Clinical Research on Non-Alcoholic Steatohepatitis

非酒精性脂肪性肝炎（NASH）是一种慢性肝病，其发生在没有显著肝损害的个体中。 酒精消耗和组织学上它类似于具有大泡脂肪变性的酒精性肝病， 点状坏死、炎症、马洛里小体和纤维化。它越来越被认为是一个 慢性肝病是美国的主要类型;然而，其患病率，发病机制和 自然历史没有得到充分的研究。为了更好地了解流行病学， 为了明确NASH的发病机制并确定最佳治疗方法，我们建议进行NASH相关的临床研究 具体目标1：目标是创建脂肪肝患者数据库 和NASH，这将使我们能够进行多学科和多中心的流行病学研究， NASH的发病机制和治疗。该数据库中包括的患者亚组是患有脂肪肝的成人。 肝脏和NASH，患有脂肪肝和NASH的儿童（<18岁），患有多囊卵巢综合征的女性， 和适当匹配的对照。该队列将通过临床、人体测量、 实验室检查和组织学检查一个储存库，包含受试者的肝脏组织，血液样本和DNA 具体目标2：这一具体目标的总体目标是， 并验证风险方程，测量和分层的风险，为先进的组织学患者的非- 酒精性脂肪肝为此，我们将对患者进行多中心、巢式病例对照研究 单纯脂肪肝、非硬化性NASH和硬化性NASH，以确定晚期组织学的风险因素， 并推导和验证临床预测规则，以可靠地识别具有高级组织学的那些; 具体目标3：我们假设胰岛素抵抗在NASH的发病机制中是关键的，并采取措施 改善胰岛素抗性将导致非糖尿病NASH中肝组织学的改善。在这里， 我们建议进行一项多中心、随机、双盲、安慰剂对照研究， 减少或不使用二甲双胍12个月。主要终点是肝脏组织学的变化 通过比较基线和12个月治疗期结束时的活检结果来测量。的 次要终点是胰岛素抵抗、脂质过氧化、氧化应激的决定因素 人体测量、肝脏生化和生活质量测量。

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.