This case highlights the possible association between the consumption of nitrous oxide and the occurrence of thrombotic events, which have rarely been described [1].

The pro-thrombotic effects are thought to be linked to the interaction of nitrous oxide with the intracellular metabolism of vitamin B12 [3, 7, 9]. Its active form, adenosyl cobalamin, decreases with the efficiency of methionine synthase, resulting in an increase in homocysteine as well as cardiovascular and thrombotic risks (see Fig. 1) [9].

The cofactor activity of vitamin B12 for methionine synthase and methylmalonyl-CoA mutase is affected by nitrous oxide. Nitrous oxide oxidizes methylcobalamin and thus inhibits the activity of methionine synthase. This enzyme catalyses the conversion of homocysteine and 5-methyl-THF to methionine and THF. We therefore observed an increase in plasma homocysteine and 5-methyl-THF. Methylcobalamin is involved in the migration of methylcobalamine-CoA mutase from the mitochondria to the cytosol, resulting in an alteration in lipid metabolism and an accumulation of methylmalonic acid [9, 10] (see Fig. 2).

Homocysteine metabolism [10]

Adenosyl-cobalamin is a cofactor of the mitochondrial methylmalonyl-CoA mutase [10]

The increase in homocysteine could be responsible for the pro-thrombotic activity resulting from nitrous oxide intoxication [3]. However, the results of clinical case reviews are ambivalent: not all patients have an increase in homocysteine, and not all have a decrease in vitamin B12 [1].

At present, no threshold or duration of exposure has been identified as being particularly likely to cause complications. This is especially true given that the action of nitrous oxide varies and likely differs depending on the metabolic pathway.

Diagnosis is therefore difficult and depends on a range of factors, including a history of the disease, nitrous oxide consumption and elevated homocysteine and methylmalonic acid levels. It is likely that other factors coexist, such as coagulation disorders and polymorphisms of the MHTFR gene, which can lead to hyperhomocysteinaemia, cannabis consumption, inflammatory conditions and others.

Treatment is based on vitamin B12 supplementation and curative anticoagulation [1, 3]. Some authors also recommend folate supplementation [1, 5, 7]. Depending on the organ affected, thrombectomy procedures are discussed. The duration of anticoagulation is unknown, but it should be assumed that hyperhomocysteinaemia persists despite the cessation of nitrous oxide consumption [3].

There is no specific marker for nitrous oxide intoxication, especially because vitamin B12 is rarely decreased and is not correlated with the severity of intoxication. However, an increase in homocysteine is associated with recent increases in nitrous oxide consumption and methylmalonic acid [11].