Glucose-6-phosphate dehydrogenase deficiency

An inherited X-linked recessive enzyme disorder of red blood cells causing impaired NADPH production and inability to replenish glutathione, rendering RBCs susceptible to oxidative stress and leading to episodic hemolytic anemia (especially after triggers like certain drugs, infections, or fava beans).

• G6PD deficiency is the world's most common enzyme deficiency (≈400 million people affected). It can lead to life-threatening hemolysis or neonatal jaundice (a significant cause of kernicterus) if not recognized. Awareness of this condition is critical for avoiding precipitants (many medications carry G6PD-related warnings, e.g., primaquine) and for understanding classic exam scenarios linking oxidative stress to hemolysis.

• Typically asymptomatic until an oxidative stressor. Classically, a male patient of African, Mediterranean, or Asian descent presents with acute hemolysis (fatigue, jaundice, dark urine) a few days after exposure to a trigger. Common triggers include infections (most frequent cause), certain drugs (e.g., sulfa antibiotics, dapsone, anti-malarials like primaquine), or fava bean ingestion.
• During an acute episode: back pain and tea-colored urine are often reported (due to hemoglobinuria). Examination may show pallor, jaundice (from unconjugated bilirubin), and possibly splenomegaly if hemolysis is significant. The episode is usually self-limited as bone marrow compensates and new RBCs are produced.
• Neonatal presentation: neonatal jaundice in the first days of life can be due to G6PD deficiency. Affected newborns (especially boys from high-risk ethnic groups) may develop severe unconjugated hyperbilirubinemia, sometimes requiring phototherapy or exchange transfusion to prevent kernicterus.

1. Recognize hemolysis: labs during a crisis show elevated LDH and indirect bilirubin, low haptoglobin, and possibly hemoglobinuria (if intravascular hemolysis is significant). The peripheral blood smear may show bite cells (RBCs with "bites" taken out due to splenic removal of Heinz bodies). Heinz bodies (denatured hemoglobin inclusions) are visible with special supravital staining.
2. Confirm the diagnosis with a G6PD assay (e.g., fluorescent spot test or quantitative spectrophotometry) once the acute episode has resolved. Testing during active hemolysis can yield false-normal results, because the older, enzyme-deficient erythrocytes have been destroyed and young reticulocytes (with normal enzyme levels) dominate. If G6PD deficiency is strongly suspected but initial testing is normal, repeat the assay ~3 months after the hemolytic event.
3. In neonates with unexplained high bilirubin, consider G6PD testing (especially in populations where G6PD mutations are prevalent). Some regions include G6PD screening in newborn screening programs or recommend testing jaundiced infants who are not responding to phototherapy.

1. During an acute hemolytic episode: stop the offending agent (if applicable) and provide supportive care. Ensure adequate hydration and oxygenation; severe anemia may require blood transfusions. Treat any precipitating infection promptly (since infections themselves can trigger hemolysis).
2. Neonatal jaundice: initiate phototherapy early to prevent bilirubin encephalopathy; if bilirubin is extremely high or rising fast, perform an exchange transfusion.
3. Prevention is key: patients should avoid known triggers (e.g., fava beans; drugs like dapsone, primaquine, high-dose sulfonamides, nitrofurantoin). Prior to prescribing high-risk medications (like certain antimalarials), at-risk individuals should be screened for G6PD deficiency.

• Mnemonic (oxidative stressors): Spleen Purges Nasty Inclusions From Damaged Cells – Sulfonamides, Primaquine, Nitrofurantoin, Isoniazid, Fava beans, Dapsone, Chloroquine are notorious triggers for hemolysis in G6PD deficiency.
• The spleen removes Heinz body inclusions by taking a bite out of the RBC, which leads to characteristic bite cells on smear (imagine a red cell with a 'chunk' missing).
• High prevalence in malaria-endemic regions because G6PD deficiency confers partial protection against malaria.

• Signs of severe hemolysis: e.g., cola-colored urine (hemoglobinuria), profound fatigue, rapid drop in hemoglobin, or acute kidney injury. These warrant urgent intervention (IV fluids, possible transfusion) to prevent shock or renal failure.
• In neonates, very high bilirubin levels or any signs of kernicterus (lethargy, hypotonia, poor feeding) are emergencies – intensive phototherapy or exchange transfusion is indicated to prevent irreversible brain damage.
• Methylene blue (used for treating methemoglobinemia) is contraindicated in G6PD deficiency, as it can precipitate massive hemolysis.

1. Suspect G6PD deficiency in patients (especially males of susceptible ethnicities) with hemolysis after oxidant exposure (infection, new medication, fava beans).
2. During acute hemolysis: confirm the hemolytic nature with labs (↑LDH, ↑indirect bilirubin, ↓haptoglobin) and examine the peripheral smear for bite cells/Heinz bodies. Provide supportive care (remove trigger, hydrate, oxygen, transfuse if needed).
3. Once the patient is stable, perform a definitive G6PD enzyme assay to confirm the diagnosis (remember to test after the acute phase to avoid false negatives).
4. Educate the patient on avoiding known triggers and alert healthcare providers to the G6PD deficiency (e.g., wear medical alert identification). For at-risk populations (e.g., family members or in newborn screening), consider proactive testing.

• Young African American or Mediterranean male who develops jaundice and dark urine a few days after taking a sulfa drug or antimalarial → acute hemolytic anemia due to G6PD deficiency.
• Sudden hemolysis in a patient after eating fava beans ("favism") → think G6PD deficiency causing oxidative stress hemolysis.
• Newborn boy with severe jaundice in the first 2–3 days of life (negative Coombs test, not attributable to Rh/ABO) → consider G6PD deficiency (neonatal hyperbilirubinemia).