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) 在美国越来越被认为是慢性肝病的原因之一。纳什是 被认为是一种严重的脂肪性肝病，其特征是 与肝脂肪变性相关的坏死性炎症改变的证据，如 肝细胞气球样变性、Mallory、S透明和不同程度 纤维化症。NASH的组织病理学特征与酗酒者相似 肝脏疾病，但在没有大量饮酒的情况下被发现。这个 与NASH相关的最常见的危险因素是II型糖尿病， 肥胖、某些药物的使用和高甘油三酯血症。一直以来 估计多达20%的人可能患有脂肪肝，多达3%的人可能患有脂肪肝 可能有纳什。NASH进展为肝硬变的几率可能很高； 此外，很可能纳什是相当大比例的 因“不明原因”肝病而接受肝移植的患者。 因此，发病率、死亡率以及直接和间接医疗费用 与NASH相关的可能是巨大的。但是，我们的理解是 NASH的临床特征、发病机制和自然病史有限 由于缺乏大规模的流行病学研究，以及缺乏标准化 诊断本病的诊断标准和组织病理学标准。 最近的数据表明，非酒精性精神分裂症患者的一个共同特征 脂肪肝是胰岛素抵抗，可能是原发性的，也可能是继发性的， 导致肝脏中游离脂肪酸的积累和脂肪变性。一直以来 假设脂肪变性可能代表“首发”，一个或多个 “二次打击”，如铁超载，线粒体功能障碍，活动 细胞色素P450 2E1、4A1或其他因素可能导致进展性 肝细胞损伤和纤维化(NASH)。目前还没有经过验证的治疗方法 纳什。尽管纠正了潜在的代谢缺陷，低脂饮食， 熊去氧胆酸治疗和减肥已经被提出，目前还不清楚。 这些治疗方法中是否有任何一种有效。NASH临床试验网络的建立将是一个极好的机会，可以建立诊断这种疾病的标准化标准，在大量患者中研究这种疾病的自然历史和进展，并迅速 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和成功的记录。他还积累了一个独特的队列，超过100名患者的活组织检查证明NASH代表了该国主要地理区域的不同种族背景。PI还可以接触到大量患有NASH的儿科人口。他目前有一个正在进行的关于发病机制和 纳什的治疗。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.