LITMUS

The liver is an extremely resilient organ that plays an essential role in the body’s metabolism. It has a unique ability to regenerate itself, but, if it becomes too damaged (which happens when fat accumulates causing scarring and cirrhosis), it eventually loses this superpower and stops working so well.

Metabolic-dysfunction associated steatotic liver disease (MASLD), formerly called non-alcoholic fatty liver disease (NAFLD) affects more than 30% of people worldwide, and that number is rising. It is estimated to cost healthcare systems worldwide over €35 billion per year in direct costs, and further societal costs of €200 billion.

If you’re overweight or obese, if you have diabetes, high blood pressure, high cholesterol or if you don’t exercise enough, then you could be at risk of MASLD.

For a person who is not drinking more alcohol that the recommended amount (14 units per week for women and 21 per week for men), the early stages of MASLD can often go unnoticed. A liver biopsy can reveal that a person has MASLD, but as these biopsies are invasive procedures, they are only recommended if the chances of a person having liver disease is very high. If clinicians diagnose a person with MASLD, then lifestyle interventions like diet and exercise that can help bring the weight down are recommended to help prevent disease progression.

In one out of ten cases of MASLD, the liver cells become increasingly damaged and inflamed. Fibrosis and scarring can start to happen. At this point, the diagnosis shifts to MASH (metabolic dysfunction-associated steatohepatitis). People with MASH may start to experience symptoms like fatigue or a mild ache in the area of the liver. But because these symptoms may not appear, or may be caused by something else that is happening in the body, it is still quite difficult to diagnose MASH, and unfortunately people are often diagnosed when it is too late to manage.

In a person with MASH, as the amount of scarring in the liver increases, the liver becomes cirrhotic and there is an increased risk of liver failure or liver cancer. Once the liver starts to fail, people may experience abdominal swelling and bruising easily, yellow discolouration in the skin and eyes (jaundice) or confusion (hepatic encephalopathy) This is the stage of advanced damage and loss of liver function, and, in the absence of licenced medicines to treat cirrhosis, the only treatment option is a liver transplant.

The gap between MASLD and MASH

It’s not yet clear why, but only about 10% of people with MASLD progress to MASH. LITMUS focused on this knowledge gap, furthering knowledge and producing resources to help researchers and clinicians to better understand who is more likely to develop MASH, as well as developing better techniques for diagnosing the severity of patients’ liver disease and monitoring changes in the severity of liver disease.

The project built on and expanded an existing patient registry, which involved collecting medical information, blood and tissue samples and a range of images collected using state-of-the-art imaging techniques such as MRI scans, until it included more than 10 000 people with MASLD. Known as the “European MASLD Registry”, this is the largest international registry of biological data on MASLD patients. It includes longitudinal data from follow-up studies to give researchers a clearer picture of how the disease progresses over time, as well as an atlas of histological images that can help to train pathologists on how to diagnose and spot liver disease in liver biopsy samples. This information will help researchers to pick out the biological similarities between those patients that eventually develop MASH, and to see whether there are signals in their blood samples or scans that could potentially predict MASH onset.

As well as studying a large number of already-established diagnostic tests (e.g. ELF, PROC3, NIS2+, etc), LITMUS undertook large multi-omics studies leveraging the power of machine learning to identify potential new signals that could become biomarkers in the future (including GDF15, TSP-2 and miRNA miR193a). LITMUS has worked closely with the FDA in USA and the EMA to advance some biomarkers towards regulatory qualification.  Specifically, a Qualification Plan (QP) has been submitted to the FDA for a diagnostic enrichment biomarker that is intended, in conjunction with clinical factors, to identify patients likely to have MASH. This QP included the markers FAST, PRO-C3 and the ADAPT score. However, other biomarkers which have been validated within LITMUS might also be suitable for regulatory qualification, either in the same context of use or a different context of use. Ultimately, one of the goals is to validate and qualify biomarkers that can decrease or eliminate the use of liver biopsy within the context of drug development for MASH.

Monitoring liver disease in MASH patients

For patients who already have MASH, up until now there has been no quantifiable way to determine how the disease was affecting their quality of life. As part of the LITMUS project, a new patient-report outcome questionnaire called the NASH-CHECK was developed with input from patients.

The tool is freely available, and a NASH-CHECK user license has already been provided to several pharmaceutical companies including Pfizer, Boehringer-Ingelheim and Novo Nordisk for use in their interventional studies. NASH-CHECK has been submitted to the European Medicine Agency for biomarker qualification scientific advice and it could become a well-accepted measure to quantitatively assess symptoms and health-related quality of life in the future.

The data generated through LITMUS is already influencing clinical guidelines, including the recently published joint EASL-EASD-EASO MASLD guidelines (2024).

Building the foundations for future research and innovation

The outputs from LITMUS are already being used in drug development pipelines. Industry partners from within the project are integrating non-invasive solutions that don’t require biopsies to learn more about how the disease progresses through patients’ bodies and their responses to potential treatments.

A European Collaborative Research Network on MASLD has been established which will continue to manage the European MASLD Registry past LITMUS’ end, ensuring that this resource remains available to researchers to extract further learnings. The registry is a potential platform to support post-marketing surveillance of the first medicine for MASH, which is already on the market in the US and is being assessed by the EMA.

Two new IHI projects, GRIPonMASH and LIVERAIM, are building on the results of LITMUS to improve conditions for liver disease patients. Both are addressing the use of existing biomarkers to support population screening and case finding for advanced liver disease due to MASLD, and will endeavour to develop a screening platform for early and personalised diagnosis in general populations.