Project Summary/Abstract: Cirrhosis and its complications including hepatocellular carcinoma (HCC) are increasingly common causes of morbidity and mortality in the United States. The central hypotheses of this application are that (1) the creation of a prospective cohort study of patients with compensated cirrhosis will facilitate the generation of novel prediction models based on the clinical, behavioral, metabolic, and biomarker data we collect to predict clinical decompensation, (2) this cohort can validate and then be supplemented by a larger electronic health record (EHR)-based virtual cohort, the latter of which will enable validation of electronic cirrhosis phenotypes and subsequent analysis of real-world data on the safety and effectiveness of individual lipid-lowering agents on multiple outcomes among patients with cirrhosis and (3) long-term statin therapy will provide clinical benefits in preventing hepatic decompensation and HCC independent of its lipid lowering effect. To investigate these hypotheses, we propose unique approaches to both the cohort study and statin-based clinical trial for the Liver Cirrhosis Network (LCN). In Aim 1a, we will create a prospective cohort of highly phenotyped patients with compensated NASH, ALD, cholestatic and cryptogenic cirrhosis, in order to facilitate the interrogation of biospecimens, patient reported behaviors and outcomes, and clinical data for novel predictors of disease progression, and to understand through serum lipoproteins measurement the complex interaction between cirrhosis and lipid metabolism. In Aim 1b, we will create a large LCN-wide EHR-based virtual cohort of patients with compensated cirrhosis, prospectively validate electronic phenotypes for cirrhosis and its clinical complications with our in-person cohort, and evaluate the use, safety and effectiveness of different classes of lipid lowering medications upon outcomes in this large real-world virtual cohort. In Aim 2, we propose to study the safety and efficacy of statins in preventing clinical decompensation among patients with NAFLD or ALD cirrhosis while exploring the potential pleiotropic mechanisms of statins. In this trial, patients with and without an established non-hepatic indication for lipid lowering will be randomized to pravastatin v. alirocumab (stratum 1) or placebo (stratum 2), respectively. This innovative approach to the statin-based clinical trial will acknowledge the patient's baseline indication for lipid-lowering therapy, and offer an alternative lipid lowering pathway in PCSK9 inhibition, which has similar or greater LDL-lowering potency but lacks the pleotropic effects of statins, to allow for novel insights into mechanisms by which statins might impact outcomes independent of its effects on lipids. Throughout the cohort and interventional trials, we will study lipoprotein metabolism, inflammatory markers, and collect microbiome and biospecimens for future translational research to better understand the m...