What is Glucose-6-phosphate dehydrogenase (G6PD) deficiency?

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

G6PD deficiency is the most common human enzyme deficiency worldwide, affecting approximately 500 million people, characterized by red blood cell vulnerability to oxidative damage that can lead to acute hemolytic anemia when triggered by certain foods, medications, or infections. 1

Pathophysiology and Genetics

G6PD deficiency is an X-linked genetic disorder caused by mutations in the G6PD gene located on chromosome X. The condition results in:

• Deficiency of glucose-6-phosphate dehydrogenase enzyme, which is crucial for generating NADPH in red blood cells 2
• Reduced ability to protect red blood cells against oxidative stress
• Approximately 200 different mutations have been identified 3
• Most mutations are missense mutations that decrease enzyme stability or catalytic activity 3

The geographic distribution of G6PD deficiency correlates strongly with regions of past or present malaria endemicity, suggesting evolutionary selection due to the protection it provides against malaria mortality 3.

Epidemiology

• Overall incidence: approximately 1/100,000 2
• Higher prevalence in Ashkenazi Jewish population (1/20,000) 2
• Males are more commonly affected than females due to X-linked inheritance 4
• Pan-ethnic disorder with mutations identified in Caucasians, Ashkenazi Jews, Hispanics, and Asians 2

Clinical Presentation

Common Manifestations

• Acute hemolytic anemia triggered by:

  • Dietary factors (most common - 83.4% of cases), especially fava beans 4
  • Medications (e.g., primaquine, rasburicase, dapsone) 1, 3
  • Infections (12.4% of cases) 4

• Clinical signs and symptoms:

  • Pallor (100% of cases) 4
  • Dark red urine (89.6% of cases) 4
  • Jaundice (87.8% of cases) 4
  • Symptoms typically appear 24-72 hours after exposure to triggers 4

Variant-Specific Presentations

• Mediterranean variant (B-): Higher risk of severe hemolysis 1
• African variant (A-): Typically milder deficiency with lower risk 1
• Severe G6PD deficiency: Can lead to susceptibility to bacterial infections due to impaired neutrophil extracellular trap (NET) formation 5

Clinical Classifications

1. Asymptomatic: Most G6PD-deficient individuals remain asymptomatic throughout life 3
2. Acute hemolytic anemia: Triggered by oxidative stress
3. Neonatal jaundice: Common presentation in newborns
4. Chronic nonspherocytic hemolytic anemia: Rare, caused by sporadic mutations 3, 6

Diagnosis

Laboratory Testing

• Quantitative enzyme activity testing: Gold standard for diagnosis 1
• Fluorescent spot test (FST): Widely used screening method 1
  • Absent fluorescence: Severe deficiency
  • Intermediate fluorescence: Partial deficiency
  • Bright fluorescence: Normal activity
• Point-of-care rapid diagnostic tests: ~100% sensitivity for severe/moderate deficiency 1
• Complete blood count: Normocytic normochromic anemia with reticulocytosis during hemolytic episodes 4
• Blood smear: May show Heinz bodies during hemolysis 4

Indications for Testing

• Before administering primaquine for malaria
• Patients with unexplained hemolysis
• Individuals from high-prevalence regions
• Newborns from high-risk populations 1

Management

Prevention of Hemolytic Episodes

• Avoid dietary triggers:

  • Fava beans (most common trigger)
  • Other legumes: falafel, chick pea, broad bean, green pea, peanuts, lentil 4

• Avoid high-risk medications:

  • Contraindicated: Primaquine (in severe deficiency), methylene blue 1
  • Use with caution: Dapsone, sulfonamides, ciprofloxacin 1
  • Known to cause hemolysis: Diclofenac sodium, ibuprofen, acetylsalicylic acid, co-trimoxazole, nitrofurantoin 4
  • Generally safe: Penicillins, cephalosporins, macrolides, tetracyclines 1

• Patient education:

  • Recognize early signs of hemolysis
  • Maintain adequate hydration, especially during illness 1
  • Document G6PD status prominently in medical records 1

Management of Acute Hemolytic Episodes

• Discontinue the offending agent immediately
• Provide supportive care:
  • Intravenous hydration
  • Blood transfusion for severe anemia
  • Monitor hemoglobin levels serially 1

Special Populations

• Pregnant women: Avoid primaquine due to risk to fetus 1
• Breastfeeding women: Avoid primaquine or discontinue nursing 1
• Heterozygous females: May have intermediate deficiency with clinical symptoms under severe oxidative stress 1
• Pediatric patients: Require careful monitoring for neonatal jaundice 1

Long-term Complications

• Liver adenomas (with age)
• Renal complications
• Increased susceptibility to infections in severe deficiency 5

Screening

Large neonatal screening programs are recommended to detect cases of G6PD deficiency before the occurrence of acute hemolysis, particularly in high-prevalence regions 4, 6.

Molecular studies to detect G6PD enzyme variants may be beneficial for population-specific management strategies 4.