Southern Liver Health Cohort - Primary liver cancer, the vast majority of which is hepatocellular carcinoma (HCC) is one of the few cancers with increasing incidence in the US. Incidence of HCC has tripled since 1980, which is particularly worrisome given that HCC confers a median survival of less than two years. The steepest increases in incidence are in Southern states and rural residents. While the prevalence of HCC had paralleled high rates of viral hepatitis in the last several decades, recent increases in the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) and its progression to metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis and cirrhosis, has fueled HCC in recent years. Yet, these factors alone do not explain the substantial variation in HCC progression. One understudied but potentially potent HCC risk factor with increasing prevalence that impacts rural residents, is exposure to environmental contaminants. These contaminants degrade slowly and therefore persist in the environment, providing a stable exogenous source for human exposure. Toxic metal(oid)s such as cadmium and arsenic are classified as probable carcinogens, and emerging data from murine models suggest that exposure is associated with hepatic steatosis, cirrhosis and liver cancer. Per- and poly-fluoroalkyl substances (PFAS) exposure in humans is associated with obesity and MASH. Further, emerging evidence indicates that these environmental exposures can induce epigenetic alterations that may promote adverse effects on the liver, but we lack longitudinal human data. These data underscore the need for longitudinal human data to assess whether and how these contaminants impact HCC risk. To address these knowledge gaps, and in response to RFA-CA-20-049, we propose the Southern Liver Health Study, a longitudinal cohort study of two sub-cohorts comprising 11,000 participants aged 40 years and older in two Southeastern states, North Carolina and Georgia. We will test the overarching hypothesis that cadmium alone or in a mixture with other toxic metals and PFAS increases the risk of progression from MASLD to liver fibrosis and HCC. The cohort will be recruited from clinics including Federally Qualified Health Centers and University Health Systems’ Primary Care Centers and Hepatology programs at Duke, UNC Chapel Hill and Emory. Sub-cohort I will comprise 6,000 otherwise healthy adults who will be followed for 1–5 years, anticipating that ~450 fibrosis cases, including cirrhosis, will develop, and sub-cohort II will comprise 5,000 advanced fibrosis cases, anticipating ~750 HCC cases will develop. In future studies, with adequate follow-up, we will nest case-control studies within the cohorts, evaluate associations between environmental exposures and HCC, fibrosis or cirrhosis incidence, and identify epigenetic marks responsive to contaminants that predict progression to HCC. Impact: This will be the first large-scale contemporary effort to longitudinally determine the link between environmental contaminants, liver disease and cancer in the United States. We will also create a data and specimen repository that will provide researchers with an invaluable resource to study HCC and other cancers.
