What is the management and treatment approach for a patient with G6PD (Glucose-6-Phosphate Dehydrogenase) deficiency?

G6PD Deficiency: Comprehensive Management Guide

Overview and Pathophysiology

G6PD deficiency is the most common enzymatic disorder of red blood cells worldwide, affecting over 400 million people, and requires strict avoidance of oxidative triggers to prevent potentially life-threatening hemolytic crises. 1, 2

• G6PD catalyzes the rate-limiting step of the pentose phosphate pathway, which generates NADPH—the only source in red blood cells for recycling reduced glutathione and protecting against oxidative stress 3
• The deficiency is inherited as an X-linked recessive disorder, predominantly affecting males, though heterozygous females can also be symptomatic 4
• Over 200 mutations exist, with approximately half being polymorphic and common in populations where malaria is or was endemic 2, 5

Genetic Variants and Clinical Severity

• The Mediterranean variant (Gdmed/B-) causes more severe, life-threatening hemolysis requiring strict oxidant drug avoidance, while the African variant (GdA-/A-) produces milder, self-limited hemolysis 1, 6, 7
• Variants are classified into five classes based on residual enzyme activity and clinical manifestations 4
• Genetic testing helps identify specific variants to determine hemolytic risk severity and guide drug contraindications 6

Screening and Diagnosis

Who to Screen

• Screen all patients with Mediterranean, African, Indian, or Southeast Asian descent before starting any oxidant drug 1, 6, 7
• Screen first-degree relatives of G6PD-deficient patients 6
• Screen infants with jaundice in the first 24 hours of life or excessive jaundice for age 6
• Screen infants with rapidly rising total serum bilirubin approaching exchange transfusion levels or not responding to phototherapy 6

Diagnostic Testing Approach

• Quantitative G6PD enzyme activity assay (measuring IU/gHb) is the gold standard confirmatory test 1
• Qualitative fluorescent spot tests are appropriate for detecting severe deficiency (<10% of normal activity) in males and homozygous females 6
• For heterozygous females and patients with concurrent hematological conditions, quantitative assays or flow cytometry are necessary 6

Critical Timing Considerations for Testing

• Avoid testing during or immediately after acute hemolytic episodes, as reticulocytes and young RBCs contain near-normal enzyme levels, potentially masking deficiency 1, 6
• Wait at least 50 days after RBC transfusion before performing enzyme assays; 120 days post-transfusion is ideal 6
• Donor RBC contamination of 6-12% can cause false-negative results 6
• If testing must occur during acute hemolysis, repeat testing after 3 months for accurate diagnosis 1
• Calculate the PK/G6PD ratio or compare to controls with similar reticulocyte counts when interpreting borderline results 6

Sample Handling Requirements

• Buffy coat removal or filtration is essential for accurate RBC enzyme measurement 6
• Testing whole blood without removing white cells and platelets prevents detection of deficiency 6
• Whole blood samples remain relatively stable at -20°C and 6°C for up to 14 days, losing only about 20% activity over 48 hours 1

Molecular Genetic Testing

• Consider molecular genetic analysis when enzymatic activity is borderline (30-70% of normal) to determine specific variant and predict severity 1, 6
• Genetic testing may be required in heterozygous females when enzymatic testing is inconclusive 1, 6
• Can detect up to 100% of mutations in homogeneous populations 1

Absolutely Contraindicated Medications

Seven medications are definitively contraindicated and must never be used in G6PD deficiency:

• Dapsone 1, 6, 7
• Methylthioninium chloride (methylene blue) 1, 7
• Primaquine 1, 6, 7, 8
• Rasburicase 1, 6
• Tafenoquine (if G6PD activity <70%) 6

FDA-Mandated Primaquine Precautions

• G6PD testing must be performed before using primaquine; primaquine should not be prescribed for patients with severe G6PD deficiency 8
• Primaquine is contraindicated in pregnant women, even if the mother is G6PD normal, as the fetus may not be 8
• If primaquine administration is considered in mild to moderate G6PD deficiency, baseline hematocrit and hemoglobin must be checked before treatment with close hematological monitoring at day 3 and 8 8
• Discontinue primaquine promptly if signs of hemolytic anemia occur (darkening of urine, marked fall of hemoglobin or erythrocyte count) 8

Medications Requiring Caution

• NSAIDs, including ibuprofen, present moderate risk and can cause hemolysis 1
• Aspirin is explicitly contraindicated as it can overwhelm the reduced antioxidant capacity in G6PD-deficient red blood cells 1
• Sulfonamides, including sulfamethoxazole/cotrimoxazole, may pose risk, though recent real-world data suggests they may be safer than previously thought 7
• Local anesthetics (benzocaine, prilocaine, lidocaine, tetracaine) can precipitate methemoglobinemia and should be used with caution 7
• Hydroxychloroquine can cause severe hemolytic anemia and methemoglobinemia in G6PD-deficient patients 9

Safe Alternative Medications

• Penicillins, such as amoxicillin, are not contraindicated and can be used in normal therapeutic doses 1
• For dermatologic conditions requiring immunosuppression: use mycophenolate, azathioprine, or methotrexate instead of dapsone 6
• For Pneumocystis prophylaxis: use atovaquone or inhaled pentamidine instead of dapsone 6

Management of Acute Hemolytic Crisis

Recognition and Monitoring

• Jaundice is a common presentation of acute hemolysis 1
• Monitor for darkening of urine, marked fall of hemoglobin or erythrocyte count 8
• Monitor hemoglobin levels closely, especially during acute hemolytic crisis 1
• Elevated indirect bilirubin (>1.0 mg/dL when total bilirubin is ≤5 mg/dL) suggests hemolysis 1

Treatment Algorithm

• Immediately discontinue the offending oxidant drug 6, 8
• Consider transfusion if hemoglobin drops below 7-8 g/dL with symptoms 1
• Folic acid supplementation (1 mg daily) is recommended 1
• For severe cases, consider exchange transfusion 6

Management of Methemoglobinemia in G6PD Deficiency

This represents a unique clinical dilemma requiring careful decision-making:

• Ascorbic acid (Vitamin C) is the treatment of choice for methemoglobinemia in G6PD-deficient patients when methylene blue is contraindicated 6, 7
• Dosing ranges from 0.2-1.0 g/day orally in divided doses 7
• For severe methemoglobinemia, doses of 0.5-10 g may be required, which exceed the FDA-mandated RDA limit for G6PD-deficient patients 6
• The benefit of treating life-threatening methemoglobinemia outweighs hemolysis risk from high-dose ascorbic acid 6
• Monitor for rebound methemoglobinemia requiring repeat dosing every 6-8 hours for up to 2-3 days 6
• Exchange transfusion should be considered for severe cases of ascorbic acid-induced hemolysis 6

Special Populations

Neonatal Management

• G6PD deficiency was identified as the cause in 31.5% of infants who developed kernicterus, highlighting the critical importance of screening 6
• Quantitative G6PD testing is required for infants with rapidly rising TSB approaching exchange transfusion levels 6
• Test infants receiving phototherapy with TSB rising rapidly and crossing percentiles unexpectedly 6

Pregnancy and Reproductive Considerations

• Sexually-active females of reproductive potential should have pregnancy testing prior to starting treatment with oxidant drugs 8
• Advise females of childbearing potential to use effective contraception during treatment and until completion of an ongoing ovulatory cycle 8
• Advise treated males whose partners may become pregnant to use condoms during treatment and for 3 months after stopping 8
• Primaquine is contraindicated in pregnancy due to toxicity to reproduction, gene mutations, chromosomal/DNA damage, teratogenicity, and injury to embryos 8

Lactation

• Because primaquine and other oxidant drugs may be excreted in human milk, decide whether to discontinue nursing or the drug based on importance to the mother 8

Cardiac Monitoring

• Monitor ECG when using primaquine or other oxidant drugs in patients with cardiac disease, long QT syndrome, history of ventricular arrhythmias, uncorrected hypokalemia/hypomagnesemia, or bradycardia (<50 bpm) 8
• Exercise caution with concomitant administration of QT interval prolonging agents 8

Patient and Family Education

• Educate patients and families about when to seek medical attention for signs of hemolysis 1
• Provide lists of medications and substances to avoid (including fava beans) 2, 5
• Emphasize that most G6PD-deficient individuals are asymptomatic under normal conditions but must avoid oxidative triggers 2, 4
• Inform patients of potential for adverse genetic and reproductive effects with certain treatments 8

Geographic and Epidemiologic Considerations

• Areas of high prevalence include Africa, Southern Europe, Mediterranean region, Middle East, South-East Asia, and Oceania 8, 5
• The geographic distribution correlates remarkably with past/present malaria endemicity, representing a unique example of X-linked human polymorphism balanced through protection of heterozygotes from malaria mortality 2, 5