DRUG- AND CAM-INDUCED LIVER INJURY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 背景和原理：处方药和非处方药引起的肝损伤在美国是一个日益频繁和重要的医学、科学和公共卫生问题。事实上，药物性肝损伤(DILI)是美国食品和药物管理局(FDA)拒绝批准、停用、限制使用和临床监测的最常见原因。然而，肝脏损伤信号的检测通常依赖于从业者在上市后监测中向卫生当局报告病例。病例报告不足、缺乏强制性报告制度以及在建立诊断方面存在困难，使得目前的制度处于次优状态。此外，随着补充和替代药物(CAM)的使用越来越多，也有越来越多的报告表明，各种非处方药、饮食和食品添加剂的补充剂会造成肝脏毒性。由于这些产品的制造、分配和测试不受监管，这些制剂的肝脏毒性潜力特征很差，或者完全未知。因此，迫切需要开发一种改进的手段来检测、定义和研究美国的帝力。 DILIN前瞻性研究是一项多中心研究，旨在收集因药物和CAM引起的疑似肝损伤病例的临床信息和生物标本。这项研究的目标包括更早地认识到DILI，特别是由于较新的药物，开发标准化的工具和术语来帮助识别DILI病例，调查预测DILI的临床和遗传风险因素，以及对DILI受试者进行仔细的纵向随访。收集的生物样本将用于未来对DILI的机制和遗传学的研究。 具体目的和目的：这项研究的主要目的是前瞻性地确定药物以及补充和替代药物在6个月内造成肝损伤的真实病例。次要目标包括收集临床数据和生物标本，包括血液、DNA、尿液和肝组织，以及用于未来机制和遗传学研究的配对对照。我们还将通过将DILI病例与具有相似药物暴露史但没有临床显著肝损伤证据的匹配对照组进行比较，来调查药物介导的肝毒性的临床、免疫学和环境风险因素。药物和CAM诱导的DILI的自然病史将在登记后至少6个月内被跟踪，对于那些在6个月时有证据表明慢性肝损伤的患者，将进行更长时间的随访。我们还将开发和测试药物和CAM诱导的肝损伤的因果关系评估工具，这些工具是敏感、特异和可重复的。 基础研究设计：DILIN前瞻性研究是一项多中心、前瞻性、流行病学研究。被转介到DILIN临床站点之一的患者，以及胃肠病专家/肝病专家认为经历过药物引起的肝损伤的患者将被纳入其中。将收集详细的临床数据和生物标本。临床数据将由DILIN因果关系委员会审查，并将最终确定受试者是否符合真正的DILI病例。每个索引案例将分别匹配最多三个匹配的控件。他们将根据年龄、接触相关药物的时间和来自相同的临床地点进行匹配。DILI病例(仅限)将被跟踪至少6个月，以得出药物和CAM诱导的肝损伤的纵向轮廓。届时将收集详细的临床数据和生物标本。符合慢性DILI定义的患者将在12个月时进行评估，此后每年进行评估。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background and Rationale: Liver injury due to prescription and non-prescription medication use is a medical, scientific, and public health problem of increasing frequency and importance in the United States. Indeed, drug-induced liver injury (DILI) is the most common reason for nonapproval, withdrawal, limitation in use, and clinical monitoring by the Food and Drug Administration (FDA). However, detection of signals for liver injury frequently relies upon the reporting of cases by practitioners to health authorities in post-marketing surveillance. Under-reporting of cases, lack of mandatory reporting systems, and difficulties in establishing a diagnosis make the current system sub-optimal. Moreover, with the growing use of complementary and alternative medications (CAM), there have also been increasing reports of liver toxicity due to various non-prescription herbal, dietary, and food additive supplements. Because the manufacturing, dispensing, and testing of these products is not regulated, the hepatotoxic potential of these formulations is poorly characterized or completely unknown. As a result, there is a great need to develop an improved means of detecting, defining, and studying DILI in the United States. The DILIN prospective study is a multi-center study designed to gather clinical information and biological specimens on cases of suspected liver injury due to drugs and CAM. The goals of this study include the earlier recognition of DILI, especially due to newer drugs, development of standardized instruments and terminology to help identify cases of DILI, investigating clinical and genetic risk factors that predict DILI, and performing a careful longitudinal follow-up of DILI subjects. The biological samples collected will be used in future studies of the mechanisms and genetics of DILI. Specific Aims and Objectives: The primary objective of this study is to prospectively identify bona fide cases of liver injury due to drugs and complementary and alternative medications within 6 months of presentation. Secondary objectives include collecting clinical data and biological specimens including blood, DNA, urine, and liver tissue from affected patients and matched controls for future mechanistic and genetic studies. We will also investigate the clinical, immunological, and environmental risk factors of drug-mediated hepatotoxicity by comparing DILI cases to matched controls with a similar drug exposure history but no evidence of clinically significant liver injury. The natural history of drug- and CAM-induced DILI will be tracked for at least 6 months following enrollment, with longer follow-up for those in whom there is evidence of chronic liver injury at 6 months. We will also develop and test causality assessment instruments for drug and CAM-induced liver injury that are sensitive, specific, and reproducible. Basic Study Design: The DILIN Prospective Study is a multi-center, prospective, epidemiological study. Patients who are referred to one of the DILIN clinical sites and who, in the opinion of a gastroenterologist / hepatologist, experienced a drug-induced liver injury will be enrolled. Detailed clinical data and biological specimens will be collected. Clinical data will be reviewed by the DILIN Causality Committee, and it will make the final determination of whether the subject qualifies as a bona fide DILI case. Up to three matched controls will be individually matched to each index case. They will be matched by age, duration of exposure to the implicated medication, and from the same clinical site. DILI cases (only) will be followed for at least 6 months to derive the longitudinal profile of drug- and CAM-induced liver injury. Detailed clinical data and biological specimens will be collected at this time point. Patients who satisfy the definition of chronic DILI will be evaluated at 12 months and yearly thereafter.