eMedicine Specialties > Hematology > Red Blood Cells and Disorders

Methemoglobinemia: Differential Diagnoses & Workup

Author: Mary Denshaw-Burke, MD, FACP, Assistant Clinical Professor, Institute for Medical Research, Program Director of Hematology/Oncology Fellowship, Education Coordinator for Oncology, Lankenau Hospital; Consulting Staff, Roxborough Memorial Hospital
Coauthor(s): Deric C Savior, MD, Fellow in Hematology/Oncology, Lankenau Hospital; John Schoffstall, MD, Associate Professor, Department of Emergency Medicine, Medical College of Pennsylvania
Contributor Information and Disclosures

Updated: Oct 4, 2009

Differential Diagnoses

Other Problems to Be Considered

The initial differential diagnosis of a patient presenting with methemoglobinemia is large. Any disease process that causes symptoms consistent with decreased oxygen delivery to the tissues can mimic methemoglobinemia. Such diseases include heart disease, lung disease, anemia, or any severe infection; however, the hallmark of methemoglobinemia is cyanosis that is unresponsive to high-flow oxygen in the absence of cardiac or pulmonary disorders.

Once these findings are elicited, the differential diagnosis narrows significantly. Aside from methemoglobinemia, only sulfhemoglobinemia, skin contamination with dye, or methylene blue should cause cyanosis that is completely unresponsive to oxygen.

  • Sulfhemoglobinemia is a disease entity that causes cyanosis at extremely low levels, is extremely rare, and only can be cured by removal of the offending agent.
  • Skin contamination can occur with any blue dye and can mimic the asymptomatic cyanotic state of mild methemoglobinemia.24,25
  • 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.
  • Argyria due to excessive exposure to silver compounds can mimic methemoglobinemia.

Workup

Laboratory Studies

  • Bedside test: To distinguish between deoxyhemoglobin and methemoglobin, place 1 or 2 drops of the patient's blood on a white filter paper. Deoxyhemoglobin brightens after exposure to atmospheric oxygen, but methemoglobin does not change color. Blowing oxygen on the filter paper speeds the reaction.
  • The limitation of arterial blood gas (ABG) is that methemoglobin can falsely elevate the calculated oxygen saturation. One possible clue to the diagnosis of methemoglobinemia is the presence of a "saturation gap." This occurs when there is a difference between the oxygen saturation measured on pulse oximetry and the oxygen saturation calculated on ABG results.
  • Pulse oximetry: Findings on bedside pulse oximetry are misleading. This device only measures the relative absorbance of 2 wavelengths of light to differentiate oxyhemoglobin from deoxyhemoglobin; however, methemoglobin absorbs both of these wavelengths equally. Therefore, at high levels of methemoglobin, the pulse oximeter reads a saturation of 85%, which corresponds to equal absorbance of both wavelengths. This is an inaccurate depiction of the hemoglobin oxygen-carrying capacity. Also important to note is that the partial pressure of oxygen (pO2) value on the ABG finding reflects plasma oxygen content, does not correspond to the oxygen-carrying capacity of hemoglobin, and should be within the reference range in patients with methemoglobinemia.
  • Co-oximetry: The co-oximeter is an accurate device for measuring methemoglobin and is the key to diagnosing methemoglobinemia. It is a simplified spectrophotometer that can measure the relative absorbance of 4 different wavelengths of light and, therefore, can differentiate methemoglobin from carboxyhemoglobin, oxyhemoglobin, and deoxyhemoglobin. Newer machines also can measure sulfhemoglobin, which can be confused with methemoglobin by co-oximetry. Unfortunately, not all clinical laboratories have these machines. Lipemic specimens may result in a falsely elevated methemoglobin level. The presence of methylene blue interferes with the accurate measurement of methemoglobin by co-oximetry. Therefore, this method cannot be used to monitor methemoglobin levels following treatment with methylene blue. Blood substitutes can also cause unreliable results.
  • Potassium cyanide test: This test can distinguish between methemoglobin and sulfhemoglobin. Methemoglobin reacts with cyanide to form cyanomethemoglobin, which has a bright red color. Sulfhemoglobin does not react with cyanide and therefore does not change to a bright red color.
  • Tests to rule out hemolysis (eg, complete blood cell [CBC] count, reticulocyte counts, lactate dehydrogenase [LDH], indirect bilirubin, haptoglobin) and to test for organ failure and general end-organ dysfunction (eg, liver function tests, electrolytes, blood urea nitrogen [BUN], creatinine) should be performed. In selected cases, a Heinz body preparation may be helpful to further evaluate hemolysis. On routine analysis, an acidic urine may appear reddish brown in color. A review of the peripheral blood smear may show evidence of bite cells (abnormal red blood cells). These bite cells are the result of removal of oxidized hemoglobin by the spleen.
  • Tests to evaluate a hereditary cause for methemoglobinemia should be ordered when appropriate. Hemoglobin M can often be diagnosed by hemoglobin electrophoresis. However, some difficult cases require more sophisticated techniques such as DNA sequencing of the globin chain gene or mass spectrometry for diagnosis. NADH-dependent methemoglobin reductase deficiencies are diagnosed by specific enzyme assays. If possible, these levels should be measured in multiple cell lines (ie, platelets, granulocytes, and fibroblasts). Type I cytochrome b5 reductase deficiency is found only in red blood cells. Type II cytochrome b5 reductase deficiency is found in multiple cell lines. These enzyme assays may have to be performed in a specialized research laboratory.

More on Methemoglobinemia

Overview: Methemoglobinemia
Differential Diagnoses & Workup: Methemoglobinemia
Treatment & Medication: Methemoglobinemia
Follow-up: Methemoglobinemia
References
Further Reading
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References

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Further Reading

Related eMedicine Topics

Clinical Trial
 Clinical Guideline

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Keywords

methemoglobinemia, cyanosis, methemoglobin, metHb, hemoglobin M, Hb M, NADH-metHb reductase deficiencies, acquired methemoglobinemia, enterogenous methemoglobinemia, secondary methemoglobinemia, congenital methemoglobinemia, hereditary methemoglobinemia, hereditary methemoglobinemic cyanosis, primary methemoglobinemia, cytochrome b5 reductase deficiency, cyt b5R

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Contributor Information and Disclosures

Author

Mary Denshaw-Burke, MD, FACP, Assistant Clinical Professor, Institute for Medical Research, Program Director of Hematology/Oncology Fellowship, Education Coordinator for Oncology, Lankenau Hospital; Consulting Staff, Roxborough Memorial Hospital
Mary Denshaw-Burke, MD, FACP is a member of the following medical societies: American College of Physicians and Pennsylvania Medical Society
Disclosure: Nothing to disclose.

Coauthor(s)

Deric C Savior, MD, Fellow in Hematology/Oncology, Lankenau Hospital
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.

Medical Editor

Paul Schick, MD, Emeritus Professor, Department of Internal Medicine, Thomas Jefferson University Medical College; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital, Wynnewood, PA
Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Hematology, International Society on Thrombosis and Haemostasis, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Marcel E Conrad, MD, (Retired) Distinguished Professor of Medicine, University of South Alabama
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: No financial interests None None

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
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