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Normal hemoglobin can be oxidized to methemoglobin. Methemoglobinemia occurs because of either increased production of oxidized hemoglobin from exposure to environmental agents or diminished reduction of oxidized hemoglobin because of underlying germline mutations. Cyanosis is virtually invariant in patients with methemoglobinemia. Hemoglobin can also bind carbon monoxide and nitric oxide, resulting in the formation of carboxyhemoglobin and nitrosohemoglobin. Sulfhemoglobinemia occurs because of increased production secondary to occupational exposure to sulphur compounds or exposure to oxidant medications. These modified hemoglobins are known as dyshemoglobins. Depending upon the severity and individual predisposition, presence of dyshemoglobins can result in varying degree of clinical manifestations. Prompt diagnosis is the key to effective and timely treatment.



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 in hemoglobin oxygen desaturation. 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 (Hb) 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 had cyanosis. The absorption spectrum of methemoglobin was abnormal and 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 now known as 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

Acronyms and Abbreviations:

AOP2, antioxidant protein 2; 2,3-BPG, 2,3-bisphosphoglycerate; cGMP, cyclic guanosine monophosphate; CO, carbon monoxide; COHb, carboxyhemoglobin; GSH, reduced glutathione; N2O3, dinitrogen trioxide; NADH, nicotinamide adenine dinucleotide (reduced form); NADPH, reduced nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; NOS, nitric oxide synthase; P50, the partial pressure of oxygen at which 50 percent of the blood hemoglobin is saturated with oxygen; RBC, red blood cells; SNO-Hb, S-nitrosohemoglobin; SpCO, arterial carboxyhemoglobin concentration; SpMet, arterial methemoglobin concentration; SpO2, arterial oxygen saturation.

The existence of abnormal hemoglobins that cause cyanosis through quite another mechanism was ...

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