Glucose-6-Phosphate Dehydrogenase Deficiency

Etiology

The G6PD gene, located on the distal long arm of the X chromosome (Xq28), encodes G6PD, and therefore, pathogenic variants follow X-linked inheritance. The gene spans approximately 18 kb, with 13 exons, and produces a 515-amino-acid enzyme.[3] Most disease-causing variants are single-nucleotide missense mutations that result in deficient proteins; small deletions and other variant types are relatively uncommon. Hundreds of variants have been cataloged (well over 200 pathogenic or likely pathogenic, with many additional variants of uncertain significance reported in recent datasets).[1] Complete absence of G6PD activity appears incompatible with life, whereas near-null and severely destabilizing variants present as chronic nonspherocytic hemolytic anemia rather than embryonic demise.[4]

Epidemiology

G6PD deficiency is among the most common human enzymopathies, affecting roughly 400 million people worldwide.[5] Males are affected more often than females because the G6PD gene is X-linked; however, due to lyonization (X-inactivation), heterozygous females can show a wide range of enzyme activity and may be clinically affected.[1] Prevalence is highest across the tropical and subtropical malaria belt—sub-Saharan Africa, the Mediterranean, the Middle East, and South and Southeast Asia—reflecting marked ethnogeographic clustering of variants.[6] Evidence suggests partial, variant- and sex-dependent protection against uncomplicated malaria, whereas protection against severe malaria is uncertain or absent in pooled analyses; the magnitude and direction of effect vary by population.

Pathophysiology

G6PD functions as the catalyst for the rate-limiting first step of the pentose phosphate pathway, using glucose-6-phosphate to convert nicotinamide adenine dinucleotide phosphate (NADP?) into its reduced form, NADPH. See Image. Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency. Within red blood cells, NADPH plays an indirect but essential role in protecting cellular structures from injury caused by oxygen-free radicals. Acting as a substrate for glutathione reductase, NADPH supports the production of reduced glutathione, which converts hydrogen peroxide into water. This reaction shields cellular components, particularly the red cell membrane, from oxidative damage.[7]

Reduced G6PD activity prevents red blood cells from producing sufficient NADPH through the pentose phosphate pathway. Inadequate NADPH impairs the ability of glutathione reductase to regenerate reduced glutathione from glutathione disulfide, causing the intracellular glutathione reserve to collapse under oxidative stress. Unneutralized reactive oxygen species then oxidize hemoglobin and membrane structures, leading to the denaturation of hemoglobin into Heinz bodies, which are visible with supravital stains, and to oxidative cross-linking and peroxidation of membrane proteins and lipids. These changes stiffen the membrane and reduce red blood cell deformability.[8]

History and Physical

Most individuals with G6PD deficiency are asymptomatic, but clinical manifestations vary by age and trigger. In newborns, G6PD deficiency is a well-established risk factor for neonatal hyperbilirubinemia; pooled data suggest an estimated 1.6 to 2 times higher risk versus the general population.[9][10] Severe cases disproportionately contribute to kernicterus. In a United States registry analysis, about 20% of infants with kernicterus had G6PD deficiency.[11] Clinically, kernicterus has early, middle, and late stages, and presents with symptoms from lethargy, poor feeding, and hypotonia to irritability, hypertonia, and seizure.

In older children and adults, episodes of hemolysis are triggered by infection, medications, and certain foods, with symptoms including pallor, jaundice, fatigue, dark urine, and even splenomegaly due to red-cell sequestration.[12][13][14]

Evaluation

Newborn Evaluation

Visual inspection alone provides an unreliable assessment of jaundice in newborns; clinicians should therefore obtain an objective bilirubin measurement, eg, total serum bilirubin (TSB), fractionated bilirubin, or transcutaneous bilirubin (TcB). Management should follow hour-specific thresholds outlined in the American Academy of Pediatrics (AAP) hyperbilirubinemia guideline. A TSB measurement should confirm TcB values that approach treatment thresholds, and all treatment decisions should rely on TSB results.

The AAP recommends that G6PD activity testing is indicated in newborns with jaundice of unknown cause, a rise in TSB despite intensive phototherapy, a sudden increase in TSB, a rebound in the TSB level after an initial decline, or when escalation of care becomes necessary. Universal newborn screening for G6PD deficiency is not advised in the United States; however, testing should occur when clinical presentation, ancestry, or family history raises suspicion.[15]

The fluorescent spot test is the most widely used qualitative screening method, but this study may fail to detect heterozygous females. When higher diagnostic precision is required, eg, in females, borderline enzyme activity, or research and policy settings, a quantitative enzyme assay should be performed, either spectrophotometric or through a validated quantitative point-of-care method.[16][17]

Evaluation of Older Children and Adults

Evaluation of older children and adults should begin with a detailed medical history and physical examination, focusing on recent medication use, oxidant exposures, eg, fava beans, and infections. Laboratory findings during oxidant-induced hemolysis typically reveal declining hemoglobin, reticulocytosis, indirect hyperbilirubinemia, elevated lactate dehydrogenase (LDH), and decreased haptoglobin, often with a negative direct antiglobulin test. Peripheral smears may display bite and blister cells, while supravital staining demonstrates Heinz bodies. Confirmation requires a G6PD enzyme activity assay, and molecular testing may be indicated when clarification of the specific variant is needed.[18][19]

Treatment / Management

In neonatal patients, treatment focuses on managing jaundice and preventing kernicterus. This includes phototherapy based on standard published guidelines. In severe cases, an exchange transfusion may be necessary.[15] In older patients, management depends primarily on the overall clinical picture. Less severe presentations may be managed with supportive care and the discontinuation or avoidance of offending agents. Infections should be treated as indicated by history and exam. More severe cases may require transfusions.[20][21](A1)

The optimal care for G6PD deficiency involves an interprofessional approach. Core team members include the pediatrician or internist, hematologist, pharmacist, nursing staff, and the clinical laboratory (for timely enzyme testing and interpretation). Genetics professionals (medical geneticist or genetic counselor) are valuable for variant counseling, carrier testing, especially in females, and family education.

Newborn Management

Priorities include early identification of hyperbilirubinemia, adherence to hour-specific AAP thresholds, prompt phototherapy when indicated, and escalation (eg, NICU transfer, possible exchange transfusion) for rapidly rising or treatment-refractory bilirubin levels. Clinicians should ensure a predischarge bilirubin measurement is performed, arrange time-bound follow-up, and educate caregivers about the warning signs of jaundice in neonates. G6PD activity testing should also be considered in neonatal jaundice that has an early onset, is severe, is poorly responsive to phototherapy, or occurs in infants with suggestive ancestry and family history.

Management in Children and Adults

Management strategies for children and adults with G6PD deficiency depend on the degree of clinical severity.

Mild to moderate episodes

Management focuses on eliminating or avoiding triggers, eg, oxidant medications, fava beans, and naphthalene, while treating concurrent infections. Supportive measures include adequate hydration, rest, and close monitoring of hemoglobin, reticulocyte count, bilirubin, LDH, and haptoglobin levels.

Individuals with severe hemolysis

Patients with significant anemia may require packed red blood cell transfusion. Continuous monitoring for acute kidney injury through urine output and serum creatinine is essential, along with correction of electrolyte and acid–base disturbances. Hospitalization becomes necessary when clinical instability develops.

Special scenarios

Methylene blue must be avoided in suspected or confirmed G6PD deficiency when treating methemoglobinemia, as it can worsen hemolysis. Alternative treatments include high-flow oxygen, intravenous ascorbic acid, transfusion-based therapy, or hyperbaric oxygen in selected cases.

Medication safety and stewardship

Pharmacists, working with prescribers, should review all current and new medications to identify agents with oxidant or hemolytic potential, eg, dapsone, rasburicase, pegloticase, primaquine, and tafenoquine. Caution is warranted with nitrofurantoin and phenazopyridine depending on the clinical context. Patients should receive an updated and accurate list of medications and substances to avoid, and their G6PD status should be clearly documented in the medical record.

Education and prevention

Nurses and clinicians should educate patients and families about recognizing symptoms of hemolysis, eg, dark urine, jaundice, fatigue, and pallor, emphasizing the importance of seeking urgent care when they occur. Counseling should include avoidance of triggers, including specific foods, chemicals, and drugs, and the need to inform all healthcare practitioners of G6PD status before initiating new treatments. Females should be informed about variable expression due to lyonization, which may justify quantitative testing even when qualitative screening appears normal.

Follow-up management

After resolution of an acute episode, clinicians should repeat a quantitative G6PD assay to confirm enzyme deficiency, as testing during hemolysis can yield false-normal results. The patient’s problem list and allergy section should be updated with “G6PD deficiency—risk of hemolysis.” Discharge instructions must include written guidance on avoidance strategies and arrangements for timely follow-up with primary care and hematology clinicians.

Differential Diagnosis

Many disease processes may exhibit similar clinical features of G6PD deficiency. Therefore, differential considerations should include:

• Autoimmune hemolytic anemia
• ABO or Rh hemolytic disease
• Breastmilk Jaundice
• Suboptimal intake hyperbilirubinemia
• Crigler–Najjar syndrome types I and II
• Gilbert syndrome
• Pyruvate kinase deficiency
• Glutathione pathway defects
• Infection-related hemolysis (eg, malaria)
• Hereditary spherocytosis
• Sickle cell anemia
• Thalassemia

Prognosis

Most people with G6PD deficiency have an excellent prognosis. Hemolytic episodes are typically episodic and self-limited when triggers are avoided; chronic hemolysis is uncommon and confined mainly to severe variants. With counseling on oxidant drugs/foods and prompt care during infections, life expectancy is normal.

Complications

In G6PD deficiency, complications cluster around hemolysis. Newborns are prone to significant hyperbilirubinemia with risk of kernicterus. Older patients can develop acute hemolytic anemia after oxidant stress (eg, drugs, infections, fava beans), occasionally with hemoglobinuria and acute kidney injury, and a small subset with severe variants experiences chronic nonspherocytic hemolytic anemia.