Chronic hepatitis C and steatosis

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In overweight but not lean patients with HCV, there was a significant increase in insulin levels with increasing fibrosis. This suggests that increased circulating insulin may be one factor responsible for the association between BMI and fibrosis in patients with chronic HCV. Kumar D, Farrell GC, Fung C, George J: Hepatitis C virus genotype 3 is cytopathic to hepatocytes: reversal of hepatic steatosis after sustained therapeutic response. Hepatology 2002, 36:1266–1272. Reversal of steatosis after successful antiviral treatment provided proof of the role of viral factors in promoting steatosis in genotype 3-infected individuals. Moriya K, Yotsuyanagi H, Shintani Y, et al.: Hepatitis C virus core protein induces hepatic steatosis in transgenic mice. J Gen Virol 1997, 78:1527–1531. Lerat H, Honda M, Beard MR, et al.: Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus. Gastroenterology 2002, 122:352–365. Perlemuter G, Sabile A, Letteron P, et al.: Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis. FASEB J 2002, 16:185–194. This study proposes a mechanism for viral-induced steatosis, with core protein interfering with assembly and secretion of VLDL through a reduction in MTP activity. Lonardo A, Adinolfi LE, Loria P, et al.: Steatosis and hepatitis C virus: mechanisms and significance for hepatic and extrahepatic disease. Gastroenterology 2004, 126:586–597. Cardin R, Saccoccio G, Masutti F, et al.: DNA oxidative damage in leukocytes correlates with the severity of HCV-related liver disease: validation in an open population study. J Hepatol 2001, 34:587–592. Farinati F, Cardin R, Bortolami M, Rugge M: The mechanisms underlying hepatitis C virus genotype 3-mediated liver damage. J Hepatol 2003, 39:292–294. Day CP, James OF: Steatohepatitis: a tale of two "hits"? Gastroenterology 1998, 114:842–845. Clouston AD, Powell EE: Interaction of non-alcoholic fatty liver disease with other liver diseases. Baillieres Best Pract Clin Gastroenterol 2002, 16:767–781. Clouston AD, Jonsson JR, Purdie DM, et al.: Steatosis and chronic hepatitis C: analysis of fibrosis and stellate cell activation. J Hepatol 2001, 34:314–320. Hickman IJ, Clouston AD, Macdonald GA, et al.: Effect of weight reduction on liver histology and biochemistry in patients with chronic hepatitis C. Gut 2002, 51:89–94. Feldstein AE, Canbay A, Angulo P, et al.: Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology 2003, 125:437–443. Walsh MJ, Vanags DM, Clouston AD, et al.: Steatosis and liver cell apoptosis in chronic hepatitis C: a mechanism for increased liver injury. Hepatology 2004, 39:1230–1238. Hui JM, Sud A, Farrell GC, et al.: Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression. Gastroenterology 2003, 125:1695–1704. Ratziu V, Munteanu M, Charlotte F, et al.: Fibrogenic impact of high serum glucose in chronic hepatitis C. J Hepatol 2003, 39:1049–1055. Svegliati-Baroni G, Ridolfi F, Di Sario A, et al.: Insulin and insulin-like growth factor-1 stimulate proliferation and type I collagen accumulation by human hepatic stellate cells: differential effects on signal transduction pathways. Hepatology 1999, 29:1743–1751. Paradis V, Perlemuter G, Bonvoust F, et al.: High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology 2001, 34(4 Pt 1):738–744. Sud A, Hui JM, Farrell GC, et al.: Improved prediction of fibrosis in chronic hepatitis C using measures of insulin resistance in a probability index. Hepatology 2004, 39:1239–1247. Romero-Gomez M, Castellano-Megias VM, Grande L, et al.: Serum leptin levels correlate with hepatic steatosis in chronic hepatitis C. Am J Gastroenterol 2003, 98:1135–1141. Piche T, Vandenbos F, Abakar-Mahamat A, et al.: The severity of liver fibrosis is associated with high leptin levels in chronic hepatitis C. J Viral Hepat 2004, 1:91–96. Zhang BH, Hornsfield BP, Farrell GC: Chronic ethanol administration to rats decreases receptor-operated mobilization of intracellular ionic calcium in cultured hepatocytes and inhibits 1,4,5-inositol trisphosphate production: relevance to impaired liver regeneration. J Clin Invest 1996, 98:1237–1244. Yang SQ, Lin HZ, Mandal AK, et al.: Disrupted signaling and inhibited regeneration in obese mice with fatty livers: implications for nonalcoholic fatty liver disease pathophysiology. Hepatology 2001, 34(4 Pt 1):694–706. Roskams T, Yang SQ, Koteish A, et al.: Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease. Am J Pathol 2003, 163:1301–1311. Yang S, Koteish A, Lin H, et al.: Oval cells compensate for damage and replicative senescence of mature hepatocytes in mice with fatty liver disease. Hepatology 2004, 39:403–411. Hepatic progenitor cells and their fate may prove to have a central role in fibrosis and tumorigenesis in a range of liver diseases where steatosis impairs the normal regenerative programs of hepatocytes. Giambartolomei S, Covone F, Levrero M, Balsano C: Sustained activation of the Raf/MEK/Erk pathway in response to EGF in stable cell lines expressing the Hepatitis C Virus (HCV) core protein. Oncogene 2001, 20:2606–2610. Michalopoulos GK, DeFrances MC: Liver regeneration. Science 1997, 276:60–66. Sell S: Heterogeneity and plasticity of hepatocyte lineage cells. Hepatology 2001, 33:738–750. Lewindon PJ, Pereira TN, Hoskins AC, et al.: The role of hepatic stellate cells and transforming growth factor-beta(1) in cystic fibrosis liver disease. Am J Pathol 2002, 160:1705–1715. Ramm GA, Greco SA, Bridle KR, et al.: Monocyte chemotaxis protein-1, derived from hepatocytes isolated form bile ductligated rats, causes recruitment of hepatic stellate cells [abstract]. Hepatology 2002, 36(4 Part 2):260A. Ezure T, Sakamoto T, Tsuji H, et al.: The development and compensation of biliary cirrhosis in interleukin-6-deficient mice. Am J Pathol 2000, 156:1627–1639. Clouston AD, Jonsson JR, Letizia B, et al.: Fibrosis in chronic hepatitis C is associated with hepatic progenitor cell proliferation and a periportal ductular reaction, which is exacerbated by steatosis: a new model for disease progression. Hepatology 2003, 38(4 suppl 1):566A. Hickman IJ, Jonsson JR, Prins JB, et al.: Modest weight loss and physical activity in overweight patients with chronic liver disease results in sustained improvements in alanine aminotransferase, fasting insulin, and quality of life. Gut 2004, 53:413–419. As an alternative therapy when antiviral treatment has failed, this preliminary trial of weight loss shows promise as an adjunct therapy for patients with chronic liver disease. Ohata K, Hamasaki K, Toriyama K, et al.: Hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C virus infection. Cancer 2003, 97:3036–3043. Introducing a new role for steatosis in disease progression in HCV, this study may have implications for screening and treatment of steatosis in the long term. Moriya K, Nakagawa K, Santa T, et al.: Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. Cancer Res 2001, 61:4365–4370. This transgenic study found that oxidative stress increased in aging mice and was a function of viral protein expression and not inflammation. The excess oxidative stress emerged as the antioxidant pathways became less efficient with age. Kato T, Miyamoto M, Date T, et al.: Repeated hepatocyte injury promotes hepatic tumorigenesis in hepatitis C virus transgenic mice. Cancer Sci 2003, 94:679–685.