The liver performs more than 500 vital functions in the body, such as processing all of the blood leaving the stomach and intestines as well as breaking down nutrients and metabolising drugs. It can even regenerate itself, but fat deposits can block this ability and lead to liver disease and cancer.
Liver disease affects more than 30% of people worldwide, and kills more than 1.5 million people per year. A person can develop liver disease if they get a viral infection like hepatitis B, if they consume a lot of highly-processed foods and alcohol, or if a medication that they are taking causes damage to their liver.
IHI and IMI projects have been investigating how liver disease progresses, with the goal of better predicting who is more likely to develop severe forms.
Combatting fat-associated liver disease
About a quarter of all adults have fatty deposits building up upon their livers – a condition known as metabolic dysfunction-associated steatotic liver disease (MASLD). Nine out of ten people with this condition may never even know they have it.
But 10% go on to develop hepatitis, then liver cirrhosis or liver cancer and finally death.
Despite the prevalence of this disease, little is known about MASLD and how it progresses. The IMI2 LITMUS project set out to develop tools to help researchers to better identify who has MASLD and how to predict who will go on to develop metabolic dysfunction-associated steatohepatitis (MASH).
If those who are likely to develop MASH can be detected earlier, then lifestyle changes can be implemented to prevent disease onset.
“MASH is known as a "silent disease" because it has few or no symptoms, especially in its early stages. But with this alarming continued increase, we are no longer talking about a ‘silent disease’ but about a ‘silent epidemic’, which now requires a different approach,” says Yiannoula Koulla, the president of the Cyprus Liver Patients Association and leader of the European Liver Patients’ Association’s work on fatty liver disease.
“It is not just a liver issue—it also increases risks for cardiovascular disease and type 2 diabetes. Early intervention helps mitigate these risks and improves overall health outcomes.”
Spotting early-stage liver disease
LITMUS grew an existing patient register, the European MASLD Registry/Biobank, to more than 10 000 people, making it the largest international register of biological data on MASLD patients.
The biobank contains longitudinal data from follow-up studies which can give researchers a clearer picture of how the disease progresses over time, as well as an atlas of histological images that can train pathologists to spot early-stage liver disease. This information will help researchers to pick out the biological similarities between those patients that eventually develop MASH, to see if there are any warning signs.
LITMUS also undertook multi-omics studies to identify potential new signals that could become biomarkers in the future. The project has worked closely with the FDA in USA and the EMA to advance some biomarkers towards regulatory qualification.
This is an important result because at present, to determine if someone has MASLD or MASH or not, surgical biopsies need to be performed. If there was a simpler and less invasive way to replace these biopsies - such as a blood test - then more people could be tested for MASLD and MASH, and steps could be taken to prevent liver disease.
New IHI projects building on the foundations laid by IMI
Two brand-new IHI projects, GRIPonMASH and LiverAIM, will build on previous work done by IMI projects to improve early diagnosis of people at risk of fat-associated liver disease.
GRIPonMASH aims to develop a new platform that will screen for people with risk factors of MASLD (e.g. diabetes, metabolic syndrome, obesity and high blood pressure). Tools based on AI will then identify who is at the greatest risk of developing MASH.
GRIPonMASH will also search for alternatives to biopsies for diagnosing MASH, for instance using imaging and organ-on-a-chip technologies. The platform will also provide personalised advice to patients to help improve their lifestyles and prevent liver deterioration.
Although a number of biological markers of liver damage have been identified, many of them have not been tested on large numbers of people. LIVERAIM will take biological samples and data from LITMUS and other projects to evaluate the accuracy of existing biomarkers in predicting fibrosis in people that are healthy as well as people that have MASLD.
“LiverAIM is a revolution in liver health—a project that turns hope into action for patients everywhere. For the patient community, it signifies more than progress; it’s a promise of earlier diagnoses, better treatments, and a future where no one is left behind,” says Milan Mishkovikj, the director of the European Liver Patients’ Association (ELPA) and leader of the ELPA working group on liver cancer.
A third recently-launched IHI project, VIROMARKERS, is working on developing biomarkers that could drastically improve the care of people living with hepatitis D. Hepatitis D is a particularly severe form of hepatitis and a new drug, bulevirtide, has been a game-changer in the treatment of this disease. However, it's not clear which patients will respond best to the drug, and VIROMARKERS will shed light on that.
A beacon of hope
For patients, the work of projects such as these is vital.
“This research is a beacon of hope, empowering individuals and transforming lives and systems. It reminds us that through collaboration, innovation, and compassion, we can overcome challenges and create a world where liver health is not just a dream but a reality for all. Together, we are changing lives and shaping a healthier tomorrow,” says Mishkovikj.
LITMUS is supported by the Innovative Medicines Initiative, a partnership between the European Union and the European pharmaceutical industry. GRIPonMASH, LIVERAIM and VIROMARKERS are supported by the Innovative Health Initiative.