What is glucose‑6‑phosphate dehydrogenase deficiency?

What is G6PD Deficiency?

G6PD (glucose-6-phosphate dehydrogenase) deficiency is the most common inherited enzyme disorder worldwide, affecting approximately 400-500 million people, caused by X-linked mutations that impair the red blood cell's ability to protect against oxidative damage, leading to hemolysis when exposed to specific triggers. 1, 2

Genetic Basis and Inheritance

• G6PD deficiency is an X-linked recessive disorder, meaning males are predominantly affected while females can be carriers or, less commonly, symptomatic. 1, 2
• Over 200 different G6PD mutations have been identified, with approximately half being polymorphic (common in populations) and half being sporadic (rare, causing more severe disease). 1
• The gene is located on the X chromosome, and mutations typically cause amino acid replacements that compromise enzyme stability, catalytic activity, or both. 1, 3

Pathophysiology

• G6PD is the first enzyme of the pentose phosphate pathway, responsible for producing NADPH (reduced nicotinamide adenine dinucleotide phosphate), which protects red blood cells from oxidative damage. 4, 5
• When enzyme activity is deficient, red blood cells become highly vulnerable to oxidative stress and undergo hemolysis when exposed to oxidative triggers. 1
• Most mutations decrease enzyme stability in red blood cells, possibly by disturbing protein folding or affecting the dimer interface. 3

Geographic Distribution and Epidemiology

• The condition is most prevalent in people of Mediterranean, African, Middle Eastern, Indian, and Southeast Asian descent, with an overall incidence of approximately 1 in 100,000 for severe variants. 6, 2
• In African populations, 10-15% carry the African variant (GdA-). 6, 7
• The geographic distribution remarkably correlates with past and present malaria endemicity, as G6PD deficiency provides protection against malaria mortality in heterozygotes. 1

Clinical Manifestations

Asymptomatic Carriers

• Most individuals with polymorphic G6PD mutations remain asymptomatic throughout their lifetime unless exposed to specific triggers. 1, 2

Acute Hemolytic Anemia

• Acute hemolysis occurs when triggered by oxidative stressors: fava beans, certain medications (primaquine, dapsone, rasburicase, methylene blue, sulfonamides), or infections. 6, 1, 2
• The Mediterranean variant (Gdmed) typically causes more severe, potentially life-threatening hemolysis compared to the African variant (GdA-), which usually produces milder, self-limited episodes. 7, 8
• Clinical signs include dark urine, sudden fatigue or pallor, jaundice, and abdominal or back pain. 7

Neonatal Jaundice

• Newborns may present with severe hyperbilirubinemia requiring phototherapy or exchange transfusion to prevent kernicterus. 8, 2
• G6PD testing should be performed in newborns with severe jaundice not responding to phototherapy. 6

Chronic Nonspherocytic Hemolytic Anemia

• Rare patients with sporadic mutations present with chronic hemolysis rather than episodic acute crises. 1, 2

Diagnostic Testing

• Quantitative G6PD enzyme activity assay is the gold standard, measuring enzyme activity in units per gram of hemoglobin. 8
• Qualitative fluorescent spot testing is sufficient for initial screening. 7, 2
• Avoid testing during or immediately after acute hemolytic episodes, as G6PD levels may be falsely elevated due to young reticulocytes having higher enzyme activity. 6, 8
• Repeat testing after 3 months may be necessary if initial testing occurs during hemolysis. 8
• Molecular genetic analysis can detect up to 100% of mutations in homogeneous populations and may be required when enzymatic testing is inconclusive, particularly in heterozygous females. 8

Key Management Principles

Trigger Avoidance

• Strictly avoid contraindicated medications: primaquine, dapsone, rasburicase, methylene blue (methylthioninium chloride), and sulfonamide antibiotics. 6, 7
• Artemisinin-based combination therapies for malaria are safe to use. 6
• Chloroquine/hydroxychloroquine in standard doses appear relatively safe in most G6PD-deficient patients. 6, 7

Acute Crisis Management

• Acute hemolytic anemia is typically self-limited but can be severe enough to warrant blood transfusion. 2
• Provide aggressive intravenous hydration to maintain renal perfusion and reduce risk of hemoglobin-induced kidney injury. 7
• Consider transfusion if hemoglobin drops below 7-8 g/dL with symptoms. 8
• Monitor continuously for acute kidney injury from hemoglobinuria. 7

Patient Education

• Patients must inform every healthcare provider about their G6PD deficiency before receiving any medication. 6
• Screen first-degree relatives (parents, siblings, children) for G6PD deficiency. 6
• Educate patients to recognize early signs of hemolysis: dark urine, sudden fatigue, pallor, jaundice, abdominal or back pain. 7

Important Clinical Distinctions

G6PD deficiency should not be confused with glycogen storage disease type I (GSD I), which is caused by deficiency of glucose-6-phosphatase (G6Pase), a completely different enzyme involved in glucose production rather than red blood cell protection. 9