Harvey's Garden

Thalassemia

3 min read

Epidemiology

  • Beta thalassemia: most commonly seen in people of Mediterranean descent
  • Alpha thalassemia: most commonly seen in people of Asian and African descent

Mnemonic

Alpha thalassemia is common in Asia and Africa.

Etiology

  • Beta thalassemia: usually due to point mutations in promoter sequences or splicing sites
    • β-globin locus - short arm of chromosome 11
  • Alpha thalassemia: usually due to deletion of at least one out of the four existing alleles
    • The α-globin gene cluster is located on chromosome 16

Pathophysiology

  • Inefficient erythropoiesis → anemia
    • Beta-thalassemia minor and major: faulty β-globin chain synthesis → ↓ β-chains→ ↑ γ-,δ-chains → ↑ HbF and ↑ HbA2.
    • Alpha-thalassemia intermedia (HbH disease) and alpha-thalassemia major (Bart’s disease): faulty α-globin chain synthesis → ↓ α-chains → impaired pairing of α-chains with β-chains and γ-chains→ ↑ free β-, γ-chains → ↑ HbH, ↑ Hb Barts
    • Sickle cell anemia: Point mutation in the β-globin gene (chromosome 11) → glutamic acid replaced with valine (single amino acid substitution) → 2 α-globin and 2 mutated β-globin subunits create pathological hemoglobin S (HbS).
  • Increased hemolysis: One of the chains (either α or β) is reduced → compensatory overproduction of other chains → excess globin chains precipitate and form inclusions within RBCs → erythrocyte instability with hemolysis
  • Anemia → ↑ erythropoietin → bone marrow hyperplasia and skeletal deformities

Tip

Hemoglobin A2 is elevated in beta-thalassemia to compensate for beta-globin–chain underproduction, but results in microcytic red cells that are prone to hemolysis. Increased erythrocyte turnover results in a misleadingly low hemoglobin A1c level. In such cases, measurement of glycated serum proteins (ie, fructosamine) is sometimes used to estimate glycemic control. See Hyperglycemia tests

Clinical features

  • Alpha (α)-Thalassemia
    • 1 gene deletion (Silent Carrier): Asymptomatic, no treatment needed.
    • 2 gene deletions (α-Thalassemia Trait): Usually asymptomatic with mild microcytic anemia.
    • 3 gene deletions (HbH Disease): Excess β-chains form HbH (β₄) tetramers. This leads to moderate-to-severe chronic hemolytic anemia and splenomegaly.
    • 4 gene deletions (Hb Barts): Incompatible with life, resulting in hydrops fetalis. Excess γ-chains (from fetal Hb) form Hb Barts (γ₄).
      • Mechanism: Hb Barts has an extremely high affinity for oxygen. It binds O2 in the placenta but fails to release it to fetal tissues.
      • Result: This leads to profound tissue hypoxia, causing a cascade of:
        1. High-Output Heart Failure: The heart overworks to compensate for the lack of oxygen delivery.
        2. Massive Edema (Anasarca): The combination of heart failure and liver dysfunction (from extramedullary hematopoiesis) causes fluid to leak out of the vessels.
  • Beta (β)-Thalassemia
    • β-Thalassemia Minor (Trait): Heterozygous (one defective gene). Typically asymptomatic with mild microcytic anemia. A classic finding is a normal or increased RBC count despite low Hb and MCV.
    • β-Thalassemia Major (Cooley Anemia): Homozygous (two defective genes). Severe anemia becomes symptomatic around 6 months of age as fetal hemoglobin (HbF) levels decline.
      • Clinical Features: Massive hepatosplenomegaly from extramedullary hematopoiesis, “crewcut” appearance on skull x-ray, and “chipmunk” facies due to bone marrow expansion.
      • Requires lifelong blood transfusions.

Diagnostics

  • Hb-electrophoresis

Tip

α-thalassemia minima vs β-thalassemia minor:

  • Both asymptomatic
  • α-thalassemia minima is normal on electrophoresis, while β-thalassemia shows narrowed HbA band and widened HbA2 band
  • Peripheral blood smear findings include:
    • Target cells
      • ↑ surface area-to-volume ratio
    • Teardrop cells

Treatment

Graph View

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