What every physician needs to know about methemoglobinemia:

Methemoglobinemia is a condition in which the oxidation/reduction state of hemoglobin iron is pathologically altered, as described below. It can result from rare congenital abnormalities in the redox system of the red cell, or from toxic oxygen exposure. Those exposures, if of sufficient magnitude, can be life threatening. A methemoglobin level above 15 to 30% is thus one of a handful of true hematologic medical emergencies.

The iron residue within each heme group of normal hemoglobin molecules is in the reduced or ferrous (Fe++). Methemoglobin is hemoglobin in which those iron residues have been oxidized to the ferric (Fe++) state. Small amounts of methemoglobin are generated daily as a result of the normal oxygenation-deoxygenation cycle of hemoglobin, and of the exposure to red cells to oxide stress in the circulation. Acquired increases in methemoglobin levels are almost always due to toxic exposures. Methemoglobin is a poor transporter of oxygen. Thus, when present in amounts of about 15 to 20%, oxygen delivered to tissues is frequently compromised, despite an arterial pO2 level (partial pressure of oxygen in the blood).

Methemoglobin has a bluish/brownish slate color. When present as a sufficiently high percentage of total hemoglobin, patients exhibit an appearance roughly like that of cyanosis. In contrast to true cyanosis, methemoglobinemia is usually associated with a normal arterial pO2 (except in patients so severely poisoned that they are suffering respiratory compromise). Methemoglobinemia should thus be suspected in cyanotic appearing patients, who do not manifest other signs or symptoms of true cyanosis, or have a higher than expected pO2 for the clinical circumstances.

There are two basic etiologies of methemoglobinemia:

  • Congenital abnormality in hemoglobin or the enzymatic system in red cells that reduces methemoglobin to hemoglobin:

- M Hemoglobins: mutant forms of hemoglobin that have amino acid substitutions rendering the iron moiety resistant to reduction back to the reduced (ferrous) state.

- Cytochrome b5 reductate deficiency or cytochrome b3 deficiency: These enzyme systems, especially cytochrome b5, reduce methemoglobin to hemoglobin.

  • Acquired methemoglobinemia

Due to toxic exposure of compounds tending to oxidize hemoglobin iron. Inorganic nitrates and nitrites are particularly notorious, as are organic compounds containing nitrous or nitrate residues. Certain antimalarials, analine dyes, lidocaine and related local anesthetics, certain quinones, naphthalene, phenylhydramine and resorcinol are notorious. The increasing use of nitrous or nitric residue containing medications, especially in surgical and intensive care settings, can produce non-trivial amounts of methemoglobinemia.

M hemoglobins and congenital methemoglobin reductase deficiencies are quite rare. Patients may have striking pseudocyanosis, but rarely require therapeutic intervention, except, perhaps, for cosmetic reasons.

Diagnosis is usually suspected on the basis of history or physical in an individual with cyanosis out of proportion to arterial hypoxia or other etiologies of cyanosis, such as congenital heart disease, etcetera. Any suspicion of methemoglobinemia should prompt a request for laboratory measurement of the percent of methemoglobin in the blood. This spectroscopic test that is readily available in most laboratories on an emergent basis. A thorough history should be taken, searching for evidence of toxic exposure. Medical and laboratory personnel who have access to these compounds are at particular risk for methemoglobinemia in the form of inadvertent ingestion or sometimes as a suicide gesture.

Methemoglobin levels above 30% of total hemoglobin can produce life threatening tissue hypoxia and present with CNS (central nervous system) symptoms, coma, respiratory depression, and cardiovascular compromise. This is a true medical emergency that needs to be treated rapidly with methylene blue, as described below. Patients with lesser levels of toxic exposure can present with typical symptoms of acute hypoxia, confusion, dizziness, somnolence, and the appearance of cyanosis.

What features of the presentation will guide me toward possible causes and next treatment steps:

As noted above, signs and symptoms of tissue hypoxia such as confusion, dizziness, somnolence, coma, etcetera, especially if there is nothing else about the clinical setting that points to other causes of hypoxia. Presence of a slate bluish/brownish color resembling cyanosis on the extremities, lips, and mucous membranes, especially if arterial pO2 is higher than would be expected on the basis of this physical finding.

Any historical evidence suggesting exposure to oxidizing compounds such as nitrates, nitrites, antimalarials, nitrates in well water, etcetera. In hospitalized patients, any recent exposure to nitrous or nitrix containing medication.

Presentation at early stages of life, especially in patients with dramatic pseudocyanosis, but no other signs of clinical distress should lead to consideration of a congenital form of methemoglobinemia.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Laboratory spectroscopic analysis for methemoglobin. This test may not yield interpretable results in patients who have glucose-6-phosphate dehydrogenase (G6PD) deficiency. Individuals known to have this condition require special laboratory testing. The laboratory should be alerted to this situation.

What conditions can underlie methemoglobinemia:

As noted above, for acquired methemoglobinemia, exposure to medications or toxic compounds that oxidize hemoglobin iron such as nitrates, nitrites, certain antimalerials, well water (that is rich in nitrates), etcetera .

Congenital methemoglobinemia: Inheritance of an M-hemoglobin or a defect in the methemoglobin reductate enzyme system.

When do you need to get more aggressive tests:

The simple laboratory test for methemoglobin is readily available and is usually all there is needed. In patients with G6PD deficiency, additional analysis will be needed. Arterial blood gases or pulse oximetry will be needed to corroborate the diagnosis.

What imaging studies (if any) will be helpful?

No specific imaging studies. However, in milder cases, routine radiologic studies to rule out other causes of cyanosis or hypoxia may be useful.

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

If the patient presents in critical condition with cardiopulmonary distress or coma and cyanosis, and methemoglobinemia is suspected, treatment should be initiated emergently with intravenous methylene blue, 1 to 2mg/kg in a 1% solution in saline. It is usually infused rapidly over about 5 minutes. Oral methylene blue, 100 to 300mg/day or 500mg/day of oral ascorbic acid can be used for milder cases or for follow-up therapy once the acute crisis has been resolved. Oral therapy is also used infrequently to correct the cosmetic complications of congenital methemoglobinemia.

Methemoglobin levels of less than 20% (with no clinical compromise) can usually be managed by observation alone for 1 to 2 days, provided that clear evidence is available that exposure to the toxic substance has been terminated.

Methylene blue works through the methemoglobin reductate system. It is thus ineffective in patients with cytochrome b5 deficiency or congenital methemoglobin reductase deficiency. In these cases, ascorbic acid or riboflavin are alternatives for mild-moderate cases and follow-up therapy. However, exchange transfusion may be the only option for emergent treatment.

What other therapies are helpful for reducing complications?


What should you tell the patient and the family about prognosis?

Toxic exposures to methemoglobin, if weathered without permanent cardiovascular or central nervous system damage, have an excellent prognosis. Follow-up should be provided if there is any concern that exposure is a form of suicide attempt, in which case the prognosis would depend on the underlying neuropsychiatric disorder.

Congenital methemoglobinemias usually have a good long term prognosis, although cosmetic issues due to pseudocyanosis are a concern.

Management by an experienced hematologist who is familiar with enzyme defects or hemoglobin defects in the red cell, is recommended.

“What if” scenarios.

The most common pitfall associated with the diagnosis of methemoglobinemia is failure to consider it in patients with apparent cyanosis and/or symptoms of tissue hypoxia. One should also make an effort to rule out G6PD deficiency, particularly in African-American males, who are the most common group experiencing this disorder. However, G6PD defects occur in all populations, especially in individuals with Mediterranean, Asian and near and Middle Eastern relations.


Please see "What every physician needs to know about methemoglobinemia".

The final common pathway of all methemoglobinemias, is oxidation of the iron within the hemoglobin molecule to the ferric state. This is the basis of methemoglobin generation, regardless of whether it arises from oxidative toxins, inadequacy of the hemoglobin anti-oxidant enzyme system on the red cell, or abnormal structures of the globin chains, that fails to protect the Fe moiety from oxidation.

What other clinical manifestations may help me to diagnose methemoglobinemia?

Please see "What every physician needs to know about methemoglobinemia".

The cardinal symptoms are the appearance of a slate grey (pseudocyanosis) complexion and symptoms of tissue hypoxia, such as confusion, drowsiness, dizziness, or coma.

What other additional laboratory studies may be ordered?

Methemoglobin level and arterial blood gases.

What’s the evidence?

Benz, EJ, Hoffman, R, Benz, E, Shattil, S. "Hemoglobin Variants associated with Hemolytic Anemia, Altered Oxygen Affinity, and Methemoglobinemia". Hematology: Principles and Practice. Elsevier. 2005. pp. 645-653.

[This chapter puts methemoglobinemia in the context of the inherited and acquired abnormalities of hemoglobin and describes the diagnosis and practical approaches to treatment.]

Gregg, XT, Prchal, JT, Hoffman, R, Benz, E, Shattil, S. "Red Cell Enzymopathies". Hematology: Principles and Practice. Elsevier. 2005. pp. 653-659.

[This chapter provides a great description of inherited metabolic defects that can cause methemoglobinemia and provides practical approaches to management.]
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