Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Clinical features, diagnosis, and treatment of methemoglobinemia

Josef T Prchal, MD
Section Editors
Stanley L Schrier, MD
Donald H Mahoney, Jr, MD
Michele M Burns, MD, MPH
Deputy Editors
Jennifer S Tirnauer, MD
Carrie Armsby, MD, MPH


There are two types of methemoglobinemia: congenital and acquired.

Congenital methemoglobinemia is characterized by diminished enzymatic reduction of methemoglobin (hemoglobin with its iron in the ferric [oxidized; Fe+++] state, which cannot reversibly bind oxygen) back to functional hemoglobin (hemoglobin with its iron in the ferrous [reduced; Fe++] state) or a mutant globin that facilitates spontaneous oxidation of the ferrous iron to ferric state. Affected patients have life-long cyanosis but are generally asymptomatic unless they have type II congenital methemoglobinemia.

Acquired methemoglobinemia typically results from ingestion of specific drugs or agents that cause an increase in the production of methemoglobin. It can be a fatal disease.

The clinical features, diagnosis, and treatment of methemoglobinemia will be reviewed here. The genetics and pathogenesis of methemoglobinemia are discussed separately but will be briefly summarized below. (See "Genetics and pathogenesis of methemoglobinemia".)


Methemoglobin is an altered state of hemoglobin in which the ferrous (Fe++) irons of heme are oxidized to the ferric (Fe+++) state. The ferric hemes of methemoglobin are unable to reversibly bind oxygen. In addition, the oxygen affinity of any remaining ferrous hemes in the hemoglobin tetramer is increased [1]. As a result, the oxygen dissociation curve is "left-shifted" (figure 1). (See "Genetic disorders of hemoglobin oxygen affinity".)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: May 2017. | This topic last updated: Jun 07, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Darling R, Roughton F. The effect of methemoglobin on the equilibrium between oxygen and hemoglobin. Am J Physiol 1942; 137:56.
  2. Warang PP, Kedar PS, Shanmukaiah C, et al. Clinical spectrum and molecular basis of recessive congenital methemoglobinemia in India. Clin Genet 2015; 87:62.
  5. Yubisui T, Takeshita M, Yoneyama Y. Reduction of methemoglobin through flavin at the physiological concentration by NADPH-flavin reductase of human erythrocytes. J Biochem 1980; 87:1715.
  6. Agarwal N, Nagel RL, Prchal JT. Dyshemoglobinemias. In: Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management, 2nd ed, Steinberg M (Ed), 2009. p.607.
  7. Hegesh E, Hegesh J, Kaftory A. Congenital methemoglobinemia with a deficiency of cytochrome b5. N Engl J Med 1986; 314:757.
  8. Congenital methemoglobinemia with cytochrome b5 deficiency. N Engl J Med 1986; 315:893.
  9. Coleman MD, Coleman NA. Drug-induced methaemoglobinaemia. Treatment issues. Drug Saf 1996; 14:394.
  10. Ash-Bernal R, Wise R, Wright SM. Acquired methemoglobinemia: a retrospective series of 138 cases at 2 teaching hospitals. Medicine (Baltimore) 2004; 83:265.
  11. Kane GC, Hoehn SM, Behrenbeck TR, Mulvagh SL. Benzocaine-induced methemoglobinemia based on the Mayo Clinic experience from 28 478 transesophageal echocardiograms: incidence, outcomes, and predisposing factors. Arch Intern Med 2007; 167:1977.
  12. Falkenhahn M, Kannan S, O'Kane M. Unexplained acute severe methaemoglobinaemia in a young adult. Br J Anaesth 2001; 86:278.
  13. McKinney CD, Postiglione KF, Herold DA. Benzocaine-adultered street cocaine in association with methemoglobinemia. Clin Chem 1992; 38:596.
  14. Esbenshade AJ, Ho RH, Shintani A, et al. Dapsone-induced methemoglobinemia: a dose-related occurrence? Cancer 2011; 117:3485.
  15. Swartzentruber GS, Yanta JH, Pizon AF. Methemoglobinemia as a complication of topical dapsone. N Engl J Med 2015; 372:491.
  16. Woodhouse KW, Henderson DB, Charlton B, et al. Acute dapsone poisoning: clinical features and pharmacokinetic studies. Hum Toxicol 1983; 2:507.
  17. Hall NM, Jones FJ, Ainsworth CR, Fincher RK. Methemoglobinemia in patients undergoing esophagogastroduodenoscopy: a randomized controlled trial. Mil Med 2013; 178:701.
  18. Higuchi R, Fukami T, Nakajima M, Yokoi T. Prilocaine- and lidocaine-induced methemoglobinemia is caused by human carboxylesterase-, CYP2E1-, and CYP3A4-mediated metabolic activation. Drug Metab Dispos 2013; 41:1220.
  19. Spiller HA, Russell JL, Casavant MJ, et al. Identification of N-Hydroxy-para-aminobenzoic acid in a cyanotic child after benzocaine exposure. Clin Toxicol (Phila) 2014; 52:976.
  20. Hartman NR, Mao JJ, Zhou H, et al. More methemoglobin is produced by benzocaine treatment than lidocaine treatment in human in vitro systems. Regul Toxicol Pharmacol 2014; 70:182.
  21. Hamon I, Gauthier-Moulinier H, Grelet-Dessioux E, et al. Methaemoglobinaemia risk factors with inhaled nitric oxide therapy in newborn infants. Acta Paediatr 2010; 99:1467.
  22. Bizzarro M, Gross I, Barbosa FT. Inhaled nitric oxide for the postoperative management of pulmonary hypertension in infants and children with congenital heart disease. Cochrane Database Syst Rev 2014; :CD005055.
  23. Kusin S, Tesar J, Hatten B, et al. Severe methemoglobinemia and hemolytic anemia from aniline purchased as 2C-E (4-ethyl-2,5-dimethoxyphenethylamine), a recreational drug, on the Internet - Oregon, 2011. MMWR Morb Mortal Wkly Rep 2012; 61:85.
  24. Management guidelines for aniline exposure. http://www.atsdr.cdc.gov/mmg/mmg.asp?id=448&tid=79 (Accessed on February 23, 2012).
  25. Sankar J, Gupta A, Pathak S, Dubey NK. Death in an adolescent girl with methemoglobinemia and malaria. J Trop Pediatr 2012; 58:154.
  26. Jaffe E. Hereditary methemoglobinemias associated with abnormalities in the metabolism of erythrocytes. Am J Med 1962; 32:512.
  27. Leroux A, Junien C, Kaplan J, Bamberger J. Generalised deficiency of cytochrome b5 reductase in congenital methaemoglobinaemia with mental retardation. Nature 1975; 258:619.
  28. Ewenczyk C, Leroux A, Roubergue A, et al. Recessive hereditary methaemoglobinaemia, type II: delineation of the clinical spectrum. Brain 2008; 131:760.
  29. Takeshita M, Tamura M, Kugi M, et al. Decrease of palmitoyl-CoA elongation in platelets and leukocytes in the patient of hereditary methemoglobinemia associated with mental retardation. Biochem Biophys Res Commun 1987; 148:384.
  30. Takeshita M, Tamura M, Yoshida S, Yubisui T. Palmitoyl-CoA elongation in brain microsomes: dependence on cytochrome b5 and NADH-cytochrome b5 reductase. J Neurochem 1985; 45:1390.
  31. Junien C, Leroux A, Lostanlen D, et al. Prenatal diagnosis of congenital enzymopenic methaemoglobinaemia with mental retardation due to generalized cytochrome b5 reductase deficiency: first report of two cases. Prenat Diagn 1981; 1:17.
  32. Kaftory A, Freundlich E, Manaster J, et al. Prenatal diagnosis of congenital methemoglobinemia with mental retardation. Isr J Med Sci 1986; 22:837.
  33. Cortazzo JA, Lichtman AD. Methemoglobinemia: a review and recommendations for management. J Cardiothorac Vasc Anesth 2014; 28:1043.
  34. US FDA benzocaine warning. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm250264.htm (Accessed on March 13, 2014).
  35. Henry LR, Pizzini M, Delarso B, Ridge JA. Methemoglobinemia: early intraoperative detection by clinical observation. Laryngoscope 2004; 114:2025.
  36. Cohen RJ, Sachs JR, Wicker DJ, Conrad ME. Methemoglobinemia provoked by malarial chemoprophylaxis in Vietnam. N Engl J Med 1968; 279:1127.
  37. Maran J, Guan Y, Ou CN, Prchal JT. Heterogeneity of the molecular biology of methemoglobinemia: a study of eight consecutive patients. Haematologica 2005; 90:687.
  38. Kelner MJ, Bailey DN. Mismeasurement of methemoglobin ("methemoglobin revisited"). Clin Chem 1985; 31:168.
  39. Molthrop DC Jr, Wheeler RH, Hall KM, Prchal JT. Evaluation of the methemoglobinemia associated with sulofenur. Invest New Drugs 1994; 12:99.
  40. Haymond S, Cariappa R, Eby CS, Scott MG. Laboratory assessment of oxygenation in methemoglobinemia. Clin Chem 2005; 51:434.
  41. Evelyn K, Malloy H. Microdetermination of oxyhemoglobin, methemoglobin, and sulfhemoglobin in a single sample of blood. J Biol Chem 1938; 126:655.
  42. Jaffé ER. Hereditary methemoglobinemias associated with abnormalities in the metabolism of erythrocytes. Am J Med 1966; 41:786.
  43. Jaffe ER, Hsieh HS. DPNH-methemoglobin reductase deficiency and hereditary methemoglobinemia. Semin Hematol 1971; 8:417.
  45. Barker SJ, Tremper KK, Hyatt J. Effects of methemoglobinemia on pulse oximetry and mixed venous oximetry. Anesthesiology 1989; 70:112.
  46. Barker SJ, Curry J, Redford D, Morgan S. Measurement of carboxyhemoglobin and methemoglobin by pulse oximetry: a human volunteer study. Anesthesiology 2006; 105:892.
  47. Annabi EH, Barker SJ. Severe methemoglobinemia detected by pulse oximetry. Anesth Analg 2009; 108:898.
  48. Feiner JR, Bickler PE, Mannheimer PD. Accuracy of methemoglobin detection by pulse CO-oximetry during hypoxia. Anesth Analg 2010; 111:143.
  49. Board PG, Pidcock ME. Methaemoglobinaemia resulting from heterozygosity for two NADH-methaemoglobin reductase variants: characterization as NADH-ferricyanide reductase. Br J Haematol 1981; 47:361.
  50. González R, Estrada M, Wade M, et al. Heterogeneity of hereditary methaemoglobinaemia: a study of 4 Cuban families with NADH-Methaemoglobin reductase deficiency including a new variant (Santiago de Cuba variant). Scand J Haematol 1978; 20:385.
  51. Hegesh E, Calmanovici N, Avron M. New method for determining ferrihemoglobin reductase (NADH-methemoglobin reductase) in erythrocytes. J Lab Clin Med 1968; 72:339.
  52. Prchal JT, Borgese N, Moore MR, et al. Congenital methemoglobinemia due to methemoglobin reductase deficiency in two unrelated American black families. Am J Med 1990; 89:516.
  53. Vieira LM, Kaplan JC, Kahn A, Leroux A. Four new mutations in the NADH-cytochrome b5 reductase gene from patients with recessive congenital methemoglobinemia type II. Blood 1995; 85:2254.
  54. Jaffe ER, Hultquist DE. Cytochrome b5 reductase deficiency and enzymopenic hereditary methemoglobinemia. In: The Metabolic and Molecular Bases of Inherited Disease, 7th ed, Scriver CR, Beaudet AL, Sly WS, Valle D (Eds), McGraw-Hill, New York 1995. p.3399.
  55. Shirabe K, Landi MT, Takeshita M, et al. A novel point mutation in a 3' splice site of the NADH-cytochrome b5 reductase gene results in immunologically undetectable enzyme and impaired NADH-dependent ascorbate regeneration in cultured fibroblasts of a patient with type II hereditary methemoglobinemia. Am J Hum Genet 1995; 57:302.
  56. Board PG. NADH-ferricyanide reductase, a convenient approach to the evaluation of NADH-methaemoglobin reductase in human erythrocytes. Clin Chim Acta 1981; 109:233.
  57. Jenkins MM, Prchal JT. A novel mutation found in the 3' domain of NADH-cytochrome B5 reductase in an African-American family with type I congenital methemoglobinemia. Blood 1996; 87:2993.
  58. Yubisui T, Naitoh Y, Zenno S, et al. Molecular cloning of cDNAs of human liver and placenta NADH-cytochrome b5 reductase. Proc Natl Acad Sci U S A 1987; 84:3609.
  59. Beutler E. Methemoglobinemia and other causes of cyanosis. In: Williams' Hematology, 5th ed, Beutler E, Lichtman MA, Coller B, Kipps TJ (Eds), McGraw-Hill, New York 1995. p.654.
  60. Kaplan JC, Chirouze M. Therapy of recessive congenital methaemoglobinaemia by oral riboflavine. Lancet 1978; 2:1043.
  61. D'sa SR, Victor P, Jagannati M, et al. Severe methemoglobinemia due to ingestion of toxicants. Clin Toxicol (Phila) 2014; 52:897.
  62. Rino PB, Scolnik D, Fustiñana A, et al. Ascorbic acid for the treatment of methemoglobinemia: the experience of a large tertiary care pediatric hospital. Am J Ther 2014; 21:240.
  63. Goldstein GM, Doull J. Treatment of nitrite-induced methemoglobinemia with hyperbaric oxygen. Proc Soc Exp Biol Med 1971; 138:137.
  64. Patnaik S, Natarajan MM, James EJ, Ebenezer K. Methylene blue unresponsive methemoglobinemia. Indian J Crit Care Med 2014; 18:253.
  65. Su YF, Lu LH, Hsu TH, et al. Successful treatment of methemoglobinemia in an elderly couple with severe cyanosis: two case reports. J Med Case Rep 2012; 6:290.
  66. Park SY, Lee KW, Kang TS. High-dose vitamin C management in dapsone-induced methemoglobinemia. Am J Emerg Med 2014; 32:684.e1.
  67. Guay J. Methemoglobinemia related to local anesthetics: a summary of 242 episodes. Anesth Analg 2009; 108:837.
  68. Harvey JW, Keitt AS. Studies of the efficacy and potential hazards of methylene blue therapy in aniline-induced methaemoglobinaemia. Br J Haematol 1983; 54:29.
  69. GOLUBOFF N, WHEATON R. Methylene blue induced cyanosis and acute hemolytic anemia complicating the treatment of methemoglobinemia. J Pediatr 1961; 58:86.
  70. Rosen PJ, Johnson C, McGehee WG, Beutler E. Failure of methylene blue treatment in toxic methemoglobinemia. Association with glucose-6-phosphate dehydrogenase deficiency. Ann Intern Med 1971; 75:83.
  71. Bilgin H, Ozcan B, Bilgin T. Methemoglobinemia induced by methylene blue pertubation during laparoscopy. Acta Anaesthesiol Scand 1998; 42:594.
  72. Reading NS, Ruiz-Bonilla JA, Christensen RD, et al. A patient with both methemoglobinemia and G6PD deficiency: A therapeutic conundrum. Am J Hematol 2017; 92:474.
  73. MedWatch Safety Alert. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm265476.htm (Accessed on March 13, 2014).
  74. Top WM, Gillman PK, de Langen CJ, Kooy A. Fatal methylene blue associated serotonin toxicity. Neth J Med 2014; 72:179.
  75. Shopes E, Gerard W, Baughman J. Methylene blue encephalopathy: a case report and review of published cases. AANA J 2013; 81:215.
  76. Coleman MD, Rhodes LE, Scott AK, et al. The use of cimetidine to reduce dapsone-dependent methaemoglobinaemia in dermatitis herpetiformis patients. Br J Clin Pharmacol 1992; 34:244.
  77. Coleman MD. Dapsone: modes of action, toxicity and possible strategies for increasing patient tolerance. Br J Dermatol 1993; 129:507.
  78. Vichinsky EP, Lubin BH. Unstable hemoglobins, hemoglobins with altered oxygen affinity, and m-hemoglobins. Pediatr Clin North Am 1980; 27:421.