Lessons learned from yet another episode of diethylene glycol poisoning: it happened before and it happened again.

In September 2006, aPanamanianphysiciannoted that there were an unusual number of mostly elderly patients presentingwith signs of acute kidney injury, gastroenteritis, and central andperipheralneurological effectsofunclear etiology. A cluster of this nature suggests a common-source etiology, which typically could be infectious or toxicological. This prompted the Panamanian Ministry of Health to seek investigative assistance fromtheUSCenters forDiseaseControl and Prevention (CDC). ByOctober, investigators from the CDC set upa case-control study,with casesdefined as individuals presenting, on or after August 2006, with apparent acute kidney injury of unknown etiology. Controls consisted of individuals admitted to the samehospital for reasons other than renal injury and were matched to cases by age and date of admission. Forty-two patients met the case definition. The evaluation of cases included a questionnaire assessing potential recentchemical exposures.Medications takenandurinesamples were sent to theCDC.Diethylene glycol (DEG), a knownnephrotoxin,wasquickly identifiedas theputativeculprit inacough syrup preparation.1 Fortuitously, DEG was prominent on the CDC’s radar screen. Theywere involvedwith similar outbreaks of poisonings from DEG-contaminated pharmaceuticals in Nigeria in 1990andHaiti in 1996. In these2outbreaks, theDEGwas found in acetaminophen syrups. Tragically, these are but three 3 of the 13 such episodes of mass DEG poisonings that have been identifiedsince 1938.Ofgreat concern is the fact that 12of these 13episodes involvedpharmaceuticalsofvariouskinds.Theone nonpharmaceutical episode involved DEG-tainted Austrian wines. Diethylene glycol is characterized by its sweet taste and aqueous miscibility. It has a relatively low order of toxicity but is hepatically metabolized by alcohol and aldehyde dehydrogenases to hydroxyethoxy acetic acid (HEAA), which can be further oxidized to diglycolic acid (DGA). Studies from Kenneth McMartin’s laboratory at the Louisiana State University Health Sciences Center have demonstrated that contrary to earlier beliefs, DGA, and not HEAA, appears to be the nephrotoxic metabolite, at least in rats.2 The nephrotoxic potential of DGA appears to derive from its ability to inhibit succinate dehydrogenase, causing mitochondrial dysfunction and consequently reduced energy production in the renal proximal tubule. Whether this same mechanism applies to humans has not been demonstrated. However, confidence that it might is heightened by the fact that the rat model is known to reasonably replicate the human pathophysiological changes induced by the related compound ethylene glycol. We have learned a number of lessons from the Panamanian DEG episode. It has provided an opportunity to characterize the concentrations of DEG and metabolites in the serum and urine of DEG-poisoned patients and corresponding control participants. Using biological samples from participants in the case-control study, investigators found that urinary DGA concentrations were significantly associated with being a case and were found in 100% of case samples despite being mostly collected days after exposure. Much smaller amounts ofDGAweredetected in 23%of the controls. The low level of DGA found in some control participantswas probably due to environmental exposure to DGA, which can be found in low concentrations in food, cosmetics, and dietary supplements, or perhaps low-dose exposure to the tainted cough syrup. Themedian serumDGAconcentration in the caseswas 41 μg/mL, which is almost 10 times higher than that reported to cause nephrotoxicity in the rat model of DEG poisoning.2,3 SerumHEAAconcentrationswere significantlyhigher in cases than in controls. The median serum DGA concentration was more than 14 times higher than that of HEAA.3 This contrasts sharplywiththeratmodelofDEGpoisoning, inwhichtheblood HEAAconcentrationwas 100 times thatofDGA.2However, the extended period between exposure and the collection of samples in the Panamanian cases could have allowed HEAA to be oxidized to DGA. In these cases, themedian HEAA concentrationswerebelow thedetection limit in theurine inboth cases and controls.3 These data support the concept that DGA appears to be the nephrotoxic metabolite after DEG poisoning. Given that the median serum DGA concentration was 41 μg/mL in cases, and below the limit of detection in controls, it couldbe reasonablyhypothesized that inhumans, as in rats, HEAA is converted to DGA, leaving the latter to interact with renal tissue. Diglycolic acid is concentrated in the kidney.2 If DEG poisoning is suspected, inhibition of its metabolism by inhibiting alcohol dehydrogenase enzymes is a logical treatment and has been shown to be effective in the rat model.2 Fomepizole is the preferred antidote for this purpose, although in situations where it is not available ethanol could be used.4 Diethylene glycol is excreted through the kidneys,5 so if renal function is intact, this might be the only treatment necessary. If renal function is compromised, hemodialysis could be used to clear DEG. However, there are no easily available biomarkers of DEG concentrations, and hence stopping therapy must be done using indirect indicators. It would be expected that DEG metabolism to significant quantities of its acidic metabolites would be accompaRelated article page 912 Research Original Investigation Outcomes Among Survivors of DEG Poisoning