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Mac-2 binding protein glycosylation isomer as a novel predictive biomarker for patient survival after hepatitis C virus eradication by DAAs

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

It is crucial to identify risk factors for life prognosis after hepatitis C virus (HCV) eradication among patients with or without a high risk of liver cancer or complications.

Methods

This is a prospective, multicenter and observational study using the database of 1031 patients after HCV eradication by direct-acting antiviral agents (DAAs) to evaluate the development of hepatocellular carcinoma (HCC) and patients’ survival after a sustained virological response (SVR). The Cox proportional hazards regression model was used to estimate hazard ratios associated with HCC development and survival.

Results

AFP at SVR was significantly associated with HCC recurrence in the adjusted model. Liver fibrosis, Mac-2 binding protein glycosylation isomer (M2BPGi) at SVR and smoking status before treatment were positively associated with the development of HCC and M2BPGi was positively associated with HCC recurrence, although not reaching statistical significance. Among patients without a history of HCC, M2BPGi and estimated glomerular filtration rate (eGFR) at SVR were significantly associated with death after viral eradication [M2BPGi (HR 4.07, 95% CI 1.22, 13.57), eGFR (HR 0.97, 95% CI 0.94, 0.99)]. Strikingly, of 16 patients who died, among participants without a history of HCC, only two died of liver cancer associated with HCV, whereas 11 died of non-HCV- related cancer or cardiovascular diseases.

Conclusion

M2BPGi at SVR is a potential predictor for patients’ survival and a candidate biomarker for detecting individuals who are at greater risk of death due to cancer-related and unrelated to HCV, as well as cardiovascular diseases, after viral eradication.

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Abbreviations

HCV:

Hepatitis C virus

DAAs:

Direct-acting antiviral agents

HCC:

Hepatocellular carcinoma

CHC:

Chronic hepatitis C

SVR:

Sustained virological response

WFA:

Wisteria floribunda agglutinin

M2BP:

Mac-2 binding protein

M2BPGi:

Mac-2 binding protein glycosylation isomer

eGFR:

Estimated glomerular filtration rate

HR:

Hazard ratio

Fib-4 index:

Fibrosis-4 index

APRI:

Aspartate aminotransferase-to-platelet ratio index

RBV:

Ribavirin

ASV:

Asunaprevir

DCV:

Daclatasvir

SOF:

Sofosbuvir

LDV:

Ledipasvir

OBV:

Ombitasvir

PTV:

Paritaprevir

EBV:

Elbasvir

GZR:

Grazoprevir

GLE:

Glecaprevir

PIB:

Pibrentasvir

US:

Ultrasonography

CT:

Computed tomography

MRI:

Magnetic resonance imaging

CCC:

Cholangiocellular carcinoma

AMI:

Acute myocardial infarction

CPA:

Cardiopulmonary arrest

d-ROM:

Derivatives of reactive oxygen metabolites

LDL-C:

Low-density lipoprotein cholesterol

EHM:

Extra-hepatic manifestations

References

  1. Stanaway JD, Flaxman AD, Naghavi M, et al. The global burden of viral hepatitis from 1990 to 2013: findings from the global burden of disease study 2013. Lancet. 2016;388:1081–8.

    Article  Google Scholar 

  2. Asrani SK, Devarbhavi H, Eaton J, et al. Burden of liver diseases in the world. J Hepatol. 2019;70:151–71.

    Article  Google Scholar 

  3. Tanaka J, Akita T, Ko K, et al. Countermeasures against viral hepatitis B and C in Japan: an epidemiological point of view. Hepatol Res. 2019;49:990–1002.

    Article  Google Scholar 

  4. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet. 1997;349:825–32.

    Article  CAS  Google Scholar 

  5. Shiratori Y, Imazeki F, Moriyama M, et al. Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy. Ann Intern Med. 2000;132:517–24.

    CAS  PubMed  Google Scholar 

  6. Hamada H, Yatsuhashi H, Yano K, et al. Impact of aging on the development of hepatocellular carcinoma in patients with posttransfusion chronic hepatitis C. Cancer. 2002;95:331–9.

    Article  Google Scholar 

  7. Asahina Y, Tsuchiya K, Tamaki N, et al. Effect of aging on risk for hepatocellular carcinoma in chronic hepatitis C virus infection. Hepatology. 2010;52:518–27.

    CAS  PubMed  Google Scholar 

  8. Asahina Y, Tsuchiya K, Nishimura T, et al. α-fetoprotein levels after interferon therapy and risk of hepatocarcinogenesis in chronic hepatitis C. Hepatology. 2013;58:1253–62.

    CAS  PubMed  Google Scholar 

  9. Gumber SC, Chopra S. Hepatitis C: a multifaceted disease Review of extrahepatic manifestations. Ann Intern Med. 1995;123:615–20.

    CAS  PubMed  Google Scholar 

  10. Nagata H, Nakagawa M, Asahina Y, et al. Effect of interferon-based and -free therapy on early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C. J Hepatol. 2017;67:933–9.

    Article  CAS  Google Scholar 

  11. Nagata H, Nakagawa M, Asahina Y. Imaging basis of AFP and WFA + M2BP as indicators of the risk of HCC after SVR. J Hepatol. 2018;68:607–8.

    Article  Google Scholar 

  12. 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.

    Article  CAS  Google Scholar 

  13. Lin ZH, Xin YN, Dong QJ, et al. Performance of the aspartate aminotransferase-to-platelet ratio index for the staging of hepatitis C-related fibrosis: an updated meta-analysis. Hepatology. 2011;53:726–36.

    Article  Google Scholar 

  14. Desmet VJ, Gerber M, Hoofnagle JH, et al. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology. 1994;19:1513–20.

    Article  CAS  Google Scholar 

  15. 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.

    Article  Google Scholar 

  16. van Buuren S, Groothuis-Oudshoorn K. Mice: multivariate imputation by chained equations in R. J Stat Softw. 2011;45:1–67.

    Article  Google Scholar 

  17. Sterne JA, White IR, Carlin JB, et al. Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls. BMJ. 2009;338:b2393.

    Article  Google Scholar 

  18. Rubin DB. Multiple imputation for nonresponse in surveys. New York: NY John Wiley & Sons; 1987.

    Book  Google Scholar 

  19. Novo AA, Schafer JL. norm: Analysis of multivariate normal datasets with missing values, version 1.0–9.5. https://CRAN.R-project.org/package=norm. 2013.

  20. Sasaki T, Brakebusch C, Engel J, et al. Mac-2 binding protein is a cell-adhesive protein of the extracellular matrix which self-assembles into ring-like structures and binds beta1 integrins, collagens and fibronectin. EMBO J. 1998;17:1606–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Henderson NC, Sethi T. The regulation of inflammation by galectin-3. Immunol Rev. 2009;230:160–71.

    CAS  PubMed  Google Scholar 

  22. Sharma UC, Pokharel S, van Brakel TJ, et al. Galectin-3 marks activated macrophages in failure-prone hypertrophied hearts and contributes to cardiac dysfunction. Circulation. 2004;110:3121–8.

    CAS  PubMed  Google Scholar 

  23. Sugiura T, Dohi Y, Takase H, et al. Serum levels of Mac-2 binding protein increase with cardiovascular risk and reflect silent atherosclerosis. Atherosclerosis. 2016;251:192–6.

    CAS  PubMed  Google Scholar 

  24. Sugiura T, Dohi Y, Takase H, et al. Factors associated with longitudinal changes in serum concentrations of Mac-2 binding protein: a prospective 3-year observational study. Nutr Metab Cardiovasc Dis. 2019;29:1337–444.

    CAS  PubMed  Google Scholar 

  25. Cacoub P, Desbois AC, Isnard-Bagnis C, et al. Hepatitis C virus infection and chronic kidney disease: time for reappraisal. J Hepatol. 2016;65:S82–94.

    PubMed  Google Scholar 

  26. Nagata H, Nakagawa M, Nishimura-Sakurai Y, et al. Serial measurement of Wisteria floribunda agglutinin positive Mac-2-binding protein is useful for predicting liver fibrosis and the development of hepatocellular carcinoma in chronic hepatitis C patients treated with IFN-based and IFN-free therapy. Hepatol Int. 2016;10:956–64.

    PubMed  Google Scholar 

  27. 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.

    PubMed  PubMed Central  Google Scholar 

  28. Pons M, Rodríguez-Tajes S, Esteban JI, et al. Non-invasive prediction of liver-related events in patients with HCV-associated compensated advanced chronic liver disease after oral antivirals. J Hepatol. 2020;72:472–80.

    PubMed  Google Scholar 

  29. Mizuno K, Toyoda H, Yasuda S, et al. The course of elderly patients with persistent hepatitis C virus infection without hepatocellular carcinoma. J Gastroenterol. 2019;54:829–36.

    CAS  PubMed  Google Scholar 

  30. Ioannou GN, Feld JJ. What are the benefits of a sustained virologic response to direct-acting antiviral therapy for hepatitis C virus infection? Gastroenterology. 2019;156:446–460e442.

    Article  CAS  Google Scholar 

  31. Cacoub P, Desbois AC, Comarmond C, et al. Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: a meta-analysis. Gut. 2018;67:2025–34.

    Article  CAS  Google Scholar 

  32. Ramos-Casals M, Zignego AL, Ferri C, et al. Evidence-based recommendations on the management of extrahepatic manifestations of chronic hepatitis C virus infection. J Hepatol. 2017;66:1282–99.

    Article  Google Scholar 

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Acknowledgements

This study is based on the participation of nineteen multicenter hospitals (Tokyo Medical and Dental University Hospital, Kashiwa City Hospital, Tsuchiura Kyodo General Hospital, Tokyo Metropolitan Bokutoh Hospital, Toride Kyodo General Hospital, Tokyo Metropolitan Toshima Hospital, Tokyo Metropolitan Otsuka Hospital, Tokyo Kyosai Hospital, Showa General Hospital, Soka Municipal Hospital, Mishima General Hospital, Ome Municipal General Hospital, Yokosuka Kyosai Hospital, Tokyo Metropolitan Tama Medical Center, Yokohama City Minato Red Cross Hospital, Kudanzaka Hospital, Musashino Red Cross Hospital, Koizumi Clinic, and Oobayashi Clinic). This work was supported by Japan Agency for Medical Research and Development (AMED) under Grant Numbers 19fk0210060, 19fk0210047, 19fk0210058, and Grant-in-Aid for Scientific Research (C) (KAKENHI grant numbers 19K08415, 19H03635) and by grants for research received from Sysmex Corporation.

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Author notes

  1. Mina Nakagawa and Nobutoshi Nawa contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan

    Mina Nakagawa, Eiko Takeichi, Taro Shimizu, Jun Tsuchiya, Ayako Sato, Masato Miyoshi, Fukiko Kawai-Kitahata, Miyako Murakawa, Sayuri Nitta, Yasuhiro Itsui, Seishin Azuma, Sei Kakinuma, Mamoru Watanabe & Yasuhiro Asahina

  2. Institute of Education, Tokyo Medical and Dental University, Tokyo, Japan

    Mina Nakagawa & Nobutoshi Nawa

  3. Department of Liver Disease Control, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan

    Sei Kakinuma & Yasuhiro Asahina

  4. Department of General Medicine, Tokyo Medical and Dental University, Tokyo, Japan

    Yasuhiro Itsui

  5. Department of Clinical Laboratory, Tokyo Medical and Dental University, Tokyo, Japan

    Miyako Murakawa

  6. Department of Medical Education Research and Development, Tokyo Medical and Dental University, Tokyo, Japan

    Nobutoshi Nawa & Yujiro Tanaka

  7. Department of Global Health Promotion, Tokyo Medical and Dental University, Tokyo, Japan

    Nobutoshi Nawa & Takeo Fujiwara

  8. Advanced Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

    Mamoru Watanabe

Authors
  1. Mina Nakagawa
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  2. Nobutoshi Nawa
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Consortia

the Ochanomizu Liver Conference Study Group

Contributions

Study concept and design: MN, YA. Acquisition of data: MN, ET, TS, JT, AS, MM, FKK, MM, SN, YI, SA, SK. Analysis and interpretation of data: MN, NN. Drafting of the manuscript: MN, NN. Statistical analysis: NN, TF. Study supervision: YA, MW, YT. Final approval: All of the authors. Agreement to be accountable for all aspects of the work: All of the authors.

Corresponding author

Correspondence to Yasuhiro Asahina.

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Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1975 Declaration of Helsinki and its later amendments or comparable ethical standards.

Informed consent

Written informed consent was obtained from all patients. The Ethical Committee of TMDU or affiliated hospitals participating in the Ochanomizu–Liver Conference Study group approved this study, which was conducted in accordance with the Declaration of Helsinki (confirmation number: G2000-189).

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Nakagawa, M., Nawa, N., Takeichi, E. et al. Mac-2 binding protein glycosylation isomer as a novel predictive biomarker for patient survival after hepatitis C virus eradication by DAAs. J Gastroenterol 55, 990–999 (2020). https://doi.org/10.1007/s00535-020-01715-6

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  • DOI: https://doi.org/10.1007/s00535-020-01715-6

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