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Ethylene Glycol Poisoning

Dateline: 06/28/99

By Alan Bruzel

Unadulterated automobile antifreeze owes its sweet taste to its main constituent, ethylene glycol. It is this sweet taste that leads to accidental ingestion. Once in the body, ethylene glycol relentlessly follows metabolic pathways leading to the production of toxic products.

Ethylene glycol, itself, is relatively harmless and can be removed by the kidney. Problems arise when the liver enzyme, alcohol dehydrogenase, converts ethylene glycol to glycoaldehyde. The below reaction occurs in the absence of alcohol dehydrogenase's normal substrate, ethanol.

Ethylene glycol: Oxidized to glycoaldehyde by alcohol dehydrogenase

Ethanol infusion is recommended in the early stages of poisoning – that is, when blood levels of ethylene glycol are high. Ethanol, not ethylene glycol, is the preferred substrate of alcohol dehydrogenase. The strategy is to saturate alcohol dehydrogenase with ethanol so that the enzyme is occupied with ethanol oxidation and doesn't metabolize ethylene glycol. The ethylene glycol, untouched by the enzyme, can then be excreted in the urine.

Ethanol: Oxidized to acetaldehyde by alcohol dehydrogenase

During infusion, the blood levels of ethanol are to be maintained between 100 to 200 mg/dl. This is a controlled intoxication, requiring constant monitoring, and is performed in the setting of an intensive care unit. (In most of the United States, drivers with a blood alcohol level of 100 mg/dl or more are considered intoxicated.) To avoid the problems associated with ethanol therapy, a new treatment, approved by the US Food and Drug Administration in December 1997, uses the alcohol dehydrogenase inhibitor 4-methylpyrazole (trade name = Antizol; generic name = fomepizole). Unlike ethanol, 4-methylpyrazole is not a substrate for the enzyme, is therefore not metabolized, and needs to be administered by injection only twice daily.

4-Methylpyrazole

Neither ethanol infusion nor 4-methylpyrazole is of much use late in ethylene glycol poisoning when most of the ethylene glycol has already been metabolized by alcohol dehydrogenase. At this point, the glycoaldehyde produced is further metabolized to glycolic acid by another liver enzyme, aldehyde dehydrogenase.

Glycoaldehyde: Oxidized to glycolic acid by aldehyde dehydrogenase

Acetaldehyde is the normal substrate of aldehyde dehydrogenase, but cannot be used therapeutically, as was the case with ethanol, because of its toxicity.

Acetaldehyde: Oxidized to acetic acid by aldehyde dehydrogenase

Without medical intervention, the glycolic acid is further metabolized to glyoxylic acid and then to oxalic acid.

Glyoxylic acid	Oxalic acid

Glycolic acid and glyoxylic acid produce a dangerous metabolic acidosis, and oxalic acid will remove calcium from the bloodstream resulting in deposition of the insoluble calcium oxalate in the kidney. (Hypocalcemia is but another potential complication.) Consequently, in these later stages of ethylene glycol poisoning, toxic metabolites must be removed by hemodialysis.

Recommended Web resources for additional information:

Antizol (fomepizole)
Medical information about 4-methylpyrazole. From Orphan Medical, Inc.

Ethylene Glycol
Symptoms, clinical course, and treatment in ethylene glycol poisoning. From Emergency Medicine and Primary Care.

Fomepizole for the Treatment of Ethylene Glycol Poisoning
Abstract from the New England Journal of Medicine.

4-Methylpyrazole
June 1998 article from the Clinical Toxicology Review of the Massachusetts Poison Control System.

Toxicity, Ethylene Glycol
Emergency medicine management of ethylene glycol poisoning. From emedicine, Inc.

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