Methemoglobinemias

Oxidation of the heme iron in hemoglobin from Fe²⁺ to Fe³⁺ produces methemoglobin, which cannot bind O₂. This oxidation may be acquired and caused by the action of certain drugs, such as nitrates, or endogenous products such as reactive oxygen species . The oxidation may also result from congenital defects, for example, a deficiency of NADHcytochrome b₅ reductase (also called NADH-methemoglobin reductase), the enzyme responsible for the conversion of methemoglobin (Fe³⁺) to hemoglobin (Fe²⁺), leads to the accumulation of methemoglobin (Fig.1). [Note: The RBC of newborns have approximately half the capacity of those of adults to reduce methemoglobin.] Additionally, rare mutations in the α- or β-globin chain can cause the production of HbM, an abnormal hemoglobin that is resistant to the reductase. The methemoglobinemias are characterized by “chocolate cyanosis” (a blue coloration of the skin and mucous membranes and brown-colored blood) as a result of the darkcolored methemoglobin. Symptoms are related to the degree of tissue hypoxia and include anxiety, headache, and dyspnea. In rare cases, coma and death can occur. Treatment is with methylene blue, which is oxidized as Fe³⁺ is reduced.

Figure1: Formation of methemoglobin and its reduction to hemoglobin by NADH-cytochrome b₅ reductase.