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01-06-2011 | Original Article—Liver, Pancreas, and Biliary Tract

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

Authors: 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

Published in: Journal of Gastroenterology | Issue 6/2011

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.

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

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.

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.

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.PubMedCrossRef

19.

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

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

24.

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

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.CrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

Title: Post-challenge hyperglycemia is a significant risk factor for the development of hepatocellular carcinoma in patients with chronic hepatitis C
Authors: 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
Publication date: 01-06-2011
Publisher: Springer Japan
Published in: Journal of Gastroenterology / Issue 6/2011
Print ISSN: 0944-1174
Electronic ISSN: 1435-5922
DOI: https://doi.org/10.1007/s00535-011-0381-2

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

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Results

Conclusion

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