Glucose-6-phosphate dehydrogenase (G6PDH) is a key enzyme in the Hexose Monophosphate Shunt (HMS), the endogenous source of antioxidant. The HMS pathway generates reducing power in the form of NADPH, which maintains an adequate level of reduced glutathione (GSH). G6PD is present in all human cells but is particularly important to red blood cells. It is required to make NADPH in red blood cells but not in other cells. NADPH protects the sulfhydryl groups (-SH) of hemoglobin and the red cell membrane from oxidation by the reactive oxygen spieces (oxygen radicals). Defects in the HMS pathway due to defective G6PD can lead to inadequate protection against oxidation, resulting in oxidation of sulfhydryl groups, precipitation of hemoglobin, and lysis of RBCs (i.e., hemolysis). Multiple hemolysis episodes in a short time span lead to a condition known as hemolytic anemia.
The major symptoms of hemolytic anemia are jaundice, dark urine, abdominal pain, back pain, lowered red blood cell count, and elevated bilirubin. People who suffer from severe and chronic forms of G6PD deficiency in addition may have gallstones, enlarged spleens, defective white blood cells, and cataracts.
Attacks of hemolytic anemia are serious for infants. Brain damage and death are possible but preventable outcomes. Newborns with G6PD deficiency are about 1.5 times as likely to get neonatal jaundice than newborns without G6PD deficiency. It is important to screen newborns who are likely to have G6PD deficiency to ensure that G6PD-deficient babies won't be subjected to any of the triggers of hemolytic anemia. Pregnant women in areas where G6PD deficiency is prevalent should avoid eating fava beans.

The release of hemoglobin during hemolysis and the subsequent therapeutic transfusion in some cases lead to systemic iron overloading that further potentiates the generation of reactive oxygen species (ROS).

G6P DH deficiency is an X-linked (inherited) genetic defect. It can cause hemolytic anemia of varying severity. The episodes of hemolytic anemia are usually triggered by oxidants, infection, or by eating fava beans.
G6P DH deficiency is perhaps to be the most common enzyme deficiency in the world, affecting about 400 million people. It is most prevalent in people of African, Mediterranean, and Asian origins. The incidence in different populations varies from zero in South American Indians to nearly 50% of Kurdish males. In the United States, 10 to 15% of African American males are G6P DH-deficient.
There is considerable genetic heterogeneity among affected individuals with over 400 variants of the enzyme identified. Therefore the severity of the problem can vary from hemolysis even in the absence of oxidative stress to hemolysis only on exposure to marked oxidant stress.

The G6P DH gene is located on the X chromosome. Thus the deficiency state is an sex-linked trait seen only in hemizygote males. Most female carriers are asymptomatic. (Males have only one copy of the G6PD gene, but females have two copies. Recessive genes are masked in the presence of a gene that encodes normal G6PD. Accordingly, females with one copy of the gene for G6PD deficiency are usually normal, while males with one copy have the trait. ).

Hemolytic episodes may be triggered by viral or bacterial infections and by drugs or toxins that have an oxidating potential: acetanilid, chloramphenicol, dapsone, doxorubicin, furazolidone, methylene blue, nalidixic acid, napthalene, niridazole, nitrofurantoin, pamaquine, phenazopyridine, phenylhydrazine, phytonadione (vitamin K), primaquine, quinidine, quinine, sulfacetamide, sulfamethoxazole, sulfonamide, sulfapyridine, thiazolesulfone, toluidine blue, and trinitrotoluene. etc. Also, naphthalene balls can cause hemolysis in G6P DH- deficient individuals.

The hemolytic crisis may manifest within hours of exposure to the oxidant stress. In severe cases, hemoglobinuria and peripheral circulatory collapse can occur. Since in most cases, only older red cells are affected the most, the problem is usually self-limiting. There can be a rapid drop in hematocrit, a rise in plasma hemoglobin and unconjugated bilirubin. Heinz bodies can be seen on crystal violet staining. These are removed in the spleen in a day or two and 'bite cells', with loss of a portion of the periphery of the red cell, may be seen.

The diagnosis can be confirmed by G6PD assay. The test may be negative during a hemolytic crisis when the older and defective RBCs are replaced by younger cells. In such cases, the test has to be repeated.

No specific treatment is needed since the condition is usually self limiting. Rarely blood transfusions are indicated. Adequate urine output should be ensured through hydration.

In patients with mild G6PD deficiency, primaquine can be given at a dose of 0.6 mg/kg once weekly for 8 weeks. Primaquine and Pyrimethamine+sulfadoxine should not be administered on the same day to avoid hemolysis.

References

1. Eichelbaum M and Evert B. Influence of pharmacogenetics on drug disposition and response. Clin Exp Pharmacol Physiol. 1996; 23:983-5.
2. Morse EE. Toxic effects of drugs on erythrocytes. Ann Clin Lab Sci. 1988;18:13-8.