Unstable hemoglobins: influence of environment on phenotypic expression of a genetic disorder.

Unstable hemoglobins account for approximately one fifth of the abnormal hemoglobins identified to date. Clinical expression ranges from a continuing and severe hemolytic anemia which may or may not be abated by splenectomy to a compensated hemolytic state with exacerbations of hemolysis after exposure to drugs or during febrile episodes. Other clinical indicators of the disorder include the voiding of urine darkened by the presence of dipyrroles, as well as intermittent episodes of scleral icterus. Recognition and definition of the unstable hemoglobins can be difficult. Approximately one third are spontaneous mutations; many are neutral substitutions, so that routine electrophoretic methods are of limited value; and in some the molecule is so unstable that it is lost during preparative techniques employed for its identification. Most informative are those methods designed to demonstrate the instability of the molecule, including the exposure of red cells or hemolysate to heat, redox dyes, or isopropanol. Each of these tests is easily performed and should be employed in the evaluation of any patient with an unexplained hemolytic disorder, and especially in those patients with drug-or hyperthermic-induced hemolysis. A review of red cell indices of our patients, together with those reported in the literature, indicates the subjects with moderate to severe forms of the unstable hemoglobinopathies have macrocytosis with abnormally low MCHCs. Incubating normal or Hb Zürich red cells in vitro at 37 degrees and 41 degrees C effects similar changes in the red cells, the phenomenon occurring more rapidly in Hb Zürich than in normal cells. The phenotypic expression of the unstable hemoglobinopathies may be influenced by a variety of environmental factors, including smoking, pyrexia, exposure to oxidants, and the presence or absence of splenic function. Especially noteworthy is the effect of smoking on the clinical and laboratory findings in subjects with Hb Zürich. As a result of the 65-fold increase in the affinity of the abnormal beta-globin chain of Hb Zürich for CO, the molecule is stabilized, followed by resistance to oxidative injury, a decreased rate of hemolysis, and a marked increase in oxygen affinity.