Southern Liver Health Cohort

PROJECT SUMMARY/ABSTRACT
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
rural states and among ethnic minorities. While the prevalence of HCC had paralleled high rates of viral hepatitis
in the last several decades, recent increases in the prevalence of nonalcoholic fatty liver disease (NAFLD) and
its progression to nonalcoholic steatohepatitis (NASH) with fibrosis and cirrhosis, has fueled HCC in recent years.
Yet, these factors alone do not explain the substantial regional and ethnic variation in HCC progression. One
understudied but potentially potent HCC risk factor with increasing prevalence that disproportionately affects
ethnic minorities, 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 NASH. 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 16,000 males and females 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 NAFLD to liver fibrosis and HCC. The cohort will
be recruited from community 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
10,000 otherwise healthy adults who will be followed for 1–5 years, anticipating that ~800 fibrosis cases,
including cirrhosis, will develop, and sub-cohort II will comprise 6,000 advanced fibrosis cases, anticipating ~750
HCC cases will develop. We will nest case-control studies within the cohorts, evaluate associations between
environmental exposures and HCC incidence, and identify epigenetic marks responsive to contaminants that
predict progression to HCC. Impact: This will be the first large-scale effort to longitudinally determine the link
between environmental contaminants, liver disease and cancer in a residentially and ethnically diverse
population. Additionally, we will create a data and specimen repository that will provide the research community
with an invaluable resource to study HCC and other cancers.