To maintain normal shape and flexibility as well as to combine with and release oxygen, RBCs must generate energy. The needed energy is produced almost exclusively through the breakdown of glucose, a process that is catalyzed by a number of enzymes. Deficiencies of these enzymes are associated with hemolytic anemia. Two of the most common deficiencies, both hereditary, involve the RBC enzymes glucose-6-phosphate dehydrogenase and pyruvate kinase.
Glucose-6-Phosphate Dehydrogenase
Glucose-6-phosphate dehydrogenase is an enzyme pivotal in generating the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) through the pentose pathway in glucose metabolism. More than 100 structural and functional variants of the normal G-6-PD molecule (called type B) have been identified, most of which are clinically insignificant. One variant form (called type A) does, however, produce clinical disease. The type A variant is caused by a sex-linked genetic defect. The abnormal gene is carried by women and is transmitted to men who inherit the disorder.
Persons with the type A enzyme (15 percent of blacks) experience no difficulty until challenged by an oxidative stressor, which induces rapid intravascular hemolysis of susceptible cells. Among these stressors are systemic infections, septicemia, metabolic acidosis, and exposure to oxidant drugs (aspirin, chloramphenicol [Chloromycetin], nitrofurantoin [Furadantin], phenacetin, primaquine, probenecid [Benemid], quinidine, quinine, sulfonamides, thiazide diuretics, and tolbutamide [Orinase]).
A Mediterranean variant also may occur, especially in individuals of Greek and Italian descent and in some small, inbred Jewish populations. This variant severely reduces enzymatic activity and leads to more severe hemolytic episodes, which are triggered by a greater variety of stimuli and are less likely to be self-limited than in persons with the type A variant. In addition to the oxidative stressors just listed, ingestion of fava beans is known to precipitate hemolytic events in individuals with Mediterranean-type G-6-PD deficiency.32
Pyruvate kinase (PK) functions in the formation of pyruvate and adenosine diphosphate (ADP) in glycolysis. The pyruvate thus formed is subsequently converted to lactate. RBCs that lack PK have a low affinity for oxygen. Episodes of hemolysis in individuals lacking this enzyme are severe and chronic and are exacerbated by stressors such as infection.
The inherited form of this disorder is transmitted as an autosomal recessive trait; both parents must carry the abnormal gene for the child to be affected. The acquired form of PK deficiency is usually caused by either drug ingestion or metabolic liver disease.