University of Edinburgh

Innovate UK

DL_2024_021

Metabolic dysfunction-associated steatotic liver disease is the commonest cause of liver disease, affecting 1 in 4 adults. However, not everyone with a fatty liver goes on to have serious liver problems; only about 20% progress to the more severe form, called non-alcoholic steatohepatitis (NASH), which can lead to liver cirrhosis (where healthy cells are replaced by scar tissue), liver cancer and premature death. Currently, we have no way of telling which people with MASLD might develop NASH or cirrhosis and there are no medicines ‘on the market’ to treat this condition. The crucial question is why does MASLD progress in some people but not in others? The answer to this will lead to new diagnostic tests, and effective treatments. To address this, we aim to build up a large group (n=1000) of MASLD cases from across Scotland, using NHS liver samples that are no longer needed and collecting relevant clinical information from electronic health records. This information will help us to understand about: 1) the sort of liver damage that can develop in MASLD; 2) which genes are present in the liver as MASLD gets more severe; and 3) how this relates to various health problems in people with MASLD. We will keep this information in a secure database and analyse it using bioinformatics (an approach that uses computer science to understand biological data) in order to improve the care of people with MASLD.

The clinical problem and unmet need: MASLD represents a public health crisis, affecting ~25% of the UK population, and is a government health priority (e.g. All-Party Parliamentary Hepatology Group Inquiry; Lancet Standing Commission). It has massive and disproportionate healthcare and societal impacts, particularly in Scotland which has the 3rd highest adult prevalence rate of overweight and obesity in the world. The progressive form of MASLD (NASH) can lead to liver cirrhosis, liver cancer and premature death. Death rates from chronic liver disease in Scotland are 70% higher than the UK average and 60% higher than 30 years ago (Scottish Public Health Observatory). MASLD is also associated with an increased risk of morbidity and mortality from cardiovascular disease, chronic kidney disease and many cancers. In the Europe-4 countries alone, there are ∼52 million people with MASLD at an annual healthcare cost of ~€35 billion (Younossi et al 2016, Hepatology 64:1577). In the UK, the projected increase in total cases of NASH between 2015-2030 is +43% (Estes et al 2018, Hepatology 67:123), and there is a strong correlation with social deprivation. MASLD predominantly affects those in working life, reflected in the 201,724 years of working life lost in England due to chronic liver disease in 2012-14, more than the number lost due to lung and colorectal cancers combined. Health-related quality of life (HRQoL) is impaired in patients with MASLD, with a range of symptoms, especially fatigue, and the impact on individuals and society in general is broad. Therefore, the wider impacts of MASLD include medical and non-medical costs (direct costs), loss of productivity (indirect costs) and health-related quality of life (HRQoL) (intangible costs). However, MASLD has a highly variable rate of progression, with a lack of effective biomarkers to predict longer-term clinical outcomes. Additionally, there are no approved medicines for the treatment of NASH or liver cirrhosis. Benefits to patients and the NHS: Via a ‘big data’ approach utilising archival liver tissues, RNA sequencing, data extracted from patient health records and other administrative datasets, key outputs of the SteatoSITE project are to identify: i) reliable biomarkers that predict MASLD progression and clinical outcomes, and ii) actionable treatment targets for repurposed or novel drugs. Gene transcriptional changes will be linked to liver histological features and clinical outcomes in order to determine the optimal treatment approach for patients at different stages of MASLD. The Data Commons platform will also facilitate the future development of a widely-applicable clinical decision support system (CDSS) that will transform the clinical management of MASLD. Accurate stratification of the risk of progression would lead to a step-change in referral patterns and clinical pathways (focussing resources on those patients who need close monitoring in secondary care whilst reassuring other patients at low risk of clinical outcomes), streamlined clinical trial design and a personalised approach to MASLD. Early and effective intervention in MASLD would mitigate chronic ill health, reduce NHS costs, address government health policy targets, improve HRQoL and increase workforce productivity. Education and public empowerment: Among patients with diseases most associated with NASH (type 2 diabetes, obesity, and hypertension) only 6% had heard of MASLD (Continuum Clinical, 2019). Low public awareness is a barrier to preventative health strategies and to clinical trial enrolment. We will work closely with our PPI group to identify opportunities to maximise public and patient benefit. We will also engage with the British Liver Trust and liver support groups to disseminate the research through their websites and networks. Our Public Engagement Officer will craft plain English summaries and visual representations for the public section of our institutional website and for the annual International NASH Day (a public education campaign to raise visibility and urgency around MASLD) to ensure our research has global reach. We will also identify opportunities and produce materials for participation in Science Festivals, public lectures and other events. Benefits to broader industry and the UK economy: Development of a marketable CDSS for MASLD will position the project partners and UK PLC at the forefront of advanced diagnostic solutions for this condition. This would avoid potential foreign dependency in emerging products (e.g. Genfit’s NIS-4 algorithm). Efficient stratification of patients for clinical trials will benefit Contract Research Organisations, biopharmaceutical companies and catalyse UK trial activity in NASH (a potential global drug market of $21.5 billion by 2025).

Public Health Research

28/08/2024

De-Personalised

TRE