What are the biochemical findings in methanol toxicity? Outline the specific management along with its physiological rationale. (50% marks)
College answer
High anion gap metabolic acidosis, osmolar gap, elevated plasma methanol level.
Antidote therapy, often using ethanol or fomepizole, is directed towards delaying methanol metabolism until the methanol is eliminated from the patient’s system either naturally or via dialysis. Like methanol, ethanol is metabolized by ADH, but the enzyme’s affinity for ethanol is 10-20 times higher than it is for methanol. Fomepizole is also metabolized by ADH; however, its use is limited because of high cost and lack of availability
Dialysis: The toxic products of methanol and ethanol are formic acid and oxalic acid respectively. They are small molecules, are not protein bound and have low volume of distribution so are easily dialysable.
Folic acid – can accelerate the metabolism of formate via tetrahydrofolate.
Discussion
The characteristic features of toxic alcohol toxicity in general are:
- High anion gap (all except isopropyl acohol)
- High osmolar gap (all). Methanol is the alcohol molecule with the lowest molecular weight (32.04), and therefore a glass of methanol will raise the osmolar gap more than ethanol (MW= 46) or any of the others.
- High toxic alcohol level is a fairly unimaginative biochemical feature to mention. By extension of the same concept, one may also list serum formaldehyde levels and serum formate levels. In case you're wondering, the upper range of normal formate levels is 0.4 mmol/L.
As for specific management:
Decontamination
- Activated charcoal is useless. Absorption is too rapid.
Enhanced elimination
- Haemodialysis: toxic alcohols and their metabolites are rapidly cleared in this manner
- Folate and leucovorin enhance the clearance of formate; specifically formate binds with tetrahydrofolate to produce 10-formyl-tetrahydrofolate, which is then incorporated into purine metabolism (Morrow et al, 2015)
- Alkalinization of urine with a bicarbonate infusion promotes dissociation of formic acid (it is less toxic in its ionised state) and improves its clearance by ion trapping in the urine
Specific antidotes
- Alcohol - the precise use of this substance in overdose is discussed in the chapter on ethylene glycol and its toxic acid metabolytes.
- In brief, one should sustain a blood ethanol concentration of 20 to 30 mmol/L (100 to 150 mg/dL) - this equates to a blood alcohol level of 0.1-0.15%.
- Fomepizole as it is known, is basically a competitive antagonist to alcohol dehydrogenase. It does what ethanol would do, except it does so with great expense, and without ethanol intoxication. The advantage of using it is its lack of CNS effects - if the patient is confused already you do not want to add alcohol into the mix.
References
Morrow, Gregory P., et al. "In vivo kinetics of formate metabolism in folate-deficient and folate-replete rats." Journal of Biological Chemistry 290.4 (2015): 2244-2250.
Kraut, Jeffrey A., and Ira Kurtz. "Toxic alcohol ingestions: clinical features, diagnosis, and management." Clinical Journal of the American Society of Nephrology 3.1 (2008): 208-225.
Henderson, William R., and Jeffrey Brubacher. "Methanol and ethylene glycol poisoning: a case study and review of current literature." Cjem 4.1 (2002): 34-40.
Hovda, Knut Erik, Petter Urdal, and Dag Jacobsen. "Increased serum formate in the diagnosis of methanol poisoning." Journal of analytical toxicology 29.6 (2005): 586-588.