Collaborative Clinical Research on Hepatotoxicity

描述（由申请人提供）： 药物诱导的肝损伤通常是轻度的，导致肝脏生物化学的短暂升高，但有时可能导致严重的肝损伤，导致死亡或肝移植。由于越来越多的美国人口使用药物以及补充和替代药物（CAM），其临床负担预计将恶化。然而，关于药物肝毒性的流行病学、诊断、危险因素、机制和结局的数据非常缺乏。为了更好地了解药物肝毒性的流行病学和发病机制，我们建议进行药物肝毒性相关研究，具体目标如下：具体目标#1：目的是收集大量疑似由药物、草药或毒素引起的肝毒性患者，以便将其纳入药物肝毒性数据库。我们建议从多个来源收集药物肝毒性和适当控制的横截面和前瞻性病例，每个来源提供独特的流行病学方面和研究潜力。我们将利用Regenstrief医疗保健研究所建立的医学信息系统来识别捕获的药物肝毒性疑似病例，并开发药物肝毒性数据库，使我们能够对药物肝毒性进行多学科、多中心研究。该数据库将包括具有药物肝毒性的成人和儿童以及适当的对照。该数据库将根据致病因子的性质（药物vs毒素vs CAM）进行分层。将通过实验室检查和组织学（如适用）对数据库中的受试者进行临床表征。具体目标3：目的是使用生物化学、血清学和遗传学技术，开发药物肝毒性受试者的生物样本（血液、尿液和DNA样本以及肝组织（如可用））库。我们建议为当前和未来的遗传研究收集和使用DNA提供一个样本知情同意书。我们还提出了一个战略，确定遗传变异，可能会导致药物肝毒性使用一个既定的NIGMS药物遗传学核心实验室。

DESCRIPTION (provided by applicant): Drug Induced liver injury is usually mild resulting in transient elevations in liver biochemistries, but sometimes can cause sever liver injury leading to death or liver transplantation. Its clinical burden is anticipated to worsen due to increasing number of U.S. population consuming medications and complementary and alternative medicines (CAM). However, there is a paucity of data regarding the epidemiology, diagnosis, risk factors, mechanisms, and outcomes of drug hepatotoxicity. In order to better understand the epidemiology and pathogenesis of drug hepatotoxicity, we propose to conduct drug hepatotoxicity-related research with the following specific aims: Specific Aim #1: The objective is to collect a large number of patients with suspected hepatotoxicity caused by drugs, herbals, or toxins in order to enroll them into a drug hepatotoxicity database. We propose to collect cross-sectional and prospective cases of drug hepatotoxicity and appropriate controls from multiple sources, each providng distinctive epidemiological facets and research potential. We will utilize the medical informatics system established by the Regenstrief Institute for Health Care to identify suspected cases of drug hepatotoxicity captured and to develop a database of drug hepatotoxicity that will enable us to conduct multidisciplinary, multicenter studies on drug hepatotoxicity. This database will consist of adults and children with drug hepatotoxicity and appropriate controls. This database will be stratified according to the nature of offending agent (drugs vs toxins vs CAM). The subjects in the database will be characterized clinically, through laboratory tests and histologically (whenever available). Specific Aim # 3: The objective is to develop a repository of biological samples (blood, urine, and DNA sample and liver tissue whenever available) from] subjects with drug hepatotoxicity using biochemical, serological, and genetic techniques. We propose a sample informed consent for collecting and using DNA for current and future genetic studies. We also propose a strategy for identifying genetic variations that may cause drug hepatotoxicity using an established NIGMS Pharmacogenetic Core Laboratory.