Hyperinsulinemia and the pathogenesis of NASH

非酒精性脂肪性肝病(NAFL或NAFLD)及其亚型非酒精性脂肪性肝炎(NASH)越来越被认为是常见的肝病形式。在没有伴随细胞损伤的情况下，脂肪肝是一种良性疾病，可能会导致肝酶升高、疲劳和腹痛。MASH是通过肝脏中脂肪的存在加上肝细胞损伤、炎症和不同程度的肝纤维化来确定的。在美国，多达3%的成年人患有这种疾病，其中三分之一的人可能有发展为肝硬变的风险。NASH也会影响儿童，尽管它在儿科人群中的流行率还不是很清楚。目前，在美国进行的肝脏移植中有2%是因为已知的NASH诊断而进行的。胰岛素抵抗及其主要相关疾病肥胖症和2型糖尿病正在成为一种主要的并存疾病。本申请建议在合作临床研究网络的背景下进行两项临床研究，以实现确立高胰岛素血症在NASH发病机制中的作用以及确定预防和治疗NASH的合理和有效策略的长期目标。这些目标将通过这项提案的具体目标来解决，这些目标旨在寻求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在药理上改善了与NASH相关的坏死性炎症变化。建议进行两项临床研究。第一项研究确定了NASH在高胰岛素血症患者中的患病率以及脂肪肝的影像证据。患病率研究的第二个目标是确定患NASH风险的种族差异，因为NASH在非裔美国人中可能代表不足或诊断不足。招生将包括足够的非裔美国人，以便进行亚群分析。第二项拟议的研究是对NASH患者进行48周的治疗试验，使用PPAR-伽玛配体罗格列酮，如果需要控制高胰岛素血症，则使用二甲双胍。从所有临床中心招募的患者的肝活检将与接受标准减肥治疗的患者的肝活检进行比较。主要终点将是肝脏活检坏死性炎症评分的改善。

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.