A new direction for “liquid biopsy” technique. Detection of liver fibrosis using DNA sequencing technology.

Medical scientists at Newcastle University in the UK have recently published a study demonstrating the possibility of using a “liquid biopsy” technique to assess the degree of liver scarring in people with non-alcoholic fatty liver disease (NAFLD).

Liquid biopsy is a new technique for sequencing short pieces of DNA found in a sample of blood plasma and obtaining information previously only available from an invasive tissue biopsy. A previous article in the Lab Tests Online news section discussed liquid biopsy in relation to detection and management of cancer. This new study shows how it may be possible to assess non-malignant diseases as well.

In NAFLD and some other liver diseases there is slow development of liver scarring called liver fibrosis. This may eventually cause severe liver scarring called cirrhosis and may be fatal. It is important in the management of these diseases to be able to identify when liver scarring is occurring and how severe it is. The gold standard test for this is liver biopsy and examination of the tissue under the microscope by a pathologist. However liver biopsy is invasive and carries a risk of complications. There are existing blood tests that can be used to detect liver fibrosis and these are based on the measurement of combinations of multiple markers in the blood. Some are quite simple and some complex with six or more markers. Some of these have been evaluated and compared for several different liver diseases and they show promise but have not yet replaced liver biopsies.

This new test is the first to use DNA technology for this purpose. The test goes a step beyond most liquid biopsy techniques in that it measures what are called epigenetic changes in the DNA. Epigenetic changes are changes in the DNA that do not affect the DNA sequence. The most common epigenetic marker is DNA methylation where some of the bases in the DNA have methyl groups added to them. This test measures the amount of DNA methylation of a specific part of the genome called the peroxisome proliferator-activated receptor gamma (PPARγ) gene promoter. Patients with liver fibrosis were found to have increased DNA methylation at specific areas within this gene promoter.

While these results are very interesting because it is the first use of DNA technology for assessing this problem it is still far too early to tell whether this technique will be of practical use in the future. This study was small and needs to be repeated in a larger sample. The researchers did assess the technique in a few patients with another fibrosing liver disease – alcoholic liver disease and it seems that it may be useful in this disease as well but it has not yet been assessed in any other fibrosing liver disease such as those caused by hepatitis B and C. It is also not known whether the changes in the DNA methylation are actually caused by the disease or whether they identify groups of people who are more susceptible to the development of fibrosis. Prospective studies will be required to answer this question.

Liquid biopsies are a promising area of research and as DNA sequencing technology has become faster, simpler and cheaper it is likely that it will be found to be useful in other areas of medicine as well in the future. It is the first time an epigenetic signature in blood has been discovered which is diagnostic of the severity of fibrosis for people with Non-alcoholic Fatty Liver Disease (NAFLD).

NAFLD, caused by being overweight or having diabetes, affects one in three people in the UK and may progress to cirrhosis and liver failure, requiring a transplant.

Scientific breakthrough
Publishing in the academic journal Gut, the Newcastle team describe the proof of principle research in which they measure specific epigenetic markers to stratify NAFLD patients into mild or severe liver scarring, known as fibrosis.

Dr Quentin Anstee, Clinical Senior Lecturer at Newcastle University, Consultant Hepatologist within the Newcastle Hospitals and joint senior author explained what it could mean for patients:
"This scientific breakthrough has great promise because the majority of patients show no symptoms. Routine blood tests can't detect scarring of the liver and even more advanced non-invasive tests can really only detect scarring at a late stage when it is nearing cirrhosis. We currently have to rely on liver biopsy to measure fibrosis at its early stages -- by examining a piece of the liver under the microscope. We know that the presence of even mild fibrosis of the liver predicts a worse long-term outcome for patients with NAFLD and so it's important to be able to detect liver scarring at an early stage."

Providing a scale of damage
In this first stage of research the team developed the blood analysis in 26 patients with NAFLD. The test detects chemical changes on tiny amounts of "cell-free" DNA that are released into the blood when liver cells are injured. Changes in DNA methylation at genes like PPARγ that controls scar formation are then used to stratify patients by fibrosis severity.

Senior author Dr Jelena Mann of Newcastle University's Institute for Cellular Medicine added: "This is the first time that a DNA methylation 'signature' from the blood has been shown to match the severity of a liver disease. It opens up the possibility of an improved blood test for liver fibrosis in the future."

Dr Timothy Hardy is a hepatology registrar within Newcastle Hospitals and a Medical Research Council-funded clinical research training fellow at the University. He conducted the research as part of his PhD project and said: "We are now working on confirming these findings in a larger group of patients. If we are able to accurately tell the extent of a person's liver damage with a blood test, and even track the scarring as it gets better or worse, it could provide reassurance for patients, save NHS resources and avoid patients having to undergo a liver biopsy."

This research is part of Newcastle University's response to the challenges and opportunities presented by an aging population. Newcastle University is a world leader in the field at its Campus for Ageing and Vitality, the location for a new £40m National Centre for Ageing Science and Innovation (NASI). This research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre.

The research was made possible through Newcastle Academic Health Partners, a collaboration involving Newcastle Upon Tyne Hospitals NHS Foundation Trust, Northumberland, Tyne and Wear NHS Foundation Trust and Newcastle University. This partnership harnesses world-class expertise to ensure patients benefit sooner from new treatments, diagnostics and prevention strategies.
Text: Gut journal article

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