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Chronic HCV infection was associated with severe insulin resistance and mild atherosclerosis: a population-based study in an HCV hyperendemic area

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

Background

Hepatitis C virus (HCV) affects glucose and lipid metabolism in vitro; however, it is unclear whether HCV infection is associated with insulin resistance and atherosclerosis at the population level. We aimed to investigate this association in a Japanese cohort of the Seven Countries Study, and our investigation was conducted in Tanushimaru, an HCV hyperendemic area.

Methods

A total of 1908 inhabitants of Tanushimaru were classified into 3 groups according to HCV infection status: those who were uninfected (n = 1780), those with transient infection (n = 88), and those with chronic infection (n = 40). Insulin resistance and atherosclerosis were evaluated by homeostasis model assessment for insulin resistance (HOMA-IR) and carotid intima–media thickness (IMT), respectively. Intergroup differences in variables were evaluated by age- and sex-matched multivariate regression analysis.

Results

Significant intergroup differences were seen in fasting glucose and insulin levels. The HOMA-IR value was significantly higher in the group with chronic infection than the values in the uninfected and transiently infected groups (3.0 ± 0.39 vs. 1.3 ± 0.03 vs. 1.5 ± 0.14; P < 0.001). In contrast, low-density lipoprotein (LDL)-cholesterol and triglyceride levels were significantly lower in the group with chronic infection than the levels in the other groups. IMT was reduced in the group with chronic infection, with a significant intergroup difference (0.67 ± 0.02 vs. 0.71 ± 0.003 vs. 0.72 ± 0.01 mm; P = 0.003).

Conclusions

This population-based study in an HCV hyperendemic area revealed that chronic HCV infection was associated with severe insulin resistance and with mild atherosclerosis, suggesting a unique characteristic of HCV-related metabolic abnormality.

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Abbreviations

ALT:

Alanine aminotransferase

ANCOVA:

Analysis of covariance

ANOVA:

Analysis of variance

APRI:

Aspartate aminotransferase to platelet ratio index

AST:

Aspartate aminotransferase

HCV:

Hepatitis C virus

HDL:

High-density lipoprotein

HOMA-IR:

Homeostasis model assessment for insulin resistance

IBW:

Ideal body weight

IMT:

Intima–media thickness

LDL:

Low-density lipoprotein

References

  1. Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis. 2005;5:558–67.

    Article  PubMed  Google Scholar 

  2. Weinman SA, Belalcazar LM. Hepatitis C: a metabolic liver disease. Gastroenterology. 2004;126:917–9.

    Article  PubMed  Google Scholar 

  3. Kawaguchi T, Izumi N, Charlton MR, Sata M. Branched-chain amino acids as pharmacological nutrients in chronic liver disease. Hepatology. 2011;54:1063–70.

    Article  PubMed  CAS  Google Scholar 

  4. Allison ME, Wreghitt T, Palmer CR, Alexander GJ. Evidence for a link between hepatitis C virus infection and diabetes mellitus in a cirrhotic population. J Hepatol. 1994;21:1135–9.

    Article  PubMed  CAS  Google Scholar 

  5. Eslam M, Aparcero R, Kawaguchi T, Del Campo JA, Sata M, Khattab MA, et al. Meta-analysis: insulin resistance and sustained virological response in hepatitis C. Aliment Pharmacol Ther. 2011;34:297–305.

    Article  PubMed  CAS  Google Scholar 

  6. Kawaguchi T, Yoshida T, Harada M, Hisamoto T, Nagao Y, Ide T, et al. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am J Pathol. 2004;165:1499–508.

    Article  PubMed  CAS  Google Scholar 

  7. Voeks JH, McClure LA, Go RC, Prineas RJ, Cushman M, Kissela BM, et al. Regional differences in diabetes as a possible contributor to the geographic disparity in stroke mortality: the REasons for Geographic And Racial Differences in Stroke Study. Stroke. 2008;39:1675–80.

    Article  PubMed  Google Scholar 

  8. Agnello V, Abel G, Elfahal M, Knight GB, Zhang QX. Hepatitis C virus and other flaviviridae viruses enter cells via low density lipoprotein receptor. Proc Natl Acad Sci USA. 1999;96:12766–71.

    Article  PubMed  CAS  Google Scholar 

  9. Nahmias Y, Casali M, Barbe L, Berthiaume F, Yarmush ML. Liver endothelial cells promote LDL-R expression and the uptake of HCV-like particles in primary rat and human hepatocytes. Hepatology. 2006;43:257–65.

    Article  PubMed  CAS  Google Scholar 

  10. Icard V, Diaz O, Scholtes C, Perrin-Cocon L, Ramiere C, Bartenschlager R, et al. Secretion of hepatitis C virus envelope glycoproteins depends on assembly of apolipoprotein B positive lipoproteins. PLoS One. 2009;4:e4233.

    Article  PubMed  Google Scholar 

  11. Negro F. Abnormalities of lipid metabolism in hepatitis C virus infection. Gut. 2010;59:1279–87.

    Article  PubMed  CAS  Google Scholar 

  12. Miyazaki T, Honda A, Ikegami T, Saitoh Y, Hirayama T, Hara T, et al. Hepatitis C virus infection causes hypolipidemia regardless of hepatic damage or nutritional state: an epidemiological survey of a large Japanese cohort. Hepatol Res. 2011;41:530–41.

    Article  PubMed  CAS  Google Scholar 

  13. Mostafa A, Mohamed MK, Saeed M, Hasan A, Fontanet A, Godsland I, et al. Hepatitis C infection and clearance: impact on atherosclerosis and cardiometabolic risk factors. Gut. 2010;59:1135–40.

    Article  PubMed  CAS  Google Scholar 

  14. Ishizaka N, Ishizaka Y, Takahashi E, Tooda E, Hashimoto H, Nagai R, et al. Association between hepatitis C virus seropositivity, carotid-artery plaque, and intima–media thickening. Lancet. 2002;359:133–5.

    Article  PubMed  Google Scholar 

  15. Yang KC, Chen MF, Su TC, Jeng JS, Hwang BS, Lin LY, et al. Hepatitis B virus seropositivity is not associated with increased risk of carotid atherosclerosis in Taiwanese. Atherosclerosis. 2007;195:392–7.

    Article  PubMed  CAS  Google Scholar 

  16. Adachi H, Goetz FC, Jacobs DR, Tsuruta M, Hirai Y, Fujiura Y, et al. The role of obesity in the association of cardiovascular risk factors and glucose intolerance in small Japanese and North American communities. Diabetes Res Clin Pract. 2000;49:41–51.

    Article  PubMed  CAS  Google Scholar 

  17. Adachi H, Hino A. Trends in nutritional intake and serum cholesterol levels over 40 years in Tanushimaru, Japanese men. J Epidemiol. 2005;15:85–9.

    Article  PubMed  Google Scholar 

  18. Enomoto M, Adachi H, Fukami A, Furuki K, Satoh A, Otsuka M, et al. Serum dehydroepiandrosterone sulfate levels predict longevity in men: 27-year follow-up study in a community-based cohort (Tanushimaru study). J Am Geriatr Soc. 2008;56:994–8.

    Article  PubMed  Google Scholar 

  19. Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38:518–26.

    Article  PubMed  Google Scholar 

  20. Lackner C, Struber G, Liegl B, Leibl S, Ofner P, Bankuti C, et al. Comparison and validation of simple noninvasive tests for prediction of fibrosis in chronic hepatitis C. Hepatology. 2005;41:1376–82.

    Article  PubMed  Google Scholar 

  21. Keys A, Aravanis C, Blackburn HW, Van Buchem FS, Buzina R, Djordjevic BD, et al. Epidemiological studies related to coronary heart disease: characteristics of men aged 40–59 in seven countries. Acta Med Scand Suppl. 1966;460:1–392.

    PubMed  CAS  Google Scholar 

  22. Kobayashi S, Honda S, Murakami K, Sasaki S, Okubo H, Hirota N, et al. Both comprehensive and brief self-administered diet history questionnaires satisfactorily rank nutrient intakes in Japanese adults. J Epidemiol. 2012;22:151–9.

    Article  PubMed  Google Scholar 

  23. Oya J, Nakagami T, Sasaki S, Jimba S, Murakami K, Kasahara T, et al. Intake of n-3 polyunsaturated fatty acids and non-alcoholic fatty liver disease: a cross-sectional study in Japanese men and women. Eur J Clin Nutr. 2010;64:1179–85.

    Article  PubMed  CAS  Google Scholar 

  24. Kobayashi S, Murakami K, Sasaki S, Okubo H, Hirota N, Notsu A, et al. Comparison of relative validity of food group intakes estimated by comprehensive and brief-type self-administered diet history questionnaires against 16 d dietary records in Japanese adults. Public Health Nutr. 2011;14:1200–11.

    Article  PubMed  Google Scholar 

  25. Sasaki S, Yanagibori R, Amano K. Self-administered diet history questionnaire developed for health education: a relative validation of the test-version by comparison with 3-day diet record in women. J Epidemiol. 1998;8:203–15.

    Article  PubMed  CAS  Google Scholar 

  26. Alborino F, Burighel A, Tiller FW, van Helden J, Gabriel C, Raineri A, et al. Multicenter evaluation of a fully automated third-generation anti-HCV antibody screening test with excellent sensitivity and specificity. Med Microbiol Immunol. 2011;200:77–83.

    Article  PubMed  CAS  Google Scholar 

  27. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–9.

    Article  PubMed  CAS  Google Scholar 

  28. Furuki K, Adachi H, Matsuoka H, Enomoto M, Satoh A, Hino A, et al. Plasma levels of asymmetric dimethylarginine (ADMA) are related to intima–media thickness of the carotid artery: an epidemiological study. Atherosclerosis. 2007;191:206–10.

    Article  PubMed  CAS  Google Scholar 

  29. Altman DG, Bland JM. Standard deviations and standard errors. BMJ. 2005;331:903.

    Article  PubMed  Google Scholar 

  30. Mehta SH, Brancati FL, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med. 2000;133:592–9.

    PubMed  CAS  Google Scholar 

  31. Nagao Y, Kawaguchi T, Tanaka K, Kumashiro R, Sata M. Extrahepatic manifestations and insulin resistance in an HCV hyperendemic area. Int J Mol Med. 2005;16:291–6.

    PubMed  Google Scholar 

  32. 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;126:840–8.

    Article  PubMed  CAS  Google Scholar 

  33. Kawaguchi T, Ide T, Taniguchi E, Hirano E, Itou M, Sumie S, 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;102:570–6.

    Article  PubMed  Google Scholar 

  34. Reaven GM. Insulin resistance, hyperinsulinemia, hypertriglyceridemia, and hypertension. Parallels between human disease and rodent models. Diabetes Care. 1991;14:195–202.

    Article  PubMed  CAS  Google Scholar 

  35. Grundy SM. Hypertriglyceridemia, insulin resistance, and the metabolic syndrome. Am J Cardiol. 1999;83:25F–9F.

    Article  PubMed  CAS  Google Scholar 

  36. Aizaki H, Morikawa K, Fukasawa M, Hara H, Inoue Y, Tani H, et al. Critical role of virion-associated cholesterol and sphingolipid in hepatitis C virus infection. J Virol. 2008;82:5715–24.

    Article  PubMed  CAS  Google Scholar 

  37. Honda A, Matsuzaki Y. Cholesterol and chronic hepatitis C virus infection. Hepatol Res. 2011;41:697–710.

    Article  PubMed  CAS  Google Scholar 

  38. Perlemuter G, Sabile A, Letteron P, Vona G, Topilco A, Chretien Y, 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;16:185–94.

    Article  PubMed  CAS  Google Scholar 

  39. Ishizaka Y, Ishizaka N, Takahashi E, Unuma T, Tooda E, Hashimoto H, et al. Association between hepatitis C virus core protein and carotid atherosclerosis. Circ J. 2003;67:26–30.

    Article  PubMed  CAS  Google Scholar 

  40. Konishi M, Iso H, Iida M, Naito Y, Sato S, Komachi Y, et al. Trends for coronary heart disease and its risk factors in Japan: epidemiologic and pathologic studies. Jpn Circ J. 1990;54:428–35.

    Article  PubMed  CAS  Google Scholar 

  41. Bianchi G, Marchesini G, Zoli M, Bugianesi E, Fabbri A, Pisi E. Prognostic significance of diabetes in patients with cirrhosis. Hepatology. 1994;20:119–25.

    PubMed  CAS  Google Scholar 

  42. Fujiwara F, Ishii M, Taneichi H, Miura M, Toshihiro M, Takebe N, et al. Low incidence of vascular complications in patients with diabetes mellitus associated with liver cirrhosis as compared with type 2 diabetes mellitus. Tohoku J Exp Med. 2005;205:327–34.

    Article  PubMed  Google Scholar 

  43. Kawaguchi T, Sata M. Importance of hepatitis C virus-associated insulin resistance: therapeutic strategies for insulin sensitization. World J Gastroenterol. 2010;16:1943–52.

    Article  PubMed  CAS  Google Scholar 

  44. Kawaguchi T, Taniguchi E, Morita Y, Shirachi M, Tateishi I, Nagata E, et al. Association of exogenous insulin or sulphonylurea treatment with an increased incidence of hepatoma in patients with hepatitis C virus infection. Liver Int. 2010;30:479–86.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported, in part, by a Grant-in-Aid for Young Scientists (B) (No. 22790874 to T.K.) and a Grant-in-Aid for Scientific Research (C) (No. 21590865 to M.S.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and by Health and Labour Sciences Research Grants for Research on Hepatitis from the Ministry of Health, Labour and Welfare of Japan.

Conflict of interest

Michio Sata received lecture fees from Chugai Pharmaceutical Co., Ltd. Takumi Kawaguchi and Michio Sata belongs to a department funded by donations from MSD K.K.

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Authors and Affiliations

  1. Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan

    Ichiro Miyajima, Takumi Kawaguchi & Michio Sata

  2. Department of Digestive Disease Information and Research, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan

    Takumi Kawaguchi, Yumiko Nagao & Michio Sata

  3. Division of Cardio-Vascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan

    Ako Fukami & Tsutomu Imaizumi

  4. Department of Community Medicine, Kurume University School of Medicine, Kurume, Japan

    Hisashi Adachi

  5. Department of Social and Preventive Epidemiology, School of Public Health, The University of Tokyo, Tokyo, Japan

    Satoshi Sasaki

Authors
  1. Ichiro Miyajima
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  2. Takumi Kawaguchi
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  4. Yumiko Nagao
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Corresponding author

Correspondence to Takumi Kawaguchi.

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Miyajima, I., Kawaguchi, T., Fukami, A. et al. Chronic HCV infection was associated with severe insulin resistance and mild atherosclerosis: a population-based study in an HCV hyperendemic area. J Gastroenterol 48, 93–100 (2013). https://doi.org/10.1007/s00535-012-0610-3

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  • DOI: https://doi.org/10.1007/s00535-012-0610-3

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