Deficiency of G6PD, a ubiquitous X-linked enzyme, is the most common disease-producing enzyme defect of humans, estimated to affect 400 million people worldwide; one allele, the A variant, is found in 1 in 20 Black males in the United States. With over 300 variants described, G6PD deficiency also appears to be the most genetically heterogeneous disorder yet recognized (Luzzatto and Mehta, 1989). The high gene frequency of G6PD variants in some populations appears to reflect the fact that G6PD deficiency, like sickle cell hemoglobin and thalassemia, confers some protection against malaria. This enzymopathy originally came to attention when the antimalarial drug primaquine was found to induce hemolytic anemia in Black males, who were subsequently found to have G6PD deficiency.
The mechanism of the drug-induced hemolysis is reasonably clear. One of the products of G6PD, nicotinamide-adenine dinucleotide phospate (NADPH), is the major source of reducing equivalents in the red blood cell. NADPH protects the cell against oxidative damage by regenerating reduced glutathione from the oxidized form. In G6PD deficiency, oxidant drugs such as primaquine deplete the cell of reduced glutathione, and the consequent oxidative damage leads to hemolysis. Additional offending compounds include sulfonamide antibiotics, sulfones such as dapsone (widely used in the treatment of leprosy and Pneumocystis carinii infection), naphthalene (moth balls), and a few others. The role of some drugs in producing hemolysis in G6PD deficiency is ambiguous because of the uncertain significance of other genetic factors (such as genetically determined ethnic and individual variation in pharmacokinetics) and nongenetic determinants (such as infection, which itself can induce hemolysis in severe variants of G6PD deficiency).
Favism, a sever hemolytic anemia that results from ingestion of the broad bean Vicia faba and that has been known since ancient times in parts of the Mediterranean, is due to extreme G6PD deficiency. The enzyme defect makes the cells vulnerable to oxidnants in fava beans (Pythagoras, the Greek mathematician, warned his followers of the danger of eating these beans). In areas where severe deficiency variants like the Mediterranean allele are prevalent, they are a major cause of both neonatal jaundice and congenital nonspherocytic hemolytic anemia.
The common deficiency alleles of American Blacks and of the Mediterranean region migrate electrophoretically at the same rate as A and B variants but have much lower activities, and so are called A -ve and B -ve variants, respectively. Although G6PD deficiency is far more common in males, an appreciable number (at least 1 in 400) of American Black females are genetically A-ve/A-ve, and are clinically susceptible to drug-induced hemolysis.
The A-ve Variant has decreased stability
In addition to reduced catalytic activity, instability of the A-ve variant is a major factor in the pathological response to drug ingestion. Synthesis of the A-ve protein is unaffected by the mutation, but because the molecule is relatively unstable, its abundance decreases more quickly than the normal as the red cell ages. (Remember that the mature cell is nucleate, and thus new protein synthesis is limited). After drug ingestion, patients with this allele have hemolysis only as long as it takes (usually about a week) to destroy the fraction of older red cells that have lost, through aging, a critical amount of G6PD activity. Even if the drug administration is continued, the hemolytic phase comes to an end because the young cells produced in response to hemolysis have sufficient newly synthesized G6PD A-ve prevent oxidative damage.