Skip to main content

Advertisement

SpringerLink
Log in

The prognosis of hepatitis B inactive carriers in Japan: a multicenter prospective study

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

Abstract

Background

Hepatitis B e antigen (HBeAg)-negative inactive carriers, the majority of hepatitis B virus (HBV) carriers, are considered to have a good prognosis. The definition of the inactive HBV carrier state has been based on HBV DNA and alanine aminotransferase (ALT) levels. Here we conducted a prospective study involving 18 hospitals to clarify the prognosis of HBeAg-negative inactive carriers.

Methods

Three hundred eighty-eight HBeAg-negative inactive carriers at the baseline were observed prospectively from January 2011 to November 2015. We evaluated the primary end point, defined as the development of cirrhosis, hepatocellular carcinoma (HCC), or liver-related death. Also, we analyzed the factors associated with inactive carrier dropout and markedly increased levels of ALT or HBV DNA or both during the follow-up period.

Results

At the baseline, the mean age was 57.5 ± 13.1 years and 42 % of patients were male. No individual developed cirrhosis, HCC, or liver-related death during the follow-up period (1035 ± 252 days). Loss of inactive carrier status was seen in 75 patients (19.3 %). Factors associated with failure to meet the inactive carrier criteria in the multivariate analysis were the levels of ALT (hazard ratio 1.13, 95 % confidence interval 1.07–1.19, p < 0.001), HBV DNA (hazard ratio 2.70, 95 % confidence interval 1.63–4.49, p < 0.001), and γ-glutamyl transpeptidase (hazard ratio 1.01, 95 % confidence interval 1.00–1.02, p = 0.003) at the baseline.

Conclusions

Most inactive carriers in Japan had a good prognosis. However, despite the short observation period, some patients had loss of IC status. The long-term prognosis of inactive carriers remains unclear; therefore, careful follow-up of inactive carriers is needed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Chen DS. From hepatitis to hepatoma: lessons from type B viral hepatitis. Science. 1993;262:369–70.

    Article  CAS  PubMed  Google Scholar 

  2. Kao JH. Hepatitis B virus genotypes and hepatocellular carcinoma in Taiwan. Intervirology. 2003;46:400–7.

    Article  PubMed  Google Scholar 

  3. Liaw YF, Chu CM. Hepatitis B virus infection. Lancet. 2009;373:582–92.

    Article  CAS  PubMed  Google Scholar 

  4. Kao JH, Chen DS. Global control of hepatitis B virus infection. Lancet Infect Dis. 2002;2:395–403.

    Article  PubMed  Google Scholar 

  5. Tseng TC, Liu CJ, Chen CL, et al. Serum hepatitis B virus-DNA levels correlate with long-term adverse outcomes in spontaneous hepatitis B e antigen seroconverters. J Infect Dis. 2012;205:54–63.

    Article  CAS  PubMed  Google Scholar 

  6. Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65–73.

    Article  CAS  PubMed  Google Scholar 

  7. Hsu YS, Chien RN, Yeh CT, et al. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B. Hepatology. 2002;35:1522–7.

    Article  PubMed  Google Scholar 

  8. Tai DI, Lin SM, Sheen IS, et al. Long-term outcome of hepatitis B e antigen-negative hepatitis B surface antigen carriers in relation to changes of alanine aminotransferase levels over time. Hepatology. 2009;49:1859–67.

    Article  CAS  PubMed  Google Scholar 

  9. Iloeje UH, Yang HI, Su J, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006;130:678–86.

    Article  PubMed  Google Scholar 

  10. Villa E, Fattovich G, Mauro A, et al. Natural history of chronic HBV infection: special emphasis on the prognostic implications of the inactive carrier state versus chronic hepatitis. Dig Liver Dis. 2011;43(Suppl 1):S8–14.

    Article  PubMed  Google Scholar 

  11. Tseng TC, Liu CJ, Yang HC, et al. High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load. Gastroenterology. 2012;142:1140–9.

    Article  CAS  PubMed  Google Scholar 

  12. Tseng TC, Liu CJ, Su TH, et al. Serum hepatitis B surface antigen levels predict surface antigen loss in hepatitis b e antigen seroconverters. Gastroenterology. 2011;141:517–25.

    Article  CAS  PubMed  Google Scholar 

  13. Brunetto MR, Oliveri F, Colombatto P, et al. Hepatitis B surface antigen serum levels help to distinguish active from inactive hepatitis B virus genotype D carriers. Gastroenterology. 2010;139:483–90.

    Article  CAS  PubMed  Google Scholar 

  14. Arai M, Togo S, Kanda T, et al. Quantification of hepatitis B surface antigen can help predict spontaneous hepatitis B surface antigen seroclearance. Eur J Gastroenterol Hepatol. 2012;24:414–8.

    CAS  PubMed  Google Scholar 

  15. Martinot-Peignoux M, Boyer N, Colombat M, et al. Serum hepatitis B virus DNA levels and liver histology in inactive HBsAg carriers. J Hepatol. 2002;36:543–6.

    Article  CAS  PubMed  Google Scholar 

  16. Chu CM, Liaw YF. Spontaneous relapse of hepatitis in inactive carriers. Hepatol Int. 2007;1:311–8.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Chu Chia-Ming, Liaw Yun-Fan. Incidence and risk factors of progression to cirrhosis in inactive carriers of hepatitis B virus. Am J Gastroenterol. 2009;104:1693–9.

    Article  PubMed  Google Scholar 

  18. Bland JM, Altman DG. Calculating correlation coefficients with repeated observations: part 2—correlation between subjects. BMJ. 1995;310:633.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Youden WJ. Index for rating diagnostic tests. Cancer. 1950;3:32–5.

    Article  CAS  PubMed  Google Scholar 

  20. Sharma SK, Saini N, Chwla Y. Hepatitis B virus: inactive carriers. Virol J. 2005;2:82.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507–39.

    Article  CAS  PubMed  Google Scholar 

  22. Keeffe EB, Dieterich DT, Han SH et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: 2008 update. Clin Gastroenterol Hepatol 2008; 6: 1315–41; quiz 1286.

  23. Tong MJ, Hsien C, Song JJ, et al. Factors associated with progression to hepatocellular carcinoma and to death from liver complications in patients with HBsAg-positive cirrhosis. Dig Dis Sci. 2009;54:1337–46.

    Article  CAS  PubMed  Google Scholar 

  24. Chen JD, Yang HI, Iloeje UH, et al. Carriers of inactive hepatitis B virus are still at risk for hepatocellular carcinoma and liver-related death. Gastroenterology. 2010;138:1747–54.

    Article  PubMed  Google Scholar 

  25. Tseng TC, Liu CJ, Yang HC, et al. Serum hepatitis B surface antigen levels help predict disease progression in patients with low hepatitis B virus loads. Hepatology. 2013;57(441–50):5.

    Google Scholar 

  26. Petta S, Macaluso FS, Barcellona MR, et al. Serum γ-glutamyl transferase levels, insulin resistance and liver fibrosis in patients with chronic liver diseases. PLoS One. 2012;7(12):e51165. doi:10.1371/journal.pone.0051165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Myers RP, Tainturier MH, Ratziu V, et al. Prediction of liver histological lesions with biochemical markers in patients with chronic hepatitis B. J Hepatol. 2003;39:222–30.

    Article  CAS  PubMed  Google Scholar 

  28. Vardar R, Vardar E, Demiri S, et al. Is there any non-invasive marker replace the needle liver biopsy predictive for liver fibrosis, in patients with chronic hepatitis? Hepatogastroenterology. 2009;56:1459–65.

    CAS  PubMed  Google Scholar 

  29. Eminler AT, Irak K, Ayyildiz T, et al. The relation between liver histopathology and GGT levels in viral hepatitis: more important in hepatitis B. Turk J Gastroenterol. 2014;25:411–5.

    Article  PubMed  Google Scholar 

  30. Spradling PR, Bulkow L, Teshale EH, et al. Prevalence and causes of elevated serum aminotransferase levels in a population-based cohort of persons with chronic hepatitis B virus infection. J Hepatol. 2014;61:785–91.

    Article  CAS  PubMed  Google Scholar 

  31. Tokushige K, Hyogo H, Nakajima T, et al. Hepatocellular carcinoma in Japanese patients with nonalcoholic fatty liver disease and alcoholic liver disease: multicenter survey. J Gastroenterol. 2016;51(6):586–96

    Article  CAS  PubMed  Google Scholar 

  32. Tong MJ, Blatt LM, Kao JH, et al. Basal core promoter T1762/A1764 and precore A1896 gene mutations in hepatitis B surface antigen-positive hepatocellular carcinoma: a comparison with chronic carriers. Liver Int. 2007;27:1356–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lai M, Hyatt BJ, Nasser I, et al. The clinical significance of persistently normal ALT in chronic hepatitis B infection. J Hepatol. 2007;47:760–7.

    Article  CAS  PubMed  Google Scholar 

  34. Gigi E, Lalla T, Orphanou E, et al. Long term follow-up of a large cohort of inactive HBsAg (+)/HBeAg (-)/anti-HBe (+)carriers in Greece. J Gastrointestin Liver Dis. 2007;16:19–22.

    PubMed  Google Scholar 

  35. Chen JD, Yang HI, Iloeje UH, et al. Carriers of inactive hepatitis B virus are still at risk for hepatocellular carcinoma and liver-related death. Gastroenterology 2010;138:1747–1754.

Download references

Acknowledgments

The authors thank the staff of Chiba University Hospital and the members of research group.

Author information

Authors and Affiliations

  1. Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chiba, 260-8670, Japan

    Takashi Taida, Makoto Arai, Tatsuo Kanda & Osamu Yokosuka

  2. Department of Gastroenterology, Sapporo-Kosei General Hospital, Sapporo, Hokkaido, Japan

    Shuhei Hige

  3. Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata, Japan

    Yoshiyuki Ueno

  4. Safety and Health Organization, Chiba University, Chiba, Japan

    Fumio Imazeki

  5. Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan

    Namiki Izumi

  6. Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan

    Eiji Tanaka

  7. Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan

    Noboru Shinkai

  8. Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, Toyoake, Aichi, Japan

    Kentaro Yoshioka

  9. Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan

    Yasunari Nakamoto

  10. Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan

    Shuhei Nishiguchi

  11. Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan

    Masataka Tsuge

  12. Departments of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Matsuyama, Ehime, Japan

    Masanori Abe

  13. Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan

    Michio Sata

  14. Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan

    Hiroshi Yatsuhashi

  15. Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

    Akio Ido

  16. Department of Gastroenterology, Chiba Kaihin Municipal Hospital, Chiba, Japan

    Kazuhiko Kita

  17. Department of Gastroenterology, Kimitsu Chuo Hospital, Kisarazu, Chiba, Japan

    Ryousaku Azemoto

  18. Department of Gastroenterology, Chiba Aoba Municipal Hospital, Chiba, Japan

    Yoshio Kitsukawa

  19. Department of Gastroenterology, Numazu City Hospital, Numazu, Shizuoka, Japan

    Nobuaki Goto

Authors
  1. Takashi Taida
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Makoto Arai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tatsuo Kanda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shuhei Hige
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoshiyuki Ueno
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fumio Imazeki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Namiki Izumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Eiji Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Noboru Shinkai
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kentaro Yoshioka
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yasunari Nakamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Shuhei Nishiguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Masataka Tsuge
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Masanori Abe
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Michio Sata
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Hiroshi Yatsuhashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Akio Ido
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Kazuhiko Kita
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Ryousaku Azemoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Yoshio Kitsukawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Nobuaki Goto
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Osamu Yokosuka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Makoto Arai.

Ethics declarations

Conflict of interest

This study was supported by Practical Research on Hepatitis from the Ministry of Health, Labour and Welfare (H24-Kanen-Ippan-007).

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PPTX 355 kb)

Supplementary material 2 (DOCX 16 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Taida, T., Arai, M., Kanda, T. et al. The prognosis of hepatitis B inactive carriers in Japan: a multicenter prospective study. J Gastroenterol 52, 113–122 (2017). https://doi.org/10.1007/s00535-016-1229-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-016-1229-6

Keywords

Search

Navigation