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UK Researchers Validate Biomarker Test for Liver Injury Due to Paracetamol Overdose

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NEW YORK (360Dx) – A research team led by the University of Edinburgh and the University of Liverpool has shown that a combined biomarker model consisting of microRNA-122 (MiR-122), keratin-18 (K18), and high mobility group box-1 (HMGB1) showed better sensitivity and specificity than alanine aminotransferase (ALT) concentration, a gold standard marker, in detecting liver injury from paracetamol overdose.

In a study published earlier this week in the Lancet Gastroenterology & Hepatology, the researchers proposed that the combination of biomarkers could be used to stratify patients according to risk of liver injury when they have overdosed on paracetamol. There is an unmet need "for accurate biomarkers that predict liver injury that will not be prevented by standard acetylcysteine treatment soon after overdose," they said.

"A big challenge for clinicians is working out who needs treatment and who doesn't, and the tools we've had for that are pretty blunt," said James Dear, a researcher in the center for cardiovascular science at the University of Edinburgh and an author of the study. "In this paper, we've identified novel markers of liver injury, and we've tested them in 1,200, or so, patients," he said. "We confirmed that the markers are very sensitive and specific for identifying those patients [who] have overdosed on paracetamol and are going to get liver injury when they first present to the emergency department."

The team completed a derivation study in eight UK hospitals and a validation study in 10 UK hospitals. In both cohorts, clinicians diagnosed adult patients with paracetamol overdose. They measured circulating biomarkers within the blood of patients who needed intravenous acetylcysteine, a treatment for paracetamol overdose. The primary endpoint was acute liver injury, indicating need for continued acetylcysteine treatment beyond the standard course, the researchers said.

"MiR-122 is almost exclusively expressed in the liver, so we knew that it had very high concentration inside liver cells," Dear said. "The other markers are proteins that are released by cells when they die by necrosis, and necrosis is the key histological feature of paracetamol injury."

Although the combined set of markers fared better than the standard of care, HMGB1 had the most favorable positive and negative predictive values and the highest sensitivity at 95 percent specificity for the prediction of the secondary endpoint, hepatic synthetic dysfunction, in both cohorts, the researchers said.

Paracetamol, also named acetaminophen, is the most common cause of drug-induced liver injury and acute liver failure in the Western world, Dear said. In the UK, 100,000 people every year arrive at hospital emergency rooms having overdosed, and half of them need to be admitted to hospital for emergency treatment. In the US, there are about 400,000 overdoses of the drug per year, he added.

"Paracetamol, taken in safe quantities, is a very safe drug but in overdose can cause liver injury and liver failure," Dear said.

People innocently consume too much paracetamol by taking the drug at the same time as cold and flu medications that also contain it, for example. In some cases, liver damage can be so severe that the patient needs a transplant, and in rare instances, it can be fatal, the researchers said.

Patients with life-threatening levels of paracetamol in their blood can be treated with acetylcysteine, an antidote given by intravenous drip. Treatment involves applying an intravenous drip to the patient for at least 21 hours. Because the treatment is associated with side effects, doctors don't treat patients longer than necessary, the researchers said.

"The antidote is effective if it's given soon after the overdose, but it becomes less effective if it's given later," Dear said, adding that the new biomarker panel could help to quickly pinpoint whether patients are likely to benefit from treatment.

At present, when a patient presents to the emergency room with a suspected overdose of paracetamol, the clinician first explores the patient's story about the consumption of the drug, Dear said. That might allow physicians to work out the dose that a patient has taken, but because that analysis can be imprecise, the next step is to measure the concentration of paracetamol in the blood, he added.

"We're looking at the concentration of paracetamol compared to how long ago the patient took it," Dear said, adding that although clinicians use ALT as a biomarker, it is slow in elevating and lacking in specificity.

"In practice, as doctors, we treat far more patients than need it," Dear said. "We naturally err on the side of caution, and end up admitting a lot of people to hospital who don't need to be admitted."

With their study shows that the test has clinical utility in the diagnosis of patients affected by paracetamol overdose, the researchers are now speaking with companies in the US and the UK, including Quanterix and Destina Genomics, with a view toward developing a commercial test they can introduce into clinical practice, Dear said.

Among the team's objectives is integrating the markers within a point-of-care assay that would then undergo clinical trials.

For the recent UK-based study, the protein biomarker tests were run on a laboratory ELISA system and the MiR-122 tests on a PCR platform. In clinical practice, the protein biomarkers could in principle be integrated into a standard ELISA platform run in a hospital laboratory, or within a lateral flow assay for a point-of-care test, Dear said.

Developing a test panel that includes MiR-122 could be more challenging, he noted, but the researchers are already working on that. In July, Dear and his colleagues published the results of a validation study in the journal PLOS One in which they collaborated with Quanterix to detect MiR-122 in samples using the Quanterix Simoa platform. The firm's single-molecule counting technology is an example of the kind of system that the researchers could use to detect MiR-122 in a clinical setting, Dear said.

In the study, the Quanterix Simoa single molecule assay showed 600-fold sensitivity improvements over a conventional, analog bead-based assay. Although it exhibited lower sensitivity than a commercial RT-qPCR assay, there is "considerable scope for improving the sensitivity of this Simoa assay to approach that of PCR," the researchers said. All patients with liver injury had higher levels of MiR-122 in their serum compared to controls, and the measured concentrations correlated well with those determined using RT-qPCR, the researchers said.

Dear and his colleagues expect to begin further development of the markers in 2018, with a view to eventual clinical use. Usually, a trial can take two to three years, Dear noted. If it's successful and meets regulatory requirements, a commercial diagnostic test ready for clinical use could be available in 2020 or later.

"In the meantime, these markers have an immediate opportunity for use in specific scenarios, and indeed they are already being used by the pharma industry in development work, which gives weight to their utility," Dear said.

Liver toxicity is a major concern for drug developers, and they lose a lot of money when it turns out that one of their drugs is toxic, he noted. Therefore, the combination of markers, besides having potential for clinical use, also holds potential for application by pharma companies.