Gene discovery could help prevent liver disease deaths

A Manchester research team has discovered a gene which could hold the key to predicting which liver disease patients are at high risk of further liver damage. It also presents a new target for developing drugs to prevent liver damage, and a potential marker to detect people with undiagnosed liver disease.

Dr Varinder Athwal, a consultant clinical hepatologist (liver specialist) at Manchester University NHS Foundation Trust (MFT) has worked with Dr Karen Piper Hanley and her team at The University of Manchester to study the role played by the SOX9 gene in causing fibrosis (liver scarring) and ultimately organ failure.  They have published their findings in the journal EMBO Molecular Medicine (DOI 10.15252/emmm.201707860) and are now looking to develop a blood test screening tool for use in primary care to detect the early stages of liver disease and damage.

During development before birth, SOX9 makes proteins that form the structures around which cells sit, helping to build organs and tissues.  SOX9 functions less as we grow older, but in adults with chronic liver disease it seems to be switched back on to try to repair the damaged liver by creating a new layer of protein. Many of the proteins SOX9 makes in development are also found in scars.  As a result, switching on SOX9 in the liver during disease creates excessive layers of scar proteins to build up, creating a patchwork of tissue damage and repair that stops the liver working properly.

“We have found the number of cells switching on SOX9 in the liver increases as the disease gets worse,” said Dr Piper Hanley.  “Excitingly, we have also discovered that an early increase in SOX9 cell numbers in patients with mild liver disease tells us who will progress quickly with worse scarring.”

As part of their ongoing research, Dr Athwal and his colleagues have now detected when SOX9 is active in liver disease patients through a blood test for the proteins it makes.  This means they can regularly check the blood of these patients, rather than having to carry out invasive surgical biopsies, and predict those who are at high risk of developing fibrosis and so provide treatment before this happens.

Their findings will help with the development of potential drugs to stop SOX9 from switching back on, and Dr Athwal is also excited about the opportunity to develop a screening tool to detect people who may have undiagnosed liver disease through the presence of SOX9 or its proteins.

Liver disease is almost entirely preventable with the major risk factors – alcohol, obesity and Hepatitis B and C – accounting for up to 90% of cases, according to Public Health England data.  It is responsible for almost 12% of deaths in men aged 40 to 49 years and is now the fourth most common cause of ‘years of life lost’ in people aged under 75, after heart disease and lung cancer. 

“The Greater Manchester population has high levels of liver disease, and in many people it goes undiagnosed until it is too late to treat,” said Dr Athwal.  “We want to use our work on SOX9 to develop a standard blood test which can be used by GPs as part of regular health checks.  People who are shown to be at higher risk can then make choices about diet, lifestyle and alcohol consumption and so reduce the chance of developing liver disease and fibrosis.”

Dr Athwal was awarded fellowships by the NIHR Manchester Biomedical Research Centre and the Medical Research Council (MRC) to fund his four-year research study with Dr Piper Hanley’s lab, also funded by MRC.  He is continuing his clinical work at Manchester Royal Infirmary and Wythenshawe Hospital while also working on the next stage of the SOX9 research.