Methemoglobinemia

By Ilene B. Anderson, PharmD; and Susan Y. Kim, PharmD

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Hereditary and Acquired Methemoglobinemia

Mhgb can be divided into two broad categories: hereditary and acquired. Often, a combination of both factors is involved in the clinical presentation of Mhgb. A number of congenital disorders within the erythrocyte can result in Mhgb, which can be present at birth or be elicited after exposure to an oxidizing agent.⁶ Hereditary disorders responsible for Mhgb are listed in Table 1.

Table 1ÑHereditary Causes of Methemoglobinemia

Cause	Comments
Cytochrome b5 deficiency
NADH-cytochrome b5 reductase (also known as NADH-methemoglobin reductase) deficiency	An autosomal recessive condition that usually only manifests itself in the ÒhomozygousÓ state (or double heterozygous state of inherited mutancy from each parent). There are several types within this group.
Type I: enzyme deficiency only in RBCs	Most common category. Often asymptomatic, except for cyanosis, although it can manifest as fatigue, restlessness, headache.
Type II: enzyme deficiency in multiple cell types, including liver and brain	Associated with severe mental retardation and other neurologic abnormalities.
Type III: enzyme deficiency in RBCs, WBCs, and platelets	Not associated with neurologic manifestations.
Hemoglobin M	Autosomal dominant condition due to faulty amino acid substitution (usually tyrosine for histidine) in α or β subunit. The substituted amino acid forms a complex with the heme iron, stabilizing it in the oxidized state. This condition is associated with cyanosis from birth or within a few months of life. Patients are cyanotic but otherwise asymptomatic.
Unstable hemoglobin	Patients with this disorder have unusual susceptibility to oxidizing agents. However, Mhgb is usually not an important clinical problem but hemolysis is.

Acquired Mhgb is more common by far than congenital forms. Acquired Mhgb occurs from exposure to oxidizing agents, which can include many widely used drugs and chemicals. Exposure to these agents can occur by ingestion, by inhalation, and through absorption across skin and mucous membranes. Although certain agents (such as dapsone) produce Mhgb in a predictable dose-related fashion, other scenarios, such as Mhgb related to topical anesthetic administration, appear to have an idiosyncratic component with poorly characterized susceptibility factors. Patients with the enzymatic deficiencies are more susceptible to oxidant stresses at lower levels of exposure. Often, patients are diagnosed with an enzymatic disorder only after exposure to an oxidizer results in Mhgb. Finally, in some scenarios the precise mediators of oxidant stress or methemoglobin homeostasis disruption remain unclear, eg, in the well-described syndrome of acute illness-associated Mhgb in children and infants.

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