What is the difference between beta (beta-globin) thalassemia and alpha (alpha-globin) thalassemia?

Key Differences Between Alpha and Beta Thalassemia

Alpha and beta thalassemia differ fundamentally in which globin gene is affected, their genetic basis, clinical presentation timing, and severity patterns—with alpha thalassemia caused by deletions in alpha-globin genes (typically requiring loss of multiple genes for severe disease) and beta thalassemia caused by point mutations in the beta-globin gene (where even single gene defects cause significant disease). 1, 2

Genetic and Molecular Basis

Alpha Thalassemia:

• Results from reduced or absent synthesis of alpha-globin chains due to gene deletions or mutations in the HBA1 and HBA2 genes 1, 2
• Humans normally have four alpha-globin genes (two on each chromosome 16), creating a dose-dependent severity pattern 3
• Most commonly caused by gene deletions rather than point mutations 1
• The number of deleted genes determines clinical severity: one gene deletion (silent carrier), two genes (trait), three genes (Hemoglobin H disease), four genes (alpha thalassemia major/hydrops fetalis) 1, 2

Beta Thalassemia:

• Results from reduced (β+) or absent (β0) synthesis of beta-globin chains due to mutations in the HBB gene on chromosome 11 4, 5
• Humans have only two beta-globin genes (one on each chromosome 11) 5
• Caused predominantly by point mutations (over 200 identified), including single nucleotide substitutions, small deletions, or insertions—rarely from gross gene deletions 5, 6
• Even heterozygous mutations cause detectable hematologic changes (beta thalassemia trait) 7, 5

Clinical Presentation and Timing

Alpha Thalassemia:

• Alpha thalassemia major (four gene deletion) manifests in utero, causing hydrops fetalis that is typically fatal at birth or in utero 1, 2
• Hemoglobin H disease (three gene deletion) presents with variable hemolytic anemia, often diagnosed later in childhood or adulthood 1, 2
• Trait forms (one or two gene deletions) are asymptomatic and require no treatment 1, 2

Beta Thalassemia:

• Infants are healthy at birth because fetal hemoglobin (HbF, α2γ2) does not require beta-globin chains 4
• Symptoms emerge at approximately 1-2 years of age as fetal hemoglobin production declines and the switch to adult hemoglobin (requiring β-chains) occurs 8, 4
• Beta thalassemia major becomes life-threatening by age 1-2 years, requiring lifelong transfusions starting before age 2 8, 1
• Beta thalassemia trait causes persistent microcytic anemia that does not respond to iron supplementation 7

Severity and Clinical Manifestations

Alpha Thalassemia:

• The most severe form (alpha thalassemia major) is usually incompatible with extrauterine life 6
• Hemoglobin H disease (alpha thalassemia intermedia) causes moderate hemolytic anemia with variable compensation 1, 6
• Milder forms are asymptomatic with normal life expectancy 2

Beta Thalassemia:

• Beta thalassemia major requires more than 8 transfusion events per year in adults over 16 years 8, 4
• Before modern chelation therapy, patients died by age 10 from cardiac complications; now survival into the 7th decade is possible with optimal care 9, 8
• Cardiac iron loading accounts for approximately 70% of mortality in transfusion-dependent patients 8, 4
• Each transfused unit contains approximately 200-250 mg of elemental iron, necessitating lifelong iron chelation therapy 9, 8

Pathophysiologic Mechanisms

Both conditions cause:

• Ineffective erythropoiesis from imbalanced globin chain production 1, 5
• Premature red blood cell destruction and hemolytic anemia 1, 2
• Bone marrow expansion and extramedullary hematopoiesis in severe forms 1

Key pathophysiologic difference:

• The clinical severity relates to the extent of imbalance between alpha and non-alpha globin chains 5
• In beta thalassemia, excess alpha chains are unstable and precipitate, causing more severe red cell damage 5
• In alpha thalassemia, excess beta chains form hemoglobin H (β4 tetramers), which are more stable but functionally abnormal 2, 6

Diagnostic Approach

Both conditions present with:

• Microcytic hypochromic anemia with normal or elevated ferritin levels 7, 1
• Mean corpuscular volume (MCV) typically <80 fL 7

Critical diagnostic distinction:

• Hemoglobin electrophoresis reveals elevated HbA2 and HbF in beta thalassemia trait 5, 6
• Hemoglobin electrophoresis may show hemoglobin H or Bart's hemoglobin in alpha thalassemia, but genetic testing is required for definitive diagnosis 1, 6
• Genetic testing confirms the diagnosis for both conditions 1, 5

Common Clinical Pitfalls

• Do not prescribe iron supplementation to patients with confirmed thalassemia trait—it provides no benefit and may contribute to unnecessary iron accumulation 7
• In pregnant women of Mediterranean, Middle Eastern, Southeast Asian, or African ancestry with persistent mild anemia unresponsive to prenatal iron, evaluate with MCV, RDW, and hemoglobin electrophoresis 7
• Always check serum ferritin to rule out concurrent iron deficiency before attributing microcytic anemia solely to thalassemia trait 7
• Failure to consider ethnicity leads to missed diagnoses, as thalassemias are significantly more common in populations from malaria-endemic regions 7, 1