Methemoglobinemia refers to the clinical condition that results when more than 1% of the bloods hemoglobin has been oxidized from the usual ferrous state to the ferric form. Normally, a small amount of hemoglobin iron undergoes oxidation resulting in the production of methemoglobin. Methemoglobin is then reduced in a reaction involving reduced cytochrome b5 (RedCyt b5) back to its usual state. The regeneration of RedCyt b5 is dependent on the enzyme cytochrome b5 reductase (methemoglobin reductase). In persons who have lost the ability to reduce methemoglobin to its usual state, the level of methemoglobin increases, and once this level is greater than 1%, methemoglobinemia results. As the level of methemoglobin continues to increase to greater than 1.5 g/dL (10 % of the total hemoglobin), cyanosis becomes clinically apparent. The inability to reduce methemoglobin may result from a congenital abnormality of hemoglobin resulting in the production of M hemoglobins, a deficiency of cytochrome b5 reductase (methemoglobin reductase) or it may be an acquired disorder secondary to certain drugs or toxins.

M hemoglobins are the result of amino acid substitutions in the globulin region where heme is bound. These individuals suffer from a congenital and familial form of cyanosis that begins at or several months after birth. This disorder is inherited in an autosomal codominant manner, and cyanosis is usually the only manifestation of this disorder.

Cytochrome b5 reductase deficiency results in an inability to regenerate reduced cytochrome b5, which is needed to reduce the heme portion of methemoglobin back to the ferrous state. This enzyme deficiency is inherited in an autosomal recessive pattern. Serum assays for the level of this enzyme may be performed. Persons homozygous for this disorder have chronic cyanosis and serum methemoglobin levels over 15%. Heterozygotes manifest cyanosis that may vary in intensity and become severe if exposed to agents known to induce methemoglobinemia. Most persons have no other symptoms related to this disorder (type I disease); however, polycythemia and mental retardation (type II disease) may be associated with this condition.

Acquired methemoglobinemia results from exposure to certain substances. The susceptibility of an individual to a certain toxin or drug may be increased in persons who are heterozygous for methemoglobin reductase deficiency. Compounds known to be associated with acquired methemoglobinemia include: sodium nitrite, amyl nitrite, nitroglycerin, nitroprusside, silver nitrate, aniline dyes, acetanilid, phenacetin, sulfonamides, lidocaine, topical benzocaine, chlorate paraquat, and phenazopyridine.

Cyanosis from methemoglobinemia will resemble that seen as a result of hypoxia from heart or lung disease. Sulfhemoglobinemia is another condition which manifests as cyanosis and should also be included in the differential. When cyanosis is secondary to hypoxia, a specimen of blood will change from purple to red upon exposure to air. This will not occur in individuals with methemoglobinemia or sulfhemoglobinemia. The blood from a patient with methemoglobinemia is chocolate brown in color and remains so after exposure to air. The diagnosis may be established by measuring the methemoglobin level of an arterial blood gas specimen. A decrease in the oxyhemoglobin concentration when measured by pulse oximetry may also be noted in patients with methemoglobinemia.

Treatment is generally given for cosmetic reasons. When methemoglobinemia is the result of cytochrome b5 reductase deficiency, oral methylene blue (100-300 mg/day) or ascorbic acid (300-500 mg/day) will serve to decrease the level of methemoglobin and reverse cyanosis. Acute toxic methemoglobinemia should be treated emergently with intravenous methylene blue (1% solution) in doses of 0.1 to 0.2 mL/kg over 5 minutes. Methemoglobinemia becomes emergent when the level exceeds 50% of the total circulating hemoglobin because methemoglobin cannot transport oxygen.