Nancy A. Melville
A case of false-positive alcohol toxicology tests believed to be linked to treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitors raises concern that the widely used diabetes drugs could feasibly be a cause of innumerable false-positive test results — with a lack of proper refrigeration of the samples being a key culprit.
The case, described in a letter in the New England Journal of Medicine, involved a man in his 60s treated for diabetes with the SGLT2 inhibitor empagliflozin for 5 months.
The patient reported to his primary care clinic that he feared being sent to jail because as many as four recent urine toxicology test results taken for the city’s probation office were positive for alcohol, despite his not ingesting alcohol for 10 months. The samples otherwise showed no traces of illicit or nonprescribed substances.
When the clinic performed further laboratory testing, a new specimen showed no detectable ethanol or ethyl glucuronide; however, glycosuria was present, indicative of the patient’s adherence to empagliflozin therapy (20 mg once daily), which had been prescribed 5 months earlier to treat his diabetes mellitus.
Otherwise, the sample had no increased levels of nitrite or leukocyte esterase, and a urine culture showed less than 50,000 colony-forming units per milliliter of mixed gram-positive organisms.
A Key Clue: Lack of Refrigeration of Urine Sample
A call to the city probation office to inquire about its urine collection protocol revealed that probation office urine samples, sent only once daily to an external lab for testing, were not refrigerated prior to transportation.
With that important clue, the patient’s new urine sample at the primary care center was removed from refrigeration.
While the new test was originally negative for ethanol, a repeat test taken after the test was kept at room temperature for 24 hours indeed showed the sample to be positive, suggesting a key culprit — microbial fermentation of urinary glucose.
“This class of medications produces glycosuria even during euglycemia and increases the presence of microbes in the urinary tract — two ingredients necessary for microbial fermentation,” author Aaron L. Schwartz, MD, PhD, of the Corporal Michael J. Crescenz Department of Veterans Affairs Medical Center, Philadelphia, Pennsylvania, wrote in his report.
“In this case, the collection and storage of urine samples by the criminal justice system appear to have been inadequate for ensuring specimen stability,” he said.
While there have been several reports of false-positive urine alcohol tests under similar circumstances, such as having chronically elevated sugar levels in the urine, “to my knowledge, this is the first report of this phenomenon with respect to this type of medication,” Schwartz told Medscape Medical News.
That doesn’t mean there may not be plenty more.
Schwartz noted that several reports have described false-positive urine alcohol toxicology tests that didn’t involve SLGT2 inhibitors but had similar circumstances of chronically elevated sugar levels in the urine, including three known cases involving patients with false-positive urine alcohol tests attributed to poorly controlled diabetes that had caused high levels of glucose in their urine.
“In one case, the patient had been kept off the liver transplant list because of the false-positive alcohol tests [and] in another case, victims of rape claimed, truthfully, that they hadn’t been drinking at the time of their assault.”
In the current case, two key factors attributed to the false positives were the presence of sugar in the urine, which can attract microbes over time, and the fermentation of some of the microbes from sugar into alcohol.
The second factor is the warm conditions in which the urine was stored, which contributed to the fermentation.
“Prior studies and cases have shown that it doesn’t take very long for microbial fermentation to occur at room temperature,” Schwartz said.
In addition to many patients potentially having sugar in their urine, many employers, criminal justice institutions, and even medical facilities do not perform toxicology testing at the point of collection, he noted.
“It is very common for urine or blood samples to be collected in one place and tested at another location. Specimen integrity can be compromised in these situations.”
Freezing samples or using sodium fluoride preservatives can prevent the fermentation of urine, Schwartz added.
Meanwhile, with such measures far from standard, there is no telling how many false-positive tests could be occurring under the current circumstances.
“These drugs are widely used [and] they clearly cause sugar in urine and attract microbes to urine,” Schwartz said. “Microbes can ferment sugar into alcohol fairly quickly, and toxicology testing is widely performed. So, it’s reasonable to worry that this phenomenon could be widespread.”
With the possibility of such cases occurring, Schwartz urges clinicians to “be skeptical of positive urine alcohol tests for patients that have high level of glucose in their urine.”
Furthermore, “be especially skeptical in cases where urine is not tested immediately [and] consider using confirmatory testing like blood tests,” he said.
Fermentation of Sugars to Alcohol Well Known to Brewers
In a previous report describing false-positive urine alcohol testing related to glucosuria and bacteria in the urine, Kevin F. Foley, PhD, of the Department of Pathology, Kaiser Permanente, in Portland, Oregon, explained that the relationship between bacterial fermentation and alcohol is likely familiar to anyone involved in alcohol production — or even a passing interest in craft brewery.
“As brewers and winemakers are aware, fermentation is the biochemical process of converting sugars, in the absence of oxygen, into alcohol (and carbon dioxide),” he wrote in his report. “Bacteria and yeast can ferment sugars.”
Likewise, “if a liquid has a sufficient amount of sugar (> 500 mg/dL glucose, in the case he described), along with the presence of bacteria and the passage of time, fermentation in vitro can occur.”
Foley’s case involved a 44-year-old man who was being managed for type 2 diabetes but was also prescribed opioids for lumbar radiculopathy, shoulder, and rib pain and, as a condition of the opioid treatment, was required to abstain from alcohol and other recreational drugs and submit to urine tests.
Despite his indication that his most recent alcohol use had been a year prior, the man had positive urine ethanol results.
The necessary testing used to confirm the test results that were believed to be skewed by fermentation were a urine ethyl glucuronide (ETG) and ethyl sulfate (ETS) test.
While bacterial contamination also can cause a false-negative ETG result, due to bacterial decomposition of ETG, ETS is not affected by these contamination issues, Foley said.
The ETS and ETG results came back negative for the patient, “strongly suggesting that the ethanol was present in the urine due to bacterial fermentation,” Foley wrote.
As in the case involving SGLT inhibitors, the case reported by Foley also involved the transport of the urine sample at ambient (room) temperature over the course of the day.
“A period of 6.5 hours seems to be an ample amount of time to allow for fermentation,” he wrote, also underscoring that freezing or use of sodium fluoride as a preservative could prevent such fermentation.
“This case highlights the fact that specimens that cannot be tested immediately should be transported and held in refrigerated conditions to reduce the chances that fermentation will occur in the specimens,” Foley said.
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