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Genetics and pathogenesis of methemoglobinemia

Author
Josef T Prchal, MD
Section Editors
Stanley L Schrier, MD
Benjamin A Raby, MD, MPH
Deputy Editor
Jennifer S Tirnauer, MD

INTRODUCTION

Methemoglobinemia occurs when an imbalance due to either increased methemoglobin production or decreased methemoglobin reduction is present. Inherited and acquired processes resulting in excess methemoglobin will be described here. The diagnosis and treatment of methemoglobinemia is described separately. (See "Clinical features, diagnosis, and treatment of methemoglobinemia".)

METHEMOGLOBIN

Methemoglobin is an altered state of hemoglobin in which the ferrous (Fe++) irons of heme are oxidized to the ferric (Fe+++) state. The ferric hemes of methemoglobin are unable to bind oxygen. In addition, the oxygen affinity of any accompanying ferrous hemes in the hemoglobin tetramer is increased [1]; as a result, the oxygen dissociation curve is "left-shifted" and oxygen delivery to the tissues is impaired (figure 1). (See "Genetic disorders of hemoglobin oxygen affinity".)

Thus, the patient with increased concentrations of methemoglobin has a functional anemia, to the extent that the circulating methemoglobin-containing molecules are unable to carry oxygen, and the remaining hemoglobin, because of its increased oxygen affinity, has a decreased ability to deliver oxygen to the tissues.

Formation — During the formation of oxyhemoglobin from deoxyhemoglobin and molecular oxygen, one electron is partially transferred from heme iron to the bound oxygen, forming a ferric-superoxide anion complex (Fe3+—O2-) [2]. During deoxygenation, most of the oxygen leaves the molecule as molecular oxygen, but a small amount leaves as a superoxide (O2-) radical. Under the latter circumstance, the partially transferred electron is not returned to the iron moiety, leaving the heme iron in the ferric state (ie, methemoglobin). This autooxidation of hemoglobin occurs spontaneously at a slow rate in normal individuals, converting 0.5 to 3 percent of the available hemoglobin to methemoglobin per day [3,4].

Methemoglobin is also formed from the oxidation of hemoglobin heme iron via reactions with free radicals and endogenous compounds, including hydrogen peroxide (H2O2), nitric oxide (NO), O2-, and hydroxyl radical (OH•) [5,6]. Exogenous compounds may oxidize hemoglobin to methemoglobin directly, by means of a metabolic derivative or by generating O2- and H2O2 during their metabolism.

                         

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