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European Team Developing Blood Test for Pediatric Non-Alcoholic Fatty Liver Disease


NEW YORK (360Dx) – A team of European researchers is trialing the use of a new blood test to diagnose non-alcoholic fatty liver disease in children. While results are preliminary, the test could potentially be used in lieu of a liver biopsy in the future.

Scientists involved in the effort, called the European Pediatric Non-Alcoholic Fatty Liver Disease Registry, discussed their experience with the test at the annual meeting of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN), which was held in Glasgow, Scotland, over this past weekend.

Jake Mann, a clinical research fellow at the Institute of Metabolic Science at the University of Cambridge, is coordinating the new registry, which was established last year with the aid of a €50,000 ($57,000) grant from the European Association for the Study of the Liver (EASL).

The project was initially led by Valerio Nobili, a noted researcher of metabolic liver diseases at Hospital Bambino Gesù in Rome, who passed away earlier this year.

The aim of the registry, which involves participation from 11 institutions from six European countries, is to collect samples from children with NAFLD, a condition that according to ESPGHAN affects about one in 10 children and can lead to cirrhosis, liver failure, and cancer.

Registry participants are collecting blood samples from children for research purposes, as well as clinical and phenotypic information. They intend to study these samples using metabolomics and genomics tools. Ultimately, they hope to have samples from 2,000 pediatric cases in the registry, including 500 with biopsy-proven NAFLD, an objective that Mann said is possible, given the prevalence of the disease in Europe. They also intend to follow the cohort for up to 30 years.

"The registry has been developed over the past 18 months and is slowly gaining momentum now," Mann said. "We will do a variety of studies on the patient population," he added, noting the scientists hope the repository will "feed into a number of projects and hopefully into clinical trials in the future."

The registry's first study involved profiling 67 samples with a lipidomics platform developed by Albert Koulman's laboratory at the University of Cambridge. Koulman is scientific director of the Metabolics and Lipidomics Facility at the University of Cambridge, a component of one of the UK's National Institute for Health Research's Biomedical Research Centers (BRCs).

According to Koulman, the BRC's lipidomics platform relies on a chip-based nanospray of lipid extracts into a high-resolution mass spectrometer. "Within a two-minute analysis, we can capture data on about 400 to 500 different lipid signals in human plasma or serum samples," Koulman said.

The extraction and analysis has been automated at the center using 386-well plates, Koulman said, which means the center can analyze more than 300 samples in 24 hours. The data captured by the mass spectrometer is then processed to provide relative and absolute amounts according to a range of internal standards.

The platform has been used in various studies, including recently to study the genetic determinants of lipids and their association with coronary heart disease risk factors. The platform has also been used to identify biomarkers for NAFLD. This was the first time, though, that it was used to interrogate samples from pediatric NAFLD cases, Mann noted.

By comparing the results of Koulman's lipidomics platform with the liver biopsies collected from the sample set, Mann and colleagues found that several different fats could be used to identify inflammation and scarring in patients. Specifically, 66 percent of those surveyed had nonalcoholic steatohepatitis (NASH) or inflammation, and one in 10 had significant scarring, or fibrosis, conditions that could be associated with certain lipid markers detected in blood.

"We saw some differences in children who have NASH versus those who don't have NASH, and those who have fibrosis versus those who don't have it," said Koulman. "Those differences are still there even when we account for age, sex, and common genetic variants for NASH," he said.

The ability to determine the nature of a child's disease via a blood draw makes Koulman's mass spectrometry-based test a potential alternative to liver biopsy, the conventional diagnostic method. There currently are no noninvasive methods available to diagnose the disease. A team at the University of California, San Diego, has been working on a diagnostic signature based on patients' gut microbiomes, though, and in 2017, the European Innovative Medicines Initiative (IMI) together with the EU awarded a European consortium €34 million to improve diagnosis of the disease.

That consortium, called Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS), aims to develop, validate, and quantify better biomarkers for testing NAFLD. It is funded through 2022 and involves dozens of academic and industry participants, including many pharmaceutical companies such as Astrazeneca, BMS, Novartis, Sanofi, Takeda, and others. The University of Cambridge is also a participant in the LITMUS consortium.

Another aim of the consortium is to develop tests that predict which NAFLD patients are at greatest risk of developing NASH, and how fast their disease is likely to progress, similar to the tests the registry has been developing. Quentin Anstee, a professor at Newcastle University's Institute of Cellular Medicine, who has led the consortium, is also taking part in the new registry.

Mann said that the registry and LITMUS are currently working together to align the two efforts, "both in order to analyze data together and to facilitate the long-term follow-up of these children when they become adults."

In terms of the registry's recent study, Mann noted the small size of the sample set, and said that further work is necessary to develop the approach before one can consider applying it in routine clinical use.

"It's almost a research test at the moment, but theoretically it could become a commonly used research tool and eventually incorporated into practice, but that's a long way off," said Mann.

Koulman said there have been no efforts to commercialize the approach yet, though the method has been shared with other labs, meaning it could be used for similar purposes. Mann said the registry is currently recruiting more participants and intends to run the test on those samples, too.

"The more samples, the more statistical power to find more things," commented Mann. "We hope in the next month we will run the test on up to 300 samples."

This next batch will include children who are obese and have normal livers, as well as children who are lean and healthy. "We'll analyze the data and hopefully come to some conclusions, [and] see if we want to run it on the whole registry eventually," he said. "That's our current plan."

Once the registry has observed more samples, it will likely publish those results, Mann said.

The registry might also collect genomics data on samples, Mann added. "Our plan is to ask everyone to consent to whole-exome or whole-genome sequencing," he said. Should the registry obtain the necessary funding, it might select interesting cases for sequencing.