Skip to main content

Advertisement

SpringerLink
Log in

Factors Associated with Progression to Hepatocellular Carcinoma and to Death from Liver Complications in Patients with HBsAg-Positive Cirrhosis

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background and Aims Hepatitis B viral markers and liver tests were used as predictors for development of hepatocellular carcinoma and progression to end-stage liver disease in 128 cirrhosis patients with hepatitis B. Results During a median follow-up of 63.5 months, 28 patients (21.9%) developed HCC and 36 (28.1%) died from non-HCC liver deaths. By multivariate analysis, independent predictors of HCC development and their hazard ratios were high alfa-fetoprotein (HR2.83, 95% CI 1.60–5.00, P = 0.0003), negative HBeAg (HR2.33, 95% CI 1.04–5.29, P = 0.04), and low alanine aminotransferase value (HR1.42, 95% CI 1.08–1.89, P = 0.02). Independent predictors of non-HCC liver deaths were HBeAg positivity (HR3.39, 95% CI 1.16–9.93, P = 0.02), decrease albumin (HR1.61, 95% CI 0.99–2.63, P = 0.05), decrease platelet count (HR2.54, 95% CI 1.03–6.25, P = 0.04), high ALT value (HR1.22, 95% CI 1.03–1.43, P = 0.02), and onset of encephalopathy (HR3.34, 95% CI 1.21–9.27, P = 0.02). Concusions HBeAg negativity, elevated AFP, and low ALT values predicted HCC development, while HBeAg positivity, abnormal liver tests, and low platelet counts identified patients with non-HCC liver deaths.

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

Similar content being viewed by others

References

  1. Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat. 2004;11:97–107. doi:10.1046/j.1365-2893.2003.00487.x.

    Article  PubMed  CAS  Google Scholar 

  2. Maddrey WC. Hepatitis B: an important public health issue. J Med Virol. 2000;61:362–366. doi:10.1002/1096-9071(200007)61:3<362::AID-JMV14>3.0.CO;2-I.

    Article  PubMed  CAS  Google Scholar 

  3. Lee WM. Hepatitis B virus infection. N Engl J Med. 1997;337:1733–1745. doi:10.1056/NEJM199712113372406.

    Article  PubMed  CAS  Google Scholar 

  4. Chu CM, Liaw YF. Hepatitis B virus-related cirrhosis: natural history and treatment. Semin Liver Dis. 2006;26:142–152. doi:10.1055/s-2006-939752.

    Article  PubMed  CAS  Google Scholar 

  5. Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol. 2008;48:335–352. doi:10.1016/j.jhep.2007.11.011.

    Article  PubMed  CAS  Google Scholar 

  6. Kao JH. Role of viral factors in the natural course and therapy of chronic hepatitis B. Hepatol Int. 2007;1:415–430. doi:10.1007/s12072-007-9033-2.

    Article  PubMed  Google Scholar 

  7. Tong MJ, Blatt LM, Kao JH, Cheng JT, Corey WG. Precore/basal core promoter mutants and hepatitis B viral DNA levels as predictors for liver deaths and hepatocellular carcinoma. World J Gastroenterol. 2006;12:6620–6626.

    PubMed  CAS  Google Scholar 

  8. Tong MJ, Hsien C, Hsu L, et al. Treatment recommendations for chronic hepatitis B: an evaluation of current guidelines based on a natural history in the United States. Hepatology. 2008;48:1070–1078.

    Article  PubMed  Google Scholar 

  9. De Jongh FE, Janssen HLA, De Man RA, Hop WCJ, Schalm SW, Van Blankenstein M. Survival and prognostic indicators in hepatitis B surface antigen-positive cirrhosis of the liver. Gastroenterology. 1992;103:1630–1635.

    PubMed  Google Scholar 

  10. Realdi G, Fattovich G, Hadziyannis S, et al. Survival of prognostic factors in 366 patients with compensated cirrhosis type B: a multicenter study. J Hepatol. 1994;21:656–666. doi:10.1016/S0168-8278(94)80115-0.

    Article  PubMed  CAS  Google Scholar 

  11. Di Marco V, Lo Iacono O, Camma C, et al. The long-term course of chronic hepatitis B. Hepatology. 1999;30:257–264. doi:10.1002/hep.510300109.

    Article  PubMed  CAS  Google Scholar 

  12. Kato Y, Nakata K, Omagari K, Furukawa R, et al. Risk of hepatocellular carcinoma in patients with cirrhosis in Japan. Analysis of infectious hepatitis viruses. Cancer. 1994;74:2234–2238. doi:10.1002/1097-0142(19941015)74:8<2234::AID-CNCR2820740805>3.0.CO;2-6.

    Article  PubMed  CAS  Google Scholar 

  13. Hui AY, Chan HL, Leung NW, Hung LC, et al. Survival and prognostic indicators in patients with hepatitis B virus-related cirrhosis after onset of hepatic decompensation. J Clin Gastroenterol. 2002;34:569–572. doi:10.1097/00004836-200205000-00018.

    Article  PubMed  Google Scholar 

  14. Xu B, Hu DC, Rosenberg DM, Jiang QW, et al. Chronic hepatitis B: a long-term retrospective cohort study of disease progression in Shanghai, China. J Gastroenterol Hepatol. 2003;18:1345–1352. doi:10.1046/j.1440-1746.2003.03187.x.

    Article  PubMed  Google Scholar 

  15. Lo KJ, Tong MJ, Chien MC, et al. The natural course of hepatitis B surface antigen-positive chronic active hepatitis in Taiwan. J Infect Dis. 1982;146:205–210.

    PubMed  CAS  Google Scholar 

  16. Benvegnù L, Gios M, Boccato S, Alberti A. Natural history of compensated viral cirrhosis: a prospective study on the incidence and hierarchy of major complications. Gut. 2004;53:744–749. doi:10.1136/gut.2003.020263.

    Article  PubMed  Google Scholar 

  17. Weissberg JI, Andres LL, Smith CI, et al. Survival in chronic hepatitis B. Ann Intern Med. 1984;101:613–616.

    PubMed  CAS  Google Scholar 

  18. Cardenas CL, Soetikno R, Robinson WS, et al. Long-term follow-up of patients with chronic hepatitis B: a 25-year prospective study. Hepatol. 1999;30:300A–559. doi:10.1002/hep.510300105.

    Article  Google Scholar 

  19. Chen YC, Chu CM, Yeh CT, et al. Natural course following the onset of cirrhosis in patients with chronic hepatitis B: a long-term follow-up study. Hepatol Int. 2007;1:267–273. doi:10.1007/s12072-007-5001-0.

    Article  PubMed  Google Scholar 

  20. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208–1236. doi:10.1002/hep.20933.

    Article  PubMed  Google Scholar 

  21. Kalbfleisch JD, Prentice RL. Multivariate failure data and competing risks. The Analysis of Failure Time Data. New York: Wiley;1980:168–169.

  22. Fattovich G, Brollo L, Giustina G, Noventa F, et al. Natural history and prognostic factors for chronic hepatitis type B. Gut. 1991;32:294–298. doi:10.1136/gut.32.3.294.

    Article  PubMed  CAS  Google Scholar 

  23. Liaw YF, Chen YC, Sheen IS, et al. Impact of acute hepatitis C virus superinfection in patients with chronic hepatitis B virus infection. Gastroenterology. 2004;126:1024–1029. doi:10.1053/j.gastro.2004.01.011.

    Article  PubMed  Google Scholar 

  24. Kao JH, Chen PJ, Lai MY, Chen DS. Hepatitis B genotypes correlate with clinical outcomes in patients with cirrhosis hepatitis B. Gastroenterology. 2000;118:554–559. doi:10.1016/S0016-5085(00)70261-7.

    Article  PubMed  CAS  Google Scholar 

  25. Sumi H, Yokosuka O, Seki N, Arai M, et al. Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease. Hepatology. 2003;37:19–26. doi:10.1053/jhep.2003.50036.

    Article  PubMed  CAS  Google Scholar 

  26. Sanchez-Tapias JM, Costa J, Mas A, Bruguera M, Rodes J. Influence of hepatitis B virus genotype on the long-term outcome of chronic hepatitis B in Western patients. Gastroenterology. 2002;123:1848–1856. doi:10.1053/gast.2002.37041.

    Article  PubMed  Google Scholar 

  27. Rodriguez-Frias F, Jardi R, Buti M, Schaper M, et al. Hepatitis B virus genotypes and G1896A precore mutation in 486 Spanish patients with acute and chronic HBV infection. J Viral Hepat. 2006;13:343–350. doi:10.1111/j.1365-2893.2005.00691.x.

    Article  PubMed  CAS  Google Scholar 

  28. Song BC, Cui XJ, Kim HU, Cho YK. Sequential accumulation of the basal core promoter and the precore mutations in the progression of hepatitis B virus-related chronic liver disease. Intervirology. 2006;49:266–273. doi:10.1159/000093456.

    Article  PubMed  CAS  Google Scholar 

  29. Chen CH, Lee CM, Hung CH, Hu TH, 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. doi:10.1111/j.1478-3231.2007.01505.x.

    Article  PubMed  CAS  Google Scholar 

  30. Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006;130:678–686. doi:10.1053/j.gastro.2005.11.016.

    Article  PubMed  Google Scholar 

  31. Chu CJ, Hussain M, Lok ASF. Quantitative serum HBV DNA levels during different stages of chronic hepatitis B infection. Hepatology. 2002;36:1408–1415.

    PubMed  CAS  Google Scholar 

  32. Manesis EK, Papatheodoridis GV, Sevastianos V, Cholongitas E, et al. Significance of hepatitis B viremia levels determined by a quantitative polymerase chain reaction assay in patients with hepatitis B e antigen-negative chronic hepatitis B virus infection. Am J Gastroenterol. 2003;98:2261–2267.

    PubMed  CAS  Google Scholar 

  33. Kobayashi M, Ikeda K, Hosaka T, Sezaki H, et al. Natural history of compensated cirrhosis in the Child-Pugh class A compared between 490 patients with hepatitis C and 167 with B virus infections. J Med Virol. 2006;78:459–465. doi:10.1002/jmv.20562.

    Article  PubMed  Google Scholar 

  34. Chen YC, Chu CM, Yen CT, Liaw YF. Natural course following onset of cirrhosis in patients with chronic hepatitis B: a long-term follow-up. Hepatol Int. 2007;1:267–273. doi:10.1007/s12072-007-5001-0.

    Article  PubMed  Google Scholar 

  35. Perrillo RP. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunological mediated liver disease. Gastroenterology. 2001;120:1009–1022. doi:10.1053/gast.2001.22461.

    Article  PubMed  CAS  Google Scholar 

  36. Yang HI, Lu SN, Liaw YF, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med. 2002;347:168–174. doi:10.1056/NEJMoa013215.

    Article  PubMed  CAS  Google Scholar 

  37. Kew MC, Desmyter J, De Groote G, et al. Hepatocellular cancer in southern African blacks: HBeAg, anti-HBe, IgM anti-HBc and other markers of hepatitis B. Prog Med Virol. 1981;27:41–48.

    PubMed  CAS  Google Scholar 

  38. Tong MJ, Lo GH, Co RL. Etiology, pathology and treatment of hepatocellular carcinoma in North America. In: Tabor E, Di Bisceglie AM, Purcell RH, eds. Chronic hepatitis and hepatocellular carcinoma in Asian Americans, 13th ed. Houston: Gulf Publishing Company;1991:25–34.

  39. Chan HLY, Hui AY, Wong ML, et al. Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma. Gut. 2004;53:1494–1498. doi:10.1136/gut.2003.033324.

    Article  PubMed  Google Scholar 

  40. Ni YH, Chan MH, Wang KJ, et al. Clinical relevance of hepatitis B virus genotype in children with chronic infection and hepatocellular carcinoma. Gastroenterology. 2004;127:1733–1738. doi:10.1053/j.gastro.2004.09.048.

    Article  PubMed  CAS  Google Scholar 

  41. Kao JH, Chen PJ, Lai MY, et al. Basal core promoter mutations of hepatitis B virus increased the risk of hepatocellular carcinoma in hepatitis B carriers. Gastroenterology. 2003;124:234–327. doi:10.1053/gast.2003.50053.

    Article  CAS  Google Scholar 

  42. Liu CJ, Chen BF, Chen PJ, et al. Role of hepatitis B virus precore/core promoter mutations and serum viral load on noncirrhotic hepatocellular carcinoma: a case-control study. J Infect Dis. 2006;194:594–599. doi:10.1086/505883.

    Article  PubMed  CAS  Google Scholar 

  43. Yuen MF, Sablon E, Yuan HJ, Hui CK, et al. Relationship between the development of precore and core promoter mutations and hepatitis B e antigen seroconversion in patients with chronic hepatitis B virus. J Infect Dis. 2002;186:1335–1338. doi:10.1086/344327.

    Article  PubMed  CAS  Google Scholar 

  44. Liu CJ, Chen BF, Chen PJ, Lai MY, Huang WL, et al. Role of hepatitis B virus precore/core promoter mutations and serum viral load on noncirrhotic hepatocellular carcinoma: a case-control study. J Infect Dis. 2006;194:594–599. doi:10.1086/505883.

    Article  PubMed  CAS  Google Scholar 

  45. Chen BF, Liu CJ, Jow GM, Chen PJ, Kao JH, Chen DS. High prevalence and mapping of pre-S deletion in hepatitis B virus carriers with progressive liver diseases. Gastroenterology. 2006;130:1153–1168. doi:10.1053/j.gastro.2006.01.011.

    Article  PubMed  CAS  Google Scholar 

  46. Ito K, Tanaka Y, Orito E, et al. T1653 mutation in the box α increases the risk of hepatocellular carcinoma in patients with chronic hepatitis B virus genotype C infection. Clin Infect Dis. 2006;42:1–7. doi:10.1086/498522.

    Article  PubMed  CAS  Google Scholar 

  47. Muroyama R, Kato N, Yoshida H, et al. Nucleotide change of codon 38 in the X gene of hepatitis B virus genotype C is associated with an increased risk of hepatocellular carcinoma. J Hepatol. 2006;45:805–812. doi:10.1016/j.jhep.2006.07.025.

    Article  PubMed  CAS  Google Scholar 

  48. Ohata K, Hamasaki K, Toriyama K, Ishikawa H, et al. High viral load is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis B virus infection. J Gastroenterol Hepatol. 2004;19:670–675. doi:10.1111/j.1440-1746.2004.03360.x.

    Article  PubMed  Google Scholar 

  49. Yu MW, Yeh SH, Chen PJ, et al. Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men. J Natl Cancer Inst. 2005;97:265–272.

    Article  PubMed  CAS  Google Scholar 

  50. Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biologic gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65–78. doi:10.1001/jama.295.1.65.

    Article  PubMed  CAS  Google Scholar 

  51. 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;10:1478–3231.

    Google Scholar 

  52. Yao FY, Bass NM. Lamivudine treatment in patients with severely decompensated cirrhosis due to replicating hepatitis B infection. J Hepatol. 2000;33:301–307. doi:10.1016/S0168-8278(00)80371-2.

    Article  PubMed  CAS  Google Scholar 

  53. Perrillo RP, Wright T, Rakela J, et al. A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B. Hepatology. 2001;33:424–432. doi:10.1053/jhep.2001.21554.

    Article  PubMed  CAS  Google Scholar 

  54. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521–1531. doi:10.1056/NEJMoa033364.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The statistical analyses were performed by Jeffery Gornbein Dr. PH and Daniela Markovic MS.

Author information

Authors and Affiliations

  1. The Pfleger Liver Institute and the Division of Digestive Diseases, David Geffen School of Medicine at the University of California in Los Angeles, Los Angeles, CA, USA

    Myron John Tong, Steven-Huy Han, Francisco Antonio Durazo, Sammy Saab & Lawrence Mitchell Blatt

  2. The Liver Center, Huntington Medical Research Institutes, 660 S. Fair Oaks Ave, Pasadena, CA, 91105, USA

    Myron John Tong, Carlos Hsien, Joanna Jungeun Song, Hai-En Sun & Leeyen Hsu

  3. Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan

    Jia Horng Kao

  4. Alios Biopharma, South San Francisco, CA, USA

    Lawrence Mitchell Blatt

Authors
  1. Myron John Tong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carlos Hsien
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joanna Jungeun Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jia Horng Kao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hai-En Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Leeyen Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Steven-Huy Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Francisco Antonio Durazo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sammy Saab
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Lawrence Mitchell Blatt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Myron John Tong.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tong, M.J., Hsien, C., Song, J.J. et al. Factors Associated with Progression to Hepatocellular Carcinoma and to Death from Liver Complications in Patients with HBsAg-Positive Cirrhosis. Dig Dis Sci 54, 1337–1346 (2009). https://doi.org/10.1007/s10620-009-0747-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-009-0747-y

Keywords

Search

Navigation