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 methemoglobin is more common and is more likely to be severe and life threatening.
Hereditary methemoglobinemia is a consequence of cytochrome b5 reductase deficiency, or the presence of one of a number of abnormal hemoglobin variants termed Hemoglobin M. Deficiency of the reduced nicotinamide adenine dinucleotidephosphate (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 10–50% range. Despite these high values, these patients are often asymptomatic unless exposed to an oxidant stress. Heterozygous individuals 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 ferric (Fe+3) to the ferrous (Fe+2) state. These disorders are autosomal dominant and present early in life. These patients are cyanotic with methemoglobin percentages in the 25–30% range. There is no effective therapy. Only individuals who have the heterozygous form of the hemoglobin variant are known, as having the homozygous variant is not compatible with life.1,6,7
Acquired methemoglobinemia occurs when an individual is exposed to a heterogeneous group of drugs and chemicals that have the ability to overcome endogenous anti-oxidant 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.3,7
Agents that can produce methemoglobinemia are numerous (Table 128-1). 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.1,5,6,8 Because of the significant risk of methemoglobinemia, benzocaine and prilocaine should be avoided in the young child.9 Benzocaine-containing teething gels are particularly prone to produce methemoglobinemia because the transmucosal absorption from the oral cavity bypasses first-pass hepatic metabolism.10 Dapsone has been implicated in methemoglobinemia in both overdose and during therapeutic dosing.5,11,12
TABLE 128-1Acquired Causes of Methemoglobinemia
A relatively common, but less understood form of acquired methemoglobinemia occurs in very young infants with diarrhea. While acidosisor sepsis is usually present, significant methemoglobinemia may occur without either. The mechanism is not understood. Contributing factors likely include lower levels of cytochrome b5 reductase and that fetal hemoglobin is more easily oxidized to methemoglobin than adult hemoglobin.2,13