FACTORS ASSOCIATED WITH CHRONIC HEPATITIS C INFECTION

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。慢性丙型肝炎（CHC）肝损害的机制尚不清楚。近年来的研究支持了免疫应答机制在CHC感染肝损伤中的作用。特异性细胞因子的血清水平或细胞因子基因多态性的存在与CHC的演变和肝损伤的发展之间的关系已经被研究过。血清中高水平的辅助性T细胞2（Th 2）细胞因子与慢性肝损伤的发展相关。生长因子基因如肿瘤坏死因子α（TNF-α）和TNF-b，以及细胞因子的可变多态性也与肝损伤相关。病毒基因型的影响尚不清楚。然而，没有可用的数据，所有这些因素都在同一组患者中进行了分析。此外，已从白人或非裔美国人患者中收集了大量数据，但在西班牙裔背景患者中存在信息缺口。 本提案的目标是：1.确定显示不同阶段肝损伤的CHC患者的病毒基因组多样性。 2.检测CHC患者血清中Th 1（TNF-α、INF-γ）、Th 2（IL-10、IL-4）细胞因子水平。 3.检测不同肝损害程度CHC患者Th 1（TNF-α、INF-γ）和Th 2（IL-10）细胞因子基因多态性。 这项初步研究的初步结果将有助于我们设计一个更深入和更广泛的研究，包括更多的患者和研究更多的因素影响丙型肝炎病毒引起的慢性肝损害的发展。 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慢性肝损伤发展的贡献。在未来，它可能会提供新的论据，以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GI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血统。合格的患者必须在评价时具有丙型肝炎病毒RNA和肝活检的血清学证据。将排除具有已知引起慢性肝病的其他伴随病因的患者。接受任何丙型肝炎治疗的患者不能考虑参加本研究。其他排除标准包括HIV阳性、6个月内主动静脉注射药物。入组研究前，既往或当前酒精滥用史（定义为男性24 g/d和女性16 g/d）、自身免疫性疾病史、NSAID、类固醇或免疫调节剂使用史（6个月内）。研究入组前，轻度感染过程病史> 3个月。入组前，研究开始前6个月发生严重感染过程或6个月内发生外科手术。事先进入。 本研究将招募丙型肝炎阴性对照，也将在RCM GI门诊选择。控制必须是波多黎各人或波多黎各后裔，年龄在21至65岁之间。要求对照品符合临床排除标准。在确认初始临床资格后，将在最终资格确认前对丙型肝炎和HIV阴性进行血清学确认。 获得知情同意后，将收集所有受试者的人口统计学和医学数据，并抽取血液（所有患者约20 cc）。将使用METAVIR系统检查基线肝活检，以确定纤维化的病理分期。纤维化分期为F0至F2的患者将被分层至第1组，纤维化分期为F3至F4的患者将被分层至第2组。将对总共30例患者进行分层和选择，以便每组有15例患者参与。

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.