Methylenetetrahydrofolate Reductase deficiency and anesthesia: importance of a detailed preoperative evaluation

Methylenetetrahydrofolate Reductase is an important enzyme responsible for homocysteine and folate metabolism.¹ The deficiency of this enzyme is described as an autosomal recessive disorder that results in increased homocysteine levels in the body well known as Methylenetetrahydrofolate Reductase (MTHFR) deficiency.¹ These patients are basically classified in homozygous, less commonly seen, and heterozygous, the most prevalent variation.¹ MTHFR gene mutation have limited capacity to use the essential nutrient folate which sets off a chain reaction that would culminate in premature atherosclerosis and consequent ischemic insults.¹ The complete mechanism is not completely understood, even though hyperhomocysteinemia presents hypercoagulable properties and has been associated with endothelial dysfunction. The detection of the mutation is usually observed after an unexplained thrombotic event in a previously “healthy patient”. After the diagnosis, family members should be oriented to be genetically screened for this mutation.

If undetected, the patient is at high risk of complications during and after exposure to Nitrous Oxide (N₂O). The utilization of nitrous oxide is frequent in the operating room as a second gas and commonly used by dentists in their clinics. Methionine synthase is the enzyme responsible for the reaction that transforms homocysteine to methionine.² Nitrous oxide inhibits this enzyme resulting in elevated levels of homocysteine.² The accumulation of homocysteine, well known as hyperhomocysteinemia, increases the risk of venous and arterial thrombosis up to six times compared to the general population.² A detailed preoperative evaluation and investigation of past medical history, including family history, is the most valuable tool to diagnose a rare disease such MTHFR deficiency. An unexpected ischemic insult without diagnosis is greatly suspicious and the utilization of nitrous oxide should be avoided, especially because the prevalence of MTHFR deficiency is not known but certainly underestimated. The common use of N₂O should be reviewed due to the risk of undiagnosed population with MTHFR deficiency and possible devastated consequence of its utilization. Patients should be followed up closely in the postoperative period regardless of whether or not N₂O was used due to the susceptibility of the patients for ischemic insults. Volatile agents such as sevoflurane and Total Intravenous Anesthesia (TIVA) can be safely used in patients with an MTHFR deficiency.²

We are not advocating the elimination of the nitrous oxide from the operating room. Neither suggesting that all patients should be genetically screened for MTHFR deficiency. This letter's intention is only to remind every single anesthesia provider, including myself, that the most important preoperative assessment will never be an imaging test neither an expansive laboratory result, but a great conversation with the patient aiming for a detailed and always important past medical history.

References

• ¹
  Shay H, Frumento RJ, Bastien A. General anesthesia and methylenetetrahydrofolate reductase deficiency. J Anesth. 2007;21:493-6.
• ²
  Badner NH, Beattie WS, Freeman D, et al. Nitrous oxide-induced increased homocysteine concentrations are associated with increased postoperative myocardial ischemia in patients undergoing carotid endarterectomy. Anesth Analg. 2000;91:1073-9.

Publication Dates

• Publication in this collection
  10 Feb 2020
• Date of issue
  Nov-Dec 2019

History

• Published
  11 Oct 2019