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Methemoglobin is a metalloprotein, in which the iron in the heme group is in the Fe3+(ferric), not the Fe2+(ferrous), state of normal hemoglobin (Hb). Methemoglobinemia occurs because of either increased production of oxidized Hb due to exposure to environmental agents or diminished reduction of oxidized Hb because of underlying germline mutations. Cyanosis occurs when methemoglobin exceeds 15g/L; in comparison, cyanosis is discernible with deoxyhemoglobin at 40g/L and sulfhemoglobin at 5g/L. Hb can also bind carbon monoxide and nitric oxide, resulting in the formation of carboxyhemoglobin and nitrosohemoglobin. Sulfhemoglobinemia occurs because of occupational exposure to sulfa compounds or exposure to oxidants. These modified Hbs are known as dyshemoglobins. Depending on the severity, the presence of dyshemoglobins can result in varying degree of clinical manifestations. Prompt diagnosis is the key to the specific treatment.

Acronyms and Abbreviations

AOP2, antioxidant protein 2; 2,3-BPG, 2,3-bisphosphoglycerate; cytochrome b5R, cytochrome b5 reductase; CO, carbon monoxide; COHb, carboxyhemoglobin; cGMP, cyclic guanosine monophosphate; ETCO, end-tidal CO; GSH, reduced glutathione; iNO, inhaled nitric oxide; M, hemoglobins; those hemoglobin mutants associated with methemoglobinemia; NADH, nicotine-amide adenine dinucleotide (reduced form); N2O3, dinitrogen trioxide; NADPH, reduced nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; NOS, nitric oxide synthase; p50, the oxygen tension at which hemoglobin is 50% saturated; pO2, partial pressure of oxygen; RBC, red blood cells, SNO-Hb, S-nitroso hemoglobin, SpO2, arterial oxygen saturation; SpCO, arterial COHb concentration; SpMet, arterial methemoglobin concentration.



A bluish discoloration of the skin and mucous membrane, designated cyanosis, has been recognized since antiquity as a manifestation of lung or heart disease; however, in methemoglobinemia and sulfhemoglobinemia, it has a different molecular basis than hemoglobin (Hb) oxygen desaturation. Cyanosis resulting from drug administration has also been recognized since before 1890. Toxic methemoglobinemia occurs when various drugs or toxic substances either oxidize Hb directly in the circulation or facilitate its oxidation by molecular oxygen.1

In 1912, Sloss and Wybauw2 reported a case of a patient with idiopathic methemoglobinemia. Later, Hitzenberger3 suggested that a hereditary form of methemoglobinemia might exist, and subsequently, numerous such cases were reported.4 In 1948, Hörlein and Weber5 described a family in which eight members over four generations had cyanosis. The absorption spectrum of methemoglobin was abnormal, and the authors demonstrated that the defect must reside in the globin portion of the molecule. Subsequently, Singer6 proposed the abnormal Hbs associated with methemoglobinemia be given the designation Hb M. The cause of another form of methemoglobinemia that occurs independently of drug administration and without the existence of any abnormality of the globin portion of Hb was first explained by Gibson,7 who clearly pointed to the nature of the enzyme defect, the reduced form of nicotinamide adenine dinucleotide (NADH) diaphorase, also designated as methemoglobin reductase and now ...

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