Hepatitis B virus genotype B and mutations in basal core promoter and pre-core/core genes associated with acute-on-chronic liver failure: a multicenter cross-sectional study in China (original) (raw)

Abstract

Background and aim

In China, acute-on-chronic liver failure (ACLF) is mostly caused by hepatitis B virus (HBV). However, the mechanism remains unclear. This study aims to investigate the association between both HBV genotype and mutations in basal core promoter (BCP) and pre-core/core (pre-C/C) regions with the development of HB-ACLF.

Methods

A multicenter cross-sectional study was performed in China. Serum samples from 522 patients were analyzed, including 231 patients with mild-chronic hepatitis B (CHB-M), 84 with severe-chronic hepatitis B (CHB-S) and 207 with HB-ACLF. HBV genotype and related mutations in the BCP and pre-C/C regions were determined by direct sequencing.

Results

A significantly higher ratio of HBV genotype B to C was detected in HB-ACLF patients than in CHB-M or CHB-S patients. The A1762T/G1764A, A1846T and G1896A mutations were significantly more common in HB-ACLF patients infected with either genotype B or C as compared with CHB-M, whereas the C1913A/G and A2159G mutations were more associated with HB-ACLF in genotype C patients. Comparing with CHB-S, the A1762T/G1764A mutation in genotype B and the A2159G mutation in genotype C were significantly more common in HB-ACLF patients. A multivariate analysis showed that factors such as HBV genotype B, age ≥40 years and A1762T/G1764A, A1846T and G1896A mutations were independently associated with the development of HB-ACLF.

Conclusion

Chronic HBV infection with genotype B, A1762T/G1764A, A1846T and G1896A mutations has a higher possibility to develop HB-ACLF. These virological factors could serve as possible molecular markers for prediction of the clinical outcomes of chronic HBV infection.

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References

  1. EASL Clinical Practice Guidelines. Management of chronic hepatitis B. J Hepatol 2009;50:227–242
    Article Google Scholar
  2. Sarin SK, Kumar A, Almeida JA, et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the study of the liver (APASL). Hepatol Int 2009;3:269–282
    Article PubMed PubMed Central Google Scholar
  3. Jalan R, Williams R. Acute-on-chronic liver failure: pathophysiological basis of therapeutic options. Blood Purif 2002;20:252–261
    Article PubMed Google Scholar
  4. Duan BW, Lu SC, Wang ML, et al. Liver transplantation in acute-on-chronic liver failure patients with high model for end-stage liver disease (MELD) scores: a single center experience of 100 consecutive cases. J Surg Res 2013;183:936–943
    Article PubMed Google Scholar
  5. Baumert TF, Rogers SA, Hasegawa K, Liang TJ. Two core promotor mutations identified in a hepatitis B virus strain associated with fulminant hepatitis result in enhanced viral replication. J Clin Invest 1996;98:2268–2276
    Article PubMed CAS PubMed Central Google Scholar
  6. Hou J, Lin Y, Waters J, et al. Detection and significance of a G1862T variant of hepatitis B virus in Chinese patients with fulminant hepatitis. J Gen Virol 2002;83:2291–2298
    PubMed CAS Google Scholar
  7. Kusakabe A, Tanaka Y, Mochida S, et al. Case–control study for the identification of virological factors associated with fulminant hepatitis B. Hepatol Res 2009;39:648–656
    Article PubMed CAS Google Scholar
  8. Liang TJ, Hasegawa K, Rimon N, Wands JR, Ben-Porath E. A hepatitis B virus mutant associated with an epidemic of fulminant hepatitis. N Engl J Med 1991;324:1705–1709
    Article PubMed CAS Google Scholar
  9. Omata M, Ehata T, Yokosuka O, Hosoda K, Ohto M. Mutations in the precore region of hepatitis B virus DNA in patients with fulminant and severe hepatitis. N Engl J Med 1991;324:1699–1704
    Article PubMed CAS Google Scholar
  10. Ozasa A, Tanaka Y, Orito E, et al. Influence of genotypes and precore mutations on fulminant or chronic outcome of acute hepatitis B virus infection. Hepatology 2006;44:326–334
    Article PubMed CAS Google Scholar
  11. Sugauchi F, Orito E, Ohno T, et al. Spatial and chronological differences in hepatitis B virus genotypes from patients with acute hepatitis B in Japan. Hepatol Res 2006;36:107–114
    Article PubMed CAS Google Scholar
  12. Parekh S, Zoulim F, Ahn SH, et al. Genome replication, virion secretion, and e antigen expression of naturally occurring hepatitis B virus core promoter mutants. J Virol 2003;77:6601–6612
    Article PubMed CAS PubMed Central Google Scholar
  13. Sterneck M, Gunther S, Santantonio T, et al. Hepatitis B virus genomes of patients with fulminant hepatitis do not share a specific mutation. Hepatology. 1996;24:300–306
    Article PubMed CAS Google Scholar
  14. Chun YK, Kim JY, Woo HJ, et al. No significant correlation exists between core promoter mutations, viral replication, and liver damage in chronic hepatitis B infection. Hepatology 2000;32:1154–1162
    Article PubMed CAS Google Scholar
  15. Gandhe SS, Chadha MS, Walimbe AM, Arankalle VA. Hepatitis B virus: prevalence of precore/core promoter mutants in different clinical categories of Indian patients. J Viral Hepat 2003;10:367–382
    Article PubMed CAS Google Scholar
  16. Yuasa R, Takahashi K, Dien BV, et al. Properties of hepatitis B virus genome recovered from Vietnamese patients with fulminant hepatitis in comparison with those of acute hepatitis. J Med Virol 2000;61:23–28
    Article PubMed CAS Google Scholar
  17. Ren X, Xu Z, Liu Y, et al. Hepatitis B virus genotype and basal core promoter/precore mutations are associated with hepatitis B-related acute-on-chronic liver failure without pre-existing liver cirrhosis. J Viral Hepat 2010;17:887–895
    Article PubMed CAS PubMed Central Google Scholar
  18. Xu L, Chen EQ, Lei J, et al. Pre-core/basal-core promoter and reverse transcriptase mutations in chronic HBV infected-patients. Hepatogastroenterology 2012;59:212–215
    Article PubMed CAS Google Scholar
  19. Xu Z, Ren X, Liu Y, et al. Association of hepatitis B virus mutations in basal core promoter and precore regions with severity of liver disease: an investigation of 793 Chinese patients with mild and severe chronic hepatitis B and acute-on-chronic liver failure. J Gastroenterol 2011;46:391–400
    Article PubMed Google Scholar
  20. Xiao L, Zhou B, Gao H, et al. Hepatitis B virus genotype B with G1896A and A1762T/G1764A mutations is associated with hepatitis B related acute-on-chronic liver failure. J Med Virol 2011;83:1544–1550
    Article PubMed CAS Google Scholar
  21. Yan T, Li K, Li F, et al. T1846 and A/G1913 are associated with acute on chronic liver failure in patients infected with hepatitis B virus genotypes B and C. J Med Virol 2011;83:996–1004
    Article PubMed CAS Google Scholar
  22. Yin J, Xie J, Liu S, et al. Association between the various mutations in viral core promoter region to different stages of hepatitis B, ranging of asymptomatic carrier state to hepatocellular carcinoma. Am J Gastroenterol 2011;106:81–92
    Article PubMed CAS Google Scholar
  23. Zhu Y, Jin Y, Guo X, et al. Comparison study on the complete sequence of hepatitis B virus identifies new mutations in core gene associated with hepatocellular carcinoma. Cancer Epidemiol Biomark Prev 2010;19:2623–2630
    Article CAS Google Scholar
  24. Miyakawa Y, Mizokami M. Classifying hepatitis B virus genotypes. Intervirology 2003;46:329–338
    Article PubMed CAS Google Scholar
  25. Wang Z, Tanaka Y, Huang Y, et al. Clinical and virological characteristics of hepatitis B virus subgenotypes Ba, C1, and C2 in China. J Clin Microbiol 2007;45:1491–1496
    Article PubMed CAS PubMed Central Google Scholar
  26. Sugauchi F, Orito E, Ichida T, et al. Epidemiologic and virologic characteristics of hepatitis B virus genotype B having the recombination with genotype C. Gastroenterology 2003;124:925–932
    Article PubMed CAS Google Scholar
  27. Yuen MF, Sablon E, Tanaka Y, et al. Epidemiological study of hepatitis B virus genotypes, core promoter and precore mutations of chronic hepatitis B infection in Hong Kong. J Hepatol 2004;41:119–125
    Article PubMed CAS Google Scholar
  28. Milich D, Liang TJ. Exploring the biological basis of hepatitis B e antigen in hepatitis B virus infection. Hepatology 2003;38:1075–1086
    Article PubMed CAS Google Scholar
  29. Tsai SL, Chen PJ, Lai MY, et al. Acute exacerbations of chronic type B hepatitis are accompanied by increased T cell responses to hepatitis B core and e antigens. Implications for hepatitis B e antigen seroconversion. J Clin Invest 1992;89:87–96
    Article PubMed CAS PubMed Central Google Scholar
  30. Milich DR, McLachlan A, Raney AK, et al. Autoantibody production in hepatitis B e antigen transgenic mice elicited with a self T-cell peptide and inhibited with nonself peptides. Proc Natl Acad Sci USA 1991;88:4348–4352
    Article PubMed CAS PubMed Central Google Scholar
  31. Chen A, Kao YF, Brown CM. Translation of the first upstream ORF in the hepatitis B virus pregenomic RNA modulates translation at the core and polymerase initiation codons. Nucleic Acids Res 2005;33:1169–1181
    Article PubMed CAS PubMed Central Google Scholar
  32. Chen CH, Lee CM, Hung CH, et al. Clinical significance and evolution of core promoter and precore mutations in HBeAg-positive patients with HBV genotype B and C: a longitudinal study. Liver Int 2007;27:806–815
    Article PubMed CAS Google Scholar
  33. Lok AS, Akarca U, Greene S. Mutations in the pre-core region of hepatitis B virus serve to enhance the stability of the secondary structure of the pre-genome encapsidation signal. Proc Natl Acad Sci USA 1994;91:4077–4081
    Article PubMed CAS PubMed Central Google Scholar
  34. Pang A, Yuen MF, Yuan HJ, Lai CL, Kwong YL. Real-time quantification of hepatitis B virus core-promoter and pre-core mutants during hepatitis E antigen seroconversion. J Hepatol 2004;40:1008–1017
    Article PubMed CAS Google Scholar

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Acknowledgement

This work was supported by the National Natural Science Foundation of China (No. 81071988) and Major State Basic Research (973, grant No. 2007CB512901).

Compliance with ethical requirements and Conflict of interest

Guifeng Yang, Meifang Han, Feng Chen, Ying Xu, Enqiang Chen, Xiaojing Wang, Yu Liu, Jian Sun, Jinlin Hou, Qin Ning and Zhanhui Wang declare that we have no conflict of interest. We declare that there has been no significant financial support for this work that could have influenced its outcome. The study was approved by the ethics committee of Nanfang Hospital.

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Authors and Affiliations

  1. Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
    Guifeng Yang, Ying Xu, Yu Liu, Jian Sun, Jinlin Hou & Zhanhui Wang
  2. Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
    Meifang Han, Xiaojing Wang & Qin Ning
  3. State Key Laboratory of Infectious Disease Diagnosis and Treatment, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
    Feng Chen
  4. Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China
    Enqiang Chen

Authors

  1. Guifeng Yang
  2. Meifang Han
  3. Feng Chen
  4. Ying Xu
  5. Enqiang Chen
  6. Xiaojing Wang
  7. Yu Liu
  8. Jian Sun
  9. Jinlin Hou
  10. Qin Ning
  11. Zhanhui Wang

Corresponding authors

Correspondence toQin Ning or Zhanhui Wang.

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Yang, G., Han, M., Chen, F. et al. Hepatitis B virus genotype B and mutations in basal core promoter and pre-core/core genes associated with acute-on-chronic liver failure: a multicenter cross-sectional study in China.Hepatol Int 8, 508–516 (2014). https://doi.org/10.1007/s12072-014-9554-4

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