Most common human enzyme deficiency in the world.
Clinically characterized by
an acute red cell hemolysis resulting from intake of oxidative agents.
Glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals are more resistant
to Plasmodium falciparum (malaria-causing parasite).
Baghdad Anemia; Broad Bean Syndrome; Favism (usually in
persons of Mediterranean area descent).
Genetic enzyme deficiency (>400 variant alleles, or
different forms of the same gene). Favism has been known to exist since
antiquity; Pythagoras had warned his disciples against the dangers of eating
Most of the affected individuals reside in Africa, the
Middle East, tropical, subtropical Asia, some areas of the Mediterranean,
Papua New Guinea, and Southeast Asia (areas where malaria is common); 100
million people worldwide are believed to be affected.
X-linked (thus predominantly a male syndrome).
Most of the variants arise from a single point mutation (amino acid
substitution) in the structural gene encoding for G6PD, which is located at
the Xq28 region on the tip of the long arm of the X chromosome.
G6PD catalyzes the first step in the hexose
monophosphate pathway, producing nicotinamide adenine dinucleotide phosphate
(NADPH). This pathway is the only source of NADPH in the erythrocyte. NADPH
is required to reduce oxidized glutathione. Reduced glutathione is the
substrate for peroxide removal from the red blood cells. When G6PD-deficient patients
are given drugs that form peroxides in contact with oxyhemoglobin, the lack
of glutathione peroxide removal leads to hemolysis and formation of Heinz
bodies. There exist at least five variants of this syndrome: the rare class
1, or hereditary nonspherocytic hemolytic anemia (associated with chronic
hemolysis); class 2, or severe deficiency (<10%); class 3, or
moderate-to-mild deficiency; class 4, or very mild-to-no enzyme deficiency
(60%); and class 5, an increase in enzyme activity. The degree of
hemolysis also may be related to other non-G6PD-related issues, such as
acetylator status (i.e., a rapid acetylator will metabolize drug quicker
than a slow or nonacetylator, and the lack of drug accumulation prevents hemolysis).
A variety of laboratory tests are available for patients
who have not hemolyzed, including the dye reduction test and the
fluorescent spot test. Oxidant stress causes hemoglobin denaturation and the
formation of Heinz bodies. For patients who have hemolyzed, the most
powerful diagnostic technique is genomic DNA analysis.
Class 1: Chronic hemolysis without exposure to
“classic” trigger agents (Table G-1), often beginning at birth (neonatal
jaundice potentially leading to kernicterus). Classes 2 and 3: Variable degrees of
hemolysis, depending on pharmacologic exposure. Hemolysis usually occurs 1
to 2 days after drug exposure and may be associated with back pain and dark
urine. Numerous bacterial, viral, and rickettsial infections have been
reported as precipitants.
Table G-1 Drugs to Avoid in All Class 1 Variant Patients