• Methemoglobin is dysfunctional hemoglobin in which the deoxygenated heme moiety has been oxidized from the ferrous (Fe2+) to the ferric (Fe3+) state.
  • Methemoglobinemia is an undue accumulation of methemoglobin within the blood.


  • Toxic methemoglobinemia, resulting from exposure to oxidant chemicals or drugs, is the most common cause of methemoglobinemia among children >6 months of age.
  • Enteritis-associated methemoglobinemia is the most common cause among children <6 months of age:
    • As many as 2/3 of infants with severe diarrhea have methemoglobinemia.


  • Hemoglobin in the allosteric configuration of methemoglobin cannot carry oxygen.
  • Methemoglobin increases the oxygen affinity of normal heme moieties in the blood and results in impaired oxygen delivery to tissues.
  • NADH-dependent cytochrome b5 methemoglobin reductase is the major source of physiologic reduction of methemoglobin.
  • A normally dormant NADPH-dependent methemoglobin reductase is the site of action for antidotal methylene blue therapy.


  • Toxic methemoglobinemia
    • Dietary or environmental chemicals:
      • Chlorates
      • Chromates
      • Copper sulfate fungicides
      • Naphthalene
      • Nitrates
      • Nitrites
    • Industrial chemicals: aniline and other nitrogenated organic compounds
    • Drugs (e.g., amyl nitrite, benzocaine, dapsone, metoclopramide, nitric oxide, nitroprusside, phenazopyridine, prilocaine)
    • Methemoglobinemia is a common iatrogenic complication of drug therapy.
  • Illness/enteritis-associated methemoglobinemia is multifactorial in origin:
    • Intestinal nitrate and nitric oxide promotes methemoglobin formation.
    • Innate enzymatic methemoglobin reduction systems may be underdeveloped during infancy.
    • Acidemia further inhibits enzymatic methemoglobin reduction systems.
    • Methemoglobinemia is also reported with nitrite-producing bacterial infections of the intestines or urinary tract.
  • Congenital methemoglobinemia (rare)
    • Hemoglobin M: Heterozygotes for autosomal dominant hemoglobin M will exhibit lifelong cyanosis.
    • NADH-dependent methemoglobin reductase deficiency: Homozygotes for this autosomal recessive enzyme will have lifelong cyanosis; heterozygotes may have increased susceptibility to oxidative hemoglobin injury.

Commonly Associated Conditions

  • Heinz body hemolytic anemia
    • Oxidant stress on the globin protein may cause hemolysis.
  • Sulfhemoglobinemia
    • Oxidant stress on the hemoglobin porphyrin ring may cause sulfhemoglobinemia.

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