G6PD Deficiency: A High-Yield USMLE Review
G6PD deficiency is the most common enzymopathy worldwide and the classic cause of episodic oxidative hemolytic anemia. It is X-linked recessive, so males are affected, and hemolysis is triggered by oxidant stress in a patient who is otherwise asymptomatic. Any sudden hemolytic anemia in a male of Mediterranean, African, or Southeast Asian descent following an oxidant exposure is G6PD deficiency until proven otherwise.
Pathophysiology
G6PD catalyzes the first, rate-limiting step of the pentose phosphate pathway, the red cell's only source of NADPH. NADPH keeps glutathione reduced, and reduced glutathione disposes of oxidative free radicals. Because the red cell has no mitochondria and no alternate route to NADPH, an oxidant stress in a G6PD-deficient cell overwhelms glutathione defenses and denatures hemoglobin into precipitated Heinz bodies. Two hemolytic mechanisms then operate: splenic macrophages pluck out the Heinz bodies as cells pass through the spleen, generating bite cells and extravascular hemolysis, while direct oxidative injury to the RBC membrane causes cells to rupture within the vasculature, producing intravascular hemolysis with hemoglobinuria. Patients are spared most of the time because baseline NADPH demand is low enough for residual enzyme activity, and acute episodes are usually self-limited because the oldest, most deficient cells lyse first.
Presentation
- Acute hemolytic anemia developing 1–2 days after an oxidant trigger (sulfa drugs, primaquine, dapsone, nitrofurantoin, methylene blue, fava beans, or infection)
- Dark urine and back pain reflecting intravascular hemolysis; jaundice may be present
- Acute drop in hemoglobin from baseline with laboratory signs of hemolysis (elevated LDH, low haptoglobin)
- Peripheral smear showing bite cells and Heinz bodies
- Silent between episodes — patient is well until oxidant exposure exposes the missing pathway
Diagnosis
- Peripheral blood smear: bite cells and Heinz bodies — the smear serves as a mechanism readout
- Hemolysis labs: elevated LDH, low haptoglobin, and a fall in hemoglobin from baseline
- G6PD enzyme activity assay — but repeat it 6–8 weeks after the acute episode, since during a crisis the surviving young cells have relatively preserved activity and can falsely normalize the result
- Clinical history (drug/oxidant exposure, ancestry, episodic pattern) anchors the diagnosis when the acute assay is misleading
Management
- Identify and withdraw the offending oxidant trigger
- Supportive care during the acute hemolytic episode, which is usually self-limited as the most deficient cells lyse first
- Prevent rechallenge — repeat oxidant exposure can be lethal; counsel the patient to avoid known triggers
High-yield
- Most common enzymopathy worldwide; X-linked recessive (males affected through carrier mothers)
- Bite cells + Heinz bodies = oxidative hemolysis → think G6PD
- Classic triggers: sulfa drugs, primaquine, dapsone, nitrofurantoin, methylene blue, fava beans, and infection
- Carrier frequency is sustained in malarial regions by heterozygote advantage against falciparum malaria
- Red cells are uniquely vulnerable because they lack mitochondria and have no alternate route to NADPH
- Classic vignette: male of Mediterranean, African, or Southeast Asian descent with hemolysis after trimethoprim-sulfamethoxazole
Pitfalls
- A normal G6PD assay during an acute crisis does NOT exclude the diagnosis — young surviving cells falsely normalize enzyme activity; retest after re-equilibration
- Do not confuse with autoimmune hemolytic anemia (spherocytes, positive Coombs), hereditary spherocytosis (chronic, not drug-triggered), or PNH (chronic hemolysis with venous thrombosis) — none produce bite cells
- Treating only the acute episode without warning against rechallenge is dangerous, since repeat oxidant exposure can be lethal
Don't just memorize Deficiency of glucose-6-phosphate dehydrogenase (G6PD deficiency) — practice reasoning through it on branching cases where your decisions shape the patient.