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Dyshemoglobinemias are disorders in which the hemoglobin molecule is functionally altered and prevented from carrying oxygen. The most clinically relevant dyshemoglobinemias are carboxyhemoglobin, methemoglobin, and sulfhemoglobin.1 Carboxyhemoglobin is created during carbon monoxide exposure and, because of its unique importance and prevalence, is usually considered an environmental emergency (see chapter 222, "Carbon Monoxide").
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The iron moiety within deoxyhemoglobin normally exists in the ferrous (bivalent or Fe2+) state. Ferrous iron avidly interacts with compounds seeking electrons, such as oxygen or other oxidizing agent, and in the process is oxidized to the ferric (trivalent or Fe3+) state. Hemoglobin in the ferric form is unable to bind oxygen for transport and is termed methemoglobin. Under normal circumstances, <1% to 2% of circulating hemoglobin exists as methemoglobin; higher concentrations define the condition of methemoglobinemia.
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Methemoglobin accumulation is enzymatically prevented by the rapid reduction of the ferric iron back to the ferrous form. Cytochrome b5 reductase is primarily responsible for this reduction, in which reduced nicotinamide adenine dinucleotide donates its electrons to cytochrome b5, which subsequently reduces methemoglobin to hemoglobin (Figure 207-1). This pathway is responsible for reducing nearly 95% of methemoglobin produced under typical circumstances. Methemoglobinemia occurs when this enzymatic reduction is overwhelmed by an exogenous oxidant stress, such as a drug or chemical agent (Table 207-1).
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Methemoglobin can also be reduced by a second enzymatic pathway using the reduced form of nicotinamide adenine dinucleotide phosphate (or NADPH) and NADPH-methemoglobin reductase.2 This pathway is normally of minimal importance and is responsible for less than 5% of total reduction under typical circumstances. However, this enzyme and pathway are crucial for the antidotal effect of ...