Clinical Research on Non-Alcoholic Steatohepatitis

非酒精性脂肪性肝炎(NASH)是一种慢性肝病，发生在没有明显 酒精摄入和组织学上类似于酒精性肝病伴巨大水泡脂肪变性， 点状坏死、炎症、马洛里小体和纤维化。它越来越被认为是一种 美国慢性肝病的主要类型；然而，其流行率、发病机制和 自然史还没有得到充分的研究。为了更好地了解流行病学和 为了探讨NASH的发病机制和寻找最佳治疗方法，我们建议开展NASH相关的临床研究 在以下具体目标中：具体目标1：目标是建立脂肪肝患者数据库 和NASH，这将使我们能够对流行病学进行多学科和多中心的研究， NASH的发病机制及治疗。这个数据库中包括的患者亚组是患有肥胖症的成年人 肝脏和NASH，患有脂肪肝和NASH的儿童(18岁)，多囊卵巢综合征妇女， 和适当匹配的对照组。该队列将通过临床、人体测量、 实验室检测和组织学检查。包含受试者的肝组织、血液样本和DNA的存储库 将制定疾病和控制措施；具体目标2：这一具体目标的总目标是 并验证风险方程，该方程衡量和分层晚期组织学患者的风险 酒精性脂肪肝。为此，我们将对患者进行多中心嵌套病例对照研究 通过单纯性脂肪肝、非肝硬化性NASH和肝硬化性NASH来确定晚期组织学的危险因素， 并推导和验证临床预测规则，以可靠地识别组织学进展者； 具体目标3：我们假设胰岛素抵抗在NASH的发病机制中起关键作用并采取措施 改善胰岛素抵抗将导致非糖尿病NASH患者肝脏组织学的改善。这里, 我们建议进行一项多中心、随机、双盲、安慰剂对照的中等体重研究。 使用或不使用二甲双胍进行12个月的减量。主要终点是肝脏组织学的改变。 通过比较基线和12个月治疗期末的活检结果来衡量。这个 次要终点是胰岛素抵抗、脂质过氧化、氧化应激决定因素的变化， 人体测量、肝脏生化和生活质量的测量。

Non-alcoholic steatohepatitis (NASH) is a chronic liver disease that occurs in individuals without significant alcohol consumption and histologically it resembles alcoholic liver disease with macrovesicularsteatosis, spotty necrosis, inflammation, Mallory bodies, and fibrosis. It is increasingly being recognized as a predominant type of chronic liver disease in the United States; however, its prevalence, pathogenesis, and natural history have not been adequately studied. In order to better understand the epidemiology and pathogenesis and to identify optimal therapy for NASH, we propose to conduct NASH-related clinical research in the following specific aims: Specific Aim 1: The objective is to create a database of patients with fatty liver and NASH that will enable us to perform multidisciplinary and multicentered studies on the epidemiology, pathogenesis, and therapy of NASH. The subgroups of patients included in this database are adults with fatty liver and NASH, children (< 18yrs of age) with fatty liver and NASH, women with polycystic ovarysyndrome, and appropriately matched controls. The cohort will be characterized clinically, anthropometrically, through laboratory tests, and histologically. A repository containing liver tissue, blood samples, and DNA from subjects with disease and controls will be developed; Specific Aim 2:The overall goal of this specific aim is to derive and validate risk equations that measure and stratify the risk for advanced histology in patients with non- alcoholic fatty liver disease. To this end, we will conduct a multicenter, nested case-control study of patients with simple fatty-liver, non-cirrhotic NASH, and cirrhotic NASH to identify risk factors for advanced histology, and to derive and validate a clinical prediction rule for reliable identification of those with advancedhistology; Specific Aim 3: We hypothesize that insulin resistance is pivotal in the pathogenesis of NASH and measures that improve insulin resistance would lead to an improvement in liver histology in non-diabetic NASH. Here, we propose to conduct a multicenter, randomized, double-blind, placebo-controlled study of moderate weight reduction with or without metformin for 12-months. The primary end-point is the change in liver histology measured by comparing biopsy findings at baseline and at the end of 12-month treatment period. The secondary end-points are changes in insulin resistance, lipid peroxidation, determinants of oxidative stress, anthropometric measurements, liver biochemistry, and the measures of quality of life.