Skip to main content

Advertisement

SpringerLink
Log in

Post-challenge hyperglycemia is a significant risk factor for the development of hepatocellular carcinoma in patients with chronic hepatitis C

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

Several epidemiological studies have reported that diabetes mellitus is a risk factor for hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-positive patients. However, it is unclear whether or not post-challenge hyperglycemia is a risk factor. The purpose of this study was to determine the association between post-challenge hyperglycemia and hepatocarcinogenesis in HCV-positive patients.

Methods

A total of 203 HCV-RNA-positive subjects (108 males, mean age 54.3 ± 10.8 years; 95 females, mean age 56.6 ± 10.3 years; genotype 1b/2a/2b/3a: 152/38/12/1) who underwent liver biopsy and a 75-g oral glucose tolerance test, and who were treated with interferon (IFN) were enrolled in this study. None of the subjects had been treated with antidiabetic drugs. The subjects underwent ultrasonography and/or computed tomography every 6 months after the end of the IFN therapy.

Results

Thirteen patients, including one patient who achieved a sustained viral response (SVR) with IFN, developed HCC. On multivariate analysis, male sex, age >65 years, excessive alcohol consumption, non-SVR, liver steatosis area >5% in liver specimens, and 120-min post-challenge hyperglycemia were risk factors for the development of HCC. After matching subjects for sex, age, alcohol intake, and response to the IFN therapy, advanced fibrosis stages [hazard ratio (HR) 2.8], liver steatosis (HR 5.4), and 120-min post-challenge hyperglycemia (HR 4.9) were significant risk factors for the development of HCC. Furthermore, after matching for the fibrosis stage, liver steatosis (HR 5.7) and 120-min post-challenge hyperglycemia (HR 6.9) remained as significant factors for HCC development.

Conclusion

Post-challenge hyperglycemia is an independent risk factor for HCC in HCV-positive patients.

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

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

HCV:

Hepatitis C virus

HBV:

Hepatitis B virus

HCC:

Hepatocellular carcinoma

DM:

Diabetes mellitus

HR:

Hazard ratio

BMI:

Body mass index

ALT:

Alanine aminotransferase

HbA1c:

Hemoglobin A1c

IFN:

Interferon

OGTT:

Oral glucose tolerance test

PCR:

Polymerase chain reaction

HOMA-IR:

Homeostasis model assessment for insulin resistance

SVR:

Sustained viral response

References

  1. Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med. 2001;345:41–52.

    Article  PubMed  CAS  Google Scholar 

  2. Poynard T, Bedossa P, Oplon P, for the OBSTIRC, METAVIR, CLINIVIR and DOSVIRC groups. Nature history of liver fibrous progression in patients with chronic hepatitis C. Lancet. 1997;349:825–32.

    Google Scholar 

  3. Kenny-Walsh E. Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. Irish Hepatology Research Group. N Engl J Med. 1999;340:1228–33.

    Article  PubMed  CAS  Google Scholar 

  4. Wiley TE, McCarthy M, Breidi L, McCarthy M, Layden TJ. Impact of alcohol on the histological and clinical progression of hepatitis C infection. Hepatology. 1998;28:805–9.

    Article  PubMed  CAS  Google Scholar 

  5. Liaw YF, Chen YC, Sheen IS, Chien RN, Yeh CT, Chu CM. Impact of acute hepatitis C virus superinfection in patients with chronic hepatitis B virus infection. Gastroenterology. 2004;126:1024–9.

    Article  PubMed  Google Scholar 

  6. Hung CH, Chen CH, Lee CM, Wu CM, Hu TH, Wang JH, et al. Association of amino acid variations in the NS5A and E2-PePHD region of hepatitis C virus 1b with hepatocellular carcinoma. J Viral Hepat. 2008;15:58–65.

    PubMed  Google Scholar 

  7. Veldt BJ, Chen W, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP, et al. Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus. Hepatology. 2008;47:1856–62.

    Article  PubMed  Google Scholar 

  8. Chen CL, Yang HI, Yang WS, Liu CJ, Chen PJ, You SL, et al. Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow-up study in Taiwan. Gastroenterology. 2008;135:111–21.

    Article  PubMed  CAS  Google Scholar 

  9. Tung HD, Wang JH, Tseng PL, Hung CH, Kee KM, Chen CH, et al. Neither diabetes mellitus nor overweight is a risk factor for hepatocellular carcinoma in a dual HBV and HCV endemic area: community cross-sectional and case–control studies. Am J Gastroenterol. 2010;105:624–31.

    Article  PubMed  Google Scholar 

  10. Lai MS, Hsieh MS, Chiu YH, Chen TH. Type 2 diabetes and hepatocellular carcinoma: a cohort study in high prevalence area of hepatitis virus infection. Hepatology. 2006;43:1295–302.

    Article  PubMed  Google Scholar 

  11. Yoshida H, Shiratori Y, Moriyama M, Arakawa Y, Ide T, Sata M, et al. Inhibition of hepatocarcinogenesis by interferon therapy. Ann Intern Med. 1999;131:174–81.

    PubMed  CAS  Google Scholar 

  12. Fattovich G, Giustina G, Degos F, Diodati G, Tremolada F, Nevens F, et al. Effectiveness of interferon alfa on incidence of hepatocellular carcinoma, decompensation in cirrhosis type C. European Concerted Action on Viral Hepatitis (EUROHEP). J Hepatol. 1997;27:201–5.

    Article  PubMed  CAS  Google Scholar 

  13. Tarao K, Rino Y, Ohkawa S, Shimizu A, Tamai S, Miyakawa K, et al. Association between high serum alanine aminotransferase levels and more rapid development and higher rate of incidence of hepatocellular carcinoma in patients with hepatitis C virus associated cirrhosis. Cancer. 1999;86:589–95.

    Article  PubMed  CAS  Google Scholar 

  14. Pekow JR, Bhan AK, Zheng H, Chung RT. Hepatic steatosis is associated with increased frequency of hepatocellular carcinoma in patients with hepatitis C-related cirrhosis. Cancer. 2007;109:2490–946.

    Article  PubMed  Google Scholar 

  15. 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 

  16. Ikeda Y, Suehiro T, Nakamura T, Kumon Y, Hashimoto K. Clinical significance of the insulin resistance index as assessed by homeostasis model assessment. Endocr J. 2001;48:81–6.

    Article  PubMed  Google Scholar 

  17. Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology 1996; 24: 289-293.

    Google Scholar 

  18. Monnier L, Mas E, Ginet C, Michel F, Villon L, Cristol JP, et al. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA. 2006;295:1681–7.

    Article  PubMed  CAS  Google Scholar 

  19. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005;54:1615–25.

    Article  PubMed  CAS  Google Scholar 

  20. Tanaka H, Fujita N, Sugimoto R, Urawa N, Horiike S, Kobayashi Y, et al. Hepatic oxidative DNA damage is associated with increased risk for hepatocellular carcinoma in chronic hepatitis C. Br J Cancer. 2008;98:580–6.

    Article  PubMed  CAS  Google Scholar 

  21. Jüngst C, Cheng B, Gehrke R, Schmitz V, Nischalke HD, Ramakers J, et al. Oxidative damage is increased in human liver tissue adjacent to hepatocellular carcinoma. Hepatology. 2004;39:1663–72.

    Article  PubMed  Google Scholar 

  22. Oka R, Hifumi S, Kobayashi J, Mabuchi H, Asano A, Yagi K, et al. The relationship between post-prandial plasma glucose and post-challenge plasma glucose in Japanese population. Diabetes Res Clin Pract. 2007;78:282–8.

    Article  PubMed  CAS  Google Scholar 

  23. Ito C, Maeda R, Ishida S, Sasaki H, Harada H. Correlation among fasting plasma glucose, two-hour plasma glucose levels in OGTT and HbA1c. Diabetes Res Clin Pract. 2000;50:225–30.

    Article  PubMed  CAS  Google Scholar 

  24. Tsugane S, Inoue M. Insulin resistance and cancer: epidemiological evidence. Cancer Sci. 2010;101:1073–9.

    Article  PubMed  CAS  Google Scholar 

  25. El-Serag HB, Hampel H, Javadi F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol. 2006;4:369–80.

    Article  PubMed  Google Scholar 

  26. 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 

  27. 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 

  28. Persico M, Masarone M, La Mura V, Persico E, Moschella F, Svelto M, et al. Clinical expression of insulin resistance in hepatitis C and B virus-related chronic hepatitis: differences and similarities. World J Gastroenterol. 2009;15:462–6.

    Article  PubMed  CAS  Google Scholar 

  29. Eguchi Y, Mizuta T, Ishibashi E, Kitajima Y, Oza N, Nakashita S, et al. Hepatitis C virus infection enhances insulin resistance induced by visceral fat accumulation. Liver Int. 2009;29:213–20.

    Article  PubMed  CAS  Google Scholar 

  30. Konishi I, Hiasa Y, Shigematsu S, Hirooka M, Furukawa S, Abe M, et al. Diabetes pattern on the 75 g oral glucose tolerance test is a risk factor for hepatocellular carcinoma in patients with hepatitis C virus. Liver Int. 2009;29:1194–201.

    Article  PubMed  Google Scholar 

  31. Cacciatore L, Cozzolino G, Giardina MG, De Marco F, Sacca L, Esposito P, et al. Abnormalities of glucose metabolism induced by liver cirrhosis and glycosylated hemoglobin levels in chronic liver disease. Diabetes Res. 1988;7:185–8.

    PubMed  CAS  Google Scholar 

  32. Bando Y, Kanehara H, Toya D, Tanaka N, Kasayama S, Koga M. Association of serum glycated albumin to haemoglobin A1C ratio with hepatic function tests in patients with chronic liver disease. Ann Clin Biochem. 2009;46:368–72.

    Article  PubMed  CAS  Google Scholar 

  33. Qiao Q, Lindström J, Valle TT, Tuomilehto J. Progression to clinically diagnosed and treated diabetes from impaired glucose tolerance and impaired fasting glycaemia. Diabet Med. 2003;20:1027–33.

    Article  PubMed  CAS  Google Scholar 

  34. Nakagami T, Tajima N, Oizumi T, Karasawa S, Wada K, Kameda W, et al. Hemoglobin A1c in predicting progression to diabetes. Diabetes Res Clin Pract. 2010;87:126–31.

    Article  PubMed  CAS  Google Scholar 

  35. DECODE Study Group, European Diabetes Epidemiology Group. Is the current definition for diabetes relevant to mortality risk from all causes and cardiovascular and noncardiovascular diseases? Diabetes Care. 2003;26:688–96.

    Article  Google Scholar 

  36. Nakagami T, DECODA Study Group. Hyperglycaemia and mortality from all causes and from cardiovascular disease in five populations of Asian origin. Diabetologia. 2004;47:385–94.

    Article  PubMed  CAS  Google Scholar 

  37. Nishiguchi S, Kuroki T, Nakatani S, Morimoto H, Takeda T, Nakajima S, et al. Randomised trial of effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet. 1995;346:1051–5.

    Article  PubMed  CAS  Google Scholar 

  38. Kasai D, Adachi T, Deng L, Nagano-Fujii M, Sada K, Ikeda M, et al. HCV replication suppresses cellular glucose uptake through down-regulation of cell surface expression of glucose transporters. J Hepatol. 2009;50:883–94.

    Article  PubMed  CAS  Google Scholar 

  39. Kawaguchi Y, Mizuta T, Oza N, Takahashi H, Ario K, Akiyama T, et al. Eradication of hepatitis C virus by interferon improves whole-body insulin resistance and hyperinsulinaemia in patients with chronic hepatitis C. Liver Int. 2009;29:871–7.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Ms Yukie Watanabe, Ms Chieko Ogawa, and all the medical staff at Saga Medical School Hospital for their assistance and excellent advice.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Saga Medical School, Nabeshima, Saga, Japan

    Hirokazu Takahashi, Toshihiko Mizuta, Yuichiro Eguchi, Yasunori Kawaguchi, Takuya Kuwashiro, Satoshi Oeda, Hiroshi Isoda, Noriko Oza, Shinji Iwane, Kenichi Izumi, Keizou Anzai, Iwata Ozaki & Kazuma Fujimoto

Authors
  1. Hirokazu Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Toshihiko Mizuta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuichiro Eguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yasunori Kawaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takuya Kuwashiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Satoshi Oeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hiroshi Isoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Noriko Oza
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shinji Iwane
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kenichi Izumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Keizou Anzai
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Iwata Ozaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kazuma Fujimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toshihiko Mizuta.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Takahashi, H., Mizuta, T., Eguchi, Y. et al. Post-challenge hyperglycemia is a significant risk factor for the development of hepatocellular carcinoma in patients with chronic hepatitis C. J Gastroenterol 46, 790–798 (2011). https://doi.org/10.1007/s00535-011-0381-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-011-0381-2

Keywords

Search

Navigation