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

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

G6PD deficiency is the most common human enzymatic disorder affecting red blood cells, characterized by the inability to protect erythrocytes against oxidative damage, which can lead to acute hemolytic anemia when triggered by certain medications, fava beans, or infections. 1

Pathophysiology

• G6PD is an enzyme that catalyzes the first step in the pentose phosphate pathway, producing NADPH which protects cells against oxidative damage 1
• G6PD deficiency is an X-linked recessive disorder, affecting approximately 400 million people worldwide 1
• The deficiency compromises the stability of the G6PD protein, decreases catalytic activity, or combines both mechanisms, resulting in reduced enzyme function 1
• Over 200 mutations in the G6PD gene have been identified, with approximately half being polymorphic (common) and half being sporadic (rare) 1

Geographic Distribution and Variants

• The highest prevalence is found in Africa, southern Europe, the Middle East, Southeast Asia, and the central and southern Pacific islands 2
• The geographic distribution correlates remarkably with past/present malaria endemicity, as G6PD deficiency provides protection against malaria mortality 1
• Two major variants with clinical significance:
  • African variant (GdA-): Found in 10-15% of Black men and women, associated with milder and self-limiting hemolysis 3
  • Mediterranean variant (Gdmed): Predominant in individuals from Mediterranean regions, India, and Southeast Asia, associated with potentially life-threatening hemolysis 3

Clinical Presentation

• Most G6PD-deficient individuals remain asymptomatic throughout their lifetime 1
• Acute hemolytic anemia can occur when triggered by:
  • Ingestion of fava beans (favism)
  • Certain medications (e.g., primaquine, rasburicase)
  • Infections 1
• Patients with acute hemolytic crisis typically present with:
  • Dark reddish urine (hemoglobinuria) 4
  • Jaundice
  • Fatigue
  • Back or abdominal pain 3
• Rare patients with sporadic mutations may present with chronic nonspherocytic hemolytic anemia 1
• In severe G6PD deficiency, patients may have impaired neutrophil function leading to susceptibility to bacterial infections, similar to chronic granulomatous disease 5

Diagnosis

• The American Academy of Family Physicians recommends mandatory screening for G6PD deficiency upon entry into healthcare, before starting therapy with oxidant drugs, especially in individuals with predisposing racial or ethnic backgrounds 3
• Diagnostic approaches include:
  • Qualitative screening tests for initial assessment 3
  • Quantitative G6PD testing required before administration of certain medications like tafenoquine 3
• First-degree relatives of patients with G6PD deficiency should be tested 3

Management and Prevention

• The most effective management strategy is preventing hemolysis by avoiding oxidative stressors 2
• Medications to avoid in G6PD deficiency include:
  • Primaquine and tafenoquine (antimalarials)
  • Dapsone
  • Nitrofurantoin
  • Rasburicase
  • Methylene blue
  • Phenazopyridine
  • Toluidine blue 6
• Safe medications for pain and anxiety management include:
  • Benzodiazepines
  • Codeine/codeine derivatives
  • Propofol
  • Fentanyl
  • Ketamine 2
• Monitoring during treatment with potentially hemolytic drugs:
  • Baseline complete blood count with hemoglobin determination 3
  • Ongoing monitoring of blood cell counts and hemoglobin 3
  • Immediate discontinuation of potentially hemolytic medications if signs of hemolysis occur 3

Complications and Special Considerations

• Severe G6PD deficiency can lead to impaired neutrophil extracellular trap (NET) formation, increasing susceptibility to bacterial infections 5
• Patients with severe deficiency may require antibiotic and antimycotic prophylaxis similar to those with chronic granulomatous disease 5
• For patients requiring treatment for P. vivax or P. ovale malaria, G6PD testing should be performed before administering primaquine 3
• For patients with intermediate G6PD deficiency and non-Mediterranean variants requiring antimalarial treatment, weekly primaquine may be considered with close monitoring for hemolysis 3

Patient Education

• Patients should be informed about:
  • The genetic nature of their condition
  • Medications and foods to avoid
  • Signs and symptoms of acute hemolytic crisis
  • When to seek medical attention 2
• Healthcare providers should be able to identify both laboratory and clinical signs of hemolysis 2