Clinical Information

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzymopathy with about 400 million people affected worldwide. It is most commonly found in populations where Plasmodium falciparum malaria is (or was) endemic, but G6PD deficiency may be present in any population.

G6PD converts glucose-6-phosphate to 6-phosphoglyconolactone in the first step of the pentose phosphate pathway (PPP), this reaction also produces nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) from nicotinamide adenine dinucleotide phosphate (NADP). NADPH, through subsequent enzymatic reactions, protects erythrocytes from damage by detoxifying hydrogen peroxide and other sources of oxidative stress.

G6PD is encoded by the gene G6PD, which lies on the X-chromosome. G6PD deficiency is inherited in an X-linked recessive manner; therefore, males are more commonly affected than females, but due to the high prevalence of G6PD deficiency, homozygous and compound heterozygous females are not uncommon. A large number of G6PD pathogenic variants have been discovered. These variants are subdivided into a class system based on definitions from the World Health Organization (WHO).

 Table 1. G6PD variant WHO class and associated G6PD deficiency phenotype

With the exception of those with chronic nonspherocytic hemolytic anemia (CNSHA), individuals with G6PD deficiency are typically asymptomatic until they are challenged with an exogenous factor such as a drug, infection, or fava beans. The exogenous factor can trigger acute hemolytic anemia (AHA) in individuals with G6PD deficiency. The severity of AHA is highly variable, ranging from mild to life-threatening and can be fatal. Therefore, determining the G6PD deficiency status is recommended on the Food and Drug Administration label of several drugs either proven or suspected to cause AHA in patients with G6PD deficiency. For a list of drugs known to cause AHA in individuals with G6PD deficiency, see Pharmacogenomic Associations Tables in Special Instructions.

Preemptive genotyping allows for the identification of patients at risk for an adverse reaction to drugs known to cause AHA in those with G6PD deficiency. In most cases, genotyping provides sufficient information to avoid the use of contraindicated drugs. In some cases, including heterozygous females, the phenotyping assay is necessary to determine if such drugs should be avoided. Skewed X-inactivation in heterozygous females has been reported to result in G6PD deficiency, but the phenotyping assay is necessary to determine G6PD activity level. For more information regarding the need for G6PD enzyme activity follow-up testing to this genotyping assay, refer to the G6PD Genotyping Algorithm for Therapeutic Drug Recommendations in Special Instructions.