MASLD (formerly called NAFLD) is a common condition, strongly associated with the Metabolic Syndrome (obesity, type 2 diabetes mellitus and dyslipidaemia) and characterised by substantial inter-patient variability in severity and rate of progression. An important paradox exists: a significant proportion of the population have MASLD but only a minority progress to advanced liver disease or morbidity/mortality.
The transition from MASL to MASH and the stage of fibrosis are important discriminators between a relatively benign prognosis and an increased risk of morbidity/mortality. Liver biopsy remains the established but imperfect ‘gold standard’ investigation, being invasive, resource intensive, prone to sampling error and carrying a small but significant risk of complications. Such invasive tests are not practical outside specialist practice and are particularly unsuitable with such a large ‘at risk’ population. A lack of tractable non-invasive biomarkers has impeded the diagnosis, risk stratification and monitoring of patients. It has also hampered drug development and the conduct of clinical trials, which still depend on histological effect as an endpoint. The overarching aim of LITMUS was to develop, robustly validate and advance towards regulatory qualification biomarkers that diagnose, risk stratify and/or monitor MASLD/MASH progression and fibrosis stage. Success will help target care to those at greatest risk, and ultimately facilitate drug development and novel treatments.
The LITMUS project delivered a step-change in our understanding of biomarkers for MASLD/MASH and realised the following objectives:
1. Expanded the ‘European NAFLD Registry’ through prospective recruitment of well-characterised cases so that it is now the largest international cohort of patients with histologically characterised MASLD/MASH under longitudinal follow-up.
2. Established a robust technological and methodological platform for the definitive validation of candidate biomarkers. Thus, LITMUS has built an impartial, technology-unbiased platform for biomarker discovery, assessment and validation across the MASLD spectrum and all three FDA BEST biomarker domains (diagnostic, prognostic and
monitoring), with a clear line of sight to regulatory qualification.
3. LITMUS has identified and defined the most accurate and tractable biomarkers relevant to MASLD, publishing a series of seminal papers on biomarker performance and advancing the discovery of new biomarkers.
4. The biomarker validation work conducted by LITMUS is of the requisite standard to support regulatory qualification of biomarkers and has underpinned a number of regulatory submissions to agencies in Europe and USA.
5. LITMUS has also addressed the pre-clinical drug development space, building consensus on the phenotypic validity of preclinical models of MASLD/MASH and back-translating biomarkers for validation in these models so that they may be used in pre-clinical drug development.
