Communication is the Key to Successful Anesthesia in a Patient with Asymptomatic MTHFR Deficiency

Gregory Kozlov DO, Ivan Kukhar MD, and David J. Lang DO

Department of Anesthesiology, Advocate Illinois Masonic Medical Center, Chicago, IL 60657 USA

Introduction

Case Description DiscussionAbstractThe key to any successful anesthetic is open lines of communication between all involved parties: patients, physicians, nursing staff, and families of patients. We present a case that could have had less than desirable outcomes if information concerning a child with methyltetrahydrofolate deficincy. The dentist had called the anesthesia department and sent records for review in advance of the case. With this information, a safe and successful anesthetic was done.

5,10-Methylenetetrahydrofolate Reductase (MTHFR) deficiency, also known as Type III Homocysteinuria, is an autosomal recessive genetic disorder characterized by severe elevation in plasma and urine homocysteine and extreme deficiency of methionine. Prevalence of the disease in the general population is unknown. In European, Middle Eastern, and Japanese populations the prevalence of the homozygous mutation is 10% to 15%. In African-Americans the prevalence is below 1.4%. MTHFR deficiency affects about 200,000 Americans, females more than males (2/3 of cases), with a spectrum of manifestations including neurologic symptoms, premature atherosclerosis, venous and arterial thrombosis. The disease may manifest itself at any age from infancy to adulthood.Nitrous oxide oxidizes the cobalt atom of vitamin B12, thereby inactivating vitamin B12 as a necessary cofactor for methionine synthase function. The subsequent accumulation of 5-methyltetra-hydrofolate due to inactive methionine synthase is called folate trapping. MTHFR catalyses the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, deficiency of this enzyme also leads to folate trapping. Selzer et al.* postulated a double-hit hypothesis to explain the pathophysiology of the fatal neurologic outcome in patient with MTHFR deficiency exposed to nitrous oxide. This hypothesis links nitrous oxide-induced hyperhomocysteinemia and inhibition of folate metabolism with an underlying MTHFR gene defect.

A 13-yr-old autistic boy (height-144cm, weight-30 kg) diagnosed with MTHFR deficiency was scheduled for dental rehabilitation under general anesthesia. One day prior to the surgery, patient’s dentist contacted the anesthesia department and advised that, because of MTHFR deficiency, the anesthesiologist should not administer nitrous oxide during the surgery, or the patient would die!!! With this in mind, the nitrous oxide hose disconnected from the anesthesia machine, and the machine was flushed with oxygen for ten minutes. The patient was premedicated with midazolam 15 mg orally, and induced via mask with oxygen and sevoflurane. After a peripheral intravenous line was started, fentanyl 60 mcg (2mcg/kg), rocuronium 20 mg (0.6mg/kg) and glycopyrrolate 0.1mg were administered. Following direct laryngoscopy, the trachea was intubated with nasal RAE tube. Anesthesia was maintenaned with sevoflurane (2.2-2.4 vol%) and 50% FIO2. The duration of the case was two hours and 12.5 mcg of fentanyl, and 15 mg of ketorolac were administered. The procedure was uneventful. Neuromuscular blockade was reversed with neostigmine 1mg (0.03 mg/kg) and glycopyrrolate 0.1 mg. After successful extubation, patient taken to recovery room. The postoperative period was uneventful and patient discharged home on the same day.

The inhibition of methionine synthase by nitrous oxide has two consequences: • First: homocysteinemia causes endothelial dysfunction in blood vessels and enhanced platelet aggregation, which may lead perioperative thromboembolic events and myocardial ischemia• Second: folate trapping, severely limits the de novo synthesis of DNA resulting in apoptosis of rapidly dividing cells. This process is the cause for the megaloblastic changes observed in bone marrow neurological deterioration.

Nitrous oxide-induced homocysteinemia and folate trapping can be catastrophic when they develop in conjunction with an inherited MTHFR enzyme deficiency.Because MHFTR may be undiagnosed until adulthood, the anesthesiologist must be keenly aware of clues as to the possibility that their patient may be affected by MTHFR deficiency: combination of high risk ethnic background, family history, spina bifida, young women with coronary and carotid artery disease, and mental retardation may suggest further investigation.

There are several key features of the disease that are of particular interest to anesthesia providers:• Microcephaly leading to difficult intubation• Hypercoagulability• Predisposition to preeclampsia,• Absolute contraindication to nitrous oxide.

The anesthetic plan for patients with MTHFR deficiency should include:• anticipation of difficult airway• precautions for thromboembolic events• avoiding nitrous oxide.

With some foresight and planning, general anesthesia can be administered to these patients uneventfully.

Homocysteine PathwayGlobal Distribution of MTHFR

References

Yamada T, et al. J Clin Anesth 2005;17: 565-7.Selzer RR, et al. N Engl J Med. 2003;349:45-50.