What are the causes of Methaemoglobinaemia?

Causes of Methaemoglobinaemia

A. Genetic/hereditary:
  • NADH diaphorase deficiency (The enzyme is also known as cytochrome b5 reductase or methemoglobin reductase)
  • Hb M
B. Acquired (Drugs and toxins):
  • Phenazopyridine (Pyridium)
  • Sulphonamides (Sulfamethoxazole)
  • Dapsone (used in some street drugs)
  • Aniline dyes
  • Paraquat/monolinuron
  • Na nitroprusside
  • Nitrate
  • Nitroglycerin
  • Amyl nitrite (e.g drinking a flask of amyl nitrite in a nightclub)
  • Isobutyl nitrite
  • Sodium nitrite
  • Drinking water contaminated with nitrates and nitrites
  • Eating foods in which nitrites and nitrates are used as preservatives
  • Benzocaine
  • Prilocaine
  • Methylene blue
  • Chloramine
  • Primaquine (used as malaria prophylaxis treatment)
  • Phenacetin
  • Ferric cyanide
  • Chlorate



● NADH = Nicotinamide adenine dinucleotide (reduced form)

Methemoglobin: In normal haemoglobin (Hb), 4 globin chains surround an iron-containing porphyrin pigment molecule known as haem. Each haem molecule contains a ferrous ion (Fe2+), to which oxygen reversibly binds. The ferrous ion can be oxidized into ferric ion (Fe3+). This oxidized form of Hb is known as methemoglobin. In simple term, haemoglobin is a reduced form (iron is in ferrous form; Fe2+) and methemoglobin is an oxidized form (iron is in ferric form; Fe3+).

●Hb is continuously oxidized in vivo from the ferrous to the ferric form. Under normal circumstances, it is reduced back to the ferrous form due to intact enzymatic processes. The most important enzyme in such methemoglobin reduction pathway is cytochrome b5 reductase, also known as NADH diaphorase. In the reduction reaction, NADH acts as a hydrogen donor. In turn, the reduced cytochrome b5 reduces methemoglobin to haemoglobin.

●Haemoglobin M (Hb M) is one of the hereditary cause of methemoglobinemia. Hb M is produced due to mutation in any or both of globin chains (alpha or beta globin) where tyrosine has been substituted for histidine. It is inherited as an autosomal dominant (AD) fashion. Unlike normal individuals, the Hb M remains in oxidized form and resists its reduction to the ferrous form.

  • Williams hematology 9th Edition; page 792
  • Rapid review of clinical medicine for MRCP part 2, 2nd Edition, by Sanjay Sharma and Rashmi Kaushal; Q 316
  • Step Up To MRCP Review Note For Part I & Part II By Dr Khaled El Magraby; page 513
  • Harrison's Principles of internal medicine 19th Edition; page 636

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