally, unbalancing the alpha-to-beta ratio.
- Clinical features
Beta-thalassemia minor (trait): mild, often asymptomatic microcytic anemia (MCV 60-70 fL, hemoglobin 10-12 g/dL), frequently discovered incidentally; no transfusion requirement.
- Differential diagnosis
Iron deficiency anemia: also microcytic, but low ferritin and low serum iron with elevated total iron-binding capacity, low/normal erythrocyte count, and elevated RDW, versus the normal-to-high…
- Diagnosis
Confirm with hemoglobin electrophoresis showing elevated HbA2: the diagnostic study for beta-thalassemia trait and major is electrophoresis showing an elevated HbA2 fraction (delta-globin…
- Management
Beta-thalassemia minor (trait): no specific treatment; give genetic counseling before starting a family, add folic acid only if the patient is anemic, and avoid iron supplementation since these…
- Complications
Iron overload with cardiomyopathy: the leading cause of death, from iron-related arrhythmia and heart failure; also causes cirrhosis with portal hypertension and endocrinopathies (diabetes, hypopituitarism, hypogonadism).
- Prognosis
Genotype determines trajectory: trait carries a normal life expectancy, intermedia is variable, and major is fatal in childhood without a chronic transfusion and chelation program.
- Prevention
Carrier screening and genetic counseling: offer to individuals of Mediterranean, Middle Eastern, or Southeast Asian ancestry, and anyone with an unexplained microcytic anemia and a normal/high erythrocyte count, before family planning.
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Related articles
- Alpha-thalassemia
Alpha-thalassemia is an inherited microcytic anemia caused by deletions of one or more of the four alpha-globin genes, ranging from a silent carrier state to fatal hemoglobin Barts hydrops fetalis, and it is distinguished from iron deficiency by a normal or elevated RBC count, a normal RDW, and normal iron studies. Diagnosis of the trait requires excluding iron deficiency and often direct globin gene testing because hemoglobin electrophoresis is typically normal, while hemoglobin H disease shows a detectable beta-globin tetramer and HbH inclusions on supravital stain.
- Iron deficiency anemia
Iron deficiency anemia is the most common anemia worldwide, a microcytic hypochromic anemia driven by chronic blood loss, poor intake or malabsorption, or increased iron demand. A ferritin below 15 ng/mL confirms depleted iron stores, and confirmed disease in men or postmenopausal women mandates bidirectional endoscopy to find an occult gastrointestinal source before treating with oral or intravenous iron.
- Hemochromatosis
Hemochromatosis is a disorder of iron overload, most often hereditary HFE C282Y homozygosity causing hepcidin deficiency and excess intestinal iron absorption, that deposits iron in the liver, pancreas, heart, joints, skin, and pituitary. Screening rests on fasting transferrin saturation and ferritin, confirmation on HFE genetic testing, and treatment on regular therapeutic phlebotomy to a target ferritin of 50 to 100 ng/mL.
- Sideroblastic anemias
Sideroblastic anemias are disorders of defective mitochondrial heme synthesis in which iron accumulates around the erythroblast nucleus, producing ring sideroblasts on marrow Prussian blue stain and, unlike iron deficiency, iron overload rather than iron depletion. Causes are hereditary, clonal (myelodysplastic syndrome with ring sideroblasts), or reversible acquired (alcohol, lead, isoniazid/B6 deficiency, copper deficiency, zinc excess, chloramphenicol), and management centers on identifying and reversing the cause, a pyridoxine trial, and treating iron overload.
- Sickle cell disease
Sickle cell disease is an autosomal recessive hemoglobinopathy caused by a beta-globin point mutation that produces hemoglobin S, which polymerizes under deoxygenation to sickle erythrocytes and drive chronic hemolysis and vaso-occlusion. Diagnosis is confirmed by hemoglobin electrophoresis or HPLC showing predominant HbS, and lifelong management centers on hydroxyurea, folic acid, penicillin prophylaxis and vaccination for functional asplenia, transcranial Doppler stroke screening, and, in severe disease, transfusion, hematopoietic stem cell transplant, or gene therapy.
- Myelodysplastic syndromes
Myelodysplastic syndromes are clonal stem cell disorders producing ineffective hematopoiesis: a dysplastic, usually hypercellular bone marrow with peripheral cytopenias and a variable risk of transformation to acute myeloid leukemia. Diagnosis requires bone marrow biopsy showing dysplasia after excluding reversible mimics, risk is stratified with the IPSS-R, and treatment ranges from supportive transfusions and lenalidomide in lower-risk disease to hypomethylating agents and allogeneic transplant, the only cure, in higher-risk disease.