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Liver diseases and metabolic syndrome

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Abstract

Emerging attention has been paid to metabolic syndrome, which comprises several metabolic disorders including visceral obesity, diabetes mellitus, dyslipidemia, and hypertension. Whether the severity of each disease is mild to moderate, the comorbidity of these metabolic disorders has a serious impact on the development of atherosclerosis. Nonalcoholic fatty liver disease (NAFLD) is the major hepatic disorder in patients with metabolic syndrome, and indeed it is the most common cause of abnormal liver function tests in the working population in industrialized countries. In recent years, it has become recognized that NAFLD is no longer just a trivial disease, and a rather considerable proportion of the patients develop liver cirrhosis. Furthermore, chronic infection of hepatitis C virus also develops a pathological feature of steatohepatitis, and extended hepatic steatosis has a serious impact not only on the progression of hepatic fibrosis but also on the antiviral efficacy of interferon therapy. Emerging lines of studies indicated that insulin resistance, abnormal lipid metabolism, and dysregulation of cytokines/adipokines (e.g., tumor necrosis factor-alpha, adiponectin, and leptin) are profoundly involved in the pathogenesis of NAFLD. This review aims to integrate the reported evidence and to provide the current point of view for comprehensive understanding of the pathophysiology of steatohepatitis.

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References

  1. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285:2486–2497.

    Google Scholar 

  2. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005;365:1415–1428.

    Article  PubMed  CAS  Google Scholar 

  3. Watanabe S, Hojo M, Nagahara A. Metabolic syndrome and gastrointestinal diseases. J Gastroenterol 2007;42:267–274.

    Article  PubMed  Google Scholar 

  4. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002;346:1221–1231.

    Article  PubMed  CAS  Google Scholar 

  5. Clark JM, Brancati FL, Diehl AM. Nonalcoholic fatty liver disease. Gastroenterology 2002;122:1649–1657.

    Article  PubMed  Google Scholar 

  6. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980;55:434–438.

    PubMed  CAS  Google Scholar 

  7. Mokdad AH, Serdula MK, Dietz WH, Bowman BA, Marks JS, Koplan JP. The spread of the obesity epidemic in the United States, 1991–1998. JAMA 1999;282:1519–1522.

    Article  PubMed  CAS  Google Scholar 

  8. Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP. The continuing epidemics of obesity and diabetes in the United States. JAMA 2001;286:1195–1200.

    Article  PubMed  CAS  Google Scholar 

  9. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 2001;50:1844–1850.

    Article  PubMed  CAS  Google Scholar 

  10. Pagano G, Pacini G, Musso G, Gambino R, Mecca F, Depetris N, et al. Nonalcoholic steatohepatitis, insulin resistance, and metabolic syndrome: further evidence for an etiologic association. Hepatology 2002;35:367–372.

    Article  PubMed  CAS  Google Scholar 

  11. Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003;37:917–923.

    Article  PubMed  Google Scholar 

  12. Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology 1998;114:842–845.

    Article  PubMed  CAS  Google Scholar 

  13. Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 1999;94:2467–2474.

    Article  PubMed  CAS  Google Scholar 

  14. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999;116:1413–1419.

    Article  PubMed  CAS  Google Scholar 

  15. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology 2003;37:1202–1219.

    Article  PubMed  Google Scholar 

  16. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41:1313–1321.

    Article  PubMed  Google Scholar 

  17. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004;40:1387–1395.

    Article  PubMed  Google Scholar 

  18. Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005;129:113–121.

    Article  PubMed  Google Scholar 

  19. Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW, Powell LW. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology 1990;11:74–80.

    Article  PubMed  Google Scholar 

  20. Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri BA. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 1994;107:1103–1109.

    PubMed  CAS  Google Scholar 

  21. Teli MR, James OF, Burt AD, Bennett MK, Day CP. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology 1995;22:1714–1719.

    Article  PubMed  CAS  Google Scholar 

  22. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 2006;43:S99–S112.

    Article  PubMed  CAS  Google Scholar 

  23. Hamaguchi M, Kojima T, Takeda N, Nakagawa T, Taniguchi H, Fujii K, et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med 2005;143:722–728.

    PubMed  CAS  Google Scholar 

  24. Axen KV, Dikeakos A, Sclafani A. High dietary fat promotes syndrome X in nonobese rats. J Nutr 2003;133:2244–2249.

    PubMed  CAS  Google Scholar 

  25. Hill JO, Lin D, Yakubu F, Peters JC. Development of dietary obesity in rats: influence of amount and composition of dietary fat. Int J Obes Relat Metab Disord 1992;16:321–333.

    PubMed  CAS  Google Scholar 

  26. Carmiel-Haggai M, Cederbaum AI, Nieto N. A high-fat diet leads to the progression of non-alcoholic fatty liver disease in obese rats. FASEB J 2005;19:136–138.

    PubMed  CAS  Google Scholar 

  27. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature (Lond) 1994;372:425–432.

    Article  CAS  Google Scholar 

  28. Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature (Lond) 1996;379:632–635.

    Article  CAS  Google Scholar 

  29. Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 1996;84:491–495.

    Article  PubMed  CAS  Google Scholar 

  30. Takaya K, Ogawa Y, Isse N, Okazaki T, Satoh N, Masuzaki H, et al. Molecular cloning of rat leptin receptor isoform complementary DNAs: identification of a missense mutation in Zucker fatty (fa/fa) rats. Biochem Biophys Res Commun 1996;225:75–83.

    Article  PubMed  CAS  Google Scholar 

  31. Chitturi S, Abeygunasekera S, Farrell GC, Holmes-Walker J, Hui JM, Fung C, et al. NASH and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology 2002;35:373–379.

    Article  PubMed  CAS  Google Scholar 

  32. James O, Day C. Non-alcoholic steatohepatitis: another disease of affluence. Lancet 1999;353:1634–1636.

    Article  PubMed  CAS  Google Scholar 

  33. Tsochatzis E, Papatheodoridis GV, Archimandritis AJ. The evolving role of leptin and adiponectin in chronic liver diseases. Am J Gastroenterol 2006;101:2629–2640.

    PubMed  CAS  Google Scholar 

  34. Tilg H, Hotamisligil GS. Nonalcoholic fatty liver disease: Cytokine-adipokine interplay and regulation of insulin resistance. Gastroenterology 2006;131:934–945.

    Article  PubMed  CAS  Google Scholar 

  35. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993;259:87–91.

    Article  PubMed  CAS  Google Scholar 

  36. Crespo J, Cayon A, Fernandez-Gil P, Hernandez-Guerra M, Mayorga M, Dominguez-Diez A, et al. Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology 2001;34:1158–1163.

    Article  PubMed  CAS  Google Scholar 

  37. Feldstein AE, Werneburg NW, Canbay A, Guicciardi ME, Bronk SF, Rydzewski R, et al. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology 2004;40:185–194.

    Article  PubMed  CAS  Google Scholar 

  38. Li Z, Yang S, Lin H, Huang J, Watkins PA, Moser AB, et al. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology 2003;37:343–350.

    Article  PubMed  CAS  Google Scholar 

  39. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999;257:79–83.

    Article  PubMed  CAS  Google Scholar 

  40. Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J, et al. Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem 2002;277:25863–25866.

    Article  PubMed  CAS  Google Scholar 

  41. Kumada M, Kihara S, Sumitsuji S, Kawamoto T, Matsumoto S, Ouchi N, et al. Association of hypoadiponectinemia with coronary artery disease in men. Arterioscler Thromb Vasc Biol 2003;23:85–89.

    Article  PubMed  CAS  Google Scholar 

  42. Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology 2004;40:46–54.

    Article  PubMed  CAS  Google Scholar 

  43. Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani H, et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 2002;8:731–737.

    Article  PubMed  CAS  Google Scholar 

  44. Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest 2003;112:91–100.

    PubMed  CAS  Google Scholar 

  45. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995;83:1263–1271.

    Article  PubMed  CAS  Google Scholar 

  46. Potter JJ, Womack L, Mezey E, Anania FA. Transdifferentiation of rat hepatic stellate cells results in leptin expression. Biochem Biophys Res Commun 1998;244:178–182.

    Article  PubMed  CAS  Google Scholar 

  47. Ikejima K, Honda H, Yoshikawa M, Hirose M, Kitamura T, Takei Y, et al. Leptin augments inflammatory and profibrogenic responses in the murine liver induced by hepatotoxic chemicals. Hepatology 2001;34:288–297.

    Article  PubMed  CAS  Google Scholar 

  48. Honda H, Ikejima K, Hirose M, Yoshikawa M, Lang T, Enomoto N, et al. Leptin is required for fibrogenic responses induced by thioacetamide in the murine liver. Hepatology 2002;36:12–21.

    Article  PubMed  CAS  Google Scholar 

  49. Leclercq IA, Farrell GC, Schriemer R, Robertson GR. Leptin is essential for the hepatic fibrogenic response to chronic liver injury. J Hepatol 2002;37:206–213.

    Article  PubMed  CAS  Google Scholar 

  50. Ikejima K, Takei Y, Honda H, Hirose M, Yoshikawa M, Zhang YJ, et al. Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat. Gastroenterology 2002;122:1399–1410.

    Article  PubMed  CAS  Google Scholar 

  51. Ikejima K, Okumura K, Lang T, Honda H, Abe W, Yamashina S, et al. The role of leptin in progression of non-alcoholic fatty liver disease. Hepatol Res 2005;33:151–154.

    Article  PubMed  CAS  Google Scholar 

  52. Saxena NK, Ikeda K, Rockey DC, Friedman SL, Anania FA. Leptin in hepatic fibrosis: evidence for increased collagen production in stellate cells and lean littermates of ob/ob mice. Hepatology 2002;35:762–771.

    Article  PubMed  CAS  Google Scholar 

  53. Saxena NK, Saliba G, Floyd JJ, Anania FA. Leptin induces increased alpha2(I) collagen gene expression in cultured rat hepatic stellate cells. J Cell Biochem 2003;89:311–320.

    Article  PubMed  CAS  Google Scholar 

  54. Cao Q, Mak KM, Lieber CS. Leptin enhances alpha1(I) collagen gene expression in LX-2 human hepatic stellate cells through JAK-mediated H2O2-dependent MAPK pathways. J Cell Biochem 2006;97:188–197.

    Article  PubMed  CAS  Google Scholar 

  55. Cao Q, Mak KM, Ren C, Lieber CS. Leptin stimulates tissue inhibitor of metalloproteinase-1 in human hepatic stellate cells: respective roles of the JAK/STAT and JAK-mediated H2O2-dependant MAPK pathways. J Biol Chem 2004;279:4292–4304.

    Article  PubMed  CAS  Google Scholar 

  56. Lin S, Saxena NK, Ding X, Stein LL, Anania FA. Leptin increases tissue inhibitor of metalloproteinase I (TIMP-1) gene expression by a specificity protein 1/signal transducer and activator of transcription 3 mechanism. Mol Endocrinol 2006;20:3376–3388.

    Article  PubMed  CAS  Google Scholar 

  57. Cao Q, Mak KM, Lieber CS. Leptin represses matrix metalloproteinase-1 gene expression in LX2 human hepatic stellate cells. J Hepatol 2007;46:124–133.

    Article  PubMed  CAS  Google Scholar 

  58. Aleffi S, Petrai I, Bertolani C, Parola M, Colombatto S, Novo E, et al. Upregulation of proinflammatory and proangiogenic cytokines by leptin in human hepatic stellate cells. Hepatology 2005;42:1339–1348.

    Article  PubMed  CAS  Google Scholar 

  59. Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 2001;120:1183–1192.

    Article  PubMed  CAS  Google Scholar 

  60. Caldwell SH, Swerdlow RH, Khan EM, Iezzoni JC, Hespenheide EE, Parks JK, et al. Mitochondrial abnormalities in nonalcoholic steatohepatitis. J Hepatol 1999;31:430–434.

    Article  PubMed  CAS  Google Scholar 

  61. Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science 2005;307:384–387.

    Article  PubMed  CAS  Google Scholar 

  62. Garcia-Ruiz I, Rodriguez-Juan C, Diaz-Sanjuan T, del Hoyo P, Colina F, Munoz-Yague T, et al. Uric acid and anti-TNF antibody improve mitochondrial dysfunction in ob/ob mice. Hepatology 2006;44:581–591.

    Article  PubMed  CAS  Google Scholar 

  63. Seeff LB. Natural history of chronic hepatitis C. Hepatology 2002;36:S35–46.

    Article  PubMed  Google Scholar 

  64. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975–982.

    Article  PubMed  CAS  Google Scholar 

  65. Hadziyannis SJ, Sette H, Jr., Morgan TR, Balan V, Diago M, Marcellin P, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140:346–355.

    PubMed  CAS  Google Scholar 

  66. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958–965.

    Article  PubMed  CAS  Google Scholar 

  67. Ramesh S, Sanyal AJ. Hepatitis C and nonalcoholic fatty liver disease. Semin Liver Dis 2004;24:399–413.

    Article  PubMed  CAS  Google Scholar 

  68. Lonardo A, Adinolfi LE, Loria P, Carulli N, Ruggiero G, Day CP. Steatosis and hepatitis C virus: mechanisms and significance for hepatic and extrahepatic disease. Gastroenterology 2004;126:586–597.

    Article  PubMed  CAS  Google Scholar 

  69. Hickman IJ, Powell EE, Prins JB, Clouston AD, Ash S, Purdie DM, et al. In overweight patients with chronic hepatitis C, circulating insulin is associated with hepatic fibrosis: implications for therapy. J Hepatol 2003;39:1042–1048.

    Article  PubMed  CAS  Google Scholar 

  70. Monto A, Alonzo J, Watson JJ, Grunfeld C, Wright TL. Steatosis in chronic hepatitis C: relative contributions of obesity, diabetes mellitus, and alcohol. Hepatology 2002;36:729–736.

    Article  PubMed  Google Scholar 

  71. Camma C, Bruno S, Di Marco V, Di Bona D, Rumi M, Vinci M, et al. Insulin resistance is associated with steatosis in nondiabetic patients with genotype 1 chronic hepatitis C. Hepatology 2006;43:64–71.

    Article  PubMed  CAS  Google Scholar 

  72. Conjeevaram HS, Kleiner DE, Everhart JE, Hoofnagle JH, Zacks S, Afdhal NH, et al. Race, insulin resistance and hepatic steatosis in chronic hepatitis C. Hepatology 2007;45:80–87.

    Article  PubMed  CAS  Google Scholar 

  73. Rubbia-Brandt L, Quadri R, Abid K, Giostra E, Male PJ, Mentha G, et al. Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3. J Hepatol 2000;33:106–115.

    Article  PubMed  CAS  Google Scholar 

  74. Patton HM, Patel K, Behling C, Bylund D, Blatt LM, Vallee M, et al. The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients. J Hepatol 2004;40:484–490.

    Article  PubMed  Google Scholar 

  75. Moriya K, Yotsuyanagi H, Shintani Y, Fujie H, Ishibashi K, Matsuura Y, et al. Hepatitis C virus core protein induces hepatic steatosis in transgenic mice. J Gen Virol 1997;78(pt 7):1527–1531.

    PubMed  CAS  Google Scholar 

  76. Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Tsukamoto K, Kimura S, et al. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology 2004;126:840–848.

    Article  PubMed  CAS  Google Scholar 

  77. Bressler BL, Guindi M, Tomlinson G, Heathcote J. High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C. Hepatology 2003;38:639–644.

    Article  PubMed  CAS  Google Scholar 

  78. Charlton MR, Pockros PJ, Harrison SA. Impact of obesity on treatment of chronic hepatitis C. Hepatology 2006;43:1177–1186.

    Article  PubMed  Google Scholar 

  79. Poynard T, Ratziu V, McHutchison J, Manns M, Goodman Z, Zeuzem S, et al. Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C. Hepatology 2003;38:75–85.

    Article  PubMed  CAS  Google Scholar 

  80. Sanyal AJ, Contos MJ, Sterling RK, Luketic VA, Shiffman ML, Stravitz RT, et al. Nonalcoholic fatty liver disease in patients with hepatitis C is associated with features of the metabolic syndrome. Am J Gastroenterol 2003;98:2064–2071.

    Article  PubMed  Google Scholar 

  81. Romero-Gomez M, Del Mar Viloria M, Andrade RJ, Salmeron J, Diago M, Fernandez-Rodriguez CM, et al. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology 2005;128:636–641.

    Article  PubMed  CAS  Google Scholar 

  82. Harrison SA, Brunt EM, Qazi RA, Oliver DA, Neuschwander-Tetri BA, Di Bisceglie AM, et al. Effect of significant histologic steatosis or steatohepatitis on response to antiviral therapy in patients with chronic hepatitis C. Clin Gastroenterol Hepatol 2005;3:604–609.

    Article  PubMed  Google Scholar 

  83. Thomopoulos KC, Theocharis GJ, Tsamantas AC, Siagris D, Dimitropoulou D, Gogos CA, et al. Liver steatosis is an independent risk factor for treatment failure in patients with chronic hepatitis C. Eur J Gastroenterol Hepatol 2005;17:149–153.

    Article  PubMed  Google Scholar 

  84. D’souza R, Sabin CA, Foster GR. Insulin resistance plays a significant role in liver fibrosis in chronic hepatitis C and in the response to antiviral therapy. Am J Gastroenterol 2005;100:1509–1515.

    Article  PubMed  CAS  Google Scholar 

  85. Yaginuma R, Ikejima K, Okumura K, Kon K, Suzuki S, Takei Y, et al. Hepatic steatosis is a predictor of poor response to interferon alpha-2b and ribavirin combination therapy in Japanese patients with chronic hepatitis C. Hepatol Res 2006;35:19–25.

    Article  PubMed  CAS  Google Scholar 

  86. Jian Wu Y, Shu Chen L, Gui Qiang W. Effects of fatty liver and related factors on the efficacy of combination antiviral therapy in patients with chronic hepatitis C. Liver Int 2006;26:166–172.

    Article  Google Scholar 

  87. Soresi M, Tripi S, Franco V, Giannitrapani L, Alessandri A, Rappa F, et al. Impact of liver steatosis on the antiviral response in the hepatitis C virus-associated chronic hepatitis. Liver Int 2006;26:1119–1125.

    Article  PubMed  CAS  Google Scholar 

  88. Larrea E, Garcia N, Qian C, Civeira MP, Prieto J. Tumor necrosis factor alpha gene expression and the response to interferon in chronic hepatitis C. Hepatology 1996;23:210–217.

    PubMed  CAS  Google Scholar 

  89. Di Bona D, Cippitelli M, Fionda C, Camma C, Licata A, Santoni A, et al. Oxidative stress inhibits IFN-alpha-induced antiviral gene expression by blocking the JAK-STAT pathway. J Hepatol 2006;45:271–279.

    Article  PubMed  CAS  Google Scholar 

  90. Zein NN. Etanercept as an adjuvant to interferon and ribavirin in treatment-naive patients with chronic hepatitis C virus infection: a phase 2 randomized, double-blind, placebo-controlled study. J Hepatol 2005;42:315–322.

    Article  PubMed  CAS  Google Scholar 

  91. Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999;30:1356–1362.

    Article  PubMed  CAS  Google Scholar 

  92. Dixon JB, Bhathal PS, O’Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 2001;121:91–100.

    Article  PubMed  CAS  Google Scholar 

  93. McCullough AJ. The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease. Clin Liver Dis 2004;8:521–33, viii.

    Article  PubMed  Google Scholar 

  94. Caldwell SH, Crespo DM, Kang HS, Al-Osaimi AM. Obesity and hepatocellular carcinoma. Gastroenterology 2004;127:S97–103.

    Article  PubMed  CAS  Google Scholar 

  95. El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004;126:460–468.

    Article  PubMed  Google Scholar 

  96. Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB. Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study. Gut 2005;54:533–539.

    Article  PubMed  CAS  Google Scholar 

  97. Ohata K, Hamasaki K, Toriyama K, Matsumoto K, Saeki A, Yanagi K, et al. Hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C virus infection. Cancer (Phila) 2003;97:3036–3043.

    Article  Google Scholar 

  98. Horie Y, Suzuki A, Kataoka E, Sasaki T, Hamada K, Sasaki J, et al. Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest 2004;113:1774–1783.

    PubMed  CAS  Google Scholar 

  99. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997;275:1943–1947.

    Article  PubMed  CAS  Google Scholar 

  100. Ferrannini E, Buzzigoli G, Bonadonna R, Giorico MA, Oleggini M, Graziadei L, et al. Insulin resistance in essential hypertension. N Engl J Med 1987;317:350–357.

    PubMed  CAS  Google Scholar 

  101. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 1999;340:115–126.

    Article  PubMed  CAS  Google Scholar 

  102. Nestel P, Lyu R, Low LP, Sheu WH, Nitiyanant W, Saito I, et al. Metabolic syndrome: recent prevalence in East and Southeast Asian populations. Asia Pac J Clin Nutr 2007;16:362–367.

    PubMed  Google Scholar 

  103. Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, et al. Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation 1999;100:2473–2476.

    PubMed  CAS  Google Scholar 

  104. Zoccali C, Mallamaci F, Tripepi G, Benedetto FA, Cutrupi S, Parlongo S, et al. Adiponectin, metabolic risk factors, and car diovascular events among patients with end-stage renal disease. J Am Soc Nephrol 2002;13:134–141.

    Article  PubMed  CAS  Google Scholar 

  105. Okamoto Y, Kihara S, Ouchi N, Nishida M, Arita Y, Kumada M, et al. Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation 2002;106:2767–2770.

    Article  PubMed  CAS  Google Scholar 

  106. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279–1289.

    Article  PubMed  CAS  Google Scholar 

  107. Diehl AM. Fatty liver, hypertension, and the metabolic syndrome. Gut 2004;53:923–924.

    Article  PubMed  CAS  Google Scholar 

  108. Sanyal AJ, Banas C, Sargeant C, Luketic VA, Sterling RK, Stravitz RT, et al. Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C. Hepatology 2006;43:682–689.

    Article  PubMed  Google Scholar 

  109. Donati G, Stagni B, Piscaglia F, Venturoli N, Morselli-Labate AM, Rasciti L, et al. Increased prevalence of fatty liver in arterial hypertensive patients with normal liver enzymes: role of insulin resistance. Gut 2004;53:1020–1023.

    Article  PubMed  CAS  Google Scholar 

  110. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006;355:2297–2307.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan

    Sumio Watanabe, Reiko Yaginuma, Kenichi Ikejima & Akihisa Miyazaki

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  1. Sumio Watanabe
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  2. Reiko Yaginuma
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  3. Kenichi Ikejima
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  4. Akihisa Miyazaki
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Watanabe, S., Yaginuma, R., Ikejima, K. et al. Liver diseases and metabolic syndrome. J Gastroenterol 43, 509–518 (2008). https://doi.org/10.1007/s00535-008-2193-6

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  • DOI: https://doi.org/10.1007/s00535-008-2193-6

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