The incidence rate of hepatocellular carcinoma in the United States has been increasing in the
past several decades. Non-alcoholic fatty liver disease has become the most important risk factor
for hepatocellular carcinoma. About 25 percent of adults in the United Stated have non-alcoholic fatty liver
disease, which includes a spectrum of liver diseases from simple steatosis, non-alcoholic steatohepatitis to
fibrosis and cirrhosis. Liver fibrosis has been recognized as the key determinant of the risk of long-term health
outcome for patients with non-alcoholic fatty liver disease, which will soon be the most common indication
for liver transplantation in the United States. Currently there is no effective treatment or prevention strategy
for non-alcoholic fatty liver disease. It is an urgently unmet need to identify novel biological and environmental
factors that drive the progression of non-alcoholic fatty liver disease to the development of
hepatocellular carcinoma and end-stage liver disease that increasingly require liver transplantation, a
significant public health burden in the United States.
The liver is an organ that is constantly exposed to a wide range of immunomodulators, environmental
toxins, and gut microbial metabolites through the portal vein. To ensure upkeep of immune tolerance to self
and foreign antigens, the liver has a unique immunotolerance mechanism. Heightened immunotolerance or
immune permissive microenvironment may create a setting with compromised immunosurveillance that
promotes the tumor development and growth in the liver. The gut microbiota can produce large quantities of
metabolites such as secondary bile acids that have genotoxic and tumor-promoting effect. The gut dysbiosis
due to obesity and other metabolic diseases, which are underlying conditions for non-alcoholic fatty liver, alters
the metabolism, synthesis, and transport of bile acids, resulting in the change of bile acid pool size and
characteristics. The altered bile acids profile can elicit inflammation and cause liver injury, leading to fibrosis
and cirrhosis, and eventually hepatocellular carcinoma. We propose prospectively enroll at least 1000 patients
with non-alcoholic fatty liver disease with advanced fibrosis assessed by transient elastography at baseline and
once every 6 months. All study participants will be longitudinally followed up for the occurrence
of hepatocellular carcinoma and end-stage liver disease for up to five years. The specific aims are to
determine if immunosuppressive cytokines, altered bile acid profiles, and the gut dysbiosis have significant
impact on the risk of developing hepatocellular carcinoma and end-stage liver disease. The findings, if prove
our hypotheses, will provide much needed scientific evidence for the development of effective strategy for
management and surveillance for patients with non-alcoholic fatty liver disease with a goal to lower
its progression to hepatocellular carcinoma and other end-stage liver disease.
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