Journal of Gastroenterology

, Volume 46, Issue 3, pp 391–400

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

  • Zhihui Xu
  • Xiaoqiang Ren
  • Yan Liu
  • Xiaodong Li
  • Siyu Bai
  • Yanwei Zhong
  • Lin Wang
  • Panyong Mao
  • Huifen Wang
  • Shaojie Xin
  • Vincent Wai-Sun Wong
  • Henry Lik-Yuen Chan
  • Fabien Zoulim
  • Dongping Xu
Original Article—Liver, Pancreas, and Biliary Tract

Abstract

Objective

To investigate the features of hepatitis B virus (HBV) basal core promoter/precore (BCP/PC) mutations and genotypes in a large number of mild/severe chronic hepatitis B (CHB-M/CHB-S), and acute-on-chronic liver failure (ACLF) patients and analyze the clinical implications of the virologic features.

Patients and methods

Sera of 793 (325 CHB-M, 170 CHB-S, and 298 ACLF) patients admitted to or who had visited Beijing 302 Hospital from January 2005 to December 2008 were collected and successfully amplified for the HBV BCP/PC and a 1225-bp-long S/Pol (nt 54–1278) gene regions. Biochemical and serological parameters and HBV DNA level were routinely performed. Viral DNA was extracted and subjected to a nested PCR. Genotypes/subgenotypes were determined based on complete genomic sequence or on analysis of the 1225-bp-long S/Pol-gene sequence. HBV genotyping was performed by direct PCR sequencing followed by molecular evolutionary analysis of the viral sequences. A P value of <0.05 (two-sided) was considered to be statistically significant.

Conclusions

Our findings suggest that CHB patients infected with BCP/PC mutant viruses are more susceptible to severe hepatitis and ACLF than those with the BCP/PC wild-type virus and that ACLF patients with PC mutant viruses have an increased risk of death. As such, the HBV PC mutation is a potential predictive indicator of ACLF outcome.

Keywords

Hepatitis B virus Basal core promoter mutation Precore mutation Genotype Acute-on-chronic liver failure 

Abbreviations

ACLF

Acute-on-chronic liver failure

ALF

Acute liver failure

ALT

Alanine aminotransferase

BCP

Basal core promoter

CHB-M

Mild chronic hepatitis B

CHB-S

Severe chronic hepatitis B

HBV

Hepatitis B virus

HCC

Hepatocellular carcinoma

LC

Liver cirrhosis

PC

Precore

PTA

Prothrombin activity

TBIL

Total bilirubin

PCR

Polymerase chain reaction

References

  1. 1.
    European association for the study of the liver. EASL clinical practice guidelines: management of chronic hepatitis B. J Hepatol. 2009;50:227–42.CrossRefGoogle Scholar
  2. 2.
    Liu Y, Wang CM, Cheng J, Liang ZL, Zhong YW, Ren XQ, et al. Hepatitis B virus in tenofovir-naive Chinese patients with chronic hepatitis B contains no mutation of rtA194T conferring a reduced tenofovir susceptibility. Chin Med J. 2009;122:1585–6.PubMedGoogle Scholar
  3. 3.
    Liu Q, Liu Z, Wang T, Wang Q, Shi X, Dao W. Characteristics of acute and sub-acute liver failure in China: nomination, classification and interval. J Gastroenterol Hepatol. 2007;22:2101–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Sanchez-Tapias JM, Costa J, Mas A, Bruguera M, Rodés J. Influence of hepatitis B virus genotype on the long-term outcome of chronic hepatitis B in western patients. Gastroenterology. 2002;123:1848–56.PubMedCrossRefGoogle Scholar
  5. 5.
    Tong S, Kim KH, Chante C, Wands J, Li J. Hepatitis B virus e antigen variants. Int J Med Sci. 2005;2:2–7.PubMedGoogle Scholar
  6. 6.
    Kay A, Zoulim F. Hepatitis B virus genetic variability and evolution. Virus Res. 2007;127:164–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Inoue K, Ogawa O, Yamada M, Watanabe T, Okamoto H, Yoshiba M. Possible association of vigorous hepatitis B virus replication with the development of fulminant hepatitis. J Gastroenterol. 2006;41:383–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Kosaka Y, Takase K, Kojima M, Shimizu M, Inoue K, Yoshiba M, et al. Fulminant hepatitis B: induction by hepatitis B virus mutants defective in the precore region and incapable of encoding e antigen. Gastroenterology. 1991;100:1087–94.PubMedGoogle Scholar
  9. 9.
    Sato S, Suzuki K, Akahane Y, Akamatsu K, Akiyama K, Yunomura K, et al. Hepatitis B virus strains with mutations in the core promoter in patients with fulminant hepatitis. Ann Intern Med. 1995;122:241–8.PubMedGoogle Scholar
  10. 10.
    Baumert TF, Rogers SA, Hasegawa K, Liang TJ. Two core promoter mutation identified in a hepatitis B virus strain associated with fulminant hepatitis result in enhanced viral replication. J Clin Invest. 1996;98:2268–76.PubMedCrossRefGoogle Scholar
  11. 11.
    Inoue K, Yoshiba M, Sekiyama K, Okamoto H, Mayumi M. Clinical and molecular virological difference between fulminant hepatic failures following acute and chronic infection with hepatitis B virus. J Med Virol. 1998;55:35–41.PubMedCrossRefGoogle Scholar
  12. 12.
    Friedt M, Gerner P, Lausch E, Trübel H, Zabel B, Wirth S. Mutations in the basic core promotor and the precore region of hepatitis B virus and their selection in children with fulminant and chronic hepatitis B. Hepatology. 1999;29:1252–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Ozasa A, Tanaka Y, Orito E, Sugiyama M, Kang JH, Hige S, et al. Influence of genotypes and precore mutations on fulminant or chronic outcome of acute hepatitis B virus infection. Hepatology. 2006;44:326–43.PubMedCrossRefGoogle Scholar
  14. 14.
    Hayashi K, Katano Y, Takeda Y, Honda T, Ishigami M, Itoh A, et al. Association of hepatitis B virus subgenotypes and basal core promoter/precore region variants with the clinical features of patients with acute hepatitis. J Gastroenterol. 2008;43:558–64.PubMedCrossRefGoogle Scholar
  15. 15.
    Parekh S, Zoulim F, Ahn SH, Tsai A, Li J, Kawai S, et al. Genome replication, virion secretion, and e antigen expression of naturally occurring hepatitis B virus core promoter mutants. J Virol. 2003;77:6601–11.PubMedCrossRefGoogle Scholar
  16. 16.
    Hou J, Lin Y, Waters J, Wang Z, Min J, Liao H, et al. Detection and significance of a G1862T variant of hepatitis B virus in Chinese patients with fulminant hepatitis. J Gen Virol. 2002;83:2291–8.PubMedGoogle Scholar
  17. 17.
    Sainokami S, Abe K, Sato A, Endo R, Takikawa Y, Suzuki K, et al. Initial load of hepatitis B virus (HBV), its changing profile, and precore/core promoter mutations correlate with the severity and outcome of acute HBV infection. J Gastroenterol. 2007;42:241–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Wai CT, Fontana RJ, Polson J, Hussain M, Shakil AO, Han SH. Clinical outcome and virological characteristics of hepatitis B-related acute liver failure in the United States. J Viral Hepat. 2005;12:192–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Sterneck M, Günther S, Santantonio T, Fischer L, Broelsch CE, Greten H, et al. Hepatitis B virus genomes of patients with fulminant hepatitis do not share a specific mutation. Hepatology. 1996;24:300–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Yuasa R, Takahashi K, Dien BV, Binh NH, Morishita T, Sato K, 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;61:23–8.PubMedCrossRefGoogle Scholar
  21. 21.
    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;10:367–82.PubMedCrossRefGoogle Scholar
  22. 22.
    Chun YK, Kim JY, Woo HJ, Oh SM, Kang I, Ha J, et al. No significant correlation exists between core promoter mutations, viral replication and liver damage in chronic hepatitis B infection. Hepatology. 2005;32:1154–62.CrossRefGoogle Scholar
  23. 23.
    Liu CJ, Kao JH, Lai MY, Chen PJ, Chen DS. Precore/core promoter mutations and genotypes of hepatitis B virus in chronic hepatitis B patients with fulminant or subfulminant hepatitis. J Med Virol. 2004;72:545–50.PubMedCrossRefGoogle Scholar
  24. 24.
    Chinese Society of Infectious Diseases and Parasitology; and Chinese Society of Hepatology. Management scheme of diagnostic and therapy criteria of viral hepatitis. Zhonghua Gan Zang Bing Za Zhi (Chin J Hepatol). 2000;8:324–9.Google Scholar
  25. 25.
    Liver Failure and Artificial Liver Group, Chinese Society of Infectious Diseases and Parasitology, Severe Liver Diseases and Artificial Liver Group, Chinese Society of Hepatology. Diagnostic and treatment guidelines for liver failure. J Clin Hepatol (Chinese). 2006;9:321–4.Google Scholar
  26. 26.
    Zou Z, Li B, Xu D, Zhang Z, Zhao JM, Zhou G, et al. Imbalanced intrahepatic cytokine expression of interferon-γ, tumor necrosis factor-α, and interleukin-10 in patients with acute-on-chronic liver failure associated with hepatitis B virus infection. J Clin Gastroenterol. 2008;43:182–90.CrossRefGoogle Scholar
  27. 27.
    Zou Z, Xu D, Li B, Xin S, Zhang Z, Huang L, et al. Compartmentalization and its implication for peripheral immunologically-competent cells to the liver in patients with HBV-related acute-on-chronic liver failure. Hepatol Res. 2009;39:1178–207.CrossRefGoogle Scholar
  28. 28.
    Sarin SK, Kumar A, Almeida JA, Chawla YK, Fan ST, Garg H, et al. Acute-on-chronic liver failure; consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL). Hepatol Int. 2009;3:269–82.PubMedCrossRefGoogle Scholar
  29. 29.
    Liu Y, Zhong Y, Zou Z, Xu Z, Li B, Ren X, et al. Features and clinical implications of hepatitis B virus genotypes and mutations in basal core promoter/precore region in 507 Chinese patients with acute and chronic hepatitis B. J Clin Virol. 2010;47:243–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Bartholomeusz A, Locarnini S. Hepatitis B virus mutants and fulminant hepatitis B: fitness plus phenotype. Hepatology. 2001;34:432–4.PubMedCrossRefGoogle Scholar
  31. 31.
    Tsai WL, Lo GH, Hsu PI, Lai KH, Lin CK, Chan HH, et al. Role of genotype and precore/basal core promoter mutations of hepatitis B virus in patients with chronic hepatitis with acute exacerbation. Scand J Gastroenterol. 2008;43:196–201.PubMedCrossRefGoogle Scholar
  32. 32.
    Kusumoto K, Yatsuhashi H, Nakao R, Hamada R, Fukuda M, Tamada Y. Detection of HBV core promoter and precore mutations helps distinguish flares of chronic hepatitis from acute hepatitis B. J Gastroenterol Hepatol. 2008;23:790–3.PubMedCrossRefGoogle Scholar
  33. 33.
    Xu D, Zhang Z, Wang FS. SARS-associated coronavirus quasispecies in individual patients. N Engl J Med. 2004;350:1366–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Xu D, Zhang Z, Chu FL, Li YG, Jin L, Zhang L, et al. Genetic variation of SARS coronavirus in Beijing hospital. Emerg Infect Dis. 2004;10:789–94.PubMedGoogle Scholar
  35. 35.
    Chen CH, Lee CM, Lu SN, Changchien CS, Eng HL, Huang CM, et al. Clinical significance of hepatitis B virus (HBV) genotypes and precore and core promoter mutations affecting HBV e antigen expression in Taiwan. J Clin Microbiol. 2005;43:6000–6.PubMedCrossRefGoogle Scholar
  36. 36.
    Yuen MF, Sablon E, Tanaka Y, Kato T, Mizokami M, Doutreloigne J, 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;41:119–25.PubMedCrossRefGoogle Scholar
  37. 37.
    Kramvis A, Kew MC. Relationship of genotypes of hepatitis B virus to mutations, disease progression and response to antiviral therapy. J Viral Hepat. 2005;12:456–64.PubMedCrossRefGoogle Scholar
  38. 38.
    Chauhan R, Kazim SN, Bhattacharjee J, Sakhuja P, Sarin SK. Basal core promoter, precore region mutations of HBV and their association with e antigen, genotype, and severity of liver disease in patients with chronic hepatitis B in India. J Med Virol. 2006;78:1047–54.PubMedCrossRefGoogle Scholar
  39. 39.
    Jammeh S, Tavner F, Watson R, Thomas HC, Karayiannis P. Effect of basal core promoter and pre-core mutations on hepatitis B virus replication. J Gen Virol. 2008;89:901–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Guo X, Jin Y, Qian G, Tu H. Sequential accumulation of the mutations in core promoter of hepatitis B virus is associated with the development of hepatocellular carcinoma in Qidong, China. J Hepatol. 2008;49:718–25.PubMedCrossRefGoogle Scholar
  41. 41.
    Takahashi K, Aoyama K, Ohno N, Iwata K, Akahane Y, Baba K, et al. The precore/core promoter mutant (T1762A1764) of hepatitis B virus: clinical significance and an easy method for detection. J Gen Vriol. 1995;76:3159–64.CrossRefGoogle Scholar
  42. 42.
    Fang ZL, Sabin CA, Dong BQ, Wei SC, Chen QY, Fang KX, et al. The association of HBV core promoter double mutations (A1762T and G1764A) with viral load differs between HBeAg positive and anti-HBe positive individuals: a longitudinal analysis. J Hepatol. 2009;50:273–80.PubMedCrossRefGoogle Scholar
  43. 43.
    Rodriguez-Frias F, Jardi R, Buti M, Schaper E, Hermosilla E, Valdes A, et al. Hepatitis B virus genotypes and G1896A precore mutation in 486 spanish patients with acute and chronic HBV infection. J Viral Hepat. 2006;13:443–50.CrossRefGoogle Scholar
  44. 44.
    Kalinina T, Riu A, Fischer L, Santantonio T, Will H, Sterneck M. Selection of a secretion-incompetent mutant in the serum of a patient with severe hepatitis B. Gastroenterology. 2003;125:1077–84.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2010

Authors and Affiliations

  • Zhihui Xu
    • 1
    • 2
  • Xiaoqiang Ren
    • 1
    • 2
  • Yan Liu
    • 1
    • 2
  • Xiaodong Li
    • 1
    • 2
  • Siyu Bai
    • 1
    • 2
  • Yanwei Zhong
    • 1
    • 2
  • Lin Wang
    • 1
    • 2
  • Panyong Mao
    • 1
    • 2
  • Huifen Wang
    • 1
    • 2
  • Shaojie Xin
    • 1
    • 2
  • Vincent Wai-Sun Wong
    • 3
  • Henry Lik-Yuen Chan
    • 3
  • Fabien Zoulim
    • 4
    • 5
  • Dongping Xu
    • 1
    • 2
  1. 1.Viral Hepatitis Research LaboratoryBeijing Institute of Infectious DiseasesBeijingChina
  2. 2.Liver Failure Research CenterBeijing 302 HospitalBeijingChina
  3. 3.Department of Medicine and Therapeutics and Institute of Digestive DiseaseThe Chinese University of Hong KongHong KongChina
  4. 4.INSERM, U871LyonFrance
  5. 5.Department of Hepatology and Gastroenterology, Hospices Civils de LyonHôtel Dieu HospitalLyonFrance

Personalised recommendations