When to Suspect G6PD Deficiency Clinically
Suspect G6PD deficiency in any patient of African, Asian, Mediterranean, or Middle-Eastern descent who presents with acute hemolysis (pallor, dark red/brown urine, and jaundice) occurring 24-72 hours after exposure to oxidative triggers such as infections, certain medications, or fava beans. 1, 2
High-Risk Populations Requiring Clinical Suspicion
- Ethnic/Geographic ancestry: Mediterranean, African, Indian, or Southeast Asian descent 1, 3
- Sex predilection: Males are predominantly affected (93.2% in one large cohort), though heterozygous females can be symptomatic 2, 4
- Age of presentation: Most commonly presents between 1-3 years of age (mean age 22.8 months at first hemolytic crisis) 2
Classic Clinical Triad of Acute Hemolysis
The presentation typically occurs 24-72 hours (mean 36 hours) after oxidative stress exposure and includes: 2
- Pallor (100% of cases) 2
- Dark red/brown urine (89.6% of cases) - this is hemoglobinuria, not hematuria 5, 2
- Jaundice (87.8% of cases) 3, 2
Specific Oxidative Triggers That Should Raise Suspicion
Dietary Triggers (Most Common - 83.4% of cases)
- Fava beans (32.6%) - the most common precipitant 2
- Falafel (19.4%), chickpeas (10.8%), broad beans (7.6%), green peas (4.4%), peanuts (3.8%), lentils (2.8%), black-eyed peas (2%) 2
Infectious Triggers (Second Most Common - 12.4% of cases)
- Pneumonia (3.4%), tonsillitis (3.2%), typhoid fever (2.8%), hepatitis A (1.8%), urinary tract infections (1.2%) 2
- Any acute infection can precipitate hemolysis 6, 4
Medication Triggers (4.2% of cases)
Absolutely contraindicated medications that should immediately raise suspicion: 1, 3
- Dapsone (potent oxidant causing methemoglobinemia and hemolysis) 1
- Methylene blue (methylthioninium chloride) - causes severe hemolytic anemia 1
- Primaquine (contraindicated in severe deficiency) 1
- Rasburicase 3
Common medications associated with hemolysis in clinical practice: 2
- NSAIDs: Diclofenac sodium (2.4%), ibuprofen (0.8%) 3, 2
- Aspirin (explicitly contraindicated) 3
- Co-trimoxazole (0.4%), nitrofurantoin (0.2%) 2
Additional Clinical Scenarios Warranting Suspicion
Neonatal Presentation
- Neonatal jaundice (likely due to impaired liver function rather than pure hemolysis) 6, 4
- Elevated indirect bilirubin (>1.0 mg/dL when total bilirubin ≤5 mg/dL) suggests hemolysis 3
Chronic Presentation
- Chronic non-spherocytic hemolytic anemia in the absence of acute stressors (rare, due to functionally severe variants) 6, 4
Variant-Specific Clinical Severity
Mediterranean variant (Gdmed): 1, 5
- Found in Mediterranean regions, India, and Southeast Asia
- Causes potentially life-threatening hemolysis - highest clinical suspicion warranted 1, 5
- Found in 10-15% of Black individuals
- Causes milder, self-limited hemolysis 1, 5
- Relatively resistant to severe primaquine-induced hemolysis 7
Laboratory Clues That Support Clinical Suspicion
- Normocytic normochromic anemia with reticulocytosis 2
- Heinz bodies on peripheral smear 2
- Hemoglobinuria (dark urine without RBCs on microscopy) 5, 2
Common Pitfall to Avoid
Do not test during acute hemolytic crisis - G6PD levels can be falsely elevated during active hemolysis because young reticulocytes have higher enzyme activity. 3 Repeat testing after 3 months may be necessary for accurate diagnosis. 3