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.
WHO Classes of G6PD deficiency
Class I: severe, associated with chronic extravascular non-spherocytic hemolytic anemia
Class II: severe, associated with episodic acute hemolytic anemia (enzyme level <10%)
Class III: moderate, associated with episodic acute hemolytic anemia (enzyme level 10-60%)
Class IV: normal activity (enzyme level 60-150%). Normal.
Class V: increased activity (enzyme level >150%). No known clinical sequelae.
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, CMV, 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 1 week and begins to recover 10 days after cessation. Splenomegaly, gallstones, and recurrent jaundice are additional clinical symptoms. Because it is X-linked, males are usually more severely affected, but homozygous females are seen due to the prevalence of genetic variants. Heterozygous females (carriers) range from asymptomatic to severe anemia due to mosaicism/lyonization. Acquired G6PD may occur due to increasing X inactivation in aging females.(4) Acute episodic G6PD deficiency (WHO 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 manifests similarly to other enzyme deficiencies (WHO 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. FDA guidelines state to screen patients at higher risk for G6PD deficiency (eg, patients of African or Mediterranean ancestry) prior to starting therapy. 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.
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 or CQ therapy in G6PD deficient African 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 HCQ sulfate tablets, USP per FDA label information.