FACTORS ASSOCIATED WITH CHRONIC HEPATITIS C INFECTION

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。慢性丙型肝炎(CHC)感染的肝损害机制尚不清楚。最近的研究支持免疫反应机制在CHC感染所致肝损伤中的作用。血清中特定细胞因子水平或细胞因子基因多态性与慢性丙型肝炎的演变和肝损害的发展之间的关系已有研究。血清中高水平的辅助性T细胞因子2(Th2)与慢性肝损伤的发生有关。生长因子基因，如肿瘤坏死因子-a和肿瘤坏死因子-b，以及细胞因子的可变多态也与肝损伤有关。病毒基因分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现有数据。此外，已经从高加索或非裔美国人血统的患者那里收集了许多数据，但西班牙裔背景的患者的信息差距很大。本研究的目的是：1.检测慢性丙型肝炎患者肝损害不同阶段的病毒基因组多样性。2.检测慢性丙型肝炎患者血清中Th1(TNF-α、INF-g)和Th2(IL-10、IL-4)细胞因子的变化。3.检测慢性丙型肝炎患者肝损害不同阶段Th1(TNF-α、INF-g)和Th2(IL-10)细胞因子基因的多态性。这项先导性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，纳入更多的患者，研究更多影响丙型肝炎病毒诱导的慢性肝损伤发生的因素。这些特定的目标将帮助我们了解病毒和遗传因素在具有西班牙裔遗传背景的人群中对慢性肝损伤的发展所起的作用。在未来，它可能会提供新的论据来支持新的治疗或预防方法的发展。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挑选。符合条件的候选人必须在21至65岁之间，并且是波多黎各人或波多黎各一级血统。符合条件的患者必须有丙型肝炎病毒RNA的血清学证据，在评估时肝活检将排除有其他已知导致慢性肝病的伴随病因的患者。接受过任何丙型肝炎治疗的患者不能纳入这项研究。其他排除标准包括HIV阳性、在6个月内使用有效的静脉注射药物。入选前，既往或目前酒精滥用定义为男性24g/d，女性16g/d，自身免疫性疾病病史，非甾体抗炎药病史，S，类固醇或免疫调节剂使用在6个月内。入选前，轻度感染病史3个月。入院前，在研究开始前6个月或手术前6个月内有严重感染过程。之前的记录。丙型肝炎阴性对照将被招募到这项研究中，也将在RCM GI门诊诊所选择。控制人员必须是波多黎各人或波多黎各人后裔，年龄在21至65岁之间。对照将被要求满足临床排除标准。在初步临床资格确认后，丙型肝炎和艾滋病毒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学数据，并抽取血液(所有患者约20毫升)。使用METAVIR系统对基线肝活检进行检查，以确定纤维化的病理阶段。纤维化分期为F0~F2的患者将被分成组1，纤维化期为F3至F4的患者将被分成组2。共30例患者将被分层挑选，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.