Alpha-thalassemia

Overview
  • Alpha-thalassemia is a subtype of thalassemia characterized by reduced synthesis of the alpha-globin chain, resulting in a relative excess of beta-globin within erythrocytes. See the thalassemia page for a general discussion of these disorders.
Genetics
  • Alpha-globin is coded on two consecutive genes on Chromosome 16, meaning each diploid erythrocyte precursor carries four total alpha-globin alleles. Individuals with alpha-thalassemia carry deletions that affect any combination of these loci, meaning there might be absent synthesis from one, two, three, or all four alpha-globin loci.
Incidence
  • Deletions of the alpha-globin gene is most frequently encountered in Asian and African American populations.
Pathogenesis
  • Reduced synthesis of alpha-globin results in a relative excess of beta-globin chain production as well as reduced total production of hemoglobin. The reduced total hemoglobin production yields the classic microcytic anemia of thalassemia. However, a relative excess of beta-globin production yields hemoglobin tetramers composed entirely of beta-globin tetramers, known as Hb H. Although Hb H is somewhat soluble, it is more easily oxidized and has a higher affinity for oxygen than the normal Hb A. Not only does this make for inefficient oxygen delivery to tissues, but also oxidized Hb H tends to accumulate in erythrocytes, yielding an extravascular hemolytic anemia and thus splenomegaly. Hb H also appears to induce a certain degree of ineffective erythropoiesis. The degree of these biochemical defects and thus the intensity of clinical consequences depends on the number of alpha loci affected as described below.
Clinical and Laboratory Consequences
  • Overview
    • Given the four loci of alpha-globin, four possible alpha-thalassemia syndromes can result depending on what number of loci are affected.
  • One deletion: Silent Carrier
    • Patients with only one alpha-globin deletion are asymptomatic and typically do not display anemia or microcytosis.
  • Two deletions: Alpha-thalasemia Minor
    • Patients with two alpha-globin deletions are still asymptomatic but typically display a microcytic anemia on laboratory examination.
  • Three deletions: Hb H Disease
    • Patients with three alpha-globin deletions display a symptomatic microcytic anemia with moderate extravascular hemolysis that may yield splenomegaly. Most patients survive to adult life and only become transfusion-dependent in their later years.
  • Four Deletions: Hydrops Fetalis
    • Deletion of all four alpha-globin chains is not compatible with life and results in hydrops fetalis.