Beta Thalassemia: An Overview of Epidemiology, Clinical Features, Diagnosis, and Management

EXTENDED ABSTRACT

Background

Beta-thalassemia is an autosomal-recessive inherited hemolytic anemia caused by reduced or absent synthesis of beta-globin chains. The beta-globin genes are located on chromosome 11, whereas alpha-globin genes are located on chromosome 16 [2, 3]. In beta-thalassemia, beta-chain production may be reduced (β+) or absent (β0), producing a spectrum from asymptomatic microcytosis to severe transfusion-dependent anemia [4-6]. Hemoglobin disorders are among the most common genetic diseases worldwide, especially in regions historically endemic for malaria. Beta-thalassemia is most prevalent in the Mediterranean region, the Middle East, and Southeast Asia, and migration has increased its frequency in traditionally non-endemic regions [6, 7]. Approximately 1.5% of the global population carries a beta-thalassemia gene [7]. Iran lies within the thalassemia belt; approximately three million people are carriers, with reported carrier prevalence reaching about 10% in Sistan and Baluchestan and approximately 4%-8% in other regions of the country [8, 9]. The clinical burden reflects ineffective erythropoiesis, chronic hemolysis, marrow expansion, increased intestinal iron absorption, and, in transfusion-dependent disease, progressive iron overload [10-14]. This review summarizes the epidemiology, inheritance, pathophysiology, clinical phenotypes, diagnostic approach, current management, major complications, and prevention of beta-thalassemia.

Methods

This article is a narrative review of beta-thalassemia and synthesizes the evidence cited by the source article across epidemiology, molecular inheritance, pathophysiology, phenotype classification, laboratory diagnosis, transfusion therapy, iron chelation, splenectomy, fetal-hemoglobin induction, newer pharmacologic therapies, hematopoietic stem-cell transplantation, gene therapy, complications, and preventive strategies. The source article does not report a formal database search strategy, predefined eligibility criteria, or a systematic-review protocol; therefore, the evidence is summarized as presented in the article rather than interpreted as a systematic evidence synthesis.

Results

Beta-thalassemia is inherited equally in both sexes. When both parents are carriers, each pregnancy carries a 25% probability of an unaffected child, a 50% probability of a carrier, and a 25% probability of a child with severe disease [10]. More than 350 beta-globin mutations, predominantly point mutations, have been identified [4]. Disease severity is commonly described as beta-thalassemia minor, intermedia, or major. Minor disease is generally asymptomatic, with hemoglobin usually above 10 g/dL, reduced MCV and MCH, an increased RBC count, HbA2 of at least 3.5%, and HbF usually below 5% [10, 15]. Intermedia usually becomes clinically evident at 2-6 years, with hemoglobin approximately 7-10 g/dL and variable transfusion requirements; HbF is commonly 10%-50% [10, 16]. Major disease typically presents between 6 months and 2 years, with severe anemia and hemoglobin below 7 g/dL, marrow expansion, skeletal changes, hepatosplenomegaly, jaundice, and growth impairment. HbA is usually absent and HbF commonly exceeds 90% [10, 18]. CBC, peripheral blood smear, hemoglobin electrophoresis, and DNA analysis are the principal diagnostic tools; prenatal diagnosis can identify affected fetuses and define mutations [17, 18].

Table 1. Types of beta-thalassemia according to beta-chain production, hemoglobin electrophoresis findings, and HbF level.

Management is phenotype-dependent. Beta-thalassemia minor requires no disease-specific treatment, although iron deficiency should be treated when present and genetic counseling is important [5]. Intermedia may require folic acid, intermittent transfusion, hydroxyurea, iron chelation according to iron burden, and splenectomy in selected patients [15, 19]. Patients with beta-thalassemia major require regular red-cell transfusions. The review recommends a pretransfusion hemoglobin target of approximately 9-10.5 g/dL and a post-transfusion level of 13-14 g/dL, with transfusions generally every 3-5 weeks; packed red cells should not exceed 15-20 mL/kg/day [10, 20]. Because each packed-cell unit contains about 200 mg of iron, repeated transfusion causes progressive iron accumulation [5]. Available chelators include deferoxamine, deferiprone, and deferasirox [21-25]. Deferoxamine is commonly administered subcutaneously or intravenously over 8-12 hours, 5-7 times weekly; deferiprone is given at 75-100 mg/kg/day in three divided doses; and deferasirox is administered orally once daily, with dose ranges depending on formulation [21-25]. Oral chelation is associated with better quality of life than injectable chelation in the cited evidence [26].

Table 2. Clinical features, diagnosis, and management of the major beta-thalassemia phenotypes.

Splenectomy may reduce transfusion requirements and iron burden in selected patients with hypersplenism, but is not recommended before 5 years of age; vaccination against encapsulated organisms before surgery and antimicrobial prophylaxis afterward are emphasized because infection, pulmonary hypertension, and thromboembolic complications may increase after splenectomy [5, 15, 27]. Hydroxyurea at 10-20 mg/kg/day can stimulate fetal-hemoglobin production and improve hematologic findings in some patients with intermedia [28]. Luspatercept reduces transfusion requirements in transfusion-dependent adults and is administered at 1 mg/kg subcutaneously every three weeks; safety and efficacy below 18 years were not established in the reviewed article [29]. Hematopoietic stem-cell transplantation from an HLA-identical sibling remains a curative treatment, with disease-free survival exceeding 90% in patients without major pretransplant risk factors [15]. Gene therapy uses autologous hematopoietic stem/progenitor cells modified to express normal beta- or gamma-globin and is presented as another potentially curative strategy [31, 32]. Major chronic complications are predominantly related to iron overload and include cardiomyopathy, liver fibrosis or cirrhosis, diabetes, hypothyroidism, hypoparathyroidism, hypogonadism, adrenal insufficiency, and growth disorders [13, 14, 21, 37, 38]. Osteoporosis occurs in an estimated 14%-50% of adequately treated patients, with fracture risk reported up to 44% [36]. Cardiac surveillance from approximately 8 years of age and serial ferritin, liver iron concentration, and cardiac/liver T2* MRI are important components of long-term monitoring [10, 13, 33, 34]. The review also notes persistent risks of transfusion-transmitted viral infections despite improved blood screening [35], and reports both hematologic and non-hematologic malignancies among patients with beta-thalassemia [39, 40].

Conclusion

Beta-thalassemia ranges from an asymptomatic carrier state to severe transfusion-dependent disease. Contemporary care combines phenotype-based transfusion support, timely iron chelation, monitoring and treatment of organ complications, selected use of splenectomy and HbF-inducing or erythroid-maturation therapies, and curative approaches such as hematopoietic stem-cell transplantation and gene therapy. Prevention remains central in high-prevalence regions. Identification of carriers, premarital and genetic counseling, and prenatal diagnosis can reduce new cases of severe homozygous beta-thalassemia; prenatal testing may be performed by amniotic-fluid analysis at approximately 4-5 months of gestation or chorionic-villus sampling around the 11th week [9, 41]. Reliable national and regional thalassemia registries are also important for evaluating prevention programs and planning services [42].

Keywords: Anemia, Beta Thalassemia, Blood Transfusion, Gene Therapy, Iron Chelation, Iron Overload, Splenectomy

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