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Table of Contents
Vol. 51, No. 5, 2008
Issue release date: February 2009
Intervirology 2008;51:352–361
(DOI:10.1159/000187720)

Influence of Occult Hepatitis B Virus Coinfection on the Incidence of Fibrosis and Hepatocellular Carcinoma in Chronic Hepatitis C

Matsuoka S. · Nirei K. · Tamura A. · Nakamura H. · Matsumura H. · Oshiro S. · Arakawa Y. · Yamagami H. · Tanaka N. · Moriyama M.
Department of Medicine, Division of Gastroenterology and Hepatology, Nihon University School of Medicine, Tokyo, Japan
email Corresponding Author

Abstract

We examined prospectively the influence of occult hepatitis B virus (HBV) infection on the histopathological features and clinical outcome of HCV RNA-positive chronic hepatitis (CH-C) and detected hepatitis B core (HBc) particles in hepatocytes. The subjects were 468 patients with CH-C or liver cirrhosis (LC) who were negative for serum hepatitis B surface antigen (HBsAg) by enzyme-linked immunosorbent assay. HBV DNA was detected in serum by nested PCR. HBsAg and HBc antigen (HBcAg) in liver were investigated using immunohistochemical techniques and light (LM) and electron microscopy (EM). Serum HBV DNA was detected in 43.6% of the patients studied. There were no significant differences between HBV DNA-positive and DNA-negative patients in terms of their clinical profiles. For HBV DNA-positive patients, the degree of inflammatory cell infiltration and irregular regeneration of hepatocytes was significantly greater than for HBV DNA-negative patients. The cumulative probability of development of hepatocellular carcinoma (HCC) was significantly higher for HBV DNA-positive patients than for HBV DNA-negative patients. HBV DNA positivity was a risk factor for the occurrence of HCC according to multivariate analysis. HBsAg and HBcAg were detected in 8.5 and 72.3%, respectively, of the livers of serum HBV DNA-positive individuals. Core particles were detected in the nuclei of the hepatocytes by IEM. The histopathological features and long-term outcome of CH-C or LC could be affected by occult HBV infection.


 goto top of outline Key Words

  • Occult hepatitis B virus infection
  • Chronic hepatitis C
  • Liver cirrhosis
  • Hepatocellular carcinoma
  • Electron microscopy

 goto top of outline Abstract

We examined prospectively the influence of occult hepatitis B virus (HBV) infection on the histopathological features and clinical outcome of HCV RNA-positive chronic hepatitis (CH-C) and detected hepatitis B core (HBc) particles in hepatocytes. The subjects were 468 patients with CH-C or liver cirrhosis (LC) who were negative for serum hepatitis B surface antigen (HBsAg) by enzyme-linked immunosorbent assay. HBV DNA was detected in serum by nested PCR. HBsAg and HBc antigen (HBcAg) in liver were investigated using immunohistochemical techniques and light (LM) and electron microscopy (EM). Serum HBV DNA was detected in 43.6% of the patients studied. There were no significant differences between HBV DNA-positive and DNA-negative patients in terms of their clinical profiles. For HBV DNA-positive patients, the degree of inflammatory cell infiltration and irregular regeneration of hepatocytes was significantly greater than for HBV DNA-negative patients. The cumulative probability of development of hepatocellular carcinoma (HCC) was significantly higher for HBV DNA-positive patients than for HBV DNA-negative patients. HBV DNA positivity was a risk factor for the occurrence of HCC according to multivariate analysis. HBsAg and HBcAg were detected in 8.5 and 72.3%, respectively, of the livers of serum HBV DNA-positive individuals. Core particles were detected in the nuclei of the hepatocytes by IEM. The histopathological features and long-term outcome of CH-C or LC could be affected by occult HBV infection.

Copyright © 2009 S. Karger AG, Basel


 goto top of outline References
  1. Chazouilleres O, Mamish D, Kim M, Carely K, Ferrell L, Roberts J, Ascher NL, Wright T: Occult hepatitis B virus as source of infection in liver transplant recipients. Lancet 1994;343:142–146.
  2. Uemoto S, Sugiyama K, Marusawa H, Inomata Y, Asonima K, Egawa H, Kiuchi T, Miyake Y, Tanaka K, Chiba T: Transmission of hepatitis B virus from hepatitis B core antibody-positive donors in living related liver transplants. Transplantation 1998;65:494–499.
  3. Levicnik-Stezinar S, Rahne-Potokar U, Candotti D, Lelie N, Allain JP: Anti-HBs positive occult hepatitis B virus carrier blood infections in two transfusion recipients. J Hepatol 2008;48:1022–1025.
  4. Uchida T, Kaneita Y, Gotoh K, Kanagawa H, Kouyama H, Kawanishi T, Mima S: Hepatitis C virus is frequently coinfected with serum marker-negative hepatitis B Virus. J Med Virol 1997;52:399–405.
  5. Fukuda R, Ishimura N, Kushiyama Y, Moriyama N, Ishihara S, Chowdhury A, Tokuda A, Sakai S, Akagi S, Watanabe M, Fukumoto S: Hepatitis B virus with X gene mutation is associated with majority of serologically ‘silent’ non-B, non-C chronic hepatitis. Microbiol Immunol 1996;40:481–488.
  6. Cacciola I, Pollicino T, Squadrito G, Cerenzia G, Orlando ME, Raimondo G: Occult hepatitis B virus infection in patients with chronic hepatitis C liver disease. N Engl J Med 1999;341:22–26.
  7. Koike K, Kobayashi M, Gondo M, Hayashi I, Osuga T, Takada S: Hepatitis B virus DNA is frequently found in liver biopsy samples from hepatitis C virus-infected chronic hepatitis patients. J Med Virol 1998;54:249–255.
  8. Kazemi-Shirazi L, Petermann D, Muller C: Hepatitis B virus DNA in sera and liver tissues of HBsAg negative patients with chronic hepatitis C. J Hepatol 2000;33:785–790.
  9. Sagnelli E, Imparato M, Coppola N, Pisapia R, Sagnelli C, Messina V, Piai G, Stanzione M, Bruno M, Moggio G, Caprio N, Pasquale G, Del Vacchio Blanco C: Diagnosis and clinical impact of occult hepatitis B infection in patients with biopsy proven chronic hepatitis C: a multicenter study. J Med Virol 2008;80:1547–1553.
  10. Mrani S, Chemin I, Menousar K, Guillaud O, Pradat P, Borghi G, Trabaud MA, Chevallier P, Chevallier M, Zoulim F, Trepo C: Occult HBV infection may present a major risk factor of non-response to anti-viral therapy of chronic hepatitis C. J Med Virol 2007;79:1075–1081.
  11. Hwang S, Moon DB, Lee SG, Park KM, Kim KH, Ahn CS, Lee YJ, Chu CW, Yang HS, Cho SH, Oh KB, Ha TY, Min PC: Safety of anti-hepatitis B core antibody-positive donors for living-donor liver transplantation. Transplantation 2003;75:S45–S48.
  12. Ikeda K, Marusawa H, Osaki Y, Nakamura T, Kitajima N, Yamashita Y, Kudo M, Sato T, Chiba T: Antibody to hepatitis B core antigen and risk for hepatitis C-related hepatocellular carcinoma: a prospective study. Ann Intern Med 2007;146:649–656.
  13. Giannini E, Ceppa P, Botta F, Fasoli A, Romagnoli P, Ansaldi F, Durando P, Risso D, Lantieri PB, Icardi GC, Testa R: Previous hepatitis B virus infection is associated with worse disease stage and occult hepatitis B virus infection has low prevalence and pathogenicity in hepatitis C virus-positive patients. Liver 2003;23:12–18.

    External Resources

  14. Kao JH, Chen PJ, Lai MY, Chen DS: Occult hepatitis B virus infection and clinical outcomes of patients with chronic hepatitis C. J Clin Microbiol 2002;40:4068–4071.
  15. Hu KQ: Occult hepatitis B virus infection and its clinical implications. J Viral Hepatitis 2002;9:243–257.
  16. Nirei K, Kaneko M, Moriyama M, Arakawa Y: The clinical feature of chronic hepatitis C are not affected by the coexistence of hepatitis B virus DNA in patients negative for hepatitis B virus surface antigen. Intervirology 2000;43:95–101.
  17. Matsumura H, Moriyama M, Goto I, Tanaka N, Okubo H, Arakawa Y: Natural course of progression of liver fibrosis in Japanese patients with chronic liver disease type C: a study of 527 patients at one establishment. J Viral Hepatitis 2000;7:268–275.
  18. Moriyama M, Matsumura H, Shimizu T, Shioda A, Kaneko M, Saito H, Miyazawa K, Tanaka N, Sugitani M, Komiyama K, Arakawa Y: Hepatitis G virus coinfection influences the liver histology of patients with chronic hepatitis C. Liver 2000;20:397–404.
  19. Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ: Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 1994;19:1513–1520.
  20. Moriyama M, Matsumura H, Shimizu T, Shioda A, Kaneko M, Miyazawa K, Miyata H, Tanaka N, Uchida T, Arakawa Y: Histopathologic impact of TT virus infection on the liver of C-viral chronic hepatitis and liver cirrhosis in Japan. J Med Virol 2001;63:1–8.
  21. Uchida T: Small hepatocellular carcinoma: Its relationship to multistep hepatocarcinogenesis. Pathol Intl 1995;45:175–184.
  22. Uchida T: Pathology of hepatitis C. Intervirology 1994;37:126–132.
  23. Shibata M, Uchida T, Yamagami T, Onozaki Y, Nakao M, Mitamura K, Ueno Y: Irregular regeneration of hepatocytes and risk of hepatocellular carcinoma in chronic hepatitis and cirrhosis with hepatitis-C virus infection. Lancet 1998;351:1773–1777.
  24. Ueno Y, Moriyama M, Uchida T, Arakawa Y: Irregular regeneration of hepatocytes is an important factor in the hepatocarcinogenesis of liver disease. Hepatology 2001;33:357–362.
  25. Abe K, Edamoto Y, Park YN, Nomura AM, Taltavull TC, Tani M, Thung SN: In situ detection of hepatitis B, C, and G virus nucleic acids in human hepatocellular carcinoma tissues from different geographic regions. Hepatology 1998;28:568–572.
  26. Okamoto H, Tsuda F, Sakugawa H, Sastrosoewignjo RI, Imai M, Miyakawa Y, Mayumi M: Typing hepatitis B virus homology in nucleotide sequence: comparison of surface antigen subtypes. J Gen Virol 1988;69:2575–2583.
  27. Naito H, Hayashi S, Abe K: The entire nucleotide sequence of two hepatitis G virus isolates to a novel genotype: isolation in Myanmar and Vietnam. J Gen Virol 2000;81:189–194.
  28. Saitou N, Nei M: The neighbor-joining method: a new method for reconstructing phylogenetic tree. Mol Biol Evol 1987;4:406–425.
  29. Page RDM: TreeView: an application to display phylogenetic trees on personal computers. Comput Appl Biosci 1996;12:357–358.
  30. Shintani Y, Yotsuyanagi H, Moriya K, Fujie H, Tsutsumi T, Takayama T, Makuuchi M, Kimura S, Koike K: The significance of hepatitis B virus DNA detected in hepatocellular carcinoma of patients with hepatitis C. Cancer 2000;88:2478–2486.
  31. Takeuchi M, Fujimoto J, Niwamoto H, Yamamoto Y, Okamoto E: Frequent detection of hepatitis B virus X-gene DNA in hepatocellular carcinoma and adjacent liver tissue in hepatitis B surface antigen-negative patients. Dig Dis Sci 1997;42:2264–2269.
  32. Pollicino T, Squadrito G, Cerenzia G, Cacciola I, Raffa G, Crax A, Farinati F, Missale G, Smedile A, Tiribelli C, Villa E, Raimondo G: Hepatitis B virus maintains its pro-oncogenic properties in the case of occult HBV infection. Gastroenterology 2004;126:102–110.
  33. Kannangai R, Molmenti E, Arrazola L, Klein A, Choti M, Thomas DL, Torbenson M: Occult hepatitis B viral DNA in liver carcinomas from a region with a low prevalence of chronic hepatitis B infection. J Viral Hepat 2004;11:297–301.
  34. Fujiwara K, Tanaka Y, Orito E, Ohno T, Kato T, Sugauchi F, Suzuki S, Hattori Y, Sakurai M, Hasegawa I, Ozasa T, Kanie F, Kano H, Ueda R, Mizokami M: Lack of association between occult hepatitis B virus DNA viral load and aminotransferase levels in patients with hepatitis C virus-related chronic liver disease. J Gastroenterol Hepatol 2004;19:1343–1347.
  35. Fabris P, Brown D, Tositti G, Bozzola L, Giordani MT, Bevilacqua P, de Lalla F, Webster GJ, Dusheiko G: Occult hepatitis B virus infection does not affect liver histology or response to therapy with interferon alpha and ribavirin in intravenous drug users with chronic hepatitis C. J Clin Virol 2004;29:160–166.
  36. Adachi S, Shibuya A, Miura Y, Takeuchi A, Nakazawa T, Saigenji K: Impact of occult hepatitis B virus infection and prior hepatitis B virus infection on development of hepatocellular carcinoma in patients with liver cirrhosis due to hepatitis C virus. Scand J Gastroenterol 2008;43:849–856.
  37. Minuk GY, Sun DF, Uhanova J, Zhang M, Caouette S, Nicolle LE, Gutkin A, Doucette K, Martin B, Giulivi A: Occult hepatitis B virus infection in a North American community-based population. J Hepatol 2005;42:480–485.
  38. Fabrizi F, Messa PG, Lunghi G, Aucella F, Bisegna S, Mangano S, Villa M, Barbisoni F, Rusconi E, Martin P: Occult hepatitis B virus infection in dialysis patients: a multicentre survey. Aliment Pharmacol Ther 2005;21:1341–1347.

 goto top of outline Author Contacts

Mitsuhiko Moriyama, MD, PhD
Division of Gastroenterology and Hepatology, Department of Medicine
Nihon University School of Medicine
30-1 Oyaguchi kamimachi, Itabashiku, Tokyo 173-8610 (Japan)
Tel. +81 3 3972 8111, Fax +81 3 3956 8496, E-Mail moriyama@med.nihon-u.ac.jp


 goto top of outline Article Information

Received: August 28, 2006
Accepted after revision: October 22, 2008
Published online: January 7, 2009
Number of Print Pages : 10
Number of Figures : 3, Number of Tables : 6, Number of References : 38


 goto top of outline Publication Details

Intervirology (International Journal of Basic and Medical Virology)

Vol. 51, No. 5, Year 2008 (Cover Date: February 2009)

Journal Editor: Liebert U.G. (Leipzig)
ISSN: 0300-5526 (Print), eISSN: 1423-0100 (Online)

For additional information: http://www.karger.com/INT


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

We examined prospectively the influence of occult hepatitis B virus (HBV) infection on the histopathological features and clinical outcome of HCV RNA-positive chronic hepatitis (CH-C) and detected hepatitis B core (HBc) particles in hepatocytes. The subjects were 468 patients with CH-C or liver cirrhosis (LC) who were negative for serum hepatitis B surface antigen (HBsAg) by enzyme-linked immunosorbent assay. HBV DNA was detected in serum by nested PCR. HBsAg and HBc antigen (HBcAg) in liver were investigated using immunohistochemical techniques and light (LM) and electron microscopy (EM). Serum HBV DNA was detected in 43.6% of the patients studied. There were no significant differences between HBV DNA-positive and DNA-negative patients in terms of their clinical profiles. For HBV DNA-positive patients, the degree of inflammatory cell infiltration and irregular regeneration of hepatocytes was significantly greater than for HBV DNA-negative patients. The cumulative probability of development of hepatocellular carcinoma (HCC) was significantly higher for HBV DNA-positive patients than for HBV DNA-negative patients. HBV DNA positivity was a risk factor for the occurrence of HCC according to multivariate analysis. HBsAg and HBcAg were detected in 8.5 and 72.3%, respectively, of the livers of serum HBV DNA-positive individuals. Core particles were detected in the nuclei of the hepatocytes by IEM. The histopathological features and long-term outcome of CH-C or LC could be affected by occult HBV infection.



 goto top of outline Author Contacts

Mitsuhiko Moriyama, MD, PhD
Division of Gastroenterology and Hepatology, Department of Medicine
Nihon University School of Medicine
30-1 Oyaguchi kamimachi, Itabashiku, Tokyo 173-8610 (Japan)
Tel. +81 3 3972 8111, Fax +81 3 3956 8496, E-Mail moriyama@med.nihon-u.ac.jp


 goto top of outline Article Information

Received: August 28, 2006
Accepted after revision: October 22, 2008
Published online: January 7, 2009
Number of Print Pages : 10
Number of Figures : 3, Number of Tables : 6, Number of References : 38


 goto top of outline Publication Details

Intervirology (International Journal of Basic and Medical Virology)

Vol. 51, No. 5, Year 2008 (Cover Date: February 2009)

Journal Editor: Liebert U.G. (Leipzig)
ISSN: 0300-5526 (Print), eISSN: 1423-0100 (Online)

For additional information: http://www.karger.com/INT


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Chazouilleres O, Mamish D, Kim M, Carely K, Ferrell L, Roberts J, Ascher NL, Wright T: Occult hepatitis B virus as source of infection in liver transplant recipients. Lancet 1994;343:142–146.
  2. Uemoto S, Sugiyama K, Marusawa H, Inomata Y, Asonima K, Egawa H, Kiuchi T, Miyake Y, Tanaka K, Chiba T: Transmission of hepatitis B virus from hepatitis B core antibody-positive donors in living related liver transplants. Transplantation 1998;65:494–499.
  3. Levicnik-Stezinar S, Rahne-Potokar U, Candotti D, Lelie N, Allain JP: Anti-HBs positive occult hepatitis B virus carrier blood infections in two transfusion recipients. J Hepatol 2008;48:1022–1025.
  4. Uchida T, Kaneita Y, Gotoh K, Kanagawa H, Kouyama H, Kawanishi T, Mima S: Hepatitis C virus is frequently coinfected with serum marker-negative hepatitis B Virus. J Med Virol 1997;52:399–405.
  5. Fukuda R, Ishimura N, Kushiyama Y, Moriyama N, Ishihara S, Chowdhury A, Tokuda A, Sakai S, Akagi S, Watanabe M, Fukumoto S: Hepatitis B virus with X gene mutation is associated with majority of serologically ‘silent’ non-B, non-C chronic hepatitis. Microbiol Immunol 1996;40:481–488.
  6. Cacciola I, Pollicino T, Squadrito G, Cerenzia G, Orlando ME, Raimondo G: Occult hepatitis B virus infection in patients with chronic hepatitis C liver disease. N Engl J Med 1999;341:22–26.
  7. Koike K, Kobayashi M, Gondo M, Hayashi I, Osuga T, Takada S: Hepatitis B virus DNA is frequently found in liver biopsy samples from hepatitis C virus-infected chronic hepatitis patients. J Med Virol 1998;54:249–255.
  8. Kazemi-Shirazi L, Petermann D, Muller C: Hepatitis B virus DNA in sera and liver tissues of HBsAg negative patients with chronic hepatitis C. J Hepatol 2000;33:785–790.
  9. Sagnelli E, Imparato M, Coppola N, Pisapia R, Sagnelli C, Messina V, Piai G, Stanzione M, Bruno M, Moggio G, Caprio N, Pasquale G, Del Vacchio Blanco C: Diagnosis and clinical impact of occult hepatitis B infection in patients with biopsy proven chronic hepatitis C: a multicenter study. J Med Virol 2008;80:1547–1553.
  10. Mrani S, Chemin I, Menousar K, Guillaud O, Pradat P, Borghi G, Trabaud MA, Chevallier P, Chevallier M, Zoulim F, Trepo C: Occult HBV infection may present a major risk factor of non-response to anti-viral therapy of chronic hepatitis C. J Med Virol 2007;79:1075–1081.
  11. Hwang S, Moon DB, Lee SG, Park KM, Kim KH, Ahn CS, Lee YJ, Chu CW, Yang HS, Cho SH, Oh KB, Ha TY, Min PC: Safety of anti-hepatitis B core antibody-positive donors for living-donor liver transplantation. Transplantation 2003;75:S45–S48.
  12. Ikeda K, Marusawa H, Osaki Y, Nakamura T, Kitajima N, Yamashita Y, Kudo M, Sato T, Chiba T: Antibody to hepatitis B core antigen and risk for hepatitis C-related hepatocellular carcinoma: a prospective study. Ann Intern Med 2007;146:649–656.
  13. Giannini E, Ceppa P, Botta F, Fasoli A, Romagnoli P, Ansaldi F, Durando P, Risso D, Lantieri PB, Icardi GC, Testa R: Previous hepatitis B virus infection is associated with worse disease stage and occult hepatitis B virus infection has low prevalence and pathogenicity in hepatitis C virus-positive patients. Liver 2003;23:12–18.

    External Resources

  14. Kao JH, Chen PJ, Lai MY, Chen DS: Occult hepatitis B virus infection and clinical outcomes of patients with chronic hepatitis C. J Clin Microbiol 2002;40:4068–4071.
  15. Hu KQ: Occult hepatitis B virus infection and its clinical implications. J Viral Hepatitis 2002;9:243–257.
  16. Nirei K, Kaneko M, Moriyama M, Arakawa Y: The clinical feature of chronic hepatitis C are not affected by the coexistence of hepatitis B virus DNA in patients negative for hepatitis B virus surface antigen. Intervirology 2000;43:95–101.
  17. Matsumura H, Moriyama M, Goto I, Tanaka N, Okubo H, Arakawa Y: Natural course of progression of liver fibrosis in Japanese patients with chronic liver disease type C: a study of 527 patients at one establishment. J Viral Hepatitis 2000;7:268–275.
  18. Moriyama M, Matsumura H, Shimizu T, Shioda A, Kaneko M, Saito H, Miyazawa K, Tanaka N, Sugitani M, Komiyama K, Arakawa Y: Hepatitis G virus coinfection influences the liver histology of patients with chronic hepatitis C. Liver 2000;20:397–404.
  19. Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ: Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 1994;19:1513–1520.
  20. Moriyama M, Matsumura H, Shimizu T, Shioda A, Kaneko M, Miyazawa K, Miyata H, Tanaka N, Uchida T, Arakawa Y: Histopathologic impact of TT virus infection on the liver of C-viral chronic hepatitis and liver cirrhosis in Japan. J Med Virol 2001;63:1–8.
  21. Uchida T: Small hepatocellular carcinoma: Its relationship to multistep hepatocarcinogenesis. Pathol Intl 1995;45:175–184.
  22. Uchida T: Pathology of hepatitis C. Intervirology 1994;37:126–132.
  23. Shibata M, Uchida T, Yamagami T, Onozaki Y, Nakao M, Mitamura K, Ueno Y: Irregular regeneration of hepatocytes and risk of hepatocellular carcinoma in chronic hepatitis and cirrhosis with hepatitis-C virus infection. Lancet 1998;351:1773–1777.
  24. Ueno Y, Moriyama M, Uchida T, Arakawa Y: Irregular regeneration of hepatocytes is an important factor in the hepatocarcinogenesis of liver disease. Hepatology 2001;33:357–362.
  25. Abe K, Edamoto Y, Park YN, Nomura AM, Taltavull TC, Tani M, Thung SN: In situ detection of hepatitis B, C, and G virus nucleic acids in human hepatocellular carcinoma tissues from different geographic regions. Hepatology 1998;28:568–572.
  26. Okamoto H, Tsuda F, Sakugawa H, Sastrosoewignjo RI, Imai M, Miyakawa Y, Mayumi M: Typing hepatitis B virus homology in nucleotide sequence: comparison of surface antigen subtypes. J Gen Virol 1988;69:2575–2583.
  27. Naito H, Hayashi S, Abe K: The entire nucleotide sequence of two hepatitis G virus isolates to a novel genotype: isolation in Myanmar and Vietnam. J Gen Virol 2000;81:189–194.
  28. Saitou N, Nei M: The neighbor-joining method: a new method for reconstructing phylogenetic tree. Mol Biol Evol 1987;4:406–425.
  29. Page RDM: TreeView: an application to display phylogenetic trees on personal computers. Comput Appl Biosci 1996;12:357–358.
  30. Shintani Y, Yotsuyanagi H, Moriya K, Fujie H, Tsutsumi T, Takayama T, Makuuchi M, Kimura S, Koike K: The significance of hepatitis B virus DNA detected in hepatocellular carcinoma of patients with hepatitis C. Cancer 2000;88:2478–2486.
  31. Takeuchi M, Fujimoto J, Niwamoto H, Yamamoto Y, Okamoto E: Frequent detection of hepatitis B virus X-gene DNA in hepatocellular carcinoma and adjacent liver tissue in hepatitis B surface antigen-negative patients. Dig Dis Sci 1997;42:2264–2269.
  32. Pollicino T, Squadrito G, Cerenzia G, Cacciola I, Raffa G, Crax A, Farinati F, Missale G, Smedile A, Tiribelli C, Villa E, Raimondo G: Hepatitis B virus maintains its pro-oncogenic properties in the case of occult HBV infection. Gastroenterology 2004;126:102–110.
  33. Kannangai R, Molmenti E, Arrazola L, Klein A, Choti M, Thomas DL, Torbenson M: Occult hepatitis B viral DNA in liver carcinomas from a region with a low prevalence of chronic hepatitis B infection. J Viral Hepat 2004;11:297–301.
  34. Fujiwara K, Tanaka Y, Orito E, Ohno T, Kato T, Sugauchi F, Suzuki S, Hattori Y, Sakurai M, Hasegawa I, Ozasa T, Kanie F, Kano H, Ueda R, Mizokami M: Lack of association between occult hepatitis B virus DNA viral load and aminotransferase levels in patients with hepatitis C virus-related chronic liver disease. J Gastroenterol Hepatol 2004;19:1343–1347.
  35. Fabris P, Brown D, Tositti G, Bozzola L, Giordani MT, Bevilacqua P, de Lalla F, Webster GJ, Dusheiko G: Occult hepatitis B virus infection does not affect liver histology or response to therapy with interferon alpha and ribavirin in intravenous drug users with chronic hepatitis C. J Clin Virol 2004;29:160–166.
  36. Adachi S, Shibuya A, Miura Y, Takeuchi A, Nakazawa T, Saigenji K: Impact of occult hepatitis B virus infection and prior hepatitis B virus infection on development of hepatocellular carcinoma in patients with liver cirrhosis due to hepatitis C virus. Scand J Gastroenterol 2008;43:849–856.
  37. Minuk GY, Sun DF, Uhanova J, Zhang M, Caouette S, Nicolle LE, Gutkin A, Doucette K, Martin B, Giulivi A: Occult hepatitis B virus infection in a North American community-based population. J Hepatol 2005;42:480–485.
  38. Fabrizi F, Messa PG, Lunghi G, Aucella F, Bisegna S, Mangano S, Villa M, Barbisoni F, Rusconi E, Martin P: Occult hepatitis B virus infection in dialysis patients: a multicentre survey. Aliment Pharmacol Ther 2005;21:1341–1347.