Management of Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
Diagnostic Approach
Use quantitative G6PD enzyme assays normalized to hemoglobin as the gold standard for diagnosis, avoiding qualitative fluorescent spot tests for medication-related decisions. 1
Critical Timing Considerations for Testing
Never test during or within 50–120 days after an acute hemolytic episode, as reticulocytes and young red blood cells contain near-normal enzyme levels that will mask true deficiency and produce false-negative results. 1
Wait at least 50 days after any red blood cell transfusion before performing enzyme assays, since donor RBC contamination of just 6–12% can cause false-negative results; ideally wait 120 days post-transfusion. 1
Record the reticulocyte count at the time of sampling and calculate the PK/G6PD ratio or compare to controls with similar reticulocyte counts when interpreting borderline results. 1
Test Selection by Clinical Context
Qualitative fluorescent spot tests are appropriate only for detecting severe deficiency (<10% activity) in males and homozygous females, but fail to identify heterozygous females and patients with intermediate deficiency. 1
Quantitative assays or flow cytometry are mandatory for heterozygous females and patients with concurrent hematological conditions. 1
Molecular genetic analysis is required when enzymatic testing is inconclusive, particularly in heterozygous females, and helps identify specific variants (Mediterranean vs. African) that determine hemolytic risk severity. 1, 2
Sample Preparation Requirements
Ensure proper red-cell purification before analysis by removing the buffy coat or using filtration to eliminate white-cell and platelet interference that can obscure deficiency detection. 1
Testing whole blood without removing white cells and platelets prevents detection of deficiency in all cases examined. 1
Interpretation of Quantitative Results
Calculate the percentage of normal activity by dividing the patient's G6PD value by the laboratory's upper limit of normal and multiplying by 100; this percentage directly guides medication safety decisions. 1
Risk Stratification by Enzyme Activity
Values <30% of normal indicate severe deficiency, for which oxidant drugs such as primaquine, tafenoquine, dapsone, rasburicase, and methylene blue are absolutely contraindicated. 1
Values between 30% and 70% represent intermediate deficiency, requiring variant-specific management (e.g., modified primaquine dosing of 45 mg once weekly for 8 weeks for African-type variants with close hematological monitoring). 3
For P. vivax radical cure with tafenoquine, quantitative G6PD testing is required and the drug must not be used if activity is <70%. 1
Variant-Specific Considerations
The Mediterranean variant (Gdmed) causes life-threatening hemolysis requiring strict oxidant drug avoidance, while the African variant (GdA-) produces milder, self-limited hemolysis. 1, 3
The Mediterranean variant is found predominantly in men from Mediterranean regions, India, and Southeast Asia, while the GdA- variant is found in 10–15% of Black men and women. 3
Screening Recommendations
Screen all patients of Mediterranean, African, Indian, or Southeast Asian descent before initiating any oxidant drugs. 1, 3
Neonatal Screening Indications
Measure quantitative G6PD in infants with rapidly rising total serum bilirubin approaching exchange transfusion levels or not responding to phototherapy. 1
Test infants with jaundice appearing in the first 24 hours of life or excessive jaundice for age, as G6PD deficiency was identified as the cause in 31.5% of infants who developed kernicterus in one series. 1
Elevated indirect bilirubin (>1.0 mg/dL when total bilirubin is ≤5 mg/dL) suggests hemolysis and warrants G6PD testing. 4
Pre-Treatment Screening
All symptomatic patients with methemoglobinemia should undergo G6PD-deficiency testing before receiving methylene blue, and ideally every patient considered for methylene blue should be tested. 1
When immediate methylene-blue therapy is unavoidable, obtain a rapid family-history inquiry for G6PD deficiency before drug administration. 1
The National Comprehensive Cancer Network recommends measurement of G6PD levels before starting dapsone therapy. 3
Absolutely Contraindicated Medications
Seven medications are definitively contraindicated in G6PD deficiency and must never be used until G6PD diagnostic testing confirms normal activity. 4, 2
High-Risk Oxidant Drugs
Dapsone is a potent oxidant that causes methemoglobinemia and red blood cell hemolysis by overcoming the reductive capacity of G6PD. 3
Methylene blue (methylthioninium chloride) is contraindicated as it precipitates severe hemolytic anemia and paradoxically worsens methemoglobinemia in G6PD-deficient patients because they cannot generate sufficient NADPH to reduce methylene blue to leukomethylene blue. 1, 3
Primaquine is contraindicated in severe G6PD deficiency (<30% activity) and should only be used in mild to moderate deficiency (>30% to <70% activity) at reduced dosing of 45 mg once weekly for 8 weeks with close hematological monitoring. 3
Rasburicase must be avoided in all G6PD-deficient patients. 1, 2
Aspirin is explicitly contraindicated in G6PD deficiency, as it can overwhelm the reduced antioxidant capacity in G6PD-deficient red blood cells. 4
Antimalarial Considerations
Both primaquine and tafenoquine are contraindicated during pregnancy regardless of G6PD status. 3
Artemisinin-based combination therapies (ACTs) including artesunate, artemether-lumefantrine, and dihydroartemisinin-piperaquine can be used safely for malaria treatment in G6PD-deficient patients. 3
Chloroquine/hydroxychloroquine in standard doses appears to be relatively safe in most G6PD-deficient patients and may be used during pregnancy. 3
Moderate-Risk Medications
NSAIDs, including ibuprofen, are listed among drugs that can cause hemolysis, presenting a moderate risk in G6PD deficiency. 4
Penicillins, such as amoxicillin, are not among the contraindicated medications in G6PD deficiency and can be used in normal therapeutic doses. 4
Management of Acute Hemolytic Crisis
Immediately discontinue any suspected oxidant drug and monitor hemoglobin levels closely, considering transfusion if hemoglobin drops below 7–8 g/dL with symptoms. 4
Clinical Recognition
Educate patients to recognize early signs of hemolysis: dark urine, sudden fatigue or pallor, jaundice, and abdominal or back pain. 3
Symptoms typically appear 24–72 hours after exposure to precipitating factors (mean: 36±17.73 hours). 5
Normocytic normochromic anemia with reticulocytosis and Heinz bodies will be present in pre-transfusion complete blood picture. 5
Common Precipitating Factors
Diets are the most common precipitating factor (83.4% of cases), especially fava beans (32.6%), falafel (19.4%), chickpea (10.8%), and broad beans (7.6%). 5
Infections are the second most common cause (12.4% of cases), including pneumonia, tonsillitis, typhoid fever, hepatitis A, and urinary tract infections. 5
Drugs are the least common cause (4.2% of cases), including diclofenac sodium, ibuprofen, acetylsalicylic acid, co-trimoxazole, and nitrofurantoin. 5
Management of Methemoglobinemia in G6PD-Deficient Patients
If G6PD deficiency is suspected or confirmed and methylene blue cannot be safely used, use high-dose ascorbic acid (0.5–10 g) or exchange transfusion as alternative therapies. 1
Ascorbic Acid Dosing
Ascorbic acid is the treatment of choice for methemoglobinemia in G6PD-deficient patients when methylene blue is contraindicated. 1
The doses recommended for treating methemoglobinemia (0.5–10 g) exceed the FDA-mandated RDA limit for G6PD-deficient patients, creating a clinical dilemma where the benefit of treating life-threatening methemoglobinemia outweighs hemolysis risk. 1
Exchange transfusion should be considered for severe cases of ascorbic acid-induced hemolysis in G6PD-deficient patients. 1
Alternative Therapies
The American Academy of Ophthalmology recommends using atovaquone or inhaled pentamidine for Pneumocystis prophylaxis in patients with G6PD deficiency. 1
The American Academy of Dermatology suggests using alternative immunosuppressants such as mycophenolate, azathioprine, or methotrexate for dermatologic conditions in patients with G6PD deficiency. 1
Supportive Care and Monitoring
Provide folic acid supplementation (1 mg daily) for all patients with G6PD deficiency. 4
Monitoring Parameters
Monitor hemoglobin levels closely during acute hemolytic crisis. 4
Consider transfusion if hemoglobin drops below 7–8 g/dL with symptoms. 4
Monitor for signs of hemolysis when starting any new medication, including jaundice. 4
Family Screening
Test first-degree relatives of patients with hereditary G6PD deficiency. 6, 1
Children of any age can develop hemolysis from contraindicated medications, and the same restrictions apply. 3
The fetus may be G6PD-deficient even if the mother is normal. 3
Common Pitfalls to Avoid
Never rely on historical G6PD results when the timing of the test, transfusion history, or reticulocyte count are unknown; repeat quantitative testing under optimal conditions is required. 1
Never use qualitative spot tests alone for medication-related decision-making; quantitative assays are essential for accurate risk stratification. 1
Never perform testing during an acute hemolytic crisis, as the resulting false-elevated activity can lead to inappropriate clinical decisions. 1
Never test during transfusion or immediately post-transfusion, as this will give falsely elevated results. 4