Pathogenesis, prognosis, and treatment of NAFLD patients

描述（由申请人提供） 非酒精性脂肪性肝病（NAFLD）在组织学上被定义为 肝脏疾病谱，从脂肪变性到脂肪性肝炎（NASH）， 和肝硬化。个体间的倾向有很大的差异 发展为肝硬化，这是NAFLD的一个阶段， 肝脏相关的发病率和死亡率。NAFLD的可变进展可能是 用“多重打击假说”来解释根据这一假设，A 主要损伤（即，“hit”）导致正常肝脏积累脂肪。证据 表明导致脂肪在肝脏中积聚的第一个“打击”是 胰岛素抵抗，这可能是原发性或继发性肥胖。脂肪 肝脏通常易受各种二次损伤的损害， 当脂肪肝经历第二次“打击”时，如暴露于 肠道细菌产物，诱导炎性细胞因子， 氧化应激和进一步的线粒体功能障碍。因为NASH不 总是在肝硬化达到高潮，很可能是额外的“命中”可能是 是肝纤维化发生的必要条件从临床代偿期进展 失代偿性肝硬化可能需要进一步的损伤。如果这个“多重打击 假设”解释了NAFLD的组织学和临床进展， 通过逆转肝脏来消除脆弱状态的干预措施 脂肪变性，或防止继发性“命中”的叠加， 是有效的治疗方法。为了测试这些治疗策略的有效性， 我们提出三个具体目标。目标#1是创建和维护NAFLD注册表。 这将通过筛选具有高表达的各种人群来实现。 以确定是否存在宿主或环境因素（即， “点击”），区分没有脂肪肝的受试者和有脂肪肝的受试者 肝脏，以及区分不同组织学阶段的因素 的NAFLD。目标#2是确定有希望的治疗方法，可以防止 通过改善一个或多个“命中”来改善NAFLD的进展。这将是 完成了对已经尝试的试验的回顾性分析， 提高推定的主要“命中率”（目标2a），并对 肠道细菌过度生长的重要性，这可能会产生假定的 二次“命中”（目标#2b）。目标#3是设计和实施全网络 NAFLD患者的随机对照试验。假设胰岛素 耐药性成为一个有希望的治疗目标，我们将测试 假设12个月的二甲双胍治疗将产生显著的 改善肝脏脂肪变性和NAFLD相关代谢因子， 不良影响完成这些目标将提供重要信息 关于促进NAFLD的宿主和环境因素， 确定预防从脂肪变性进展为NASH的治疗， 肝损伤的晚期

DESCRIPTION (provided by the applicant) Non-Alcoholic Fatty Liver Disease (NAFLD) is defined histologically as a spectrum of liver diseases, ranging from steatosis to steatohepatitis (NASH), and cirrhosis. There is tremendous inter-individual variability in the tendency to develop cirrhosis, the stage of NAFLD that is associated with the greatest liver-related morbidity and mortality. The variable progression of NAFLD may be explained by the "multiple hit hypothesis". According to this hypothesis, a primary insult (i.e., "hit") causes normal livers to accumulate fat. Evidence suggests that the first "hit" that causes fat to accumulate in the liver is insulin resistance, which may be either primary or secondary to obesity. Fatty livers are unusually vulnerable to damage from various secondary insults and NASH develops when fatty livers experience a second "hit", such as exposure to intestinal bacterial products that induce inflammatory cytokines, which cause oxidative stress and further mitochondrial dysfunction. Because NASH does not always culminate in cirrhosis, it is likely that additional "hits" may be required for hepatic fibrosis to occur. Progression from clinically-compensated to decompensated cirrhosis may require further insults. If this "multiple-hit hypothesis" explains the histological and clinical progression of NAFLD, then interventions which remove the vulnerability state by reversing hepatic steatosis, or which prevent the superimposition of the secondary "hits" should be effective treatments. To test the validity of these therapeutic strategies, we propose 3 SPECIFIC AIMS. Aim #1 is to create and maintain a NAFLD registry. This will be accomplished by screening various populations that have a high risk of NAFLD to determine if there are host or environmental factors (i.e., "hits") that distinguish subjects without fatty liver from those with fatty livers, as well as factors that distinguish among the various histologic stages of NAFLD. Aim #2 is to identify promising treatments that may prevent the progression of NAFLD by improving one or more of the "hits". This will be accomplished y retrospective analysis of trials that have already tried to improve the putative, primary "hit" (Aim #2a) and by a prospective valuation of the importance of intestinal bacterial overgrowth, which may generate putative secondary "hits"(Aim #2b). Aim #3 is to design and conduct a Network-wide randomized, controlled trial in patients with NAFLD. Assuming that insulin resistance emerges as a promising target for therapy, we will test the hypothesis that a 12-month course of metformin therapy will produce significant improvement in hepatic steatosis and in NAFLD-related metabolic factors without adverse effects. Completion of these Aims will provide important information about host and environmental factors that promote NAFLD and is likely to identify treatments that prevent the progression from steatosis to NASH and more advanced stages of liver damage.