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)的组织学定义为 各种肝脏疾病，从脂肪变性到脂肪性肝炎(NASH)， 和肝硬变。在这种趋势中，个体之间存在着巨大的差异。 发展为肝硬化，NAFLD的阶段与最大的 与肝脏相关的发病率和死亡率。NAFLD的可变进展可能是 可以用“多次命中假说”来解释。根据这一假设，一个 原发侮辱(即“Hit”)会导致正常肝脏积累脂肪。证据 这表明，导致脂肪在肝脏积聚的第一个“打击”是 胰岛素抵抗，这可能是肥胖的原发或继发性症状。胖子 肝脏特别容易受到各种二次侮辱和 当脂肪肝经历第二次“打击”时，如暴露于 诱导炎性细胞因子的肠道细菌产品，后者会引起 氧化应激和进一步的线粒体功能障碍。因为纳什没有 总是在肝硬变中达到顶峰，很可能是额外的“打击” 发生肝纤维化所必需的。从临床代偿的进展 失代偿性肝硬变可能需要进一步的侮辱。如果这个“多次命中” 假说“解释了NAFLD的组织学和临床进展，然后 通过逆转肝脏来消除脆弱状态的干预措施 脂肪变性，或防止二次“击中”的叠加应该 成为有效的治疗方法。为了测试这些治疗策略的有效性， 我们提出了三个具体目标。目标1是创建和维护NAFLD注册表。 这将通过对不同人群进行筛查来实现。 NAFLD的风险以确定是否存在宿主或环境因素(即， “点击”)，区分无脂肪肝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 非酒精性脂肪肝。目标2是找出有希望的治疗方法，以防止 通过改善一项或多项“命中”来提高非酒精性脂肪肝的进展。这将是 已经完成的对已经尝试过的试验的回顾分析 改善假定的、主要的“成功”(目标#2a)，并通过预期估值 肠道细菌过度生长的重要性，这可能会导致 二次“命中”(目标2b)。目标3是在全网络范围内设计和实施 非酒精性脂肪肝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靶点，我们将测试 假设12个月的二甲双胍治疗将产生显着的 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的信息 关于促进NAFLD的宿主和环境因素，并可能 确定防止脂肪变性进展为NASH的治疗方法和 肝脏损伤更严重的阶段。

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.