Gastroenterology
Volume 134, Issue 2 , Pages 416-423 , February 2008

Insulin Resistance in Chronic Hepatitis C: Association With Genotypes 1 and 4, Serum HCV RNA Level, and Liver Fibrosis

  • Rami Moucari

      Affiliations

    • AP-HP, Hôpital Beaujon, Service d’Hépatologie, Clichy F-92110, France; INSERM U773-CRB3, Paris, F-75018, France; Université Denis Diderot-Paris7, France
  • ,
  • Tarik Asselah

      Affiliations

    • AP-HP, Hôpital Beaujon, Service d’Hépatologie, Clichy F-92110, France; INSERM U773-CRB3, Paris, F-75018, France; Université Denis Diderot-Paris7, France
  • ,
  • Dominique Cazals–Hatem

      Affiliations

    • Service d’Anatomie Pathologique, Hôpital Beaujon, AP-HP, Clichy, France
  • ,
  • Hélène Voitot

      Affiliations

    • Service de Biochimie, Hôpital Beaujon, AP-HP, Clichy, France
  • ,
  • Nathalie Boyer

      Affiliations

    • AP-HP, Hôpital Beaujon, Service d’Hépatologie, Clichy F-92110, France; INSERM U773-CRB3, Paris, F-75018, France; Université Denis Diderot-Paris7, France
  • ,
  • Marie–Pierre Ripault

      Affiliations

    • AP-HP, Hôpital Beaujon, Service d’Hépatologie, Clichy F-92110, France; INSERM U773-CRB3, Paris, F-75018, France; Université Denis Diderot-Paris7, France
  • ,
  • Rodolphe Sobesky

      Affiliations

    • AP-HP, Hôpital Beaujon, Service d’Hépatologie, Clichy F-92110, France; INSERM U773-CRB3, Paris, F-75018, France; Université Denis Diderot-Paris7, France
  • ,
  • Michèle Martinot–Peignoux

      Affiliations

    • AP-HP, Hôpital Beaujon, Service d’Hépatologie, Clichy F-92110, France; INSERM U773-CRB3, Paris, F-75018, France; Université Denis Diderot-Paris7, France
  • ,
  • Sarah Maylin

      Affiliations

    • Service de Microbiologie, Hôpital Beaujon, AP-HP, Clichy, France
  • ,
  • Marie–Hélène Nicolas–Chanoine

      Affiliations

    • Service de Microbiologie, Hôpital Beaujon, AP-HP, Clichy, France
  • ,
  • Valérie Paradis

      Affiliations

    • Service d’Anatomie Pathologique, Hôpital Beaujon, AP-HP, Clichy, France
  • ,
  • Michel Vidaud

      Affiliations

    • Service de Biochimie, Hôpital Beaujon, AP-HP, Clichy, France
  • ,
  • Dominique Valla

      Affiliations

    • AP-HP, Hôpital Beaujon, Service d’Hépatologie, Clichy F-92110, France; INSERM U773-CRB3, Paris, F-75018, France; Université Denis Diderot-Paris7, France
  • ,
  • Pierre Bedossa

      Affiliations

    • Service d’Anatomie Pathologique, Hôpital Beaujon, AP-HP, Clichy, France
  • ,
  • Patrick Marcellin

      Affiliations

    • AP-HP, Hôpital Beaujon, Service d’Hépatologie, Clichy F-92110, France; INSERM U773-CRB3, Paris, F-75018, France; Université Denis Diderot-Paris7, France
    • Corresponding Author InformationAddress requests for reprints to: Patrick Marcellin, MD, AP-HP, Hôpital Beaujon, Service d’Hépatologie, Clichy F-92110, France; INSERM U773-CRB3, Paris, F-75018, France; Université Denis Diderot-Paris 7, France. fax: (33) 1-47 30 94 40.

Received 30 March 2007 ,Accepted 1 November 2007.

References 

  1. Mirandola S, Realdon S, Iqbal J, et al. Liver microsomal triglyceride transfer protein is involved in hepatitis C liver steatosis. Gastroenterology. 2006;130:1661–1669
  2. Okuda M, Li K, Beard MR, et al. Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. Gastroenterology. 2002;122:366–375
  3. Allison ME, Wreghitt T, Palmer CR, et al. Evidence for a link between hepatitis C virus infection and diabetes mellitus in a cirrhotic population. J Hepatol. 1994;21:1135–1139
  4. Mason AL, Lau JY, Hoang N, et al. Association of diabetes mellitus and chronic hepatitis C virus infection. Hepatology. 1999;29:328–333
  5. Caronia S, Taylor K, Pagliaro L, et al. Further evidence for an association between non-insulin-dependent diabetes mellitus and chronic hepatitis C virus infection. Hepatology. 1999;30:1059–1063
  6. Zein NN, Abdulkarim AS, Wiesner RH, et al. Prevalence of diabetes mellitus in patients with end-stage liver cirrhosis due to hepatitis C, alcohol, or cholestatic disease. J Hepatol. 2000;32:209–217
  7. Zein CO, Levy C, Basu A, et al. Chronic hepatitis C and type II diabetes mellitus: a prospective cross-sectional study. Am J Gastroenterol. 2005;100:48–55
  8. Mehta SH, Brancati FL, Sulkowski SM, et al. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med. 2000;133:592–599
  9. Metha SH, Brancati FL, Strathdee S, et al. Hepatitis C virus infection and incident type 2 diabetes. Hepatology. 2003;38:50–56
  10. Lecube A, Hernandez C, Genesca J, et al. Proinflammatory cytokines, insulin resistance, and insulin secretion in chronic hepatitis C patients. Diabetes Care. 2006;29:1096–1101
  11. Hui JM, Sud A, Farrell GC, et al. Insulin resistance is associated with chronic hepatitis C and virus infection fibrosis progression. Gastroenterology. 2003;125:1695–1704
  12. Hickman IJ, Powell EE, Prins JB, 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
  13. Kawaguchi T, Yoshida T, Harada M, et al. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of cytokine signaling 3. Am J Pathol. 2004;165:1499–1508
  14. Taura N, Ichikawa T, Hamasaki K, et al. Association between liver fibrosis and insulin sensitivity in chronic hepatitis C patients. Am J Gastroenterol. 2006;101:1–8
  15. Lecube A, Hernandez C, Genesca J, et al. High prevalence of glucose abnormalities in patients with hepatitis C virus infection. Diabetes Care. 2004;27:1171–1175
  16. Heckel RH, Grundy SM, Zimmet P. The metabolic syndrome. Lancet. 2005;365:1415–1428
  17. Alberti KG, Zimmet P, Shaw J IDF Epidemiology Task Force Consensus Group. The metabolic syndrome—a new worldwide definition. Lancet. 2005;366:1059–1061
  18. Ford ES. Prevalence of the metabolic syndrome defined by the International Diabetes Federation among adults in the US. Diabetes Care. 2005;28:2745–2749
  19. Petrides AS, Vogt C, Schulze-Berge D, et al. Pathogenesis of glucose intolerance and diabetes mellitus in cirrhosis. Hepatology. 1994;19:616–627
  20. Fartoux L, Poujol-Robert A, Guechot J, et al. Insulin resistance is a cause of steatosis and fibrosis progression in chronic hepatitis C. Gut. 2005;54:1003–1008
  21. Camma C, Bruno S, Di Marco V, et al. Insulin resistance is associated with steatosis in nondiabetic patients with genotype 1 chronic hepatitis C. Hepatology. 2006;43:64–71
  22. Conjeevaram HS, Kleiner DE, Everhart JE, et al. Race, insulin resistance and hepatic steatosis in chronic hepatitis C. Hepatology. 2007;45:80–87
  23. Sanyal AJ. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology. 2002;123:1705–1725
  24. 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
  25. Bugianesi E, Leone N, Vanni E, et al. Expanding the natural history of nonalcoholic steatohepatitis from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123:134–140
  26. El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology. 2004;126:460–468
  27. Petit JM, Bour JB, Galland-Jos C, et al. Risk for diabetes mellitus and early insulin resistance in chronic hepatitis C. J Hepatol. 2001;35:279–283
  28. Narita R, Abe S, Kihara Y, et al. Insulin resistance and insulin secretion in chronic hepatitis C virus infection. J Hepatol. 2004;41:132–138
  29. Durante-Mangoni E, Zampino R, Marrone A, et al. Hepatic steatosis and insulin resistance are associated with imbalance of adiponectin/tumor necrosis factor-α in chronic hepatitis C patients. Aliment Pharmacol Ther. 2006;24:1349–1357
  30. Muzzi A, Leandro G, Rubbia-Brandt L, et al. Insulin resistance is associated with liver fibrosis in non-diabetic chronic hepatitis C patients. J Hepatol. 2005;42:41–46
  31. 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
  32. Bugianesi E, Marchesini G, Gentilcore E, et al. Fibrosis in genotype 3 chronic hepatitis C and nonalcoholic fatty liver disease: role of insulin resistance and hepatic steatosis. Hepatology. 2006;44:1648–1655
  33. Kruszynska YT, Home PD, McIntyre N. Relationship between insulin sensitivity, insulin secretion and glucose tolerance in cirrhosis. Hepatology. 1991;14:103–111
  34. Pawlotsky JM. Molecular diagnosis of viral hepatitis. Gastroenterology. 2002;122:1554–1568
  35. Bonora E, Targher G, Alberiche M, et al. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity. Diabetes Care. 2000;23:57–63
  36. Katz A, Nambi SS, Mather K, et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab. 2000;85:2402–2410
  37. Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. Hepatology. 1996;24:289–293
  38. Strader DB, Wright T, Thomas DL, et al. Diagnosis, management and treatment of Hepatitis C. Hepatology. 2004;39:1147–1171
  39. Bauduceau B, Baigts F, Bordier L, et al. Epidemiology of the metabolic syndrome in 2045 French military personnel (EPIMIL study). Diabetes Metab. 2005;31:353–359
  40. Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology. 2005;42:987–1000
  41. Tilg H, Hotamisligil GS. Nonalcoholic fatty liver disease: cytokine-adipokine interplay and regulation of insulin resistance. Gastroenterology. 2006;131:934–945
  42. Negro F. Insulin resistance and HCV. J Hepatol. 2006;45:514–519
  43. Romero-Gomez M. Insulin resistance and hepatitis C. World J Gastroenterol. 2006;12:7075–7080
  44. Aytug S, Reich D, Sapiro LE, et al. Impaired IRS-1/PI3-kinase signaling in patients with HCV: a mechanism for increased prevalence of type 2 diabetes. Hepatology. 2003;38:1384–1392
  45. Shintani Y, Fujie H, Miyoshi H, et al. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology. 2004;126:840–848
  46. Walsh MJ, Jonsson JR, Richardson MM, et al. No-response to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signaling 3 (SOCS-3) in patients with chronic hepatitis C, viral genotype 1. Gut. 2006;55:529–535
  47. Harrison SA. Correlation between insulin resistance and hepatitis C viral load. Hepatology. 2006;43:1168
  48. Sanyal AJ, Chand N, Comar K, et al. Hyperinsulinemia blocks the inhibition of hepatitis C virus (HCV) replication by interferon: a potential mechanism for failure of interferon therapy in subjects with HCV and nonalcoholic fatty liver disease. Hepatology. 2004;40:179A
  49. Kawaguchi T, Ide T, Taniguchi E, et al. Clearance of HCV improves insulin resistance, β-cell function, and hepatic expression of insulin receptor substrates 1 and 2. Am J Gastroenterol. 2007;102:1–7
  50. Paradis V, Perlemuter G, Bonvust F, et al. High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved progression to fibrosis in nonalcoholic steatohepatitis. Hepatology. 2001;34:738–744
  51. Ratziu V, Munteanu M, Charlotte F, et al. Fibrogenic impact of high serum glucose in chronic hepatitis C. J Hepatol. 2003;39:1049–1055
  52. Marcellin P, Asselah T, Boyer N. Fibrosis and disease progression in hepatitis C. Hepatology. 2002;36:S47–S56
  53. Ghany MG, Kleiner DE, Alter H, et al. Progression of fibrosis in chronic hepatitis C. Gastroenterology. 2003;124:97–104
  54. Asselah T, Bieche I, Laurendeau I, et al. Liver gene expression signature of mild fibrosis in chronic hepatitis C. Gastroenterology. 2005;129:2064–2075
  55. Adinolfi LE, Gambardella M, Andreana A, et al. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients with specific HCV genotype and visceral obesity. Hepatology. 2001;33:1358–1364
  56. Patton HM, Patel K, Behling C, 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
  57. Fartoux L, Chazoullieres O, Wendum D, et al. Impact of steatosis on progression of fibrosis in patients with mild hepatitis C. Hepatology. 2005;41:82–87
  58. Asselah T, Boyer N, Guimont M-C, et al. Liver fibrosis is not associated with steatosis but with necroinflammation in French patients with chronic hepatitis C. Gut. 2003;52:1638–1643
  59. Perumalswami P, Kleiner DE, Lutchman G, et al. Steatosis and progression of fibrosis in untreated patients with chronic hepatitis C infection. Hepatology. 2006;43:780–787
  60. Leandro G, Mangia A, Hui J, et al. Relationship between steatosis, inflammation and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data. Gastroenterology. 2006;130:1636–1642
  61. Asselah T, Rubbia-Brandt L, Marcellin P, et al. Steatosis in chronic hepatitis C: what does it really matter?. Gut. 2006;55:123–130
  62. Romero-Gomez M, Viloria M, Andrade R, et al. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology. 2005;128:636–641

 Conflicts of interest: The authors of the study declare that they have no conflicts of interest to disclose.

PII: S0016-5085(07)02023-9

doi: 10.1053/j.gastro.2007.11.010

Gastroenterology
Volume 134, Issue 2 , Pages 416-423 , February 2008