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.
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