What is beta thalassemia?

Beta Thalassemia: A Comprehensive Overview

Beta thalassemia is a genetic blood disorder characterized by reduced or absent production of beta-globin chains of hemoglobin, resulting in ineffective erythropoiesis, anemia, and iron overload that can lead to significant morbidity and mortality if not properly managed. 1, 2

Pathophysiology

Beta thalassemia results from mutations in the beta-globin gene on chromosome 11, leading to:

• Reduced (β+) or absent (β0) synthesis of beta-globin chains 1, 3
• Excess unpaired alpha-globin chains that precipitate in erythroid precursors
• Ineffective erythropoiesis and hemolysis
• Increased gastrointestinal iron absorption due to hepcidin suppression 1
• Progressive iron accumulation in vital organs (heart, liver, endocrine glands) 2, 3

Clinical Classification

Beta thalassemia presents with variable clinical severity:

1. Beta Thalassemia Major (Cooley's Anemia)

   • Severe reduction or absence of beta-globin chain production
   • Life-threatening anemia presenting within first 2 years of life
   • Requires regular blood transfusions for survival
   • Characterized by growth retardation, pallor, jaundice, hepatosplenomegaly
   • Complications from iron overload affect multiple organ systems 1, 3

2. Beta Thalassemia Intermedia

   • Moderate anemia presenting later in life
   • Does not require regular transfusions
   • Features include hypertrophy of erythroid marrow, extramedullary hematopoiesis
   • Complications include osteoporosis, gallstones, leg ulcers, and thrombosis 3

3. Beta Thalassemia Minor (Trait)

   • Clinically asymptomatic or mild anemia
   • Carrier state with one normal and one affected beta-globin gene 3, 4

Diagnosis

Diagnosis is based on:

• Complete blood count showing microcytic, hypochromic anemia
• Peripheral blood smear examination
• Hemoglobin electrophoresis showing:
  • Elevated HbF and HbA2 in beta thalassemia minor
  • Predominantly HbF with little or no HbA in beta thalassemia major
• Molecular genetic testing to identify specific mutations 3, 4

Management of Beta Thalassemia Major

1. Blood Transfusions

• Maintain pre-transfusion hemoglobin levels of 9-10 g/dL
• Target post-transfusion hemoglobin of 13-14 g/dL
• Typically administered every 2-4 weeks 2

2. Iron Chelation Therapy

Iron chelation is essential to prevent or reverse iron overload complications:

• Deferasirox: First-line oral agent
• Deferiprone: Alternative oral agent (75 mg/kg/day in 3 divided doses)
• Deferoxamine: Administered via subcutaneous or intravenous infusion (40-50 mg/kg/day)
• Combination therapy with deferiprone and deferoxamine shows superior efficacy for severe iron overload 2

Iron chelation should be initiated when serum ferritin exceeds 1000 ng/mL to prevent irreversible organ damage 2

3. Monitoring for Iron Overload

• Serum ferritin levels
• T2* cardiovascular magnetic resonance (CMR) for cardiac iron assessment:
  • Severe cardiac iron: T2* <10 ms
  • Moderate cardiac iron: T2* 10-20 ms
  • Normal: T2* >20 ms
• Liver iron concentration via biopsy or MRI 1, 2

4. Management of Complications

Cardiac Complications

• Aggressive treatment for severe cardiac iron overload (T2* <6 ms) even if asymptomatic
• Careful use of diuretics due to unusual loading conditions in thalassemia 1, 2
• Continuous 24-hour intravenous deferoxamine at 50 mg/kg/day for acute heart failure 2

Endocrine Complications

• Regular screening for diabetes, hypothyroidism, hypoparathyroidism, and hypogonadism
• Appropriate hormone replacement therapy as needed 2, 5

Liver Complications

• Monitoring with ultrasound and transient elastography every 6-12 months
• Treatment of viral hepatitis if present 2

5. Curative Options

• Hematopoietic stem cell transplantation remains the only definitive cure currently available 3, 4
• Gene therapy approaches are in development 4

Management of Beta Thalassemia Intermedia

• Folic acid supplementation
• Splenectomy may be required for hypersplenism
• Treatment of extramedullary erythropoietic masses and leg ulcers
• Prevention and therapy of thromboembolic events 3

Special Considerations

Pregnancy

• Assessment of heart T2* and cardiac function before conception
• Careful monitoring of heart function during pregnancy
• Consider restarting iron chelation with deferoxamine in the second trimester for severe iron overload
• Thromboembolism prophylaxis with heparin or low-molecular-weight heparin, especially in splenectomized patients 2

Prognosis

Prognosis for individuals with beta-thalassemia has improved substantially in the last 20 years following advances in transfusion, iron chelation, and bone marrow transplantation therapy. However, cardiac disease remains the main cause of death in patients with iron overload 3.

Genetic Counseling

Genetic counseling is recommended for families affected by beta thalassemia. Prenatal diagnosis through amniocentesis or chorionic villus sampling with DNA analysis can be offered to at-risk couples 2, 3.