What is thalassemia (alpha and beta)?

What is Thalassemia (Alpha and Beta)?

Thalassemias are inherited autosomal recessive blood disorders caused by mutations that reduce or eliminate production of either alpha-globin or beta-globin chains, resulting in imbalanced hemoglobin synthesis, ineffective red blood cell production, and varying degrees of anemia. 1, 2

Genetic Basis

Beta-Thalassemia

• Caused by mutations in the HBB gene on chromosome 11, with over 200 identified pathogenic variants, predominantly single-nucleotide substitutions, small deletions, or insertions 1, 3
• Mutations produce either a β⁺ phenotype (reduced beta-globin synthesis) or β⁰ phenotype (complete absence of beta-globin) 1
• Follows autosomal recessive inheritance, requiring homozygosity or compound heterozygosity for severe disease 1

Alpha-Thalassemia

• Results from reduced or absent synthesis of alpha-globin chains, most prevalent among individuals of Southeast Asian ancestry 1
• Humans have four alpha-globin genes (two on each chromosome 16), and severity depends on how many genes are deleted or mutated 4
• Four-gene deletion causes hydrops fetalis and is typically fatal at birth 1, 5

Clinical Spectrum by Severity

Beta-Thalassemia Major (Transfusion-Dependent)

• Newborns are asymptomatic because fetal hemoglobin (α₂γ₂) does not require beta-globin chains 1, 2
• Symptoms emerge at 1-2 years of age as fetal hemoglobin declines and adult hemoglobin synthesis begins 1, 2
• Life-threatening by age 1-2 years without intervention, requiring lifelong regular transfusions starting before age 2 1, 2
• Adults typically require more than 8 transfusion events per year to maintain adequate hemoglobin 1, 2

Beta-Thalassemia Trait (Carrier State)

• Characterized by microcytic hypochromic anemia with MCV typically <80 fL 1, 6
• Does NOT respond to iron supplementation despite compliance—this is the critical distinguishing feature from iron deficiency anemia 6, 2
• Clinically asymptomatic but detectable on hematologic testing 6, 3
• Most prevalent in populations from Mediterranean, Middle East, Southeast Asia, and Africa—regions with historical malaria exposure 6

Thalassemia Intermedia (Non-Transfusion-Dependent)

• Includes beta-thalassemia intermedia, HbE beta-thalassemia, and HbH disease (alpha-thalassemia intermedia) 7, 8
• Variable presentation with absent or episodic transfusion requirements 7, 8
• Greater propensity for pulmonary hypertension and thrombosis compared to transfusion-dependent forms 7
• May require transfusions later in life to prevent cardiovascular and other complications 7

Iron Overload and Cardiac Complications

• Each transfused red cell unit delivers approximately 200-250 mg of elemental iron 1, 2
• Humans lack physiological mechanisms for iron excretion, leading to progressive accumulation 1
• Cardiac iron deposition accounts for approximately 70% of mortality in transfusion-dependent patients 1, 2
• Before modern iron chelation therapy, most patients died from cardiac complications by age 10; with optimal chelation, survival into the seventh decade is now achievable 1, 2
• Lifelong iron chelation therapy is essential alongside transfusions to prevent or reverse iron-related organ damage 7, 2

Diagnostic Approach

• Suspect thalassemia in patients with microcytic anemia and normal or elevated ferritin levels 2, 5
• Both alpha and beta thalassemia present with microcytic hypochromic anemia 2
• Hemoglobin electrophoresis may reveal characteristic patterns, but genetic testing confirms the diagnosis 2, 5
• Always check serum ferritin to rule out concurrent iron deficiency before attributing findings solely to thalassemia trait 6, 2

Critical Clinical Pitfalls to Avoid

• Do NOT prescribe iron supplementation to patients with confirmed thalassemia trait—it provides no therapeutic benefit and may contribute to unnecessary iron accumulation 1, 6, 2
• In pregnant women of appropriate ancestry with persistent mild anemia unresponsive to prenatal iron, evaluate with MCV, RDW, and hemoglobin electrophoresis 6, 2
• Failure to consider ethnicity leads to missed diagnoses, as thalassemias are significantly more common in populations from malaria-endemic regions 6, 2
• Cardiac disease is easier and safer to treat at an early stage rather than late stage when mortality risk is high—early identification and aggressive chelation are paramount 7