ENU mutagenesis and mouse models of steatosis, steatohepatitis and fibrosis

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Digital Intervention With Lifestyle Coach Support to Target Dietary and Physical Activity Behaviors of Adults With Nonalcoholic Fatty Liver Disease: Systematic Development Process of VITALISE Using Intervention Mapping

Background: Non-alcoholic fatty liver disease (NAFLD) is linked to excess calorie consumption, physical inactivity and being overweight. Patients with NAFLD can halt or decelerate progression, and potentially reverse their condition by changing their lifestyle behaviour. National and international guidelines recommend the use of lifestyle interventions, however there remains a discordance between published guidelines and clinical practice. This is primarily due to a lack of NAFLD-specific lifestyle interventions to support weight loss and improve liver function. Objective: To use Intervention Mapping to systematically develop a digital intervention to support patients with NAFLD to initiate and maintain changes to their dietary and physical activity behaviour to promote weight loss. Methods: Intervention Mapping consisted of 6 steps. A needs assessment with primary and secondary healthcare professionals and patients with NAFLD (step 1). Identification of the social cognitive determinants of change and behavioural outcomes of the intervention (step 2). Linking social cognitive determinants of behavioural outcomes with behaviour change techniques to effectively target dietary and physical activity behaviour (step 3). Step 4 involved the development of a prototype digital intervention that integrated the strategies from step 3, and the information content identified as important for improving knowledge and skills from steps 1 and 2. Step 5 involved development of an implementation plan with a digital provider of lifestyle behaviour change programmes to NHS patients using their delivery platform and lifestyle coaches. Finally, step 6 involved piloting the digital intervention with patients to obtain data on access, usability and content. Results: A digital intervention was developed consisting of eight modules, self-regulatory tools and provision of telephone support by trained lifestyle coaches to help facilitate behavioural intention, enactment and maintenance. A commercial provider of digital lifestyle behaviour change programmes enrolled 16 patients with NAFLD to the prototype intervention for 12 consecutive weeks. Eleven of the 16 participants successfully accessed the intervention and continued to engage with the content following initial log-in (on average four times over the piloting period). Most frequently accessed modules were “welcome to the programme”, “understanding NAFLD”, and “food and NAFLD”. Goal setting and self-monitoring tools were accessed on 22 occasions (four times per tool on average). Three out of eleven participants requested access to a lifestyle coach. Conclusions: Intervention Mapping provided a systematic methodological framework to guide a theory- and evidence-informed co-design intervention development process with patients and HCPs. The digital intervention with remote support by a lifestyle coach was acceptable to patients with NAFLD and feasible to deliver. Issues with initial access, optimisation of information content and promoting the value of remote lifestyle coach support require further development ahead of future research to establish intervention effectiveness

Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases

Key physiological functions of the liver, including glucose and lipid metabolism, become disturbed in the setting of non-alcoholic fatty liver disease (NAFLD) and may be associated with a systemic inflammatory 'milieu' initiated in part by liver-secreted cytokines and molecules. Consequently, the pathophysiological effects of NAFLD extend beyond the liver with a large body of clinical evidence demonstrating NAFLD to be independently associated with both prevalent and incident cardiovascular disease (CVD), chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). The magnitude of risk of developing these extrahepatic diseases parallels the underlying severity of NAFLD, such that patients with non-alcoholic steatohepatitis (NASH) appear to be at greater risk of incident CVD, CKD and T2DM than those with simple steatosis. Other modifiers of risk may include genetic variants (eg, patatin-like phospholipase domain-containing 3 and trans-membrane 6 superfamily member 2 polymorphisms), visceral adipose tissue accumulation, dietary intake and the gut microbiome. Emerging data also suggest that NAFLD may be a risk factor for colonic neoplasia and reduced bone mineral density, especially among men. Importantly, improvement/resolution of NAFLD is associated with a reduced incidence of T2DM and improved kidney function, adding weight to causality and suggesting liver focused treatments may reduce risk of extrahepatic complications. Awareness of these associations is important for the clinicians such that CVD risk factor management, screening for T2DM and CKD are part of the routine management of patients with NAFLD

Platform trials to overcome major shortcomings of traditional clinical trials in non-alcoholic steatohepatitis? Pros and cons

Non-alcoholic steatohepatitis; Drug development; Non-invasive biomarkersEsteatohepatitis no alcohólica; Desarrollo de fármacos; Biomarcadores no invasivosEsteatohepatitis no alcohòlica; Desenvolupament de medicaments; Biomarcadors no invasiusNon-alcoholic fatty liver disease is a condition that affects 25% of the population. Non-alcoholic steatohepatitis (NASH) is a progressive form of the disease that can lead to severe complications such as cirrhosis and hepatocellular carcinoma. Despite its high prevalence, no drugs are currently approved for the treatment of NASH. The drug development pipeline in NASH is very active, yet most assets do not progress to phase III trials and those that do reach phase III often fail to achieve the endpoints necessary for approval by regulatory agencies. Amongst other reasons, the methodological and operational features of traditional clinical trials in NASH might impede optimal drug development. In this regard, platform trials might be an attractive complement or alternative to conventional clinical trials. Platform trials use a master protocol which enables evaluation of multiple investigational medicinal products concurrently or sequentially with a single, shared control arm. Through Bayesian interim analyses, these trials allow for early exit of drugs from the trial based on success or futility, while providing participants better chances of receiving active compounds through adaptive randomisation. Overall, platform trials represent an alternative for patients, pharmaceutical companies, and clinicians in the quest to accelerate the approval of pharmacologic treatments for NASH.EU-PEARL has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 853966-2. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and Children’s Tumor Foundation, Global Alliance for TB Drug Development Non-profit Organisation, Springworks Therapeutics Inc