X-linked enzyme deficiency causing episodic oxidative hemolysis in response to drugs, infection, or fava beans.
Also known as: G6PD, glucose-6-phosphate dehydrogenase deficiency, favism
Overview
Inherited deficiency of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme of the hexose monophosphate (pentose phosphate) shunt. Reduces NADPH availability, impairing red cell defenses against oxidative stress and predisposing to acute hemolysis under oxidant exposure.
Epidemiology
Most common enzymopathy worldwide, affecting ~400 million people. X-linked recessive — males more severely affected. Highest prevalence in African (G6PD A-, ~10% of US Black males), Mediterranean, Middle Eastern, and Southeast Asian populations. Geographic overlap with malaria endemicity (heterozygote advantage).
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Question 1HematologyEasy
A 28-year-old African American man is started on primaquine for malaria prophylaxis before international travel. Two days later he develops fatigue, scleral icterus, and dark urine. Laboratory studies show a hemoglobin of 8.4 g/dL, an elevated reticulocyte count, indirect hyperbilirubinemia, and bite cells with occasional Heinz bodies on the peripheral smear. Which of the following is the most likely diagnosis?
ASickle cell disease
BAutoimmune hemolytic anemia
CCold agglutinin disease
DG6PD deficiency
Reveal answer & full explanation
Correct answer: D — G6PD deficiency
ASickle cell disease
BAutoimmune hemolytic anemia
CCold agglutinin disease
DG6PD deficiency✓
Why G6PD deficiency is correct
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive defect of the hexose monophosphate shunt that leaves red cells unable to regenerate glutathione and defend against oxidative stress.
An oxidant exposure - here primaquine (also dapsone, sulfonamides, nitrofurantoin, fava beans, or infection) - triggers acute hemolysis within hours to days, producing anemia, indirect hyperbilirubinemia, and hemoglobinuria (dark urine).
The peripheral smear shows bite cells and Heinz bodies (precipitated, denatured hemoglobin), and the African American background fits the common A- variant.
Management is to stop the offending agent with supportive care; screen for G6PD before prescribing oxidant antimalarials.
Why the others are wrong
Sickle cell disease — Causes vaso-occlusive pain from lifelong HbS polymerization, not an acute hemolytic episode newly triggered by a drug, and the smear shows sickled cells rather than bite cells and Heinz bodies (anchoring on the patient's race).
Autoimmune hemolytic anemia — Warm AIHA is Coombs-positive with spherocytes and is not precipitated by an oxidant drug; the oxidative smear findings point elsewhere (premature closure on 'hemolytic anemia').
Cold agglutinin disease — Cold agglutinin hemolysis follows cold exposure or Mycoplasma/EBV infection with red-cell agglutination on the smear, not an oxidant drug exposure (buzzword-matching hemolysis without the trigger).
Question 2HematologyEasy
A 25-year-old man of Mediterranean ancestry develops severe hemolytic anemia (Hgb 6.2 g/dL) and hemoglobinuria 2 days after starting dapsone for Pneumocystis prophylaxis. Peripheral blood smear (PBS) shows bite cells and Heinz bodies on crystal violet stain. LDH is markedly elevated. Which of the following is the most likely diagnosis?
AHereditary spherocytosis
BParoxysmal nocturnal hemoglobinuria
CAutoimmune hemolytic anemia
DG6PD deficiency
Reveal answer & full explanation
Correct answer: D — G6PD deficiency
AHereditary spherocytosis
BParoxysmal nocturnal hemoglobinuria
CAutoimmune hemolytic anemia
DG6PD deficiency✓
Why G6PD deficiency is correct
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme deficiency worldwide.
Pathophysiology: G6PD generates NADPH, which maintains reduced glutathione that protects RBCs from oxidative stress; when deficient, oxidant stress denatures hemoglobin, which precipitates as Heinz bodies, driving both extravascular (splenic) and intravascular hemolysis.
Peripheral blood smear (PBS) findings: bite (blister) cells — macrophages pluck out Heinz bodies — and Heinz bodies on crystal violet stain.
Treatment: remove the offending agent, supportive care, and transfusion for severe anemia.
Why the others are wrong
Autoimmune hemolytic anemia — has a positive direct Coombs and is not oxidant-drug triggered (confused-with an antibody-mediated hemolysis).
Paroxysmal nocturnal hemoglobinuria — also causes intravascular hemolysis with hemoglobinuria, but it is complement-mediated from loss of GPI-anchored CD55/CD59 (diagnosed by flow cytometry), is not triggered by dapsone, and does not produce Heinz bodies or bite cells (anchoring on hemoglobinuria).
Hereditary spherocytosis — a chronic inherited membrane defect with spherocytes, elevated MCHC, and a positive EMA-binding or osmotic fragility test, not an acute crisis provoked by an oxidant drug; bite cells and Heinz bodies are absent (confused-with an inherited hemolytic anemia).
Additional high-yield points
G6PD assay timing: a quantitative assay can read falsely NORMAL during an acute episode because young reticulocytes carry higher enzyme activity; retest after recovery once the reticulocytosis has resolved rather than relying on a single fixed interval.
African A- variant is milder, with partial enzyme activity retained in younger RBCs; the Mediterranean variant tends to be more severe.
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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.
TIMING CAVEAT: G6PD level may be falsely normal during acute hemolysis (older deficient cells already lysed; reticulocytes have higher enzyme activity). Repeat 2-3 months after recovery
Direct Coombs negative (rules out autoimmune hemolysis)
Imaging
Not routinely indicated
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]
G6PD deficiency hemolytic cascade — oxidant trigger to clinical hemolysis.
Treatment
First-line
Acute hemolysis: identify and remove offending agent immediately
Supportive care — IV fluids to maintain renal perfusion and clear hemoglobinuria
Transfusion for severe symptomatic anemia or hemodynamic instability
Prevention is primary: educate patient about drugs and foods to avoid; provide list of contraindicated medications
Neonatal jaundice: phototherapy, exchange transfusion if severe (to prevent kernicterus)
Second-line / adjunct
Screen for G6PD deficiency BEFORE prescribing dapsone, primaquine, tafenoquine, rasburicase in at-risk populations
Avoid in family members; X-linked inheritance counseling
Folic acid for chronic hemolytic variants
Splenectomy rarely indicated (chronic non-spherocytic severe variants only)
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
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