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

摘要 近年来，美国肝细胞癌的发病率一直在上升。 过去几十年。非酒精性脂肪肝已成为最重要的危险因素 用于治疗肝细胞癌。大约25%的美国成年人患有非酒精性脂肪肝。 疾病，包括一系列的肝脏疾病，从单纯性脂肪变性，非酒精性脂肪性肝炎到 纤维化和肝硬变。肝纤维化已被认为是长期健康风险的关键决定因素 非酒精性脂肪性肝病患者的预后，这将很快成为最常见的适应症 在美国进行肝脏移植。目前还没有有效的治疗或预防策略。 治疗非酒精性脂肪性肝病。识别新的生物和环境是一个迫切未得到满足的需求 推动非酒精性脂肪性肝病进展为 越来越需要肝移植的肝细胞癌和终末期肝病 美国严重的公共卫生负担。 肝脏是一个不断接触各种免疫调节剂的器官，环境 毒素和肠道微生物代谢物通过门静脉。确保维持对自身的免疫耐受性 与外来抗原相比，肝脏具有独特的免疫耐受机制。增强免疫耐受性或 免疫允许性微环境可能会造成免疫监控受损的环境 促进肝脏肿瘤的发展和生长。肠道微生物群可以产生大量的 具有遗传毒性和促进肿瘤作用的代谢物，如次级胆汁酸。肠道生物失调 由于肥胖和其他代谢性疾病，这是非酒精性脂肪肝的基础条件，改变 胆汁酸的代谢、合成和运输，导致胆酸池的大小和 特点。胆汁酸谱的改变会引发炎症，导致肝脏损伤，导致纤维化。 和肝硬变，最后是肝细胞癌。我们建议前瞻性地招募至少1000名患者 非酒精性脂肪性肝病伴晚期纤维化的患者在基线和 每6个月一次。将对所有研究参与者进行纵向跟踪，以了解其发生情况 肝细胞癌和终末期肝病的风险最高可达五年。具体目标是 确定免疫抑制细胞因子、胆汁酸谱改变和肠道生物失调是否有显著意义 对发展为肝细胞癌和终末期肝病的风险的影响。如果这些发现能证明 我们的假设，将为制定有效的战略提供亟需的科学证据 非酒精性脂肪性肝病患者的管理和监测 其进展为肝细胞癌和其他终末期肝病。

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.