PROJECT SUMMARY This application is in response to RFA-DK-20-003, which is a limited competition opportunity with the objective of establishing the Liver Cirrhosis Network (LCN). Cirrhosis has doubled in prevalence in the last decade and is now the 11th leading cause of death in the United States. The number of cirrhosis-related deaths is projected to triple by 2030, with NASH projected to overtake HCV as the leading cause of liver transplantations. Severe limits on the number of liver transplantations performed each year and anticipated increases in the cirrhosis patient population create an urgent need to better understand predictors of mortality in cirrhosis and develop effective therapies to treat cirrhosis. Studies from our group and others suggest statins may reduce future risk of HCC and decompensation in patients with cirrhosis. Among statins, lipophilic statins such as atorvastatin have shown the greatest chemopreventive effects against HCC occurrence. Atorvastatin is associated with dose-dependent reduction in incident cirrhosis in HCV patients. Data supporting statin use for cirrhosis are promising, but larger, randomized controlled trials (RCT) are needed to determine whether they may be routinely recommended. To address the needs of the cirrhosis patient population, this research plan proposes the following aims: Aim 1: To conduct a prospective, longitudinal, multicenter, multi-ethnic cohort study of patients with cirrhosis. Among Hispanic men, cirrhosis is the 6th leading cause of mortality. To address this health disparity, we will test the hypothesis that Hispanic patients with cirrhosis are at higher risk for hepatic decompensation compared to non-Hispanics. We will establish and monitor a cohort of patients who have cirrhosis due to multiple etiologies. Primary endpoints include (a) a composite endpoint of hepatic decompensation, (b) liver transplantation, or (c) all–cause mortality. Ancillary studies will investigate associations between non-invasive imaging biomarkers, cirrhosis genetic risk score, and risk of decompensation. Following up on our previous work, we will also identify a microbiome signature that may predict decompensation risk. Aim 2: Phase 2, multi-center, double-blind, placebo-controlled, RCT evaluating efficacy and safety of atorvastatin 20 mg in subjects with compensated cirrhosis. The objective is to test the hypothesis that atorvastatin is more effective than placebo in reducing risk of decompensation, all-cause mortality and other liver-related clinical outcomes in cirrhosis patients. Primary outcome measure will be time to the first occurrence of any of the following adjudicated events: all-cause mortality, MELD score ≥ 15, liver transplant, ascites requiring medical intervention, hospitalization for onset of variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, and development of hepatocellular carcinoma. Secondary outcomes include safety of atorvastatin, decrease in fibrosis, as ...