FACTORS ASSOCIATED WITH CHRONIC HEPATITIS C INFECTION

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。慢性丙型肝炎（CHC）感染的肝损伤机制尚不清楚。近年来的研究支持免疫反应机制在CHC感染肝损伤中的作用。血清特异性细胞因子水平或细胞因子基因多态性的存在与CHC的演变和肝损害的发展之间的关系已被研究过。血清中高水平的辅助性t - 2 （Th2）细胞因子与慢性肝损伤的发展有关。生长因子基因，如肿瘤坏死因子α (TNF-a)和TNF-b，以及细胞因子的可变多态性也与肝损伤有关。病毒基因型的影响还不太清楚。然而，目前还没有在同一组患者中分析所有这些因素的可用数据。此外，已经从白种人或非洲裔美国人的患者中收集了大量数据，但在西班牙裔背景的患者中存在信息缺口。本建议的目的是：1。测定不同阶段肝损害的CHC患者的病毒基因组多样性。2. 测定不同阶段肝损害CHC患者血清中th1 （TNF-a、nf -g）和th2 （IL-10、IL-4）细胞因子的水平。3. 测定不同阶段肝损害CHC患者中Th1 （TNF-a、INF-g）和Th2 （IL-10）细胞因子基因多态性。本次中试研究的初步结果将有助于我们设计一项更深入、更广泛的研究，包括更多的患者，以及更多影响hcv致慢性肝损害发展的因素的研究。这些具体的AIMS将帮助我们了解病毒和遗传因素对西班牙裔遗传背景人群中慢性肝损伤发展的贡献。在未来，它可能为支持新的治疗或预防方法的发展提供新的论据。患者将从UPR医学院附属的胃肠道和肝病门诊和研究诊所中选择。合格的候选人必须在21至65岁之间，是波多黎各人或一级波多黎各后裔。符合条件的患者在评估时必须有丙型肝炎病毒RNA的血清学证据和肝活检。有其他已知导致慢性肝病的合并病因的患者将被排除在外。接受过任何丙型肝炎治疗的患者不能被纳入本研究。其他排除标准包括艾滋病积极、活跃的静脉注射毒品在6密苏里研究入口之前,过去或当前酗酒定义为24 g / d在男性和16 g / d女性,自身免疫性疾病史,非甾体抗炎药的历史年代,类固醇,或免疫调制剂使用在6密苏里研究入口之前,轻微的感染过程的历史3密苏里条目之前,严重的感染过程研究开始前6个月或外科手术在6之前密苏里条目。本研究将招募丙型肝炎阴性对照者，并将在RCM GI门诊诊所选择。控制者必须是波多黎各人或波多黎各后裔，年龄在21至65岁之间。需要进行控制以满足临床排除标准。在初步临床资格确认后，丙型肝炎和HIV阴性将在最终资格确认之前进行血清学确认。在获得知情同意后，将收集所有受试者的人口统计和医疗数据，并抽血（所有患者约20cc）。基线肝活检将进行检查，以便使用METAVIR系统确定纤维化的病理分期。F0 ~ F2期纤维化患者分为1组，F3 ~ F4期纤维化患者分为2组。将对30例患者进行分层，每组15例。

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. The mechanism of liver damage in chronic hepatitis C (CHC) infection remains unclear. Recent studies have supported the role of immune response mechanism in liver injury of CHC infection. The association of the serum level of specific cytokines or the presence of cytokine gene polymorphisms with the evolution to CHC and development of liver damage have been studied before. High levels of T-helper 2 (Th2) cytokines in serum have been associated with the development of chronic liver damage. Growth factor genes such as tumor necrosis factor alpha (TNF-a) and TNF-b, and a variable polymorphism in cytokines have also been associated with liver damage. The impact of viral genotypes is less clear. However, there is no available data where all these factors have been analyzed in the same group of patients. In addition, much data has been collected from patients of Caucasian or African American origin but there is a gap of information in patients with a Hispanic background. The AIMS of this proposal are to: 1. Determine the viral genome diversity in patient with CHC showing varying stages of liver damage. 2. Determine the serum profile of Th 1 (TNF-a, INF-g) and Th 2 (IL-10, IL-4) cytokines in patient with CHC showing varying stages of liver damage. 3. Determine the polymorphism in Th1 (TNF-a, INF-g) and Th2 (IL-10) cytokine genes in patient with CHC showing varying stages of liver damage. The preliminary results of this pilot study will help us to design a further and more extensive study including more patients and the study of more factors affecting the development of HCV-induced chronic liver damage. These specifics AIMS will help us to understand the contribution of both viral and genetic factors to the development of chronic liver damage in a population with a Hispanic genetic background. In the future it might provide new arguments to support the development of new therapeutic or prophylactic approaches. Patients will be selected from the GI and Hepatology outpatient and research clinics affiliated with the UPR School of Medicine. Eligible candidates must be within 21 to 65 years of age and be Puerto Rican or of first degree Puerto Rican descent. Eligible patients must have serological evidence of hepatitis C virus RNA and liver biopsy at the time of evaluation Patients who have other concomitant etiologies known to cause chronic liver disease will be excluded. Patients who received any hepatitis C treatment cannot be considered for this study. Other exclusion criteria include HIV positivity, active IV drug use within 6 mo. prior to study entry, past history or current alcohol abuse defined as 24 g/d in males and 16 g/d in females, history of autoimmune disease, history of NSAID¿s, steroids, or immunomodulator use within 6 mo. prior to study entry, history of mild infectious process 3 mo. prior to entry, severe infectious process 6 months prior to study initiation or surgical procedure within 6 mo. prior entry. Hepatitis C negative controls will be recruited for this study and will also be selected at the RCM GI outpatient clinics. Controls must be Puerto Rican or Puerto Rican descent and 21 to 65 years of age. Controls will be required to meet clinical exclusion criteria. After initial clinical eligibility is confirmed, hepatitis C and HIV negativity will be confirmed serologically prior to final eligibility confirmation. After obtaining informed consent, demographic and medical data will be collected from all subjects and blood will be drawn (approx 20 cc in all patients). Baseline liver biopsies will be examined in order to establish the pathological stage of fibrosis using the METAVIR System. Patients having fibrosis stage of F0 to F2 will be stratified into Group 1 and those with fibrosis stage F3 to F4 will be stratified into Group 2. A total of 30 patients will be stratified and selected so that 15 patients are participating in each group.