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Methemoglobinemia Differential Diagnoses

  • Author: Mary Denshaw-Burke, MD, FACP; Chief Editor: Emmanuel C Besa, MD  more...
 
Updated: Jan 04, 2016
 
 

Diagnostic Considerations

Because the initial symptoms of methemoglobinemia can be vague, especially with low levels of methemoglobinemia, this condition can easily be misdiagnosed or go unrecognized. Lack of awareness of this condition often leads to delayed and missed diagnosis.

Cyanosis (presence of more than 5 g/dL of deoxygenated hemoglobin) associated with hypoxia may be caused by cardiac or pulmonary disease. Cyanosis may also be present in polycythemia but is generally without hypoxia. The hallmark of methemoglobinemia is cyanosis that is unresponsive to high oxygen concentrations in the absence of cardiac or pulmonary disorders. Pulmonary diseases generally respond to oxygen administration, whereas cardiac disease may not. Right-to-left shunts in the cardiovascular system, especially when large, do not respond to oxygen administration.

Sulfhemoglobinemia, skin contamination with blue/gray/black-colored dyes, or ingestion/treatment with methylene blue causes cyanosis that is unresponsive to oxygen. Darkish discoloration of the skin may be due to excessive exposure to silver compounds (argyria) and can mimic methemoglobinemia.[55, 56] Methylene blue can impart a cyanotic discoloration to the skin after the treatment of patients with methemoglobinemia; therefore, bluish discoloration following treatment does not necessarily imply treatment failure.

Hemoglobin variants with altered oxygen affinity should also be considered in the differential diagnosis of patients with cyanosis. In infants, this may be due to the presence of hemoglobin M (hemoglobins F M-Osaka and F M-Fort Ripley), resulting in the formation of methemoglobinemia).

Decreased oxygen affinity may also be due to the presence of a nonmethemoglobin low-affinity fetal hemoglobin variant as a result of an allosteric abnormality in the hemoglobin. Hemoglobin F-Cincinnati is a γ-chain substitution described at residue 41.[57] Substitution at residue 41 has been reported for the f3 globin chain (4l(C7) Phe → Ser) as hemoglobin Denver, which has been shown to have decreased oxygen affinity.[57]

Differential Diagnoses

 
 
Contributor Information and Disclosures
Author

Mary Denshaw-Burke, MD, FACP Clinical Assistant Professor of Medicine, Jefferson Medical College of Thomas Jefferson University; Clinical Assistant Professor, Affiliated Clinical Faculty of the Lankenau Institute for Medical Research; Program Director of Hematology/Oncology Fellowship, Education Coordinator for Oncology, Lankenau Medical Center

Mary Denshaw-Burke, MD, FACP is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

Coauthor(s)

Mudra Kumar, MD, MRCP, FAAP Professor of Pediatrics, Course Director, Course 6 MSII, Preclerkship Director, Clinical Integration, Department of Pediatrics, University of South Florida Morsani College of Medicine

Mudra Kumar, MD, MRCP, FAAP is a member of the following medical societies: American Academy of Pediatrics, American Society of Hematology, American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

Deric C Savior, MD Fellow, Department of Hematology/Oncology, Lankenau Hospital

Disclosure: Nothing to disclose.

Amy Lawser Curran, MD Fellow, Department of Hematology/Oncology, Lankenau Hospital

Amy Lawser Curran, MD is a member of the following medical societies: Alpha Omega Alpha, Sigma Xi

Disclosure: Nothing to disclose.

Elizabeth DelGiacco, DO Chief Fellow, Department of Hematology/Oncology, Main Line Health, Lankenau Medical Center

Elizabeth DelGiacco, DO is a member of the following medical societies: American Society of Hematology, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Acknowledgements

Steven K Bergstrom, MD Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland

Steven K Bergstrom, MD is a member of the following medical societies: Alpha Omega Alpha, American Society of Clinical Oncology, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, and International Society for Experimental Hematology

Disclosure: Nothing to disclose.

Matthew Bouchard, MD Consulting Staff, Department of Emergency Medicine, Altoona Regional Health System

Disclosure: Nothing to disclose.

Michael J Burns, MD Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center

Michael J Burns, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, and Southwest Oncology Group

Disclosure: Nothing to disclose.

Max J Coppes, MD, PhD, MBA Senior Vice President, Center for Cancer and Blood Disorders, Children's National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University School of Medicine; Clinical Professor of Pediatrics, George Washington University School of Medicine and Health Sciences

Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Kathy L Ferguson, DO Attending Physician, Department of Emergency Medicine, New York Hospital of Queens

Kathy L Ferguson, DO is a member of the following medical societies: American College of Emergency Physicians and American College of Medical Toxicology

Disclosure: Nothing to disclose.

Lance W Kreplick, MD, FAAEM, MMM Medical Director of Hyperbaric Medicine, Fawcett Wound Management and Hyperbaric Medicine; Consulting Staff in Occupational Health and Rehabilitation, Company Care Occupational Health Services; President and Chief Executive Officer, QED Medical Solutions, LLC

Lance W Kreplick, MD, FAAEM, MMM, is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physician Executives

Disclosure: Nothing to disclose.

David C Lee, MD Research Director, Department of Emergency Medicine, Associate Professor, North Shore University Hospital and New York University Medical School

David C Lee, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Sharada A Sarnaik, MBBS Professor of Pediatrics, Wayne State University School of Medicine; Director, Sickle Cell Center, Attending Hematologist/Oncologist, Children's Hospital of Michigan

Sharada A Sarnaik, MBBS is a member of the following medical societies: American Association of Blood Banks, American Association of University Professors, American Society of Hematology, American Society of Pediatric Hematology/Oncology, New York Academy of Sciences, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Paul Schick, MD Emeritus Professor, Department of Internal Medicine, Jefferson Medical College of Thomas Jefferson University; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital

Paul Schick, MD is a member of the following medical societies: American College of Physicians and American Society of Hematology

Disclosure: Nothing to disclose.

John Schoffstall, MD Associate Professor, Department of Emergency Medicine, Medical College of Pennsylvania

John Schoffstall, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, Pennsylvania Medical Society, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Asim Tarabar, MD Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists

Disclosure: Nothing to disclose.

Michael J Verive, MD Medical Director, Pediatric Intensive Care, Department of Pediatrics, St Mary's Hospital for Women and Children

Michael J Verive, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, Pediatric Sedation, and Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

References
  1. Bloom J, ed. Comprehensive Toxicology. Amsterdam, Netherlands: Elsevier; 1997. Vol 4: 62-6.

  2. Curry S. Methemoglobinemia. In: Rosen P, Barkin R, Danzl DF, et al, eds. Emergency Medicine: Concepts and Clinical Practice. 4th ed. St Louis, Mo: Mosby-Year Book; 1997.

  3. Hoffman R, Benz E, Shattil S, Furie B, Cohen H, eds. Hematology Basic Principles and Practice. 4th ed. New York, NY: Churchill Livingstone; 2005. 650-7.

  4. do Nascimento TS, Pereira RO, de Mello HL, Costa J. Methemoglobinemia: from diagnosis to treatment. Rev Bras Anestesiol. 2008 Nov-Dec. 58(6):657-64, 651-7. [Medline]. [Full Text].

  5. Percy MJ, McFerran NV, Lappin TR. Disorders of oxidised haemoglobin. Blood Rev. 2005 Mar. 19(2):61-8. [Medline].

  6. Mansouri A, Lurie AA. Concise review: methemoglobinemia. Am J Hematol. 1993 Jan. 42(1):7-12. [Medline].

  7. Curry S. Methemoglobinemia. Ann Emerg Med. 1982 Apr. 11(4):214-21. [Medline].

  8. Goluboff N, Wheaton R. Methylene blue induced cyanosis and acute hemolytic anemia complicating the treatment of methemoglobinemia. J Pediatr. 1961 Jan. 58:86-9. [Medline].

  9. Gebara BM, Goetting MG. Life-threatening methemoglobinemia in infants with diarrhea and acidosis. Clin Pediatr (Phila). 1994 Jun. 33(6):370-3. [Medline].

  10. Bento C, Magalhães Maia T, Carvalhais I, Moita F, Abreu G, Relvas L, et al. Transient neonatal cyanosis associated with a new Hb F variant: Hb F Viseu. J Pediatr Hematol Oncol. 2013 Mar. 35(2):e77-80. [Medline].

  11. Allen A, Fisher C, Premawardhena A, Bandara D, Perera A, Allen S. Methemoglobinemia and ascorbate deficiency in hemoglobin E ß thalassemia: metabolic and clinical implications. Blood. 2012 Oct 11. 120(15):2939-44. [Medline].

  12. Ward KE, McCarthy MW. Dapsone-induced methemoglobinemia. Ann Pharmacother. 1998 May. 32(5):549-53. [Medline].

  13. Grauer SE, Giraud GD. Toxic methemoglobinemia after topical anesthesia for transesophageal echocardiography. J Am Soc Echocardiogr. 1996 Nov-Dec. 9(6):874-6. [Medline].

  14. Ash-Bernal R, Wise R, Wright SM. Acquired methemoglobinemia: a retrospective series of 138 cases at 2 teaching hospitals. Medicine (Baltimore). 2004 Sep. 83(5):265-73. [Medline].

  15. Ohashi K, Yukioka H, Hayashi M, Asada A. Elevated methemoglobin in patients with sepsis. Acta Anaesthesiol Scand. 1998 Jul. 42(6):713-6. [Medline].

  16. Wright RO, Lewander WJ, Woolf AD. Methemoglobinemia: etiology, pharmacology, and clinical management. Ann Emerg Med. 1999 Nov. 34(5):646-56. [Medline].

  17. Forestier A, Pissard S, Cretet J, Mambie A, Pascal L, Cliquennois M, et al. Congenital Recessive Methemoglobinemia Revealed in Adulthood: Description of a New Mutation in Cytochrome b5 Reductase Gene. Hemoglobin. 2015 Jul 31. 1-4. [Medline].

  18. Fuller TD, Spracklen CN, Ryckman KK, Knake LA, Busch TD, Momany AM, et al. Genetic variation in CYB5R3 is associated with methemoglobin levels in preterm infants receiving nitric oxide therapy. Pediatr Res. 2015 Mar. 77 (3):472-6. [Medline].

  19. Fan AM, Steinberg VE. Health implications of nitrate and nitrite in drinking water: an update on methemoglobinemia occurrence and reproductive and developmental toxicity. Regul Toxicol Pharmacol. 1996 Feb. 23(1 pt 1):35-43. [Medline].

  20. Erkekoglu P, Baydar T. Evaluation of nitrite contamination in baby foods and infant formulas marketed in Turkey. Int J Food Sci Nutr. 2009 May. 60(3):206-9. [Medline].

  21. [Guideline] Greer FR, Shannon M. Infant methemoglobinemia: the role of dietary nitrate in food and water. Pediatrics. 2005 Sep. 116(3):784-6. [Medline].

  22. Moore TJ, Walsh CS, Cohen MR. Reported adverse event cases of methemoglobinemia associated with benzocaine products. Arch Intern Med. 2004 Jun 14. 164(11):1192-6. [Medline].

  23. Guay J. Methemoglobinemia related to local anesthetics: a summary of 242 episodes. Anesth Analg. 2009 Mar. 108(3):837-45. [Medline].

  24. So TY, Farrington E. Topical Benzocaine-induced Methemoglobinemia in the Pediatric Population. J Pediatr Health Care. 2008 Nov-Dec. 22(6):335-9. [Medline].

  25. Kath MA, Shupp JW, Matt SE, Shaw JD, Johnson LS, Pavlovich AR. Incidence of methemoglobinemia in patients receiving cerium nitrate and silver sulfadiazine for the treatment of burn wounds: a burn center's experience. Wound Repair Regen. 2011 Mar-Apr. 19(2):201-4. [Medline].

  26. Chowdhary S, Bukoye B, Bhansali AM, Carbo AR, Adra M, Barnett S, et al. Risk of topical anesthetic-induced methemoglobinemia: a 10-year retrospective case-control study. JAMA Intern Med. 2013 May 13. 173(9):771-6. [Medline].

  27. Watton C, Smith K, Carter E. Methemoglobinemia as a complication of topical dapsone. N Engl J Med. 2015 Jan 29. 372 (5):492. [Medline]. [Full Text].

  28. Skold A, Klein R. Symptomatic-Low Grade Methemoglobinemia Because of Dapsone: A Multiple Hit Hypothesis. Am J Ther. 2011 Jun 3. [Medline].

  29. Henretig FM, Gribetz B, Kearney T, Lacouture P, Lovejoy FH. Interpretation of color change in blood with varying degree of methemoglobinemia. J Toxicol Clin Toxicol. 1988. 26(5-6):293-301. [Medline].

  30. Góth L, Bigler NW. Catalase deficiency may complicate urate oxidase (rasburicase) therapy. Free Radic Res. 2007 Sep. 41(9):953-5. [Medline].

  31. Bauters T, Mondelaers V, Robays H, De Wilde H, Benoit Y, De Moerloose B. Methemoglobinemia and hemolytic anemia after rasburicase administration in a child with leukemia. Int J Clin Pharm. 2011 Feb. 33(1):58-60. [Medline].

  32. Geetha A, Lakshmi Priya MD, Jeyachristy SA, Surendran R. Level of oxidative stress in the red blood cells of patients with liver cirrhosis. Indian J Med Res. 2007 Sep. 126(3):204-10. [Medline]. [Full Text].

  33. Odièvre MH, Danékova N, Mesples B, Chemouny M, Couque N, Parez N, et al. Unsuspected glucose-6-phosphate dehydrogenase deficiency presenting as symptomatic methemoglobinemia with severe hemolysis after fava bean ingestion in a 6-year-old boy. Int J Hematol. 2011 May. 93(5):664-6. [Medline].

  34. Romanovsky A, Djogovic D, Chin D. A case of sodium chlorite toxicity managed with concurrent renal replacement therapy and red cell exchange. J Med Toxicol. 2013 Mar. 9(1):67-70. [Medline].

  35. Warriner DR, Morris P, Ramjiani V, Morton A, Sheridan P. Smells like a heart attack, but is it?. BMJ Case Rep. 2011. 2011:[Medline].

  36. Grundlingh J, Dargan PI, El-Zanfaly M, Wood DM. 2,4-dinitrophenol (DNP): a weight loss agent with significant acute toxicity and risk of death. J Med Toxicol. 2011 Sep. 7(3):205-12. [Medline].

  37. 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 Feb 10. 61(5):85-8. [Medline].

  38. Weichert I. Acute management of cocaine-associated methaemoglobinaemia. Case Rep Med. 2011. 2011:136396. [Medline].

  39. Hunter L, Gordge L, Dargan PI, Wood DM. Methaemoglobinaemia associated with the use of cocaine and volatile nitrites as recreational drugs: a review. Br J Clin Pharmacol. 2011 Jul. 72(1):18-26. [Medline].

  40. Carmona-Fonseca J, Alvarez G, Maestre A. Methemoglobinemia and adverse events in Plasmodium vivax malaria patients associated with high doses of primaquine treatment. Am J Trop Med Hyg. 2009 Feb. 80(2):188-93. [Medline].

  41. Loiseau PM, Cojean S, Schrével J. Sitamaquine as a putative antileishmanial drug candidate: from the mechanism of action to the risk of drug resistance. Parasite. 2011 May. 18(2):115-9. [Medline].

  42. Kunos CA, Radivoyevitch T, Ingalls ST, Hoppel CL. Management of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone-induced methemoglobinemia. Future Oncol. 2012 Feb. 8(2):145-50. [Medline]. [Full Text].

  43. Fung HT, Lai CH, Wong OF, Lam KK, Kam CW. Two cases of methemoglobinemia following zopiclone ingestion. Clin Toxicol (Phila). 2008 Feb. 46(2):167-70. [Medline].

  44. Park JS, Kim H, Lee SW, Min JH. Successful treatment of methemoglobinemia and acute renal failure after indoxacarb poisoning. Clin Toxicol (Phila). 2011 Oct. 49(8):744-6. [Medline].

  45. Mostafazadeh B, Pajoumand A, Farzaneh E, Aghabiklooei A, Rasouli MR. Blood levels of methemoglobin in patients with aluminum phosphide poisoning and its correlation with patient's outcome. J Med Toxicol. 2011 Mar. 7(1):40-3. [Medline].

  46. 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 Jul. 75(1):83-6. [Medline].

  47. Grossmann J, Neuwald S, Wiese B. [Acute respiratory failure after metoclopramide for methemoglobinemia - a rare and potentially life-threatening side effect]. Z Gastroenterol. 2012 Jun. 50(6):585-8. [Medline].

  48. Vallurupalli S, Das S, Manchanda S. Infection and the Risk of Topical Anesthetic Induced Clinically Significant Methemoglobinemia after Transesophageal Echocardiography. Echocardiography. 2009 Aug 31. [Medline].

  49. Jiminez MA, Polena S, Coplan NL, Patel K, Gintautas J. Methemoglobinemia and transesophageal echo. Proc West Pharmacol Soc. 2007. 50:134-5. [Medline].

  50. Esbenshade AJ, Ho RH, Shintani A, Zhao Z, Smith LA, Friedman DL. Dapsone-induced methemoglobinemia: a dose-related occurrence?. Cancer. 2011 Aug 1. 117(15):3485-92. [Medline].

  51. Rechetzki KF, Henneberg R, da Silva PH, do Nascimento AJ. Reference values for methemoglobin concentrations in children. Rev Bras Hematol Hemoter. 2012. 34(1):14-6. [Medline]. [Full Text].

  52. Lavezzi AM, Mohorovic L, Alfonsi G, Corna MF, Matturri L. Brain iron accumulation in unexplained fetal and infant death victims with smoker mothers--the possible involvement of maternal methemoglobinemia. BMC Pediatr. 2011 Jul 6. 11:62. [Medline]. [Full Text].

  53. Yano SS, Danish EH, Hsia YE. Transient methemoglobinemia with acidosis in infants. J Pediatr. 1982 Mar. 100(3):415-8. [Medline].

  54. Chaurasia S, Ramappa M, Bhargava A. Corneal epitheliopathy in congenital methemoglobinemia. Cornea. 2014 Apr. 33(4):422-4. [Medline].

  55. Yusim Y, Livingstone D, Sidi A. Blue dyes, blue people: the systemic effects of blue dyes when administered via different routes. J Clin Anesth. 2007 Jun. 19(4):315-21. [Medline].

  56. Zaki SA, Jadhav A, Chandane P. Methaemoglobinaemia during Holi festival. Ann Trop Paediatr. 2009 Sep. 29(3):221-3. [Medline].

  57. Kohli-Kumar M, Zwerdling T, Rucknagel DL. Hemoglobin F-Cincinnati, alpha 2G gamma 2 41(C7) Phe-->Ser in a newborn with cyanosis. Am J Hematol. 1995 May. 49(1):43-7. [Medline].

  58. US Food and Drug Administration. FDA Drug Safety Communication: Serious CNS reactions possible when methylene blue is given to patients taking certain psychiatric medications. Available at http://www.fda.gov/Drugs/DrugSafety/ucm263190.htm. Accessed: December 23, 2015.

  59. Martinez A, Sanchez-Valverde F, Gil F, Clerigué N, Aznal E, Etayo V, et al. 78 Cases Of Methemoglobinemia Induced By Vegetable Intake In Infants In North Spain. A Case-Control Study. J Pediatr Gastroenterol Nutr. 2013 Jan 1. [Medline].

  60. Bergamaschi MM, Alcantara GK, Valério DA, Queiroz RH. Curcumin could prevent methemoglobinemia induced by dapsone in rats. Food Chem Toxicol. 2011 Jul. 49(7):1638-41. [Medline].

 
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Note chocolate brown color of methemoglobinemia. In tubes 1 and 2, methemoglobin fraction is 70%; in tube 3, 20%; and in tube 4, normal.
 
 
 
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