The Midlands Liver Research Alliance: Improving obesity-related liver disease studies in high-risk and underserved communities

In Western nations, liver disease is the only chronic condition demonstrating a yearly increase in prevalence, making it the 5leading cause of death after heart disease, cancer, stroke, and respiratory disease. A major contributor to this trend is the surge in metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). The prevalence of these conditions in Europe is high, estimated at 32% and 4% (general population), respectively. High levels of obesity and type 2 diabetes mellitus (T2DM) underpin these conditions, which increases the risk of cardiovascular disease (CVD) and reduces life expectancy. th ^{1 2}

MASLD is a generic term encompassing a spectrum of pathological hepatic phenotypes. In obesity, excess accumulation of liver fat is the primary insult associated with dysglycemia and heightened cardiovascular risk. Over time, the development of hepatic inflammation and hepatocyte injury indicates a more advanced and aggressive phenotype with a more deleterious prognosis. Specifically, the subsequent development of hepatic fibrosis, sometimes termed fibrotic MASH, represents a clinical milestone in which progression to CVD and end-stage liver disease is exaggerated, multiple long-term conditions (MLTC) are common, and health-related quality of life is poor. ²

Therefore, weight loss and long-term weight loss maintenance are the primary targets in the management of MASLD. However, lifestyle approaches (diet and physical activity) are typically unable to facilitate clinically meaningful and sustained weight loss in most people. The field of anti-obesity pharmacotherapy has ignited in recent years, led by glucagon-like peptide-1 (GLP-1)-based therapies. Following the STEP phase 3 trial program, the GLP-1 receptor agonist (GLP-1 RA) semaglutide (2.4 mg) was licenced in the UK for the treatment of obesity. These trials showed that semaglutide induces clinically relevant weight loss in people with obesity, which is sustained while the treatment is maintained. More recently, the GLP-1 / gastric inhibitory polypeptide (GIP) receptor co-agonist tirzepatide (at doses of 5, 10, and 15 mg) was approved for obesity therapy in the UK. The weight loss induced by tirzepatide 15 mg is greater than semaglutide 2.4 mg. Moreover, in individuals with liver disease, tirzepatide was recently shown to resolve MASH in two-thirds of individuals and reduce fibrosis by more than one stage in approximately half. With tirzepatide, questions remain about whether longer treatment duration (to permit maximum weight loss) is able to provide greater hepatic benefits and the impact of therapy on key patient-reported outcomes, including functional health. Moreover, the extent to which the benefits of pharmacotherapy can be potentiated by lifestyle (exercise and diet) remains unclear. ^{3 4 5 6 7 8}

In addition to obesity, GLP-1-based therapies may have wider applications in liver disease, specifically in the treatment of alcohol addiction (alcohol use disorder [AUD]). In the UK, alcohol-related liver disease (ARLD) has increased sharply in recent years and is difficult to treat. Moreover, half of the people with AUD also have obesity, which potentiates adverse health effects, including mortality. The pernicious interaction between alcohol consumption and obesity-related liver disease was formally recognized in the recent update to the liver disease nomenclature, with the term 'metabolic dysfunction and alcohol-associated liver disease' (MetALD). In a global Delphi consensus study, this term was chosen to indicate patients with MASLD who regularly consumed alcohol (140–350 g/week women, 210–420 g/week men) without a diagnosis of ARLD. While GLP-1 therapies reduce appetite and food intake through central effects in the hypothalamus, wider impacts on central reward-related pathways may reduce craving for alcohol. At present, a range of pre-clinical and observational studies have shown the potential of GLP-1-based therapies in AUD. However, further experimental research is needed to demonstrate its efficacy in humans. ^{9 10 11 12 9}

The health and economic burden of liver disease is heavily biased towards advanced stages. Modelling of future disease prevalence indicates that specialist hepatology and gastroenterology services will experience increasing strain. Therefore, risk factor identification and early intervention are becoming increasingly important for patients and health services. Primary care is central to this ambition, yet liver disease is often not a priority for GPs and AHPs in general practice. Besides competing priorities, this may be due to a lack of knowledge, confidence, and ongoing training on liver disease in primary care. This may also be related to the absence of bespoke therapies in at-risk patients. A better understanding and awareness of liver disease, for healthcare professionals and patients with risk factors, is needed in a switch to a more prevention-focused mindset. ^{13 14} , ^{15 16}

The prevalence and health burdens associated with obesity-related liver disease disproportionately affect people living in poorer regions, including minority ethnic groups and coastal communities. Notably, the Chief Medical Officers' annual report in 2021 highlighted high rates of preventable diseases and low life expectancy in coastal regions, encouraging strategies to address health inequalities. Moreover, individuals from South Asian communities are known to more readily develop obesity-related conditions such as T2DM and MASLD, underscoring the importance of research in areas of greatest need. ^{17 18}

The overarching aim of our NIHR liver partnership award was to explore issues and identify research questions surrounding obesity-related liver diseases and associated health inequalities in the UK. To do this, we set out to establish a cross-sector, multidisciplinary research partnership based in the Midlands, but with support from collaborators nationally and internationally. Our specific objectives were as follows:

Our research team first engaged with our PPIE networks during the development of our NIHR liver partnership funding application. Initially, the core research team liaised with individuals who had previously acted as PPIE representatives for research. Through a series of meetings, these individuals contributed to our initial application by helping to steer the prospective partnership focus.

As explained in detail below, a wider pool of PPIE members and stakeholders become a core part of our partnership. Perhaps their most important contribution to the partnership was their input into the focus and development of funding applications conceived by the partnership. This included the provision of opinion and experience that helped to shape the key research questions, study design and recruitment approaches. For each application submitted, at least one PPIE member agreed to become part of the study team and serve on the trial steering committee.

After receiving the award, an Operational and Engagement lead was appointed to oversee the day-to-day activities associated with the MLRA to create a successful partnership. A series of regular (bi-monthly) core working group meetings were organized and held with partnership investigators, wider stakeholders, and two individuals with a lived experience of obesity-related liver disease (PPIE representatives).

Initially, these meetings strongly focused on the evolution and development of the partnership. The websiteand branding in the form of a logo were designed with the support of PPIE members. The website housed information for patients, members of the public, and healthcare professionals relating to MASLD (e.g., risk factors, risk reduction, stigma, treatments, nomenclature, and interviews with Prof. Guru Aithal and patients with lived experience). It also contained an interactive map of where the partnerships' national collaborators were located and their specialities. https://midlands-liver-research.squarespace.com↗

Core members of the MLRA team attended the launch of the four Nottingham Biomedical Research Center (BRC) partnerships in which the MLRA formed a part. This event was attended by diverse groups, including those associated with local partnerships (academics and clinicians), community and organizational stakeholders, and patients with a lived experience of liver disease. At this meeting, Dr. James King presented the rationale behind the MLRA partnership, and with Prof. Guru Aithal, discussed co-elaborative opportunities with leads from the Nottingham partnerships. Round table discussions concluded the day with key discussions, including improving inclusivity in liver research, ideas of how to build national and local liver PPIE groups, and what outcomes are important in both alcohol- and obesity-related liver research.

The MLRA launch meeting and 'Discovery' priority setting events included people with lived experience, public members, clinicians, and third-party sector organizations covering the whole of the East Midlands. At this collaborative Discovery Event, each of the four Nottingham BRC liver partnerships presented their work to ascertain interest and seek representatives to join one or more of the partnerships, to become empowered, and to enable the development of future liver research proposals. Training on PPIE was also offered in this research. The partnership collaboration event gave everyone the opportunity to talk with other delegates and liver specialists in attendance. The MLRA recruited new PPIE members as a result of this meeting.

Core MLRA members were invited to attend other partnership launch meetings, such as the ALPINE partnership, where all the partnerships were outlined, providing an opportunity for networking and, where possible, collaborative work. During the 18-month term of the partnership, the MLRA core members attended other meetings, such as the British Association of Liver Disease (BASL), British Society of Gastroenterology (BSG), and the MASLD Special Interest group (SIG). These meetings provided an opportunity to update on our progress, with whom we were collaborating, any issues we were experiencing within the partnership, and shared best practices. These meetings were attended by other partnerships, national therapy area specialists, NIHR members, and charity organizations, such as the British Liver Trust. Other topics frequently discussed were the lack of a routine primary care pathway, associated stigma with obesity-related liver disease, and potential issues with the new definitions and nomenclature for people living with MASLD and how this could be integrated within future public awareness campaigns. It also provided the opportunity to discuss potential new future research proposals and whether there would be overlaps or collaborations with other partnerships or working groups.

In conjunction with the Leicester BRC communication manager, a media and marketing plan was developed for the MLRA. Press releases were arranged in a timely manner, highlighting who we are, how you can get involved with the MLRA, and promoting understanding of MASLD and associated risk factors. The audiences that these were released were Leicester, Nottingham, and Birmingham themes and platforms, central members of the core PPIE training operations within Leicester and Nottingham, University Hospitals of Leicester colleagues, GP/primary care, and the public. Part of the campaign included broadcasts through the popular South Asian radio network Sabras radio, increasing awareness, and the risks associated with MASLD during the local GP's health-related segment.

At the core of our partnership was a focus on PPIE. We established PPIE networks within Leicester and Lincolnshire, including people with lived experience. Some of the patient and public groups consisted of Lincolnshireealthiergingatient andublicnvolvement Group (HAPPI), Leicester's Dance and Health group, sports clubs including Leicester City football in the community, Sharma Women Centre, Lincolnshire National institute for Rural Healthcare. These groups determined what activities were important to these communities and how MLRA would support them with increasing knowledge around MASLD to share within their communities. As a result, a 'Language Matters' event was held to disseminate the new agreed terminology and highlighted the stigma and perceptions around MASLD, which is now being used to inform language used in further research proposals. The MLRA also provided further researcher PPIE training and developed PPIE representatives who have gone on to co-applicant roles for the subsequent research proposals. H A P P I

The Nottingham community liver pathway became another important pillar of our PPIE network. Led by Prof. Guru Aithal and Prof. Neil Guha, clinicians in Nottingham set-up this pathway to proactively identify individuals with progressive liver disease in primary care. Patients with risk factors for liver disease (e.g. obesity, T2DM, elevated liver enzymes) are proactively invited for a Fibroscan™ test at a local GP practice or hospital. Those found to have elevated liver stiffness are subsequently invited for a consultation with a hepatologist for further investigation, while others are provided with advice about risk factor management. Members of the MLRA met with clinicians leading this pathway to discuss research priorities. They subsequently attended a series of Fibroscan™ clinics to talk to patients with risk factors and nurses conducting the scans. Investigators also visited hepatology clinics to speak with patients with more progressive disease and the hepatologists leading the clinics. A wealth of knowledge and insight was gained from these sessions. A key element of the success was the 'live PPIE' element, where with patients' consent, investigators were able to sit-in clinics and then talk with patients immediately after their appointment. This was often in the presence of the nurses and doctors, effectively creating mini focus groups – leading to rich discussion. Information gathered from these sessions directly led to two of the funding applications submitted from the MLRA.

With support from our established PPIE networks and wider partners (academic and non-academic stakeholders), research priorities were identified that would form the basis of funding applications for Stage 2 in the NIHR Liver Call. Published lists of research priorities supported this process. A proforma was circulated among our national collaborators to encourage individuals to put forward research ideas that could be developed during the course of the partnership with support from across the network. Ideas were subsequently shared with the network, with the opportunity for interested parties to express their interest in applications. Core working groups were subsequently established around these proposals, which were then developed and refined over the course of the partnership. To date, this process has led to three stage 1 funding applications submitted to the NIHR Liver Call, as detailed below.

A key aim of our partnership was to develop a multidisciplinary network of stakeholders, concentrated in the Midlands yet reaching out nationally, focused on obesity-related liver disease. In all, our network included 89 individuals involving clinicians, academics, PPIE representatives, and individuals working for relevant third-sector organisations. Expertise span obesity, lifestyle (diet and exercise), hepatology/gastroenterology, clinical trials, basic science, and research implementation. At an organisational level, our network now spans three NIHR BRCs (Leicester, Nottingham, Birmingham), three CTUs (Leicester, Nottingham, Lincoln), two clinical research networks (East & West Midlands) and the Leicester, Leicestershire, and Rutland Clinical Research Facility (see). Figure 1

This network of individuals helped define the research needs outlined in the previous section. Within this, the need to train general practice staff (GPs and AHPs) in liver disease prevention and management also emerged as a core clinical priority. Collaborative work with local ICBs (Lincolnshire and Leicester, Leicestershire, and Rutland) enabled the development and pilot testing of our 'Simplifying Liver Disease' education intervention. This intervention was pilot tested in 16 GP practices across Lincolnshire and Leicestershire, involving 34 healthcare professionals.

In relation to infrastructure and capacity to undertake multi-site research, mentorship became a key priority. In particular lead investigators within our funding applications received close mentorship from the MLRA co-directors (Prof. Melanie Davies and Prof. Guruprasad Aithal). To this end, each of our NIHR EME applications had co-leads, with Prof. Davies and Prof. Aithal supporting less experienced colleagues.

Our desire to enhance local research capacity was central to our decision to work with the Lincoln CTU for one of our NIHR EME applications. The Lincoln CTU is a new CTU currently pursuing full accreditation. The MRC CTU provides external support for its expanding portfolio of research. To date, however, the Lincoln CTU has less experience with multi-site CTIMPs. Our application has provided an opportunity to help the Lincoln CTU upskill in this area, with additional support available from our local CTUs (Leicester and Nottingham).

Our funding applications also focused on scoping of research infrastructure across our network. Equipment and expertise in relation to MRI and exercise training interventions are pertinent examples. Mechanistic sub-studies within our EME proposals include plans to harmonise MRI procedures across research sites (Nottingham, Leicester, Liverpool). We have identified the work needed to harmonise and validate processes across MRI scanners. The funding to undertake this work has been included in our application. Within our scoping, we found that many research sites in our network do not have the equipment, facilities, or trained staff to undertake exercise training interventions. To support our funding applications, we have therefore designed new protocols allowing interventions to be completed without specialised resources or the need for high levels of staff training.

With the cessation of funding for the liver partnerships, the MLRA will be incorporated as an entity within the NIHR Leicester (lifestyle theme) and Nottingham BRCs (gastrointestinal and liver themes). With oversight provided by Prof. Davies and Prof. Aithal, our focus on obesity-related liver disease will be steered forward by partnership co-investigators.

In the immediacy, our focus will depend on the outcome of our stage 1 funding applications to the NIHR Liver Call. Additionally, we envisage our research and practice efforts centring on three key areas in the short-to medium-term:

No activities within this reported required ethical approval.