Methemoglobinemia coupled with hemolytic anemia (HA) has been reported under different clinical scenarios and may have therapeutic implications for treatment of methemoglobinemia in the setting of G6PD deficiency.

Increased methemoglobin levels have been observed during the hemolytic crisis of patients with favism due to G6PD deficiency. This finding has been attributed to excessive oxidative stress generated by divicine, an oxidizing constituent of fava beans, and the inability to reduce its stress because of an insufficient G6PD-dependent hexose monophosphate shunt. ¹Hemolytic anemia may also follow drug-induced methemoglobinemia, especially with exposure to dapsone, sulfasalazine, or phenacetin, and may be a feature of hemoglobin M_Saskatoon and M_{Hyde Park} , abnormal hemoglobin variants associated with genetic methemoglobinemia. ²The concurrence of hemolysis due to G6PD deficiency and methemoglobinemia is not just an academic curiosity and may in fact pose a therapeutic quandary. This is because methylene blue, the treatment of choice for methemoglobinemia, is also an oxidant and works only after it is reduced to leukomethylene blue by (you guessed it!) nicotinamide adenine nucleotide phosphate (NADPH), a G6PD-dependent process. ^2,3 With plenty of methylene blue on hand and little leukomethylene around in G6PD-deficiency, treatment may be ineffective or even cause worsening of methemoglobinemia. It’s never simple!

Final fun fact: Did you know that methylene blue is the first synthetic drug (>100 years ago) and has been used in the prevention of UTIs in the elderly, and treatment of pediatric malaria and Alzheimer’s disease? ⁴References

1. Schuurman M, van Waardenburg D, Da Costa J, et al. Severe hemolysis and methemoglobinemia following fava beans ingestion in glucose-6-phosphate dehydrogenase: Case report and literature review. Eur J Ped 2009;168:779-782. https://link.springer.com/article/10.1007/s00431-009-0952-x
2. Rehman HU. Methemoglobinemia. West J Med 2001;175:193-96. https://www.researchgate.net/publication/11817876_Methemoglobinemia
3. Hassan KS, Al-Riyami AZ, Al-Huneini M, et al. Methemoglobinemia in an elderly patient with glucose-6-phosphate dehydrogenase deficiency: A case report. Oman Med J 2014;29:135-37. https://squ.pure.elsevier.com/en/publications/methemoglobinemia-in-an-elderly-patient-with-glucose-6-phosphate-
4. Schirmer RH, Adler H, Pickhardt M, et al. “Lest we forget you—Methylene blue…” Neurobiology of Aging 2011; 32:2325. https://www.ncbi.nlm.nih.gov/pubmed/21316815