Clinical Research Network in Non Alcoholic Steatohepatitis

描述（由申请人提供） 非酒精性脂肪肝和非酒精性脂肪性肝炎（NASH）正在被 在美国越来越多地被认为是慢性肝病的原因。NASH是 被认为是脂肪肝的一种严重形式，其特征是 肝脂肪变性与坏死性炎症变化相关，如 肝细胞气球样变性马洛里透明，程度不同 纤维化NASH的组织病理学特征类似于酒精性 肝脏疾病，但在没有大量酒精摄入的情况下被发现。的 与NASH相关的最常见的危险因素是II型糖尿病， 肥胖、使用某些药物和高脂血症。已经 据估计，高达20%的人口可能患有脂肪肝，高达3%的人可能患有脂肪肝。 可能有NASH。NASH进展为肝硬化的比率可能很高; 此外，NASH很可能是大部分患者的原因。 因“隐源性”肝病接受肝移植的患者。 因此，发病率，死亡率和直接和间接的卫生保健费用 与NASH相关的可能性很大。然而，我们的理解是， NASH的临床特征、发病机制和自然史的研究有限 由于缺乏大规模的流行病学研究， 用于诊断这种疾病的诊断和组织病理学标准。 最近的数据表明，非酒精性糖尿病患者的一个共同特点是， 脂肪肝是胰岛素抵抗，可能是原发性或继发性的， 导致游离脂肪酸的肝积累和脂肪变性。已经 假设脂肪变性可能代表“第一次打击”， “第二次打击”，例如铁超载、线粒体功能障碍、 细胞色素P450 2 E1，4A 1或其他因素可能导致进行性 肝细胞损伤和纤维化（NASH）。目前还没有有效的治疗方法 纳什虽然纠正潜在的代谢缺陷，低脂饮食， 熊去氧胆酸治疗和减肥已被建议，这是不清楚的 这些治疗方法是否有效。NASH临床试验网络的建立将是一个很好的机会，可以建立诊断这种疾病的标准化标准，在大量患者中研究疾病的自然史和进展，并快速 评估新的治疗方法。PI在多中心NIH临床试验的合作研究方面有着长期而成功的记录。他还积累了一个独特的队列，其中有100多名活检证实的NASH患者，代表了该国主要地理区域的不同种族背景。PI还可以接触大量NASH儿科人群。他目前正在进行一项关于发病机制的既定研究计划， NASH的治疗他为NASH临床研究网络提出了两项研究，这将促进我们对这种疾病的理解。

DESCRIPTION (provided by the applicant) Nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH) are being increasingly recognized as a cause of chronic liver disease in the USA. NASH is thought to represent a serious form of fatty liver disease, characterized by hepatic steatosis associated with evidence of necroinflammatory changes such as ballooning degeneration of hepatocytes, Mallory?s hyaline and variable degrees of fibrosis. The histopathologic features of NASH resemble those of alcoholic liver disease, but are found in the absence of significant alcohol intake. The most common risk factors associated with NASH are type II diabetes mellitus, obesity, use of certain medications, and hyper-triglyceridemia. It has been estimated that up to 20% of the population may have fatty liver, and up to 3% may have NASH. NASH may have a high rate of progression to cirrhosis; furthermore, it is likely that NASH is the cause in a significant proportion of patients undergoing liver transplantation for "cryptogenic" liver disease. Therefore, the morbidity, mortality and direct and indirect health care costs associated with NASH are likely to be substantial. However, our understanding of the clinical features, pathogenesis and natural history of NASH is limited by the absence of large epidemiologic studies, and the lack of standardized diagnostic and histopathologic criteria for the diagnosis of this disorder. Recent data suggest that a common feature among patients with nonalcoholic fatty liver disease is insulin resistance, which may be primary or secondary, leading to hepatic accumulation of free fatty acids and steatosis. It has been postulated that steatosis may represent the "first hit" and that one or more "second hits" such as iron overload, mitochondrial dysfunction, activity of cytochrome P450 2E1, 4A1 or other factors may lead to progressive hepatocellular injury and fibrosis (NASH). There are no proven therapies for NASH. Although correction of underlying metabolic defects, low-fat diet, ursodeoxycholic acid therapy and weight loss have been suggested, it is unclear whether any of these treatments are effective. Establishment of the NASH clinical trials network will be an excellent opportunity to establish standardized criteria for diagnosis of this disease, study the natural history and progression of the disease in a large cohort of patients and rapidly evaluate novel treatments. The PI has a long and successful track record of collaborative research in multicenter NIH clinical trials. He has also accumulated a unique cohort of over 100 patients with biopsy proven NASH representing diverse ethnic backgrounds in a major geographic region of the country. The PI also has access to a large pediatric population with NASH. He currently has an ongoing established research program on the pathogenesis and treatment of NASH. He has proposed two studies for the NASH Clinical Research Network that will advance our understanding of this disease.