Novel Determinants for Progression of Non-Alcoholic Fatty Liver Disease to Hepatocellular Carcinoma and Other Health Outcomes

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ABSTRACT 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.