The thalassemias are a group of common inherited hemoglobin disorders that result in the unbalanced synthesis of  beta and alpha globin chains.

Pathophysiology

• Symptoms result from inadequate hemoglobin (Hb) production and accumulation of globin subunits
• Disease named according to the defective or absent globin unit
• Two main types - beta thalassemia and alpha thalassemia

Beta Thalassemia

• Epidemiology
  • Prevalence - estimated 3% of world’s population is heterozygous for beta thalassemia
  • Ethnic - endemic in Mediterranean, Middle East, Indian subcontinent, Southeast Asia
  • Genetics
    • Usually autosomal recessive
    • The beta globin subunit is synthesized by the epsilon, gamma (2 copies), delta and beta genes on chromosome 11
    • Beta thalassemias are mainly caused by single nucleotide mutations
    • Over 200 known mutations are categorized into 2 classes:
      • Beta-zero (beta null)
        • No beta globin synthesis from the affected allele
      • Beta-plus (beta positive)
        • Decreased beta globin synthesis from the affected allele
    • Beta globin gene deletions are rare
      • Indian - partial deletion of beta globin gene (beta null mutation)
      • Beta delta thalassemia - deletion which removes the entire beta gene and the majority of delta that is only partially compensated by increased gamma globin production (beta positive mutation)
      • Hereditary Persistence of Fetal Hemoglobin (HPFH), African type (pancellular) - deletion which removes the beta and delta genes entirely; this deletion is almost fully compensated by increased gamma globin production
  • Forms
    • Beta-thalassemia major (Cooley anemia)
      • Homozygous, or a compound heterozygote, for two beta null mutations
      • Clinical Presentation
        • Asymptomatic at birth since neonates have not yet switched from fetal to adult hemoglobin (gamma genes to beta genes)
        • Symptoms typically first appear at 6-24 months of age
          • Growth retardation
          • Pallor
          • Hepatosplenomegaly
          • Jaundice (Hb F is protective in first 6 months)
        • Iron overload leading to cardiac and liver failure is the main cause of death
      • Treatment
        • Regular transfusions with chelation to prevent iron overload prolongs life expectancy
        • Bone marrow or cord blood transplantation may be curative
    • Beta-thalassemia intermedia
      • beta positive homozygote, beta null/beta positive compound heterozygote, or beta null in combination with a thalassemic hemoglobinopathy (eg, Hb E, Lepore)
      • Clinical Presentation
        • Variable, may be nearly as severe as thalassemia major
        • Pallor, jaundice, cholelithiasis, liver and spleen enlargement, moderate-to-severe skeletal changes, leg ulcers, extramedullary masses of hyperplastic erythroid marrow
      • Treatment
        • Patients occasionally require transfusions
        • Splenectomy controversial
    • Thalassemia minor
      • Heterozygous for beta null or beta positive mutation
      • Typically asymptomatic, mild anemia may be present which is often mistaken for iron deficiency

Alpha Thalassemia

• Epidemiology
  • Carrier frequencies in commonly affected populations: Mediterranean (1:30-50), Middle Eastern, Southeast Asian (1:20), African, African American (1:30)
• Genetics
  • The alpha globin subunit is synthesized by the alpha-1 and alpha-2 genes on chromosome 16
  • Normal individuals have four functioning alpha globin genes (alphaalpha/alphaalpha)
  • 95% of alpha thalassemia is caused by alpha-1 and alpha-2 deletions; non-deletion or regulatory region mutations are rare
• Forms
  • Hemoglobin Bart
    • Mutation of four alpha globin genes (--/--)
    • Found in Southeast Asian, Asian Indian and Mediterranean populations but unlikely in African populations
    • Clinical Presentation - hydrops fetalis
  • Hemoglobin H disease
    • Mutation of three alpha globin genes (--/-alpha)
    • Clinical Presentation
      • Moderately severe hemolytic anemia with Heinz bodies
      • Splenomegaly is always present with rare extramedullary hematopoiesis
    Alpha thalassemia-1 trait (alpha thalassemia trait)
    • Mutation of two alpha globin genes (-alpha/-alpha; --/alphaalpha)
      • Important to define phase for prenatal counseling; homozygosity for alpha-1 and alpha-2 globin gene deletions in cis leads to hydrops fetalis
    • Clinical Presentation
      • Mild microcytic anemia may be present; often misdiagnosed as iron deficiency
    Alpha thalassemia-2 trait (silent carrier)
    • Mutation of a single alpha-2 globin gene (-alpha/alphaalpha)
    • Clinical Presentation
      • Usually asymptomatic
      • Borderline anemia or mild microcytosis may be present; often misdiagnosed as iron deficiency

Beta Thalassemia

Beta-thalassemia major (Cooley anemia)

• Diagnosis
  • Laboratory testing
    • Severe, often fatal, microcytic, hypochromic anemia
    • Target cells and nucleated red blood cells present
    • No Hb A and variable amounts of Hb F and Hb A2
    • Elevated bilirubin

Beta-thalassemia intermedia

• Diagnosis
  • Laboratory testing
    • Decreased Hb A, increased Hb F, variable Hb A2 levels
    • Often associated with iron overload due to increased intestinal absorption of iron caused by ineffective erythropoiesis

Thalassemia minor

• Diagnosis
  • Laboratory testing
    • Microcytic indices present
    • Hb F may be elevated in ~30% of individuals
    • Hb A2 is almost always increased
      • Rare exceptions include beta delta thalassemia Greek beta thalassemia mutations 

Alpha Thalassemia

Hemoglobin Bart

Hemoglobin H disease

• Diagnosis
  • Laboratory testing
    • Hb H is present (tetramer of beta globin subunits)
      • Hb H may not be detected by electrophoresis in older samples as unstable hemoglobin precipitates in cells; ie, Heinz bodies or in hemolysate
    • In neonates, a large amount of Hb Bart (tetramer of gamma chain) is present

Alpha thalassemia-1 trait (alpha thalassemia trait)

• Diagnosis
  • Laboratory testing
    • Normal hemoglobin electrophoresis
    • Diagnosed by DNA analysis of alpha globin genes, globin chain synthesis assay, or in a neonate when a moderate amount of Hb Bart detected

Alpha thalassemia-2 trait (silent carrier)

• Diagnosis
  • Laboratory testing
    • Normal hemoglobin electrophoresis
    • Diagnosed by DNA analysis of alpha globin genes, globin chain synthesis assay, or in a neonate when a small amount of Hb Bart detected