Ascorbic Acid in G6PD Deficiency: Critical Dosing Restrictions
Patients with G6PD deficiency should not exceed the U.S. Recommended Dietary Allowance (RDA) or Adequate Intake (AI) level for ascorbic acid, as higher doses carry significant risk of severe hemolysis, methemoglobinemia, and acute kidney injury. 1
Dosing Restrictions and Safety Thresholds
FDA-Mandated Dose Limitations
- The FDA explicitly requires dose reduction in G6PD-deficient patients to RDA/AI levels only, regardless of the clinical indication 1
- Standard therapeutic doses (even as low as 1 g/day) have caused life-threatening hemolysis in G6PD-deficient patients 2, 3
- Monitor hemoglobin and complete blood count when any ascorbic acid is administered to G6PD-deficient patients 1
The Paradox of Ascorbic Acid in G6PD Deficiency
- At physiological doses, ascorbic acid serves as the treatment of choice for methemoglobinemia when methylene blue is contraindicated in G6PD deficiency 4, 5
- At supraphysiological doses (>RDA), ascorbic acid paradoxically causes the same oxidative hemolysis it is meant to treat 6
- This dose-dependent reversal of therapeutic effect makes strict adherence to RDA limits critical 6
Clinical Evidence of Harm
Severity and Timing of Hemolysis
- 78.6% of hemolytic events occur within 3 days of starting vitamin C supplementation 2
- Hemoglobin can drop to life-threatening levels (<50 g/L) with pharmacological doses 7
- Associated complications include acute kidney injury (50% of cases), disseminated intravascular coagulation, oxalosis, and methemoglobinemia 2
Risk Factors for Severe Hemolysis
- 71.4% of patients who developed vitamin C-induced hemolysis had G6PD deficiency, though many were undiagnosed prior to the event 2
- The Mediterranean variant (Gdmed) causes more severe reactions than the African variant (GdA-) 8, 9
- Concurrent conditions that increase vulnerability include bone marrow suppression, moderate-to-severe anemia, abnormal liver function, and renal impairment 7
Therapeutic Use in Methemoglobinemia
When Ascorbic Acid is Indicated
- Ascorbic acid is the treatment of choice for methemoglobinemia in G6PD-deficient patients when methylene blue is contraindicated 4, 5
- Methylene blue itself causes severe hemolytic anemia and can worsen methemoglobinemia in G6PD deficiency 4
- Dosing for methemoglobinemia ranges from 0.5-10 g in adults and 0.5-1 g in children, but these doses exceed RDA and carry hemolysis risk 4
Critical Caveat
- The doses recommended for treating methemoglobinemia (0.5-10 g) exceed the FDA-mandated RDA limit for G6PD-deficient patients 4, 1
- This creates a clinical dilemma: ascorbic acid is the safest option for methemoglobinemia in G6PD deficiency, yet therapeutic doses still risk hemolysis 4, 6
- In this emergency scenario, the benefit of treating life-threatening methemoglobinemia outweighs hemolysis risk, but close monitoring is mandatory 4
Monitoring and Management
Essential Monitoring
- Discontinue ascorbic acid immediately if hemolysis is suspected 1
- Monitor for dark urine, jaundice, and scleral icterus as early signs of hemolysis 3, 6
- Laboratory monitoring should include hemoglobin, reticulocyte count, indirect bilirubin, and renal function 2, 3
Treatment of Ascorbic Acid-Induced Hemolysis
- Immediate cessation of vitamin C is the first step 1, 3
- Supportive care includes steroids, hepatoprotective drugs, folic acid, and packed red blood cell transfusion 3, 7
- Early blood purification and steroid therapy may prevent acute kidney injury or death 7
- Exchange transfusion should be considered for severe cases 4
Screening Recommendations
Who Should Be Screened
- Screen all patients of Mediterranean, African, Indian, or Southeast Asian descent before prescribing any oxidant drugs including high-dose vitamin C 8, 5, 9
- Many patients with G6PD deficiency are undiagnosed until a hemolytic crisis occurs 2, 10
- G6PD deficiency was previously unrecognized in multiple reported cases of vitamin C-induced hemolysis 6, 10
Practical Pitfall
- Vitamin C is widely perceived as safe, leading to underestimation of hemolysis risk 2, 7
- Naturopathic and high-dose intravenous vitamin C formulations pose particular risk due to lack of regulatory oversight and patient self-administration 10
- Even doses as low as 30 g (relatively low for investigational high-dose protocols) have caused methemoglobinemia and hemolytic anemia in G6PD-deficient patients 6