Laboratory investigation of hemoglobinopathies and thalassemias: Review and update

Structural hemoglobin (Hb) variants typically are based on a point mutation in a globin gene that produce a single amino acid substitution in a globin chain. Although most are of limited clinical significance, a few important subtypes have been identified with some frequency. Homozygous Hb C and Hb S (sickle cell disease) produce significant clinical manifestations, wherea s Hb E and Hb D homozygotes may be mildly symptomatic. Although heterozygot es for these variants are typically asymptomatic, diagnosis may be importan t for genetic counseling. Thalassemia, in contrast, results from quantitati ve reductions in globin chain synthesis. Those with diminished beta-globin chains are termed beta-thalassemias, whereas those with decreased alpha-cha in production are called alpha-thalassemias. Severity of clinical manifesta tions in these disorders relates to the amount of globin chain produced and the stability of residual chains present in excess. The thalassemia minor syndromes are characterized clinically by mild anemia with persistent micro cytosis. Thalassemia intermedia (i.e., Hb H disease) is typified by a moder ate, variably compensated hemolytic anemia that may present with clinical s ymptoms during a period of physiologic stress such as infection, pregnancy, or surgery. The thalassemia major syndromes produce severe, life-threateni ng anemia. alpha-Thalassemia major usually is incompatible with extrauterin e life; beta-thalassemia major presents in infancy and requires life-long t ransfusion therapy and/or bone marrow transplantation for successful contro l of the disease. Double heterozygosity for certain structural variants and /or thalassemia syndromes may also lead to severe clinical disease. Several guidelines have been published that outline the required steps for hemoglo binopathy and thalassemia investigation. The availability of HPLC has strea mlined many of these requirements, allowing an efficient stepwise diagnosti c strategy for these complex disorders. (C) 2000 American Association for C linical Chemistry.