Erythrocyte glucose-6-phosphate dehydrogenase (G6PD) deficiency refers to a hereditary disorder characterized primarily by hemolysis due to decreased activity and/or altered function of the G6PD enzyme involved in the pentose phosphate pathway of red blood cell metabolism. It is the most common inherited red blood cell enzymopathy among more than 20 identified types, with over 400 million affected individuals worldwide, predominantly in tropical and subtropical regions of the Eastern Hemisphere.
Pathogenesis
The G6PD gene is located on the X chromosome (Xq28). The condition follows an X-linked incompletely dominant inheritance pattern, with males being more commonly affected than females. Based on the relationship between genotype and clinical manifestations, as well as the association between enzyme activity and specific G6PD crystal three-dimensional structural mutation sites, G6PD deficiency has been classified into five polymorphic subtypes.
The exact pathogenesis is not yet fully understood. The pentose phosphate pathway, in which G6PD is involved, is the sole source of reduced nicotinamide adenine dinucleotide phosphate (NADPH) in red blood cells. NADPH is a crucial reducing agent in these cells, responsible for converting oxidized glutathione (GSSG) back into reduced glutathione (GSH). G6PD deficiency leads to insufficient production of NADPH, resulting in a marked reduction in GSH levels, which increases red blood cells' sensitivity to oxidative stress. Oxidative damage to the sulfhydryl groups of hemoglobin (Hb) forms methemoglobin and denatured Hb, which accumulate on the red cell membrane as Heinz bodies. This reduces red blood cell deformability, making them more likely to be phagocytosed and destroyed by monocyte-derived macrophages, leading to extravascular hemolysis. Meanwhile, lipid peroxidation of the cell membrane is the primary mechanism underlying acute intravascular hemolysis.
Clinical Manifestations
With the exception of rare cases, clinical manifestations of G6PD deficiency typically emerge only during oxidative stress. Patients experiencing hemolysis exhibit clinical features similar to those of other hemolytic disorders. Based on the triggers of hemolysis, the condition is categorized into five clinical types: drug-induced hemolysis, favism, neonatal hemolysis, congenital non-spherocytic hemolytic anemia, and infection-induced hemolysis. The first two are the most common.
Drug-Induced Hemolysis
The classic presentation involves acute intravascular hemolysis occurring 2–3 days after the ingestion of oxidative drugs, with the most severe anemia appearing around one week later, potentially leading to peripheral circulatory failure or renal failure. The severity of hemolysis is related to the type of enzymatic deficiency. Hemolysis gradually subsides 7–10 days after discontinuation of the drug, as newly generated red blood cells possess near-normal G6PD activity, rendering the condition typically self-limiting (e.g., GdA-). However, in some cases (e.g., GdMed), hemolysis may persist.
Hemolysis can recur with repeated drug use. Chronic hemolysis may occur if small amounts of the drug are used intermittently or continuously. Common oxidative medications include the following:
- Antimalarials: Primaquine, quinine, and related drugs
- Antipyretic and anti-inflammatory agents: Aspirin, acetaminophen (paracetamol), etc.
- Nitrofuran derivatives: Furazolidone, etc.
- Sulfa drugs: Sulfonamides
- Dapsone and related drugs
- Other agents: Vitamin K, probenecid, naphthalene, phenylhydrazine, etc.
Favism
Favism is most common in children under 10 years of age, with males being more frequently affected than females. About 40% of cases have a family history. This condition often occurs during the annual fava bean harvest season (March to May). The onset is acute, typically occurring suddenly 2 hours to several days (commonly 1–2 days, up to 15 days) after consuming fresh fava beans or their derivatives. Acute intravascular hemolysis results, with the severity being independent of the amount of fava beans consumed. Most cases resolve spontaneously after stopping fava bean consumption, though severe cases may require blood transfusions and glucocorticoid therapy, along with measures to prevent acute renal failure.
Laboratory Tests
Screening Tests
Commonly used methods include the methemoglobin reduction test, fluorescent spot test, and paper-based nitroblue tetrazolium (NBT) assay. These methods provide semi-quantitative assessments of G6PD activity and classify results as normal, moderately abnormal, or severely abnormal. Due to multiple potential confounding factors and relatively low specificity, these tests are primarily used for preliminary screening or as supplementary references.
Quantitative Measurement of Enzyme Activity
Quantitative enzyme activity testing is the most reliable method for confirming G6PD deficiency and has diagnostic value. However, G6PD activity can appear normal or near-normal during acute hemolysis or the recovery phase. Reassessment approximately 2–3 months after an acute hemolytic episode typically provides a more accurate representation of the patient's G6PD activity.
Genetic Mutation Analysis
Genetic testing can identify specific G6PD mutations and polymorphisms and is also useful for prenatal diagnosis.
Heinz Body Formation Test
Heinz bodies may be observed within red blood cells of individuals with G6PD deficiency, with diagnostic significance if the count exceeds 5%. However, Heinz bodies can also result from other causes of hemolysis, limiting the specificity of this test.
Diagnosis
The diagnosis of G6PD deficiency primarily relies on laboratory evidence. The condition should be considered in individuals with a positive family history, a clinical history of acute hemolysis, and known triggers such as fava bean consumption or drug use. Diagnosis can be established if screening tests show two moderately abnormal results or one severely abnormal result, or if abnormalities are identified through quantitative enzyme activity testing.
Treatment
In the absence of exogenous oxidative agents, the red blood cells of most individuals with G6PD deficiency function normally, and the condition itself does not require treatment. Management primarily focuses on prevention, the elimination of potential triggers, the control of infections, and symptomatic care. For those experiencing acute hemolysis, addressing the underlying trigger is essential, alongside correcting imbalances in fluids, electrolytes, acid-base levels, and kidney dysfunction. Red blood cell transfusions (excluding transfusions from relatives) can improve the clinical condition.
For newborns with the condition experiencing hemolysis with associated kernicterus, interventions such as exchange transfusion, phototherapy, or phenobarbital injection can be used.