Methemoglobinemia

Basics

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.

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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