Hyperinsulinemia and the pathogenesis of NASH

非酒精性脂肪性肝病（NAFL或NAFLD）及其亚群非酒精性脂肪性肝炎（NASH）越来越被认为是一种常见的肝脏疾病。在没有伴随细胞损伤的情况下，脂肪肝是一种良性疾病，可引起肝酶升高、疲劳和腹痛。MASH是通过肝脏中脂肪的存在以及肝细胞损伤、炎症和不同程度的肝纤维化来确定的。在美国，它折磨着高达3%的成年人，其中三分之一的人可能有发展成肝硬化的风险。NASH也影响儿童，尽管其在儿科人群中的患病率尚未明确。目前在美国进行的肝移植手术中，有2%是由于已知的NASH诊断而进行的。胰岛素抵抗及其主要相关疾病肥胖和2型糖尿病正在成为一种主要的共存疾病。本申请拟在合作临床研究网络的背景下开展两项临床研究，以实现确立高胰岛素血症在NASH发病机制中的作用和确定合理有效的预防和治疗NASH策略的长期目标。这些目标将通过本提案的具体目的来解决，旨在更好地了解高胰岛素血症患者中NASH的患病率，并确定降低胰岛素水平是否能从药理学上改善NASH相关的坏死炎症改变。提出了两项临床研究。第一项研究确定了高胰岛素血症患者的NASH患病率和脂肪肝的影像学证据。患病率研究的第二个目标是确定发生NASH风险的种族差异，因为NASH在非裔美国人中可能未被充分代表或未被诊断。登记将包括足够的非裔美国人，以便进行亚组分析。第二项研究是对NASH患者进行为期48周的治疗试验，使用ppar - γ配体罗格列酮，如果需要控制高胰岛素血症，使用二甲双胍。从所有临床中心招募的患者的肝活检将与接受标准推荐减肥治疗的患者的肝活检进行比较。主要终点将是肝活检坏死炎症评分的改善。

Non-alcoholic fatty liver disease (NAFL or NAFLD) and its subset, non- alcoholic steatohepatitis (NASH) are increasingly recognized as common forms of liver disease.. In the absence of concomitant cellular injury, fatty liver is a benign condition that may cause elevated liver enzymes, fatigue and abdominal pain. MASH is identified by the presence of fat in the liver plus hepatocellular injury, inflammation and varying degrees of liver fibrosis. It afflicts up to 3% of adults n the United States and one third of these people may be at risk for developing cirrhosis. NASH also affects children, although its prevalence in the pediatric population is less well defined. Currently 2% of liver transplants performed in the United States are performed because of known diagnosis of NASH. Insulin resistance, with its major associated diseases of obesity and Type 2 diabetes, is emerging as a major coexisting condition. This application proposes two clinical studies to be performed in the context of a cooperative clinical research network to achieve the long-term goals of establishing the role of hyperinsulinemia in the pathogenesis of NASH and identifying rational and effect strategies to prevent and cure NASH. These goals will be addressed by specific aims of this proposal that seek to better understand the prevalence of NASH in hyperinsulinemic patients and establish whether reducing insulin levels pharmacologically improves the necroinflammatory changes associated with NASH. Two clinical studies are proposed. The first study establishes the prevalence of NASH in patients with hyprinsulinemia and imaging evidence of fatty liver. A secondary goal of the prevalence study is to establish racial differences in the risk for developing NASH because NASH may be underrepresented or underdiagnosed in African Americans. Enrollment will include adequate African Americans to allow subgroup analysis. The second proposed study is to a 48 week treatment trail of patients with NASH using the PPAR-gamma ligand rosiglitazone and, if needed to control hyperinsulinemia, metformin. Liver biopsies of patients recruited from all Clinical Centers will be compared to liver biopsies of patients treated with the standard recommendation of weight reduction. The primary endpoint will be improvement in the liver biopsy necroinflammatory score.