G6PD Deficiency

Risk factors

• Family history (X-linked)
• African, Mediterranean, Middle Eastern, Southeast Asian ancestry
• Triggers — oxidant exposure: dapsone, primaquine, tafenoquine, sulfonamides (TMP-SMX), nitrofurantoin, methylene blue, rasburicase, high-dose aspirin, naphthalene (mothballs), henna
• Infection (most common trigger overall)
• Diabetic ketoacidosis
• Fava bean ingestion (Mediterranean variant)

Pathophysiology

G6PD produces NADPH, which reduces glutathione (GSH); reduced glutathione neutralizes peroxides and other oxidants. Without adequate NADPH/GSH, oxidant exposure causes denaturation of hemoglobin (Heinz bodies) and membrane damage, leading to intravascular and extravascular hemolysis. Mature RBCs cannot synthesize new enzyme, so older cells lyse first; reticulocytes have more enzyme and survive — hemolysis is self-limited in mild variants.

Clinical presentation

Differential diagnosis

• Autoimmune hemolytic anemia — Positive direct Coombs (DAT), spherocytes; no oxidative trigger
• Hereditary spherocytosis — Chronic mild hemolysis, spherocytes, positive osmotic fragility/EMA binding; family history
• Pyruvate kinase deficiency — Chronic non-spherocytic hemolytic anemia; PK enzyme assay
• Sickle cell disease — Sickle cells on smear, hemoglobin electrophoresis; G6PD can coexist and worsen crises
• Drug-induced immune hemolysis — Positive DAT, temporally related to drug, mechanism distinct from oxidant injury
• TTP/HUS — Schistocytes, thrombocytopenia, end-organ injury

Diagnostic workup

Diagnostic algorithm

flowchart TD
  A[Oxidant exposure<br/>TMP-SMX, dapsone, primaquine,<br/>fava beans, infection] --> B[Oxidant stress on RBC]
  B --> C{Adequate NADPH<br/>from G6PD?}
  C -->|Yes - normal| D[Glutathione reduces<br/>oxidants — no hemolysis]
  C -->|No - G6PD deficient| E[Hemoglobin denaturation<br/>→ Heinz bodies]
  E --> F[Spleen removes<br/>Heinz bodies<br/>→ bite cells]
  E --> G[Membrane damage<br/>→ intravascular<br/>hemolysis]
  G --> H[Hemoglobinuria<br/>↑LDH, ↓haptoglobin,<br/>indirect ↑bili]
  F --> I[Acute anemia<br/>24-72h after trigger]
  G --> I
  I --> J[Reticulocytosis,<br/>self-limited in<br/>African A- variant]

Treatment

Complications

• Acute renal failure from hemoglobinuria (pigment nephropathy) in severe hemolysis
• Kernicterus in neonates with severe hyperbilirubinemia
• Cholelithiasis (pigment stones) from chronic hemolysis
• Drug-induced fatality if oxidant given despite known deficiency (especially rasburicase, dapsone)
• Anemia-related complications during pregnancy and intercurrent illness

PANCE pearls

• Bite cells and Heinz bodies are the hematologic signature of oxidative hemolysis. Heinz bodies require supravital staining.
• G6PD enzyme level can be FALSELY NORMAL during acute hemolysis — older deficient cells are gone, reticulocytes are enzyme-rich. Always confirm with a repeat assay 2-3 months later.
• Rasburicase is absolutely contraindicated in G6PD deficiency — causes severe acute hemolysis and methemoglobinemia. Screen before use, especially in tumor lysis prophylaxis.
• Female heterozygotes may have variable phenotype due to X-inactivation (lyonization); some experience clinically significant hemolysis.
• Hemolytic anemia 24-72 hours after starting TMP-SMX, dapsone, primaquine, or eating fava beans is the classic vignette.
• Fava bean reactions (favism) occur primarily in Mediterranean variant, not African A- variant.
• African (A-) variant: hemolysis is self-limited because reticulocytes have near-normal enzyme. Mediterranean variant: enzyme deficient even in reticulocytes, hemolysis can be severe and protracted.

References

• WHO 2022 — WHO Technical specifications series for G6PD testing
• Cappellini & Fiorelli — Glucose-6-phosphate dehydrogenase deficiency (Cappellini & Fiorelli, Lancet 2008)
• Luzzatto et al. — Favism and Glucose-6-Phosphate Dehydrogenase Deficiency (NEJM 2018)
• Beutler — G6PD deficiency (Beutler, Blood 1994)