Role of Heme Oxygenase in the Pathogenesis of Hepatocellular Injury in Chronic Hepatitis C Virus (HCV) Infection

Study Overview
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Brief Summary
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In the presented project, the role of heme oxygenase 1 and 2 in the procesess associated with fibroproduction in the chronic HCV infection will be studied. Heme oxygenase expression will be evaluated by the techniques of molecular genetics and immunohistochemistry, both in the liver tissue and in peripheral blood mononuclear cells. These parameters will be correlated with basic virological and clinical characteristics of the chronic HCV infection. The investigators' expected results may help in understanding the mechanisms of fibroproduction in chronic HVC infection and, therefore, contribute to explain individual differences in the development of chronic HCV infection.

Detailed Description
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Hepatitis C virus (HCV) is a single stranded positive RNA virus belonging to the Flaviviridae family. HCV is a major cause of chronic hepatitis and progressive liver fibrosis leading to cirrhosis. Currently, the mechanisms responsible for hepatocellular injury are not fully understood. Oxidative damage has been hypothesized to play a role in HCV-induced liver disease, with reactive oxygen species (ROS), generated from HCV-infected hepatocytes and infiltrating immune cells. Persistence of recurrent hepatocellular injury leads to wound-healing process in which oxidative stress, inflammatory response mediated by immune cells and/or cytokines, and activation of hepatic stellate cells (HSCs) contribute to cascade of fibrogenesis. HCV can infect peripheral blood mononuclear cells (PBMC) of patients with chronic HCV infection . PBMC play key roles both in innate and adaptive antigen-specific immunity and they constitute critical components of the immune response.Heme oxygenase (HO) is the rate-limiting enzyme in the heme catabolic pathway. It cleaves pro-oxidant heme into equimolar amounts of carbon monoxide (CO), free iron, and biliverdin, which is rapidly metabolized to bilirubin by biliverdin reductase.The human HO-1 gene is located at chromosome 22q12 and a variable number of tandem repeat polymorphism (VNTR) was identified in the proximal promoter region. It is suggested that these highly polymorphic (GT)n repeats could alter the transcriptional activity. In recent years, enhanced HO enzymatic activity has been reported - probably through its formation of bioactive products - to possess antioxidant, cytoprotective, and neurotransmitter activity and to play a role in anti-inflammatory functions . AIMS: AIM 1.To characterize HO expression in liver biopsies in patients with chronic hepatitis C comparing to expression in patients with other types of hepatitis (esp. autoimmune) and to normal liver tissue. To investigate the relationship between HO expression and hepatitis C virus concentration, duration of infection, level of fibrosis and inflammation, ALT, AST activities, bilirubin levels, response to the standard treatment and a level of apoptosis. AIM 2. To characterize HO expression in PBMC in patients with chronic hepatitis C before, in the week 12 and after the standard treatment (PEG-IFN+RBV). To correlate HO expression in PBMC with viral concentration in sera and a response to the standard treatment.AIM 3. To investigate HO polymorphisms in patients with chronic hepatitis C. AIM 4. To investigate UGT1A1 28 polymorphism which is responsible for benign hyperbilirubinemia. Expected results: 1. This study could elucidate a relationship between development of liver fibrosis and inflammation and HO expression. 2. This project may, for the first time, show the relationship between chronic HCV infection and regulation of HO expression in PBMC. 3.This project will answer the question whether genetic predisposition, length polymorphism in HO promoter responsible for its lower transcriptional activity, could be a risk factor for fibrosis/cirrhosis development in patients infected with hepatitis C virus. UGT1A1 28 polymorphism is connected with low prevalence of diseases in which the oxidative stress is increased. We suggest that HCV infected persons might have low prevalence of this polymorphism or this polymorphism might be connected to low efficacy of antiviral treatment in these persons.

Official Title
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Role of Heme Oxygenase in the Pathogenesis od Hepatocellular Injury in Chronic HCV Infection

Conditions
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Chronic HCV Infection, Nonalcoholic Steatohepatitis

Intervention / Treatment
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* Drug: pegylated interferon
* Drug: Ribavarin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: chronic HCV infection must undergo liver biopsy must undergo antiviral treatment Exclusion Criteria: liver sample not obtained blood samples for HCV testing not obtained in specified time points during antiviral therapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1 HCV positive pts<br>Patients with chronic HCV infection undergoing liver biopsy followed by antiviral treatment. peg-IFN alfa 2a 180ug s.c. QW + ribavirin 1000-1200mg p.o. daily 48weeks or peg-IFN alfa 2b 1.5 ug/kg s.c. QW + ribavirin 100-1200mg p.o. daily 48 weeks | Drug: pegylated interferon<br>* peg-IFN alfa 2a 180ug s.c. QW or peg-IFN alfa 2b 1.5 ug/kg s.c. QW<br>* Other names: Pegintron;Drug: Ribavarin<br>* ribavirin 1000-1200mg p.o. daily 48weeks or ribavirin 100-1200mg p.o. daily 48 weeks<br>* Other names: Rebetol;|
| No Intervention: 2 Other liver disease<br>pts. with NASH (or other liver disease) undergoing liver biopsy. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1. the relation between HO activity and basic virologic and histologic parameters in chronic HCV patients. 2. changes of HO activity within antiviral treatment 3. relation of HO gene polymorphisms to the course of disease |  | from HCV transmission in each individual patient to the time of liver biopsy and begining of antiviral treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relation of HO gene polymorphisms and UGT1A1*28 polymorphism. |  | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hepatitis C, NASH, Hem Oxygenase, Gene polymorphism