Advertisement

Journal of Gastroenterology

, Volume 53, Issue 6, pp 740–751 | Cite as

Serum Wisteria floribunda agglutinin-positive Mac-2 binding protein predicts hepatocellular carcinoma incidence and recurrence in nucleos(t)ide analogue therapy for chronic hepatitis B

  • Kazunori Kawaguchi
  • Masao HondaEmail author
  • Hajime Ohta
  • Takeshi Terashima
  • Tetsuro Shimakami
  • Kuniaki Arai
  • Taro Yamashita
  • Yoshio Sakai
  • Tatsuya Yamashita
  • Eishiro Mizukoshi
  • Takuya Komura
  • Masashi Unoura
  • Shuichi Kaneko
Original Article—Liver, Pancreas, and Biliary Tract

Abstract

Background

Hepatocellular carcinoma (HCC) occurs in chronic hepatitis B (CH-B) patients even after treatment with nucleos(t)ide analogues (NAs) by a mechanism involving an association between the oncogenic factors of integrated HBV and liver fibrosis. An association has been demonstrated between advanced chronic liver disease and elevated levels of Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA(+)-M2BP), a recently discovered serum liver fibrosis marker. Moreover, hepatitis B core-related antigen (HBcrAg) reflects intracellular HBV protein production and its relationship with liver carcinogenesis has been reported. This study aimed to determine whether the incidence and recurrence of HBV-related liver cancer could be predicted using these serum markers.

Methods

We evaluated 141 CH-B cases treated for more than 1 year with NAs. We compared 17 HCC cases with 124 non-HCC cases and evaluated serum WFA(+)-M2BP, HBV markers including HBcrAg, and other clinical factors. We also evaluated 71 CH-B-related HCC cases who started or continued NAs and compared the incidence and recurrence of HCC after successful cancer treatment.

Results

Multivariate analysis showed that the incidence of HCC was significantly associated with higher histological stage and grade before NA treatment and with WFA(+)-M2BP and HBcrAg positivity during NA treatment. The cumulative incidence of HCC was strongly associated with higher WFA(+)-M2BP levels and HBcrAg positivity. HCC recurrence after anti-cancer therapy was also significantly associated with higher WFA(+)-M2BP levels compared with those in cases without recurrence during follow-up.

Conclusion

Serum WFA(+)-M2BP and HBcrAg are useful diagnostic tests for predicting the development and recurrence of HBV-related HCC during NA treatment.

Keywords

Wisteria floribunda agglutinin-positive Mac-2 binding protein HBV core-related antigen Hepatocellular carcinoma 

Abbreviations

WFA(+)-M2BP

Wisteria floribunda agglutinin-positive Mac-2 binding protein

M2BPGi

Mac-2 binding protein glycosylation isomer

NA(s)

Nucleos(t)ide analogue(s)

HBcrAg

HBV core-related antigen

Notes

Acknowledgements

The authors thank Nami Nishiyama for management of the serum samples.

Compliance with ethical standards

Conflict of interest

None of the material in this manuscript has been or will be published and none is currently under consideration for publication elsewhere, and that the conflict of interest disclosure statement on the ScholarOne manuscript was completed at the time of submission.

Supplementary material

535_2017_1386_MOESM1_ESM.eps (3.8 mb)
Supplementary material 1 (EPS 3920 kb)
535_2017_1386_MOESM2_ESM.docx (14 kb)
Supplementary material 2 (DOCX 15 kb)
535_2017_1386_MOESM3_ESM.docx (19 kb)
Supplementary material 3 (DOCX 18 kb)

References

  1. 1.
    Fu C, Liu N, Deng Q, et al. Radiofrequency ablation vs. surgical resection on the treatment of patients with small hepatocellular carcinoma: a system review and meta-analysis of five randomized controlled trials. Hepatogastroenterology. 2014;61:1722–9.PubMedGoogle Scholar
  2. 2.
    Guo W, He X, Li Z, Li Y. Combination of transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) vs. surgical resection (SR) on survival outcome of early hepatocellular carcinoma: a meta-analysis. Hepatogastroenterology. 2015;62:710–4.PubMedGoogle Scholar
  3. 3.
    Hiramatsu N, Yamada R, Takehara T. The suppressive effect of nucleos(t)ide analogue treatment on the incidence of hepatocellular carcinoma in chronic hepatitis B patients. J Gastroenterol Hepatol. 2016;31:546–52.CrossRefPubMedGoogle Scholar
  4. 4.
    Ishikawa T. Anti-viral therapy to reduce recurrence and improve survival in hepatitis B virus-related hepatocellular carcinoma. World J Gastroenterol. 2013;19:8861–6.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Wang Q, Zhang T, Ye L, et al. Analysis of hepatitis B virus X gene (HBx) mutants in tissues of patients suffered from hepatocellular carcinoma in China. Cancer Epidemiol. 2012;36:369–74.CrossRefPubMedGoogle Scholar
  6. 6.
    Suh B, Park S, Shin DW, et al. High liver fibrosis index FIB-4 is highly predictive of hepatocellular carcinoma in chronic hepatitis B carriers. Hepatology. 2015;61:1261–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Kuno A, Ikehara Y, Tanaka Y, et al. A serum “sweet-doughnut” protein facilitates fibrosis evaluation and therapy assessment in patients with viral hepatitis. Sci Rep. 2013;3:1065.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Yamasaki K, Tateyama M, Abiru S, et al. Elevated serum levels of Wisteria floribunda agglutinin-positive human Mac-2 binding protein predict the development of hepatocellular carcinoma in hepatitis C patients. Hepatology. 2014;60:1563–70.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Umemura T, Joshita S, Sekiguchi T, et al. Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein level predicts liver fibrosis and prognosis in primary biliary cirrhosis. Am J Gastroenterol. 2015;110:857–64.CrossRefPubMedGoogle Scholar
  10. 10.
    Toshima T, Shirabe K, Ikegami T, et al. A novel serum marker, glycosylated Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA(+)-M2BP), for assessing liver fibrosis. J Gastroenterol. 2015;50:76–84.CrossRefPubMedGoogle Scholar
  11. 11.
    Nishikawa H, Enomoto H, Iwata Y, et al. Clinical significance of serum Wisteria floribunda agglutinin positive Mac-2-binding protein level and high-sensitivity C-reactive protein concentration in autoimmune hepatitis. Hepatol Res. 2016;46:613–21.CrossRefPubMedGoogle Scholar
  12. 12.
    Nishikawa H, Enomoto H, Iwata Y, et al. Clinical significance of serum Wisteria floribunda agglutinin-positive Mac-2-binding protein level in non-alcoholic steatohepatitis. Hepatol Res. 2016;46:1194–202.CrossRefPubMedGoogle Scholar
  13. 13.
    Abe M, Miyake T, Kuno A, et al. Association between Wisteria floribunda agglutinin-positive Mac-2 binding protein and the fibrosis stage of non-alcoholic fatty liver disease. J Gastroenterol. 2015;50:776–84.CrossRefPubMedGoogle Scholar
  14. 14.
    Fujiyoshi M, Kuno A, Gotoh M, et al. Clinicopathological characteristics and diagnostic performance of Wisteria floribunda agglutinin positive Mac-2-binding protein as a preoperative serum marker of liver fibrosis in hepatocellular carcinoma. J Gastroenterol. 2015;50:1134–44.CrossRefPubMedGoogle Scholar
  15. 15.
    Sasaki R, Yamasaki K, Abiru S, et al. Serum Wisteria floribunda agglutinin-positive Mac-2 binding protein values predict the development of hepatocellular carcinoma among patients with chronic hepatitis C after sustained virological response. PLoS One. 2015;10:e0129053.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Nishikawa H, Enomoto H, Iwata Y, et al. Clinical implication of serum WFA+-M2BP level on hepatitis B e antigen loss or seroconversion in hepatitis B e antigen-positive patients. Hepatol Res. 2016;46:1065–73.CrossRefPubMedGoogle Scholar
  17. 17.
    Zhou D, Wang Y, Zhang W, et al. WFA(+) -M2BP: a novel biomarker with diagnostic and therapeutic implications in liver diseases. Liver Int. 2016;36:612.CrossRefPubMedGoogle Scholar
  18. 18.
    Ishii A, Nishikawa H, Enomoto H, et al. Clinical implication of serum Wisteria floribunda agglutinin-positive Mac-2-binding protein in treatment naïve chronic hepatitis B. Hepatol Res. 2017;47:204–15.CrossRefPubMedGoogle Scholar
  19. 19.
    Zou X, Zhu MY, Yu DM, et al. Serum WFA(+) -M2BP levels for evaluation of early stages of liver fibrosis in patients with chronic hepatitis B virus infection. Liver Int. 2017;37:35–44.CrossRefPubMedGoogle Scholar
  20. 20.
    Kim SU, Heo JY, Kim BK, et al. Wisteria floribunda agglutinin-positive human Mac-2 binding protein predicts the risk of HBV-related liver cancer development. Liver Int. 2017;37:879–87.CrossRefPubMedGoogle Scholar
  21. 21.
    Heo JY, Kim SU, Kim BK, et al. Use of Wisteria floribunda agglutinin-positive human Mac-2 binding protein in assessing risk of hepatocellular carcinoma due to hepatitis B virus. Medicine (Baltimore). 2016;95:e3328.CrossRefGoogle Scholar
  22. 22.
    Kimura T, Rokuhara A, Sakamoto Y, et al. Sensitive enzyme immunoassay for hepatitis B virus core-related antigens and their correlation to virus load. J Clin Microbiol. 2002;40:439–45.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Rokuhara A, Tanaka E, Matsumoto A, et al. Clinical evaluation of a new enzyme immunoassay for hepatitis B virus core-related antigen; a marker distinct from viral DNA for monitoring lamivudine treatment. J Viral Hepat. 2003;10:324–30.CrossRefPubMedGoogle Scholar
  24. 24.
    Shinkai N, Tanaka Y, Orito E, et al. Measurement of hepatitis B virus core-related antigen as predicting factor for relapse after cessation of lamivudine therapy for chronic hepatitis B virus infection. Hepatol Res. 2006;36:272–6.CrossRefPubMedGoogle Scholar
  25. 25.
    Matsumoto A, Tanaka E, Minami M, et al. Low serum level of hepatitis B core-related antigen indicates unlikely reactivation of hepatitis after cessation of lamivudine therapy. Hepatol Res. 2007;37:661–6.CrossRefPubMedGoogle Scholar
  26. 26.
    Kimura T, Ohno N, Terada N, et al. Hepatitis B virus DNA-negative dane particles lack core protein but contain a 22-kDa precore protein without C-terminal arginine-rich domain. J Biol Chem. 2005;280:21713–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Honda M, Shirasaki T, Terashima T, et al. Hepatitis B virus (HBV) core-related antigen during nucleos(t)ide analog therapy is related to intra-hepatic HBV replication and development of hepatocellular carcinoma. J Infect Dis. 2016;213:1096–106.CrossRefPubMedGoogle Scholar
  28. 28.
    Vallet-Pichard A, Mallet V, Nalpas B, et al. FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection. comparison with liver biopsy and fibrotest. Hepatology. 2007;46:32–6.CrossRefPubMedGoogle Scholar
  29. 29.
    Menéndez-Arias L, Álvarez M, Pacheco B. Nucleoside/nucleotide analog inhibitors of hepatitis B virus polymerase: mechanism of action and resistance. Curr Opin Virol. 2014;8:1–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Xia BW, Zhang YC, Wang J, et al. Efficacy of antiviral therapy with nucleotide/nucleoside analogs after curative treatment for patients with hepatitis B virus-related hepatocellular carcinoma: a systematic review and meta-analysis. Clin Res Hepatol Gastroenterol. 2015;39:458–68.CrossRefPubMedGoogle Scholar
  31. 31.
    Triolo M, Della Corte C, Colombo M. Impact of HBV therapy on the incidence of hepatocellular carcinoma. Liver Int. 2014;34(1):139–45.CrossRefPubMedGoogle Scholar
  32. 32.
    Kuno A, Sato T, Shimazaki H, et al. Reconstruction of a robust glycodiagnostic agent supported by multiple lectin-assisted glycan profiling. Proteomics Clin Appl. 2013;7:642–7.PubMedGoogle Scholar
  33. 33.
    Matsuda A, Kuno A, Kawamoto T, et al. Wisteria floribunda agglutinin-positive mucin 1 is a sensitive biliary marker for human cholangiocarcinoma. Hepatology. 2010;52:174–82.CrossRefPubMedGoogle Scholar
  34. 34.
    Zhang XD, Wang Y, Ye LH. Hepatitis B virus X protein accelerates the development of hepatoma. Cancer Biol Med. 2014;11:182–90.PubMedPubMedCentralGoogle Scholar

Copyright information

© Japanese Society of Gastroenterology 2017

Authors and Affiliations

  • Kazunori Kawaguchi
    • 1
  • Masao Honda
    • 1
    Email author
  • Hajime Ohta
    • 2
  • Takeshi Terashima
    • 1
  • Tetsuro Shimakami
    • 1
  • Kuniaki Arai
    • 1
  • Taro Yamashita
    • 1
  • Yoshio Sakai
    • 1
  • Tatsuya Yamashita
    • 1
  • Eishiro Mizukoshi
    • 1
  • Takuya Komura
    • 1
    • 2
  • Masashi Unoura
    • 2
  • Shuichi Kaneko
    • 1
  1. 1.Department of Gastroenterology, School of Medical SciencesKanazawa UniversityKanazawa, IshikawaJapan
  2. 2.Department of GastroenterologyNational Hospital Organization Kanazawa Medical CenterKanazawaJapan

Personalised recommendations