About 60 million Americans suffer from nonalcoholic fatty liver disease (NAFLD). As the long-term prognosis of patients with NAFLD remains poorly defined, one of the research goals of the NIDDK Action Plan in fatty liver disease is the need to establish a cohort study to determine the natural history of NAFLD. The cohort study would have to be followed-up for a long period of time to have enough events (deaths, liver transplantations, development of cirrhosis'complications) to be able to determine prognosis. Our proposal can reach this research goal as we have a very large and well characterized patient population with more than 3 decades of follow-up. A recent community-based study conducted in the United States demonstrated that mortality in patients with NAFLD is significantly higher than the expected mortality in the general population of same age and sex. However, as the prevalence of overweight/obesity is significantly higher among patients with NAFLD than in the general population, it remains uncertain whether the higher mortality seen in patients with NAFLD is because of this higher prevalence of overweight/obesity, or NAFLD itself. The Rochester Epidemiology Project (REP) had indexed all medical diagnoses made by health care providers in Olmsted County, Minnesota since 1966 allowing evaluation of the health status of what is effectively the entire county. Aim 1 consists of a nested case-control, population-based cohort study using the REP resources, to determine the overall and cause- specific mortality of 554 (cases) individuals from the community with overweight or obesity who developed NAFLD in comparison to appropriately matched 1,108 (controls) individuals (1:2 marching) who did not develop NAFLD. This cohort of 1,662 individuals has been followed for up to 33 years. This will allow us to accurately determine to what extent developing NAFLD increases mortality in community individuals who suffer from overweight/obesity. It remains unknown whether long-term prognosis differs among the major NAFLD categories namely simple steatosis and NASH, and what prognostic implications can be derived from grading and staging the different histological features of NAFLD. Aim 2 consists of a longitudinal cohort study to determine the overall and cause specific mortality and liver-related morbidity among patients with simple steatosis, definitive NASH, and borderline NASH as well as to determine the prognostic significance of the major individual histological features of NAFLD namely fibrosis, inflammation, hepatocyte ballooning and severity of steatosis. A total of 1,050 patients with the whole spectrum of NAFLD confirmed by liver biopsy that had been followed for up to 32 years will be included in this study. This will allow us to determine whether any of the three subtypes of NAFLD is associated with a higher mortality, and to compare the long-term mortality of each one of these three NAFLD categories with mortality of the general United States population of same age and gender. In addition, this study will allow us to determine whether presence and/or severity of a particular histological feature can accurately predict long-term morbidity and mortality in patients with NAFLD. PUBLIC HEALTH RELEVANCE: The data generated with this research will substantially advance our current knowledge on prognosis of nonalcoholic fatty liver disease (NAFLD) and will provide a scientific compelling basis for counseling and monitoring of the several million of individuals with NAFLD in the general population in the United States. Specifically, our investigation will create the bases to select the overweight or obese individuals with NAFLD from the general population who will benefit the most from intensive diagnostic and therapeutic interventions. In addition, our investigation will provide strong data to determine whether a liver biopsy is necessary to determine long-term prognosis in an individual patient with NAFLD, and what long-term prognostic implications can be derived by grading and scoring the histological features of NAFLD.