Methemoglobinemia occurs when the ferrous (Fe⁺²) iron of hemoglobin is oxidized to the ferric (Fe⁺³) state. The amount in the blood is expressed as a percentage of the total hemoglobin. Because of its decreased affinity for oxygen, hypoxia and a shift of the oxygen dissociation curve to the left results.^1–3 Methemoglobinemia may be hereditary or acquired; the former is usually milder, occurs early in life, and may be relatively asymptomatic. The acquired form is often more severe and secondary to a diverse group of chemicals and drugs. The classic presentation of methemoglobinemia is cyanosis unresponsive to 100% oxygen.^1–3

The iron of hemoglobin is Fe⁺², which is capable of carrying oxygen. Under normal conditions, there is background oxidative stress which converts small amounts of the ferrous ion to the Fe⁺³, state resulting in the formation of small amounts of methemoglobin, which is incapable of carrying oxygen. However, the body has protective mechanisms to reverse the process.^1–4

The major protective process occurs via the cytochrome b5 methemoglobin reductase system. This two-enzyme process accounts for 99% of the methemoglobin reduction. This is the nicotinamide adenine dinucleotide + hydrogen (NADH) methemoglobin reductase in older literature.^1–3 Another enzyme that can reduce methemoglobin is reduced nicotinamide adenine dinucleotidephosphate (NADPH)-methemoglobin reductase. This system has negligible activity in normal conditions. However, it has an affinity for dyes such as methylene blue and likely plays a role in metabolizing oxidant xenobiotics.² Ascorbic acid and glutathione may also play a role in reducing small amounts of methemoglobin.²

Normally, only 1% of hemoglobin is methemoglobin at any time.^2–5 However, if significant oxidative stress is present, these protective systems may be overwhelmed, resulting in significant methemoglobinemia.

Methemoglobinemia may be either hereditary or acquired. The former is uncommon, presents very early, often in the first hours or days of life, and may be misdiagnosed as congenital cyanotic heart disease. Acquired methemoglobinemia is more common and is more likely to be severe and life threatening.

Hereditary methemoglobinemia is due to either cytochrome b5 reductase deficiency or the presence of one of a number of abnormal hemoglobin variants termed hemoglobin M.⁵ Deficiency of the reduced NADPH-methemoglobin reductase also occurs, but these patients do not manifest methemoglobinemia, as this pathway normally plays a very minor role in methemoglobin reduction.^1,2

Patients with cytochrome b5 reductase deficiency may be either homozygous or heterozygous. The former have little or no enzyme activity and rely on other endogenous pathways to reduce methemoglobin. They often have significant percentages of methemoglobin, in the 10% to 50% range. Despite these high values, these patients are often asymptomatic unless exposed to an oxidant stress. Heterozygous individuals, on the other hand, usually have insignificant methemoglobin percentages.^1,2

Hemoglobin M refers to a number of abnormal hemoglobin variants that are resistant to the normal erythrocyte mechanisms that reduce the Fe⁺³ ion to the Fe⁺² state. These disorders are autosomal dominant and present early in life. Afflicted individuals are cyanotic, with methemoglobin percentages in the 25% to 30% range. There is no effective therapy. Only those with the heterozygous form of the hemoglobin variant are known, as having the homozygous variant is not compatible with life.^1,5,7,8

Acquired methemoglobinemia occurs when an individual is exposed to a heterogeneous group of drugs and chemicals that have the ability to overcome endogenous antioxidant mechanisms, resulting in the oxidation of hemoglobin to methemoglobin. This may occur by direct oxidation of the hemoglobin molecule, or more commonly, indirectly by the production of free radicals which then oxidize hemoglobin to methemoglobin.^4,8

There are numerous substances that can produce methemoglobinemia (Table 129-1). However, because of variability in individual metabolism, exposures do not always result in the development of methemoglobinemia.² The most common methemoglobinemia inducers are dapsone, benzocaine, other local anesthetics, and various forms of nitrites.^1,6,7,9 Because of the significant risk of methemoglobinemia, benzocaine and prilocaine should be avoided in the young child.¹⁰ Benzocaine-containing teething gels are particularly prone to produce methemoglobinemia because the transmucosal absorption from the oral cavity bypasses first-pass hepatic metabolism.¹¹ Dapsone has been implicated in methemoglobinemia in both overdose and during therapeutic dosing.^6,12,13