Beta Thalassemia: Diagnosis and Treatment
Diagnosis
Beta thalassemia major should be suspected in infants presenting with severe anemia at 1-2 years of age, particularly in those of Mediterranean, Middle Eastern, Southeast Asian, or African ancestry, and confirmed through hemoglobin electrophoresis and genetic testing. 1, 2
Clinical Presentation by Subtype
Beta Thalassemia Major (Transfusion-Dependent):
- Infants are healthy at birth due to fetal hemoglobin (HbF) but develop life-threatening anemia at approximately 1-2 years of age as the switch to adult hemoglobin occurs 1
- Defined by requirement for >8 transfusion events per year in adults over 16 years 1, 2
- Without treatment, death occurs by age 10 from cardiac complications 2
Beta Thalassemia Trait (Carrier State):
- Clinically asymptomatic with microcytic hypochromic anemia 3, 4
- Mean corpuscular volume (MCV) typically <80 fL with reduced mean corpuscular hemoglobin (MCH) 3
- The defining diagnostic feature is complete lack of response to iron supplementation despite compliance 3
- This distinguishes it from iron deficiency anemia, which should show hemoglobin increase of 1 g/dL after 4 weeks of adequate iron therapy 3
Beta Thalassemia Intermedia:
- Moderate anemia with variable presentation, not initially requiring regular transfusions 2
- Patients present later in life but may eventually require transfusions as they age 2
Diagnostic Testing
Initial Laboratory Evaluation:
- Complete blood count showing microcytic anemia 5
- Serum ferritin (normal or elevated, distinguishing from iron deficiency) 3, 5
- Hemoglobin electrophoresis to identify hemoglobin patterns 4, 5
Confirmatory Testing:
- Genetic testing (DNA analysis) is required to confirm diagnosis and identify specific mutations in the HBB gene on chromosome 11 4, 5
- Over 200 disease-causing mutations have been identified, mostly single nucleotide substitutions, deletions, or insertions 4
Prenatal Diagnosis:
- Genetic testing of amniotic fluid or fetal DNA samples can detect single point mutations with high reliability 6, 7
Critical Diagnostic Pitfalls to Avoid
- Do not prescribe iron supplementation to patients with confirmed beta thalassemia trait—it provides no benefit and may contribute to unnecessary iron accumulation 3
- Do not miss the diagnosis in pregnant women of appropriate ancestry with persistent mild anemia unresponsive to prenatal iron; further evaluation with MCV, RDW, and hemoglobin electrophoresis is indicated 3
- Always check serum ferritin to rule out concurrent iron deficiency before attributing findings solely to thalassemia trait 3
Treatment
Beta Thalassemia Major
Lifelong regular red blood cell transfusions are mandatory for survival, combined with lifelong iron chelation therapy to prevent or reverse iron-related organ damage. 1, 2
Transfusion Therapy
- Regular transfusions are required starting in early childhood, often before 2 years of age 5, 7
- Each transfused unit contains approximately 200-250 mg of elemental iron 1, 2
- Humans lack physiological mechanisms for iron excretion, leading to inevitable iron overload 1
Iron Chelation Therapy
Three commercially available iron chelators are used to manage transfusional iron overload:
Deferiprone:
- Randomized controlled trials demonstrate superior efficacy of deferiprone versus deferoxamine for cardiac iron removal 8
- Combined deferiprone with deferoxamine is superior to deferoxamine alone 8
Deferasirox:
- Equivalent efficacy to deferoxamine for iron chelation 8, 9
- Starting dose of 20 mg/kg/day is recommended, as doses below 20 mg/kg/day fail to provide consistent lowering of liver iron concentration and serum ferritin 9
- Doses of 20-30 mg/kg/day demonstrate reduction of liver iron concentration and serum ferritin 9
Deferoxamine:
- Administered as continuous intravenous infusion 8
- For acute decompensated heart failure, urgent commencement of high-dose continuous IV deferoxamine is required, augmented by oral deferiprone 8
Cardiac Monitoring and Management
Heart failure is the most common cause of death in beta thalassemia major, accounting for approximately 70% of mortality, and primarily results from cardiac iron accumulation. 8, 1, 2
Cardiac Assessment:
- Cardiac T2* magnetic resonance imaging is central to early identification of cardiac iron overload 8
- Cardiac T2 <10 ms is the most important predictor of development of heart failure* 8
- Serum ferritin and liver iron concentration are NOT adequate surrogates for cardiac iron measurement 8
- Serial measurements of cardiac function are required because single absolute values are complicated by abnormal cardiovascular hemodynamics in thalassemia major 8
Cardiovascular Adaptation to Chronic Anemia:
- Non-cardiac-loaded thalassemia major patients exhibit resting tachycardia, low blood pressure, enlarged end-diastolic volume, high ejection fraction, and high cardiac output 8
- Chronic anemia leads to background dyspnea, which can mask clinical diagnosis of cardiac dysfunction 8
Acute Heart Failure Management:
- Acute decompensated heart failure is a medical emergency requiring urgent consultation with an expert center 8
- First principle: control cardiac toxicity from free iron with urgent continuous, uninterrupted infusion of high-dose IV deferoxamine, augmented by oral deferiprone 8
- Considerable care is required to not exacerbate cardiovascular problems from overuse of diuretics or inotropes due to unusual loading conditions in thalassemia major 8
Curative Treatment
Hematopoietic stem cell transplantation remains the only curative option:
- Current disease-free survival is approximately 80% with overall survival over 90% 2
- Cure rates as high as 97% have been achieved 7
- Cord blood transplantation is also utilized 7
Adjunctive Therapies
- Folic acid supplementation 6
- Splenectomy in selected cases 6, 7
- Management of endocrinopathies resulting from iron deposition 5, 7
Emerging Therapies
- Hydroxyurea for fetal hemoglobin induction 5, 7
- Luspatercept 5
- Gene therapy involving insertion of normal β-globin or γ-globin genes into hematopoietic stem cells 10, 6
- Gene editing using CRISPR/Cas9 to correct causative mutations or increase fetal hemoglobin 10
Beta Thalassemia Intermedia
Treatment is symptomatic and may include:
- Folic acid supplementation 6
- Splenectomy 6
- Transfusions as needed for symptomatic anemia 5
- Monitoring for complications as patients may transition toward a major phenotype with age 2