Background
Vitamin C is often used by complementary and alternative medicine practitioners for its antioxidant properties. We describe a case of severe hemolytic anemia and methemoglobinemia paradoxically resulting from an oxidative stress of high dose intravenous (IV) vitamin C in a patient with previously undiagnosed glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Case Presentation
A 47-year-old Puerto Rican male presented to the Emergency Department with 2 days of progressive shortness of breath and jaundice occurring two weeks after being diagnosed with oropharyngeal squamous cell carcinoma. Despite recommendations from his oncologist to consider traditional chemotherapy, our patient sought treatment from an alternative medicine provider and was provided with three days of a modified version of Myers’ Cocktail. While Myers’ Cocktail typically contains 2–5 ml magnesium chloride hexahydrate 20%, 1–3 ml calcium gluconate 10%, 1,000 mcg hydroxocobalamin (vitamin B12), 100 mg pyridoxine hydrochloride (vitamin B6), 250 mg dexpanthenol (vitamin B5), 1 ml B complex 100, and 4–20 mL of 222 mg/ml vitamin C administered as an IV infusion [1], our patient’s modified version contained added amounts of vitamin C totaling 395 g in escalating doses (65 g on day 1, 130 g on day 2, and 200 g on day 3). The 3-day infusion was completed one day prior to symptom onset and 3 days prior to his presentation to the hospital. The patient was on no other medications. He had previously received and tolerated vitamin C infusions at significantly lower doses (consistent with doses of a typical Myers’ Cocktail) but had never attempted such a high dose regimen.
On presentation, our patient was afebrile and tachycardic with oxygen saturations of 82%–85%. His skin was jaundiced with cola-colored urine and his arterial blood sample was dark purple (Figure 1). Laboratory findings were notable for a hemoglobin of 7.4 g/dl (baseline 13. 8 g/dl, Figure 2), LDH of 1492 units/l (normal 25–175 units/l), and indirect bilirubin of 5.6 mg/dl (normal <1.2 mg/dl) consistent with an intravascular hemolytic anemia. His reticulocyte count suggested an adequate bone marrow response. There was no evidence of blood loss and a peripheral smear and Coombs test did not demonstrate microangiopathic or autoimmune phenomenon. Given the low oxygen saturations and dark blood, his methemoglobin concentration was measured at 7.1%. He received a 1 mg/kg dose of methylene blue with a subsequent drop in both his hemoglobin concentration (7.4 g/dl to 5.9 g/dl) and methemoglobin fraction (7.1% to 3.0%) over the next 12 hours (Figure 2). While Vitamin C was identified as a potential culprit from patient history, a plasma concentration was not obtained at a time in the patient’s course when vitamin C would still be expected to be present. Then, managed conservatively with intravenous fluids and blood transfusions, his hemolysis eventually resolved over several days. While his G6PD level was 4.6 units/g in the setting of active hemolysis and multiple blood transfusions, repeat testing several months after the event came back deficient at 0.4 units/g. The patient reported no known previous episodes of hemolysis and was counseled on his enzyme deficiency, including avoidance of select medications.
Discussion
This case highlights the potential for severe hemolysis with methemoglobinemia in a patient with previously undiagnosed G6PD deficiency supplementing with high doses of vitamin C. Few case reports have demonstrated this previously [2,3] and recent in vitro studies have provided insight for a possible underlying mechanism [4]. While vitamin C is often considered an antioxidant, its utilization in tissues produces its oxidized form (dehydroascorbic acid) which can rapidly deplete intra-erythrocyte stores of glutathione when present in high concentrations [4,5]. These stores are typically replenished by shunting glucose down the pentose phosphate pathway [4,5], but patients with G6PD deficiency are limited in this ability to the degree that their G6PD concentrations are reduced. It is, therefore, plausible that oxidation of hemoglobin and erythrocyte membrane proteins ensues and the result is methemoglobin formation and subsequent hemolysis from the loss of cellular integrity. In our patient, the use of methylene blue potentially exacerbated the hemolysis by acting as an oxidant in the absence of sufficient NADPH.
Conclusion
While several case reports have demonstrated success in treating methemoglobinemia with high doses of vitamin C when methylene blue was either contraindicated [6] or unavailable [7], this case suggests that such practice may need to be used with caution. It is noteworthy, however, that the patient described above was exposed to approximately tenfold the amount of vitamin C used in these studies. Nevertheless, high doses of vitamin C are being increasing used by complementary and alternative medicine practitioners and its potential for life-threatening consequences should not go overlooked.
What is new?
Only a few, old case reports have described severe hemolysis resulting from vitamin C. We describe this phenomenon in a patient with previously undiagnosed glucose-6-phosphate dehydrogenase deficiency taking unusually high doses of vitamin C. It further links the case to a mechanism based on recent in vitro studies.