Increased hepatic oxidative DNA damage in patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma
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The rate of onset of hepatocellular carcinoma (HCC) in patients with nonalcoholic steatohepatitis (NASH) has been reported recently to be comparable to that of patients with chronic hepatitis C. However, the precise mechanism contributing to carcinogenesis in the former remains unclear. Although increased oxidative stress is presumed to play a role in carcinogenesis in patients with NASH, this relationship remains to be directly proven. In this study, we investigated the involvement of oxidative DNA damage in hepatocarcinogenesis in patients with NASH.
Patients with nonalcoholic fatty liver disease who were treated at our university hospital were eligible for enrolment in the study(n = 49). The study cohort included 30 patients with NASH without HCC (NASH without HCC), six HCC patients with NASH (NASH–HCC), and 13 patients with simple steatosis. Quantitative immunohistochemistry with a KS-400 image analyzing system was used for 8-hydroxy-2′-deoxyguanosine (8-OHdG) detection.
The 8-OHdG content in the liver tissue of NASH–HCC patients was significantly different from that in the other patients. The median immunostaining intensity was 8.605 in the NASH–HCC cases, which was significantly higher than that in the cases of NASH without HCC (4.845; P = 0.003). Multivariate analysis using hepatic 8-OHdG content as a factor in addition to age and fasting blood sugar revealed a significant difference in clinicopathological factors between NASH–HCC and NASH without HCC cases. Old age (P = 0.015) and high relative immunostaining intensity for intrahepatic 8-OHdG (P = 0.037) were identified as independent factors.
8-OHdG content in liver tissue may serve a marker of oxidative stress and could be a particularly useful predictor of hepatocarcinogenesis.
- Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362:1907–17. CrossRef
- Shariff MIF, Cox IJ, Gomaa AI, Khan SA, Gedroyc W, Taylor-Robinson SD. Hepatocellular carcinoma: current trends in worldwide epidemiology, risk factors, diagnosis and therapeutics. Exp Rev Gastroenterol Hepatol. 2009;3:353–67. CrossRef
- El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365:1118–27. CrossRef
- Ascha MS, Hanouneh IA, Lopez R, Tamimi TA-R, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010;51:1972–8. CrossRef
- Yasui K, Hashimoto E, Tokushige K, Koike K, Shima T, Kanbara Y, et al. Clinical and pathological progression of non-alcoholic steatohepatitis to hepatocellular carcinoma. Hepatol Res. 2012;42:767–73. CrossRef
- Yasui K, Hashimoto E, Komorizono Y, Koike K, Arii S, Imai Y, et al. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2011;9:428–33. CrossRef
- Kawamura Y, Arase Y, Ikeda K, Seko Y, Imai N, Hosaka T, et al. Large-scale long-term follow-up study of Japanese patients with non-alcoholic fatty liver disease for the onset of hepatocellular carcinoma. Am J Gastroenterol. 2011;107:253–61. CrossRef
- Hashimoto E, Yatsuji S, Tobari M, Taniai M, Torii N, Tokushige K, et al. Hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. J Gastroenterol. 2009;44[Suppl 19]:89–95. CrossRef
- Hashimoto E, Tokushige K. Hepatocellular carcinoma in non-alcoholic steatohepatitis: growing evidence of an epidemic? Hepatol Res. 2012;42:1–14. CrossRef
- Yang S, Zhu H, Li Y, Lin H, Gabrielson K, Trush MA, et al. Mitochondrial adaptations to obesity-related oxidant stress. Arch Biochem Biophys. 2000;378:259–68. CrossRef
- Bugianesi E. Non-alcoholic steatohepatitis and cancer. Clin Liver Dis. 2007;11:191–207. CrossRef
- George DK, Goldwurm S, MacDonald GA, Cowley LL, Walker NI, Ward PJ, et al. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology. 1998;114:311–8. CrossRef
- Cheng KC, Cahill DS, Kasai H, Nishimura S, Loeb LA. 8-Hydroxyguanine, an abundant form of oxidative DNA damage, causes G–T and A–C substitutions. J Biol Chem. 1992;267:166–72.
- Kasai H, Nishimura S. Hydroxylation of guanine in nucleosides and DNA at the C-8 position by heated glucose and oxygen radical-forming agents. Environ Health Perspect. 1986;67:111–6. CrossRef
- Shibutani S, Takeshita M, Grollman AP. Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodG. Nature. 1991;349:431–4. CrossRef
- Kato J, Kobune M, Nakamura T, Kuroiwa G, Takada K, Takimoto R, et al. Normalization of elevated hepatic 8-hydroxy-2′-deoxyguanosine levels in chronic hepatitis C patients by phlebotomy and low iron diet. Cancer Res. 2001;61:8697–702.
- Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology. 2003;37:1202–19. CrossRef
- Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413–9. CrossRef
- Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142:1592–609. CrossRef
- Takada A, Tsutsumi M, Okudaira M, Ohta Y, Tsujii T, Tanikawa K, et al. National survey of alcoholic liver disease in Japan (1968–91). J Gastroenterol Hepatol. 1995;10:509–16. CrossRef
- Kuzuya T, Nakagawa S, Satoh J, Kanazawa Y, Iwamoto Y, Kobayashi M, et al. Report of the committee on the classification and diagnostic criteria of diabetes mellitus. Diabetes Res Clin Pract. 2002;55:65–85. CrossRef
- Ogihara T, Kikuchi K, Matsuoka H, Fujita T, Higaki J, Horiuchi M, et al. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2009). Hypertens Res. 2009;32:3–107.
- Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94:2467–74. CrossRef
- Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208–36. CrossRef
- Rowe JW, Wands JR, Mezey E, Waterbury LA, Wright JR, Tobin J, et al. Familial hemochromatosis: characteristics of the precirrhotic stage in a large kindred. Medicine (Baltimore). 1977;56:197–211.
- Paradis V, Mathurin P, Kollinger M, Imbert-Bismut F, Charlotte F, Piton A, et al. In situ detection of lipid peroxidation in chronic hepatitis C: correlation with pathological features. J Clin Pathol. 1997;50:401–6. CrossRef
- Seki S, Kitada T, Yamada T, Sakaguchi H, Nakatani K, Wakasa K. In situ detection of lipid peroxidation and oxidative DNA damage in non-alcoholic fatty liver diseases. J Hepatol. 2002;37:56–62. CrossRef
- Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 2004;114:147–52.
- Tokushige K, Takakura M, Tsuchiya-Matsushita N, Taniai M, Hashimoto E, Shiratori K. Influence of TNF gene polymorphisms in Japanese patients with NASH and simple steatosis. J Hepatol. 2007;46:1104–10. CrossRef
- Wieckowska A, Papouchado BG, Li Z, Lopez R, Zein NN, Feldstein AE. Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. Am J Gastroenterol. 2008;103:1372–9. CrossRef
- Sugimoto K, Takei Y. Clinicopathological features of non-alcoholic fatty liver disease. Hepatol Res. 2011;41:911–20. CrossRef
- Ichiba M, Maeta Y, Mukoyama T, Saeki T, Yasui S, Kanbe T, et al. Expression of 8-hydroxy-2′-deoxyguanosine in chronic liver disease and hepatocellular carcinoma. Liver Int. 2003;23:338–45. CrossRef
- Jo M, Nishikawa T, Nakajima T, Okada Y, Yamaguchi K, Mitsuyoshi H, et al. Oxidative stress is closely associated with tumor angiogenesis of hepatocellular carcinoma. J Gastroenterol. 2011;46:809–21. CrossRef
- Nishikawa T, Nakajima T, Katagishi T, Okada Y, Jo M, Kagawa K, et al. Oxidative stress may enhance the malignant potential of human hepatocellular carcinoma by telomerase activation. Liver Int. 2009;29:846–56. CrossRef
- Fujita N, Miyachi H, Tanaka H, Takeo M, Nakagawa N, Kobayashi Y, et al. Iron overload is associated with hepatic oxidative damage to DNA in nonalcoholic steatohepatitis. Cancer Epidemiol Biomarkers Prev. 2009;18:424–32. CrossRef
- Increased hepatic oxidative DNA damage in patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma
Journal of Gastroenterology
Volume 48, Issue 11 , pp 1249-1258
- Cover Date
- Print ISSN
- Online ISSN
- Springer Japan
- Additional Links
- Nonalcoholic steatohepatitis
- Nonalcoholic fatty liver disease
- Hepatocellular carcinoma
- Oxidative DNA damage
- Industry Sectors
- Author Affiliations
- 1. Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan