Metabolic Surgery for Steato-Hepatitis

Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and type 2 diabetes mellitus (T2DM) and is characterised by excess liver fat on imaging or histology. NAFLD affects up to 25% of the Western population. It\'s more aggressive form is non-alcoholic steatohepatitis (NASH) characterised by cell injury, inflammation and fibrosis, and is associated with increased mortality from liver and cardiovascular disease. Currently, there is no specific treatment for NASH. Diet and exercise-induced weight loss remain the only recommended options. However, maintaining weight loss in the long term is difficult. There is therefore a significant unmet need for effective therapy in patients with NASH that can address the underlying mechanisms of disease. Although preliminary observational evidence suggests that bariatric/metabolic surgery, especially RYGB can improve NASH, no controlled trials to date has confirmed the efficacy of surgery compared to standard weight loss programs. Also, while animal and clinical studies have shown that bariatric surgery exerts weight-independent effects on glucose metabolism, it is yet unknown if the observed effects of bariatric/metabolic surgery on NASH are due to weight loss alone or result from additional, weight-independent mechanisms, like in the case of T2DM. If the effect of surgery on inflammation, liver fibrosis and other mechanisms of cardiometabolic risk were found to be independent on weight reduction, there would be profound and far-reaching implications for both the treatment and the understanding of NASH, cardiovascular disease and obesity-related cancers. This project will investigate the hypothesis that, similarly to surgical control of diabetes, bariatric/metabolic surgery can also exert weight-independent effects on mechanisms of disease in NAFLD/NASH (i.e. influence on lowgrade inflammation and markers of fibrosis)