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Methemoglobinemia

By Ilene B. Anderson, PharmD; and Susan Y. Kim, PharmD

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Pathophysiology

Hemoglobin is a complex comprised of four polypeptide chains, each with an embedded iron atom. This configuration serves to protect the ferrous (Fe2+) iron from oxidation. Hemoglobin is capable of transporting oxygen and carbon dioxide only when the hemoglobin is in the ferrous (Fe2+) state. During transport, the ferrous iron forms a reversible complex with the oxygen atom by temporarily donating one electron to the oxygen atom. Once the hemoglobin molecule releases the oxygen atom, the iron atom retrieves its electron, maintaining its normal reduced ferrous state. Thus it is again available to transport oxygen.

Methemoglobin is a form of hemoglobin wherein the iron atom is oxidized to the ferric (Fe3+) state. Not only is methemoglobin incapable of transporting oxygen and carbon dioxide, it also causes a left shift of the oxygen-hemoglobin dissociation curve. This compromises the ability of the remaining hemoglobin subunits on the affected molecule to release oxygen to tissues, thus further exacerbating tissue hypoxia.1

Normally, approximately 1% methemoglobin is present in the body due to endogenous oxidation of the iron atom to the Fe3+ state. This may occur as a result of intracellular hydrogen peroxide formation, other free radical formation, or, rarely, when the iron atom spontaneously retains the oxygen atom during its release from hemoglobin.

Several intracellular mechanisms exist to maintain a low level (1%) of methemoglobin under normal conditions. The primary mechanism utilizes nicotinamide-adenine dinucleotide (NADH), cytochrome, b5and cytochrome b5 reductase. This NADH pathway is predominant in normal homeostasis.2 Another mechanism utilizes reduced glutathione and ascorbic acid (vitamin C) as electron donors converting methemoglobin to hemoglobin. This mechanism accounts for only a small amount of regenerated hemoglobin. Because it is a slow process and a minor pathway, it is of little value in the context of clinically significant Mhgb. The last mechanism is normally dormant in the body and is only functional with the exogenous addition of methylene blue or some other substrate acting as an electron carrier. This enzymatic pathway utilizes the reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH) and NADPH methemoglobin reductase to convert methylene blue to leukomethylene blue. Leukomethylene blue reduces methemoglobin to hemoglobin.3

Mhgb and hemolysis both occur as a result of oxidant stress. They can be interrelated, but differ in several key respects. Mhgb is a reversible phenomenon that occurs as a result of an oxidant stress solely on the iron atom in hemoglobin. Hemolysis is an irreversible event that occurs as a result of an oxidant stress compromising the erythrocyte membrane, either directly or secondarily through hemoglobin precipitates (Heinz bodies). By these linked mechanisms, potent oxidants can cause both severe Mhgb and concomitant RBC hemolysis, although both processes need not occur together. There are numerous reports of hemolysis following methemoglobin formation after exposure to aniline dyes, phenazopyridine, nitrites, and dapsone. These morbidities are most likely to occur simultaneously when the intracellular antioxidant mechanisms have been exhausted (i>eg, glutathione, ascorbic acid, NADH, or NADPH depletion).4 Because of the potential role of NADPH depletion in this process, combined Mhgb and NADPH compromise (most importantly through NADPH-reductase deficiency) is a particular risk factor for hemolysis.

Sulfhemoglobin is another dyshemoglobin that is closely related to methemoglobin. This dyshemoglobin occurs when a sulfur atom is incorporated into the porphyrin ring of the hemoglobin moiety. First, hemoglobin is oxidized to methemoglobin, then the sulfur atom is covalently bound to the heme moiety. Like methemoglobin, sulfhemoglobin is incapable of transporting oxygen and carbon dioxide. In contrast to Mhgb, sulfhemoglobinemia causes a right shift of the oxygen-hemoglobin dissociation curve. Therefore, the remaining hemoglobin more readily releases oxygen atoms to oxygenate tissues. It may be for this reason that patients suffering from sulfhemoglobinemia are not typically as symptomatic as those suffering from an equivalent degree of Mhgb.5 Unlike Mhgb, however, sulfhemoglobinemia is not reversible.

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