Causes of methaemoglobinaemia

Methaemoglobinaemia can be innate (e.g. a genetic deficiency of enzymes involved in reduction pathways or altered haemoglobin structure) or acquired (e.g. exposure to toxins that increase oxidation reactions). Some cases are idiopathic [1].

Table 1: Causes of methaemoglobinaemia

Cause Notes
Acquired Toxins
Diet Historically well water contaminated by fertiliser was a common cause
Endogenous states of increased oxidative stress E.g. Sepsis
Metabolic acidosis? There is an association between methaemoglobinaemia and metabolic acidosis due to dehydration in young children with diarrhoea and vomiting. This is thought to be due to reduced action of cytochrome-b5-reductase in acidic conditions [3].
Innate Cytochrome-b5-reductase deficiency Loss of protective mechanism
  Pyruvate kinase deficiency Reduced NADH production. NADH is a cofactor for cytochrome-b5-reductase
  Haemoglobinopathy (HbM) Genetic mutation replaces a histidine residue with a tyrosine residue which alters the structure of the globin proteins and limits the ability of reducing enzymes to access Fe3+

In adults or older children with no previous history of methaemoglobinaemia, the most common cause is exposure to a toxin. The toxins may act directly as oxidising agents or indirectly by producing oxygen and peroxide free radicals which in turn oxidise Fe2+. The effect is variable depending on dose, timing of exposure and variability in metabolism between individuals.

Many, many, many, many toxins are implicated

The list of causative toxins reported in the literature is exhaustive but of note are local anaesthetics, nitrites (including alkyl or amyl nitrites or “poppers”), Metoclopramide and antibiotics including Dapsone [1, 2].

Table 2: Some of the commoner toxins associated with methaemoglobinaemia

Aniline (dyes, inks) Benzocaine Chlorates Chloroquine
Dapsone Hydroxylamine Lidocaine Metoclopramide
Methylene Blue Nitrates Nitric oxide Nitrites
Nitroglycerin (GTN) Paraquat Phenols Phenytoin
Prilocaine Smoke inhalation Sulfonamide + many more

Learning bite

The most common cause of methaemoglobinaemia is toxin exposure. Taking a thorough history is essential. In young children, congenital causes should also be considered

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