Clinical Information

Hemolytic anemia may be associated with deficiency of erythrocyte enzymes. The most common enzyme defect worldwide is a deficiency of glucose-6-phosphate dehydrogenase (G6PD).

As an enzyme in the hexose monophosphate pathway, G6PD plays a key role in the generation of reduced nicotinamide adenine dinucleotide phosphate (NADPH). Because red blood cells lack the citric acid cycle, this NADPH generation is critical for protection against oxidative stress. Normal conditions require approximately 2% of capacity, leaving 98% reserve for stressor events. More than 400 molecular variants of G6PD are known, and the clinical and laboratory features of G6PD deficiency vary according to the degree to which enzyme reserve is decreased. G6PD deficiency (OMIM 300908, X-linked) therefore results in various forms of anemia and is classified by World Health Organization (WHO) criteria according to enzyme activity and chronic versus acute episodic clinical course.(1-3)

In 2022, the WHO Malaria Policy Advisory Group panel proposed updated guidance for the classification of G6PD variants.(3) This revised guidance is based on the median residual enzyme activity (per allele) and seeks to resolve problems identified with the WHO G6PD classification system that has been in place since 1985 (See Table in Interpretation).

The G6PD locus is located on the X chromosome and, therefore, G6PD deficiency is a sex-linked disorder. Most people with G6PD deficiency are asymptomatic until a stressor event occurs resulting in acute hemolytic anemia that resolves after stimulus removal. Symptoms can include neonatal jaundice (presents at 1-4 days of age) or acute hemolysis triggered by medications (antimalarials, sulfonamides, dapsone, nitrofurantoin, and naphthalene), infection (hepatitis, cytomegalovirus, typhoid), or fava bean ingestion. Hemolysis and jaundice begin 24 to 72 hours after a triggering stimulus, with accompanying dark urine/hemoglobinuria. Anemia worsens for approximately one week and begins to recover ten days after cessation. Splenomegaly, gallstones, and recurrent jaundice are additional clinical symptoms. Because it is X-linked, male patients are usually more severely affected but homozygous female patients are seen due to the prevalence of genetic variants. Heterozygous female patients (carriers) range from asymptomatic to severe anemia due to mosaicism/lyonization. Acquired G6PD may occur due to increasing X inactivation in aging women.(4) Acute episodic G6PD deficiency (WHO class B, formerly class II and III) is not expected to affect length or quality of life. Less commonly seen are genetic variants that result in chronic nonspherocytic hemolytic anemia which manifest similarly to other enzyme deficiencies (WHO class A, formerly class I).

The major G6PD variants occur in specific ethnic groups. Thus, knowledge of the ethnic background of the patient is helpful. G6PD deficiency has very high frequency in persons of southeast Asian, African, southern European, and Middle Eastern descent.

Rasburicase therapy is contraindicated in patients with G6PD deficiency. US Food and Drug Administration (FDA) guidelines state to screen patients at higher risk for G6PD deficiency (eg, patients of African or Mediterranean ancestry) prior to starting therapy.(5)

Deficiency can be assessed by enzymatic and/or genetic assays. Due to limitations of genetic testing, in most cases it is preferential to perform G6PD enzyme testing to assign G6PD status. However, enzyme activity can be affected by recent red blood cell transfusion, marked reticulocytosis and very high white blood cell count. In these settings, genotyping may be useful for correlation with the red blood cell enzyme level.(6,7)

Due to historic issues with other similar antimalarial medications, questions arise if hydroxychloroquine (HCQ) or chloroquine (CQ) therapy may trigger acute hemolytic episodes in some G6PD subtypes. Data is limited in this regard. Available published data did not find hemolytic episodes associated with HCQ therapy in G6PD deficient African American (8) or CQ therapy in G6PD deficient African (9) patients. Both studied populations were assumed to have mild forms of the disorder. Data regarding these medications in populations with more severe G6PD phenotypes is lacking. While patients receiving HCQ do not routinely need G6PD levels checked before initiating therapy, testing may be considered in patients who are from ethnic backgrounds with high G6PD variant rates, such as those from Mediterranean, African, or Asian descent. Although specific details are not described, hemolysis has been reported in at least one individual with G6PD deficiency during the post-approval use of hydroxychloroquine sulfate tablets, United States Pharmacopeia (USP) per FDA label information.(10)