What is Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency?

What is G6PD Deficiency?

G6PD deficiency is an X-linked genetic disorder affecting red blood cells, making them highly vulnerable to oxidative damage and hemolysis—it is the most common enzymatic disorder of red blood cells worldwide, affecting approximately 500 million people. 1, 2

Genetic Basis and Inheritance

• G6PD deficiency is inherited as an X-linked recessive disorder, meaning it predominantly affects males (who have only one X chromosome), while females can be carriers or affected if they inherit two defective copies 3, 4
• The condition is caused by mutations in the G6PD gene, with over 200-250 different variants identified 2, 4
• Approximately 12% of Black males in the United States have G6PD deficiency 5

What the Enzyme Does

• G6PD (glucose-6-phosphate dehydrogenase) is the first enzyme in the pentose phosphate pathway, which produces NADPH—a critical molecule that protects cells against oxidative damage 2, 6
• Without adequate G6PD activity, red blood cells cannot maintain their oxidant-antioxidant balance and become susceptible to destruction (hemolysis) when exposed to oxidative stress 2, 7

Clinical Variants and Severity

The severity varies dramatically based on which genetic variant a person carries:

• The Mediterranean variant (Gdmed) typically causes more severe, potentially life-threatening hemolysis 1, 8
• The African variant (GdA-) usually causes milder, self-limited hemolysis 1, 8
• The Mediterranean variant is found predominantly in men from Mediterranean regions, India, and Southeast Asia, while the African variant affects 10-15% of Black individuals 8

Clinical Presentations

Acute Hemolytic Crisis (Most Common)

• Most G6PD-deficient individuals are completely asymptomatic throughout their lifetime until exposed to specific triggers 2, 4
• Acute hemolytic anemia can be triggered by: fava beans (causing "favism"), certain medications (dapsone, primaquine, methylene blue, rasburicase), or infections 1, 2
• Symptoms include sudden onset of jaundice, dark urine, fatigue, and pallor 1

Neonatal Hyperbilirubinemia

• Newborns with G6PD deficiency have increased risk of severe jaundice that can rapidly progress to bilirubin-induced neurologic dysfunction (kernicterus), often without obvious signs of hemolysis 7
• The mechanism differs from acute hemolysis—it involves impaired bilirubin clearance rather than just red cell destruction 7

Chronic Hemolytic Anemia (Rare)

• Approximately half of G6PD mutations are sporadic and rare, causing chronic nonspherocytic hemolytic anemia with ongoing symptoms 2

Severe Deficiency with Immune Dysfunction

• In rare cases of severe G6PD deficiency, patients may have impaired neutrophil function, absent NET formation (neutrophil extracellular traps), and increased susceptibility to bacterial infections—essentially mimicking chronic granulomatous disease 6

Geographic Distribution and Evolutionary Context

• G6PD deficiency distribution correlates remarkably with areas of past or present malaria endemicity 2
• It represents a balanced polymorphism where heterozygous females are protected from malaria mortality, explaining why the mutation persists at high frequencies 2

Critical Medications to Avoid

Seven medications are definitively contraindicated 1:

• Dapsone (causes methemoglobinemia and hemolysis) 1, 8
• Methylthioninium chloride (methylene blue) 1, 8
• Primaquine (contraindicated in severe deficiency) 1, 8
• Rasburicase 1

Aspirin is explicitly contraindicated as it overwhelms the reduced antioxidant capacity 1

Common Pitfall in Severe Disease

• G6PD deficiency is associated with fulminant Rocky Mountain Spotted Fever, with affected patients experiencing fatal disease within 5 days of onset 5
• This represents a critical clinical scenario where the underlying G6PD deficiency dramatically worsens prognosis of an acute infection 5

Who Should Be Screened

• Screening is strongly recommended for patients with Mediterranean, African, Indian, or Southeast Asian descent before starting oxidant drugs 1, 3
• First-degree relatives of affected patients should be tested 3
• The WHO recommends screening all infants in countries with high prevalence to prevent kernicterus 7