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Normal hemoglobin can be oxidized to methemoglobin. Methemoglobinemia occurs because of either increased production of oxidized hemoglobin because of exposure to environmental agents or diminished reduction of oxidized hemoglobin because of underlying germ line mutations. Hemoglobin can also bind gases such as carbon monoxide (CO) and nitric oxide (NO), resulting in the formation of carboxyhemoglobin (COHb) and nitrosohemoglobin. Sulfhemoglobinemia only occurs because of increased production secondary to occupational exposure to sulphur compounds or exposure to oxidant medications. These modified hemoglobins, also known as dyshemoglobins, depending upon the severity and individual predisposition, can result in varying degree of clinical manifestations. Prompt diagnosis is the key to effective and timely treatment.

Acronyms and Abbreviations

Acronyms and abbreviations that appear in this chapter include: AOP2, antioxidant protein 2; 2,3-BPG, 2,3-bisphosphoglycerate; cGMP, cyclic guanosine monophosphate; cNOS, constitutive nitric oxide synthase; CO, carbon monoxide; COHb, carboxyhemoglobin; eNOS, endothelial NO synthase; GSH, reduced glutathione; Hgb, hemoglobin; iNOS, inducible nitric oxide synthase; NADH, nicotinamide adenine dinucleotide (reduced form); NADPH, nicotinamide adenine dinucleotide phosphate (reduced form); NO, nitric oxide; NOS, nitric oxide synthase; SNO-Hgb, S-nitroso hemoglobin; SpCO, arterial carboxyhemoglobin concentration; SpMet, arterial methemoglobin concentration; SpO2, arterial oxygen saturation.

Definition and History

A bluish discoloration of the skin and mucous membrane, designated cyanosis, has been recognized since antiquity as a manifestation of lung or heart disease. Cyanosis resulting from drug administration has also been recognized since before 1890.1 Toxic methemoglobinemia occurs when various drugs or toxic substances either oxidize hemoglobin directly in the circulation or facilitate its oxidation by molecular oxygen.

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 manifested cyanosis. The absorption spectrum of methemoglobin was abnormal. They demonstrated that the defect must reside in the globin portion of the molecule. Subsequently, Singer6 proposed that such abnormal hemoglobins be given the designation hemoglobin 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 hemoglobin was first explained by Gibson,7 who clearly pointed to the site of the enzyme defect, nicotinamide adenine dinucleotide (reduced form; NADH) diaphorase, also designated as methemoglobin reductase, and currently cytochrome b5 reductase. More than 50 years after Gibson’s insightful studies, the genetic disorder that he had predicted was verified at the DNA level.8

The existence of abnormal hemoglobins that cause cyanosis through quite another mechanism was first recognized in 1968 with the description of hemoglobin Kansas.9 Here the cyanosis resulted not from methemoglobin, as occurs in hemoglobin M, but rather from an abnormally low oxygen affinity of the mutant hemoglobin. Thus, at normal ...

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