Skip to main content

Advertisement

SpringerLink
Log in

Hepatitis C, insulin resistance, and steatosis

  • Published:
Current Hepatitis Reports Aims and scope Submit manuscript

Abstract

Chronic hepatitis C (CHC) and nonalcoholic fatty liver disease (NAFLD) are two frequently identified liver diseases worldwide. NAFLD is related to obesity and insulin resistance, which may also be a preexisting condition in patients with CHC. The complex relationship among obesity, steatosis, and insulin resistance as it pertains to the pathogenesis, treatment, and outcomes in CHC is discussed in this article.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Armstrong GL, Wasley A, Simard EP, et al.: The prevalence of hepatitis C virus infection in the United States, 1992 through 2002. Ann Intern Med 2006, 144:705–714.

    PubMed  Google Scholar 

  2. Bialek SR, Terrault NA: The changing epidemiology and natural history of hepatitis C virus infection. Clin Liver Dis 2006, 10:697–715.

    Article  PubMed  Google Scholar 

  3. Deuffic-Burban S, Poynard T, Sulkowski MS, Wong JB: Estimating the future health burden of chronic hepatitis C and human immunodeficiency virus infections in the United States. J Viral Hepat 2007, 14:107–115.

    Article  PubMed  CAS  Google Scholar 

  4. Browning JD, Szeczepaniack LS, Dobbins R, 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 

  5. 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.

    Article  PubMed  Google Scholar 

  6. Lonardo A, Adinolfi L, Loria P, et al.: Steatosis and hepatitis C virus: mechanisms and significance for hepatic and extrahepatic disease. Gastroenterology 2004, 126:586–597.

    Article  PubMed  CAS  Google Scholar 

  7. Ong JP, Younossi ZM, Speer C, et al.: Chronic hepatitis C and superimposed non-alcoholic fatty liver disease. Liver 2001, 21:266–271.

    Article  PubMed  CAS  Google Scholar 

  8. Brunt EM, Ramrakhiani S, Cordes BG, et al.: Concurrence of histologic features of steatohepatitis with other forms of chronic liver disease. Mod Pathol 2003, 16:49–56.

    Article  PubMed  Google Scholar 

  9. Conjeevaram HS, Kleiner DE, Everhart JE, et al.: Race, insulin resistance and hepatic steatosis in chronic hepatitis C. Hepatology 2007, 45:80–87.

    Article  PubMed  CAS  Google Scholar 

  10. Verma S, Bonacini M, Govindarajan S, et al.: More advanced hepatic fibrosis in Hispanics with chronic hepatitis C infection: role of patient demographics, hepatic necroinflammation, and steatosis. Am J Gastroenterol 2006, 101:1817–1823.

    Article  PubMed  Google Scholar 

  11. Hu KQ, Currie SL, Shen H, et al.: Clinical implications of hepatic steatosis in patients with chronic hepatitis C: a multicenter study of US veterans. Dig Dis Sci 2007, 52:570–578.

    Article  PubMed  Google Scholar 

  12. Walsh MJ, Jonsson JR, Richardson MM, et al.: Non-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.

    Article  PubMed  CAS  Google Scholar 

  13. 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 

  14. Durante-Mangoni, Zampino R, Marrone A, et al.: Hepatic steatosis and insulin resistance are associated with serum imbalance of adiponectin/tumor necrosis factor-alpha in chronic hepatitis C patients. Aliment Pharmacol Ther 2006, 24:1349–1357.

    Article  PubMed  CAS  Google Scholar 

  15. Jonsson JR, Moschen AR, Hickman IJ, et al.: Adiponectin and its receptors in patients with chronic hepatitis C. J Hepatol 2005, 43:929–936.

    Article  PubMed  CAS  Google Scholar 

  16. Widjaja A, Wedemeyer H, Tillman HL, et al.: Hepatitis C and the leptin system: bound leptin levels are elevated in patients with hepatitis C and decrease during antiviral therapy. Scand J Gastroenterol 2001, 36:426–431.

    Article  PubMed  CAS  Google Scholar 

  17. 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.

    PubMed  CAS  Google Scholar 

  18. Lecube A, Hernandez C, Genesca J, Simo R: Proinflammatory cytokines, insulin resistance, and insulin secretion in chronic hepatitis C patients. Diabetes Care 2006, 29:1096–1101.

    Article  PubMed  CAS  Google Scholar 

  19. Metha SH, Brancati FL, Sulkowski MS, et al.: Prevalence of type 2 diabetes mellitus: what is the connection? Ann Intern Med 2000, 133:592–599.

    Google Scholar 

  20. Mehta SH, Brancati FL, Strathdee SA, et al.: Hepatitis C virus infection and incident type 2 diabetes. Hepatology 2003, 38:50–56.

    Article  PubMed  Google Scholar 

  21. 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.

    Article  PubMed  CAS  Google Scholar 

  22. 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.

    PubMed  CAS  Google Scholar 

  23. Kawaguchi T, Ide T, Taniguchi E, et al.: Clearance of HCV improves insulin resistance, beta-cell function, and hepatic expression of insulin receptor substrate 1 and 2. Am J Gastroenterol 2007, 102:570–576.

    Article  PubMed  Google Scholar 

  24. 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.

    PubMed  CAS  Google Scholar 

  25. Miyamoto H, Moriishi K, Moriya K, et al.: Involvement of the PA28gamma-dependent pathway in insulin resistance induced by hepatitis C core protein. J Virol 2006, 81:1727–1735.

    Article  PubMed  Google Scholar 

  26. Moriishi K, Mochizuki, Moriya K et al.: Critical role of PA28gamma in hepatitis C virus-associated steatogenesis and carcinogenesis. Proc Natl Acad Sci U S A 2007, 104:1611–1666.

    Article  Google Scholar 

  27. Castera L, Chouteau P, Hezode C, et al.: Hepatitis C virus-induced hepatocellular steatosis. Am J Gastroenterol 2005, 100:711–715.

    Article  PubMed  Google Scholar 

  28. 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.

    PubMed  CAS  Google Scholar 

  29. 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.

    Article  PubMed  CAS  Google Scholar 

  30. Cheng Y, Dharancy S, Malapel M, Desreumaux P: Hepatitis C virus infection down-regulates the expression of peroxisome proliferator-activated receptor alpha and carnitine palmitoyl acyl-CoA transferase 1A. World J Gastroenterol 2005, 11:7591–7596.

    PubMed  CAS  Google Scholar 

  31. Dharancy S, Malapel M, Perletmuter G, et al.: Impaired expression of the peroxisome proliferator-activated receptor alpha during hepatitis C virus infection. Gastroenterology 2005, 128:334–342.

    Article  PubMed  CAS  Google Scholar 

  32. Lonardo A, Loria P, Adinolfi LE, et al.: Hepatitis C and steatosis: a reappraisal. J Viral Hepat 2006, 13:73–80.

    Article  PubMed  CAS  Google Scholar 

  33. Hourioux C, Patient R, Morin A, et al.: The genotype 3-specific hepatitis C virus core protein residue phenylalanine 164 increases steatosis in an in vitro cellular model. Gut 2007, 56(9):1302–1308.

    Article  PubMed  CAS  Google Scholar 

  34. Jackel-Cram C, Babiuk L, Liu Q: Up-regulation of fatty acid synthase promoter by hepatitis C virus core protein: genotype-3a core has a stronger effect than genotype 1-b core. J Hepatol 2007, 46:999–1008.

    Article  PubMed  CAS  Google Scholar 

  35. 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.

    Article  PubMed  CAS  Google Scholar 

  36. Lok AS, Everhart JE, Chung RT, et al.: Hepatic steatosis in hepatitis C: comparison of diabetic and nondiabetic patients in the hepatitis C antiviral long-term treatment against cirrhosis trial. Clinical Gastroenterol Hepatol 2007, 5:245–254.

    Article  CAS  Google Scholar 

  37. Castera L, Hezode C, Roudot-Thoraval F, et al.: Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsies. Gut 2003, 52:288–292.

    Article  PubMed  CAS  Google Scholar 

  38. Westin J, Nordlinder H, Lagging M, et al.: Steatosis accelerates fibrosis development over time in hepatitis C virus genotype 3 infected patients. J Hepatol 2002, 37:837–842.

    Article  PubMed  Google Scholar 

  39. 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.

    Article  PubMed  CAS  Google Scholar 

  40. Taura N, Ichikawa T, Hamasaki, et al.: Association between liver fibrosis and insulin sensitivity in chronic hepatitis C patients. Am J Gastroenterol 2006, 101:2752–2759.

    Article  PubMed  CAS  Google Scholar 

  41. 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  Google Scholar 

  42. 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 Hepatol 2004, 11:91–96.

    Article  CAS  Google Scholar 

  43. Poynard T, Ratziu V, McHutchinson J, 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 

  44. 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.

    Article  PubMed  Google Scholar 

  45. Westin J, Lagging M, Dhillon AP, et al.: Impact of hepatic steatosis on viral kinetics and treatment outcome during antiviral treatment of chronic HCV infection. J Viral Hepatol 2007, 14:29–35.

    Article  CAS  Google Scholar 

  46. Harrison SA, Brunt EM, Qazi RA, 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 

  47. Romero-Gomez M, Del Mar 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.

    Article  PubMed  CAS  Google Scholar 

  48. Choi J, Ou JH: Mechanisms of liver injury. III. Oxidative stress in the pathogenesis of hepatitis C virus. Am J Physiol Gastrointest Liver Physiol 2006, 290:847–851.

    Article  Google Scholar 

  49. DiBona D, Cippitelli M, Fionda C, et al.: Oxidative stress inhibits IFN-alpha-induced antiviral gene expression by blocking the JAK-STAT pathway. J Hepatol 2006, 45:271–279.

    Article  CAS  Google Scholar 

  50. Zimmerer JM, Lesinski GB, Kondadasula SV, et al.: IFN-alpha-induced signal transduction, gene expression and antitumor activity. J Immunol 2007, 178:4832–4845.

    PubMed  CAS  Google Scholar 

  51. Sanyal AJ, Chand N, Comar K, Mirshahi F: Hyperinsulinemia blocks the inhibition of hepatitis C virus replication by interferon: the potential mechanism for failure of interferon therapy in subjects with HCV and nonalcoholic fatty liver disease. Hepatology 2004, 40:39A.

    Google Scholar 

  52. Harrison SA: Correlation between insulin resistance and hepatitis C viral load. Hepatology 2005, 42:987–1000.

    Article  Google Scholar 

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

    Article  PubMed  Google Scholar 

  54. Bressler B, Wang K, Gries JM, et al.: Pharmacokinetics and response of obese patients with chronic hepatitis C treated with different doses of PEG-IFN Alpha2A(40KD). Hepatology 2005, 42:661A.

    Google Scholar 

  55. Fried M, Jensen D, Rodriguez-Torres M, et al.: Improved sustained virological response (SVR) rates with higher, fixed doses of peginterferon Alfa-2A (40KD) plus ribavirin in patients with difficult to cure characteristics. Hepatology 2006, 44:314A.

    Article  Google Scholar 

  56. McHutchison JG, Poynard T, Pianko S, et al.: The impact of interferon plus ribavirin on response to therapy in black patients with chronic hepatitis C. Gastroenterology 2000, 199:1317–1323.

    Article  Google Scholar 

  57. Melhem A, Stern M, Shibolet O, et al.: Treatment of chronic hepatitis C virus infection via antioxidants. J Clin Gastroenterol 2005, 39:737–742.

    Article  PubMed  CAS  Google Scholar 

  58. Tanaka K, Kondo M, Sakaguchi T, et al.: Efficacy of ursodeoxycholic acid in combination with interferon-alpha in treating chronic hepatitis C: results of long-term follow-up trial. J Gastroenterol Hepatol 1996, 11:1155–1160.

    PubMed  CAS  Google Scholar 

  59. Houglum K, Venkataramani A, Lyche K, et al.: A pilot study of the effects of D-alpha-tocopherol on hepatic stellate cell activation in chronic hepatitis C. Gastroenterology 1997, 113:1069–1073.

    Article  PubMed  CAS  Google Scholar 

  60. Look MP, Gerard A, Rao GS, et al.: Interferon/antioxidant combination therapy for chronic hepatitis C-a controlled pilot trial. Antiviral Res 1999, 43:113–122.

    Article  PubMed  CAS  Google Scholar 

  61. Puri P, Sanyal A: Role of obesity, insulin resistance, and steatosis in hepatitis C virus infection. Clin Liver Dis 2006, 10:793–819.

    Article  PubMed  Google Scholar 

  62. Monazahian M, Bohme I, Bonk S, et al.: Low density lipoprotein receptors as a candidate receptor for hepatitis C virus. J Med Virol 1999, 57:223–229.

    Article  PubMed  CAS  Google Scholar 

  63. Kim SS, Peng LF, Lin W, et al.: A cell-based, high-through-put screen for small molecule regulators of hepatitis C virus replication. Gastroenterology 2007, 132:311–320.

    Article  PubMed  CAS  Google Scholar 

  64. O’Leary JG, Chan JL, McMahon CM, Chung RT: Atorvastatin does not exhibit antiviral activity against HCV at conventional doses: a pilot clinical trial. Hepatology 2007, 45:895–898.

    Article  PubMed  Google Scholar 

  65. 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.

    Article  PubMed  CAS  Google Scholar 

  66. Harrison SA: Liver disease in patients with diabetes mellitus. J Clin Gastroenterol 2006, 40:68–76.

    Article  PubMed  Google Scholar 

  67. Belfort R, Harrison SA, Brown K, et al.: A placebo controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Eng J Med 2006, 355:2297–2307.

    Article  CAS  Google Scholar 

  68. Kanatani Y, Usui I, Ishizuka K, et al.: Effects of pioglitazone on suppressor of cytokine signaling 3 expression: potential mechanisms for its effects on insulin sensitivity and adiponectin expression. Diabetes 2007, 56:796–803.

    Article  Google Scholar 

  69. Yaginuma R, Ikejima K, Okumura K, 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 

  70. Tarantino G, Conca P, Sorrentino P, et al.: Metabolic factors involved in the therapeutic response of patients with hepatitis C virus-related chronic hepatitis. J Gastroenterol Hepatol 2006, 21:1266–1288.

    Article  PubMed  CAS  Google Scholar 

  71. Guidi M, Muratori P, Granito A, et al.: Hepatic steatosis in chronic hepatitis C: impact on response to anti-viral treatment with peg-interferon and ribavirin. Aliment Pharmacol Ther 2005, 22:943–949.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Brooke Army Medical Center, 3851 Roger Brooke Drive, Fort Sam Houston, TX, 78234, USA

    Stephen A. Harrison

Authors
  1. Dawn M. Torres
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephen A. Harrison
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephen A. Harrison.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Torres, D.M., Harrison, S.A. Hepatitis C, insulin resistance, and steatosis. Curr hepatitis rep 6, 129–137 (2007). https://doi.org/10.1007/s11901-007-0015-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11901-007-0015-6

Keywords

Search

Navigation