Liver Cirrhosis Network: Longitudinal and Clinical Trial Studies

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PROJECT SUMMARY The rising prevalence of cirrhosis, the end-stage of any chronic liver injury, is a significant contributor to morbidity and mortality in the United States. Preventative measures including treatment of underlying liver disease, monitoring and screening for complications and addressing risk factors associated with disease progression are key to improved survival. As cirrhosis progresses, complications such as liver failure and liver cancer develop, resulting in death. Racial/ethnic minorities, individuals with substance use disorders, HIV infection, and those with low socioeconomic status are all at high risk for cirrhosis complications due to comorbidities and barriers to healthcare access. Liver transplantation is the only medically viable option in end stage liver disease but given the shortage of organs and even more numerous patients who are unable to be considered for liver transplantation listing, there is a significant need to improve our understanding of underlying pro- and anti-fibrotic processes and risk factors along with potential therapies to halt disease progression. In addition, evaluation of contribution of clinical risk and social determinants of health that may differentially impact cirrhosis burden in at risk populations is critical to addressing disparities in cirrhosis burden in this country. Thus, effective strategies for prevention of cirrhosis complications is a high-priority need. Accumulating evidence suggests that statin, a lipid lowering drug, has a preventative role in cirrhosis. Statins improve portal venous pressure and decrease liver cancer risk and mortality in cirrhosis in epidemiologic studies and limited clinical trials. However, large pragmatic randomized controlled trials in patients with compensated cirrhosis are required to confirm these observations. To address these gaps in knowledge about cirrhosis as well as the unmet clinical needs of patients with the disease, two sites within the University of California, San Francisco (UCSF) and their diverse community links will contribute to the Liver Cirrhosis Network with the following specific aims: 1. To assemble a longitudinal cohort with diverse etiology and stage of cirrhosis supported by comprehensive clinical measures and a biospecimen repository in order to promote clinical and translational research in cirrhosis; 2. To conduct a randomized controlled double-blind trial testing the efficacy and safety of a rosuvastatin versus placebo in patients with compensated cirrhosis. Our short-term goals are to better characterize clinical risks and social determinants of health associated with cirrhosis complications in at risk populations, to evaluate a Hippo pathway related mechanism for cirrhosis progression (the YAP score), and to assess the role of rosuvastatin in compensated cirrhosis and clinically significant portal hypertension from fatty liver disease (alcoholic and nonalcoholic) and chronic viral hepatitis in those with or without HIV infection. The results are expected to have broad implications, given that progressive fibrosis defines chronic injury not only in the liver but in essentially all epithelial tissues.