Clinical Information

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzymopathy, estimated to affect up to 500 million people worldwide. It is most frequently found in populations where Plasmodium falciparum malaria is (or was) endemic, but G6PD deficiency may be present in any population.

G6PD deficiency primarily manifests as episodic acute hemolytic anemia (AHA), chronic non-spherocytic hemolytic anemia (CNSHA), and neonatal jaundice. These clinical manifestations can be triggered in individuals with G6PD deficiency by fava beans, several types of medications (including rasburicase, dapsone-containing combinations of antimalarial drugs, and methylene blue), and infection.

G6PD converts glucose-6-phosphate to 6-phosphoglyconolactone in the first step of the pentose phosphate pathway, this reaction also produces nicotinamide adenine dinucleotide phosphate (NADPH) from 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, male patients are more commonly affected than female patients, but due to the high prevalence of G6PD deficiency, homozygous and compound heterozygous female patients are not uncommon. Over 200 G6PD variants have been discovered and are classified based on guidance from the World Health Organization (WHO). In 2022, WHO proposed updated guidance for the classification of G6PD variants (Table). This revised guidance is based on the median residual enzyme activity and seeks to resolve problems identified with the WHO G6PD classification system that has been in place since 1985 (Table).

Table. Updated and Legacy G6PD Variant WHO Classification and Associated G6PD Deficiency Phenotype

With the exception of those with 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 AHA in individuals with G6PD deficiency. The severity of AHA is highly variable, ranging from mild neonatal jaundice to life-threatening complications, such as kernicterus. Therefore, determining the G6PD deficiency status is recommended on the US Food and Drug Administration label of several drugs either proven or suspected to cause AHA in patients with G6PD deficiency. For more information on drugs known to cause AHA in individuals with G6PD deficiency, see Pharmacogenomic Associations Tables.

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 female patients, the phenotyping assay is necessary to determine if such drugs should be avoided. Skewed X-inactivation in heterozygous female patients has been reported to result in G6PD deficiency, so the phenotyping assay is necessary to determine G6PD activity level.