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      Insulin Resistance, Steatosis, and Fibrosis in Egyptian Patients with Chronic Hepatitis C Virus Infection

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          Abstract

          Background/Aim:

          Both nonalcoholic fatty liver disease (NAFLD) and chronic hepatitis C virus (HCV) infection are common in Egypt, and their coexistence is expected. There is controversy regarding the influence of NAFLD on chronic HCV disease progression. This study evaluates the effect of NAFLD on the severity of chronic hepatitis C (CHC) (necroinflammation and fibrosis) and assesses the relative contribution of insulin resistance syndrome to the occurrence of NAFLD in patients with chronic HCV infection.

          Patients and Methods:

          Untreated consecutive adults with chronic HCV infection admitted for liver biopsy were included in this study. Before liver biopsy, a questionnaire for risk factors was completed prospectively, and a blood sample was obtained for laboratory analysis.

          Results:

          Our study included 92 male patients. Their mean ± SD age and aspartate aminotransferase (AST) level were 42 ± 7.7 years (range 20-56) and 68 ± 41.7 U/L (range 16-214), respectively. The mean insulin level and insulin resistance index were 15.6 ± 18.3 mIU/mL (range 5.1-137.4) and 5.9 ± 15.2 (range 0.9-136.2), respectively. Fifty four percent of patients had steatosis and 65% had fibrosis. In multivariate analyses, steatosis was associated with insulin resistance and fibrosis was associated with high AST level, age ≥40 years, and steatosis.

          Conclusions:

          Steatosis is a histopathologic feature in >50% of patients with chronic HCV infection. Insulin resistance has an important role in the pathogenesis of steatosis, which represents a significant determinant of fibrosis together with high serum AST level and older age.

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          Most cited references45

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          Histological grading and staging of chronic hepatitis.

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            Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups.

            Our aim was to assess the natural history of liver fibrosis progression in hepatitis C and the factors associated with this progression. We recruited 2235 patients from the Observatoire de l'Hépatite C (OBSVIRC) population, the Cohorte Hépatite C Pitié-Salpétrière (DOSVIRC) population, and the original METAVIR population. All the patients had a biopsy sample compatible with chronic hepatitis C as assessed by the METAVIR scoring system (grades the stage of fibrosis on a five-point scale, F0 = no fibrosis, F4 = cirrhosis, and histological activity on a four-point scale, A0 = no activity, A3 = severe activity). No patient had received interferon treatment before the liver biopsy sample was obtained. We assessed the effect of nine factors on fibrosis progression: age at biopsy; estimated duration of infection; sex; age at infection; alcohol consumption; hepatitis C virus C (HCV) genotype; HCV viraemia; cause of infection; and histological activity grade. We defined fibrosis progression per year as the ratio between fibrosis stage in METAVIR units and the duration of infection (1 unit = one stage, 4 units = cirrhosis). The median rate of fibrosis progression per year was 0.133 fibrosis unit (95% CI 0.125-0.143), which was similar to the estimates from previous studies (0.146 to 0.154). Three independent factors were associated with an increased rate of fibrosis progression: age at infection older than 40 years, daily alcohol consumption of 50 g or more, and male sex. There was no association between fibrosis progression and HCV genotype. The median estimated duration of infection for progression to cirrhosis was 30 years (28-32), ranging from 13 years in men infected after the age of 40 to 42 years in women who did not drink alcohol and were infected before the age of 40. Without treatment, 377 (33%) patients had an expected median time to cirrhosis of less than 20 years, and 356 (31%) will never progress to cirrhosis or will not progress for at least 50 years. The host factors of ageing, alcohol consumption, and male sex have a stronger association with fibrosis progression than virological factors in HCV infection.
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              Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3.

              The pathogenesis of hepatitis C virus (HCV)-associated insulin resistance remains unclear. Therefore, we investigated mechanisms for HCV-associated insulin resistance. Homeostasis model assessment for insulin resistance was increased in patients with HCV infection. An increase in fasting insulin levels was associated with the presence of serum HCV core, the severity of hepatic fibrosis and a decrease in expression of insulin receptor substrate (IRS) 1 and IRS2, central molecules of the insulin-signaling cascade, in patients with HCV infection. Down-regulation of IRS1 and IRS2 was also seen in HCV core-transgenic mice livers and HCV core-transfected human hepatoma cells. Carbobenzoxy-l-leucyl-l-leucyl-l-leucinal, a potent proteosomal proteolysis inhibitor, blocked down-regulation of IRS1 and IRS2 in HCV core-transfected hepatoma cells. In human hepatoma cells, HCV core up-regulated suppressor of cytokine signaling (SOCS) 3 and caused ubiquitination of IRS1 and IRS2. HCV core-induced down-regulation of IRS1 and IRS2 was not seen in SOCS3(-/-) mouse embryonic fibroblast cells. Furthermore, HCV core suppressed insulin-induced phosphorylation of p85 subunit of phosphatidylinositol 3-kinase and Akt, activation of 6-phosphofructo-2-kinase, and glucose uptake. In conclusion, HCV infection changes a subset of hepatic molecules regulating glucose metabolism. A possible mechanism is that HCV core-induced SOCS3 promotes proteosomal degradation of IRS1 and IRS2 through ubiquitination.
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                Author and article information

                Journal
                Saudi J Gastroenterol
                SJG
                Saudi Journal of Gastroenterology : Official Journal of the Saudi Gastroenterology Association
                Medknow Publications (India )
                1319-3767
                1998-4049
                Jul-Aug 2011
                : 17
                : 4
                : 245-251
                Affiliations
                [1]Department of Tropical Medicine and Gastroenterology, Assiut University Hospital, Assiut, Egypt
                [1 ]Departments of Public Health and Community Medicine, Assiut University, Assiut, Egypt
                [2 ]Departments of Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt
                Author notes
                Address for correspondence: Dr. Ahmed Helmy, Department of Tropical Medicine and Gastroenterology, 6 th Floor, Assiut University Hospital, Post Code 71511, Assiut, Egypt. E-mail: ahsalem10@ 123456yahoo.com
                Article
                SJG-17-245
                10.4103/1319-3767.82578
                3133981
                21727730
                296b06d4-a7f5-4a9e-a428-8e95e2156408
                © Saudi Journal of Gastroenterology

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 14 March 2010
                : 04 November 2010
                Categories
                Original Article

                Gastroenterology & Hepatology
                hepatic steatosis,metabolic syndrome,viral hepatitis,insulin resistance,hepatic fibrosis

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