Skip to main content
SpringerLink
Log in

Long-term prognosis of patients with chronic hepatitis C who did not receive interferon-based therapy: causes of death and analysis based on the FIB-4 index

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

Abstract

Background

Interferon (IFN)-based therapy has been reported to reduce the liver-related mortality rate in patients with chronic hepatitis C virus (HCV) infection. However, predictors of survival and causes of death, including non-liver-related causes, have not been sufficiently investigated in chronic HCV patients who have not received IFN-based therapy.

Methods

A total of 1723 patients with chronic HCV infection who were not treated with IFN-based therapy were enrolled. Survival from liver-related diseases and non-liver-related diseases and causes of death were analyzed on the basis of the fibrosis-4 (FIB-4) index, an index of liver fibrosis.

Results

The median follow-up duration was 10.3 years. Of 465 patients who died during the follow-up period, 48.4 % died of liver-related diseases; of the remainder, 51.6 % died of non-liver-related diseases. On the basis of FIB-4 index, the liver-related mortality rate increased as the FIB-4 index increased: 16.1 % in the FIB-4 index < 1.45 group, 36.7 % in the 1.45 ≤ FIB-4 index ≤ 3.25 group, and 58.7 % in the FIB-4 index > 3.25 group (p < 0.001). Conversely, the non-liver-related mortality rate decreased as the FIB-4 index increased: 83.9, 63.3, and 41.3 %, respectively (p = 0.001). In the multivariate analysis, a FIB-4 index greater than 3.25 was identified as a risk factor independently associated with both liver-related death (hazard ratio 13.020; 95 % confidence interval 4.155–40.770) and non-liver-related death (hazard ratio 1.667; 95 % confidence interval 1.188–2.340).

Conclusions

Patients with chronic HCV infection and an elevated FIB-4 index may benefit from monitoring not only for the development of liver-related diseases but also for the development of non-liver-related diseases.

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

Similar content being viewed by others

Abbreviations

AFP:

α-Fetoprotein

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

FIB-4:

Fibrosis 4

HCV:

Hepatitis C virus

HCC:

Hepatocellular carcinoma

ICD:

International Statistical Classification of Diseases and Related Health Problems

IFN:

Interferon

References

  1. Armstrong GL, Wasley A, Simard EP, et al. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144:705–14.

    Article  PubMed  Google Scholar 

  2. World Health Organization. Global alert and response (GAR): hepatitis C. http://www.who.int/csr/disease/hepatitis/whocdscsrlyo2003/en/index4.html (2011). Accessed 1 Dec 2014.

  3. Marcellin P, Boyer N, Gervais A, et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy. Ann Intern Med. 1997;127:875–81.

    Article  CAS  PubMed  Google Scholar 

  4. Reichard O, Glaumann H, Frydén A, et al. Long-term follow-up of chronic hepatitis C patients with sustained virological response to alpha-interferon. J Hepatol. 1999;30:783–7.

    Article  CAS  PubMed  Google Scholar 

  5. Poynard T, Moussalli J, Ratziu V, et al. Effect of interferon therapy on the natural history of hepatitis C virus-related cirrhosis and hepatocellular carcinoma. Clin Liver Dis. 1999;3:869–81.

    Article  CAS  PubMed  Google Scholar 

  6. Yoshida H, Shiratori Y, Moriyama M, et al. Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. Ann Intern Med. 1999;131:174–81.

    Article  CAS  PubMed  Google Scholar 

  7. Ikeda K, Saitoh S, Arase Y, et al. Effect of interferon therapy on hepatocellular carcinogenesis in patients with chronic hepatitis type C: a long-term observation study of 1,643 patients using statistical bias correction with proportional hazard analysis. Hepatology. 1999;29:1124–30.

    Article  CAS  PubMed  Google Scholar 

  8. Hung CH, Lee CM, Lu SN, et al. Long-term effect of interferon alpha-2b plus ribavirin therapy on incidence of hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis. J Viral Hepat. 2006;13:409–14.

    Article  PubMed  Google Scholar 

  9. Niederau C, Lange S, Heintges T, et al. Prognosis of chronic hepatitis C: results of a large, prospective cohort study. Hepatology. 1998;28:1687–95.

    Article  CAS  PubMed  Google Scholar 

  10. Yoshida H, Arakawa Y, Sata M, et al. Interferon therapy prolonged life expectancy among chronic hepatitis C patients. Gastroenterology. 2002;123:483–91.

    Article  CAS  PubMed  Google Scholar 

  11. Kasahara A, Tanaka H, Okanoue T, et al. Interferon treatment improves survival in chronic hepatitis C patients showing biochemical as well as virological responses by preventing liver-related death. J Viral Hepat. 2004;11:148–56.

    Article  CAS  PubMed  Google Scholar 

  12. Gebo KA, Herlong HF, Torbenson MS, et al. Role of liver biopsy in management of chronic hepatitis C: a systematic review. Hepatology. 2002;36:S161–72.

    Article  PubMed  Google Scholar 

  13. Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med. 2001;344:495–500.

    Article  CAS  PubMed  Google Scholar 

  14. Castéra L, Nègre I, Samii K, et al. Pain experienced during percutaneous liver biopsy. Hepatology. 1999;30:1529–30.

    Article  PubMed  Google Scholar 

  15. Williams AL, Hoofnagle JH. Ratio of serum aspartate to alanine aminotransferase in chronic hepatitis. Relationship to cirrhosis. Gastroenterology. 1988;95:734–9.

    CAS  PubMed  Google Scholar 

  16. Wai CT, Greenson JK, Fontana RJ, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38:518–26.

    Article  PubMed  Google Scholar 

  17. Forns X, Ampurdanès S, Llovet JM, et al. Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model. Hepatology. 2002;36:986–92.

    Article  PubMed  Google Scholar 

  18. Imbert-Bismut F, Ratziu V, Pieroni L, et al. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Lancet. 2001;357:1069–75.

    Article  CAS  PubMed  Google Scholar 

  19. Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43:1317–25.

    Article  CAS  PubMed  Google Scholar 

  20. 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  PubMed  Google Scholar 

  21. Shah AG, Lydecker A, Murray K, et al. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2009;7:1104–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. American Association for the Study of Liver Diseases. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org (2015).

  23. European Association for Study of Liver. EASL clinical practice guidelines: management of hepatitis C virus infection. J Hepatol. 2014;60:392–420.

    Article  Google Scholar 

  24. Omata M, Kanda T, Ming-Lung Yu, et al. APASL consensus statements and management algorithms for hepatitis C virus infection. Hepatol Int. 2012;6:409–35.

    Article  PubMed  Google Scholar 

  25. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208–36.

    Article  PubMed  Google Scholar 

  26. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–2.

    Article  PubMed  PubMed Central  Google Scholar 

  27. World Health Organization. International Classification of Diseases (ICD). http://www.who.int/classifications/icd/en/. Accessed 1 Dec 2014.

  28. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509.

    Article  Google Scholar 

  29. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tong MJ, el-Farra NS, Reikes AR, et al. Clinical outcomes after transfusion-associated hepatitis C. N Engl J Med. 1995;332:1463–6.

    Article  CAS  PubMed  Google Scholar 

  31. Yano M, Kumada H, Kage M, et al. The long-term pathological evolution of chronic hepatitis C. Hepatology. 1996;23:1334–40.

    Article  CAS  PubMed  Google Scholar 

  32. Kobayashi M, Tanaka E, Sodeyama T, et al. The natural course of chronic hepatitis C: a comparison between patients with genotypes 1 and 2 hepatitis C viruses. Hepatology. 1996;23:695–9.

    Article  CAS  PubMed  Google Scholar 

  33. Cacoub P, Gragnani L, Comarmond C, et al. Extrahepatic manifestations of chronic hepatitis C virus infection. Dig Liver Dis. 2014;46:S165–73.

    Article  PubMed  Google Scholar 

  34. Ono E, Shiratori Y, Okudaira T, et al. Platelet count reflects stage of chronic hepatitis C. Hepatol Res. 1999;15:192–200.

    Article  Google Scholar 

  35. Matsumura H, Moriyama M, Goto I, et al. Natural course of progression of liver fibrosis in Japanese patients with chronic liver disease type C—a study of 527 patients at one establishment. J Viral Hepat. 2000;7:268–75.

    Article  CAS  PubMed  Google Scholar 

  36. Lok AS, Seeff LB, Morgan TR, et al. Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease. Gastroenterology. 2009;136:138–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kurosaki M, Matsunaga K, Hirayama I, et al. The presence of steatosis and elevation of alanine aminotransferase levels are associated with fibrosis progression in chronic hepatitis C with non-response to interferon therapy. J Hepatol. 2008;48:736–42.

    Article  CAS  PubMed  Google Scholar 

  38. Kumada T, Toyoda H, Kiriyama S, et al. Predictive value of tumor markers for hepatocarcinogenesis in patients with hepatitis C virus. J Gastroenterol. 2011;46:536–44.

    Article  CAS  PubMed  Google Scholar 

  39. Sherman M. Hepatocellular carcinoma: epidemiology, risk factors, and screening. Semin Liver Dis. 2005;25:143–54.

    Article  PubMed  Google Scholar 

  40. Lee MH, Yang HI, Lu SN, et al. Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study. J Infect Dis. 2012;206:469–77.

    Article  PubMed  Google Scholar 

  41. Omata M, Yoshida H, Toyota J, et al. A large-scale, multicentre, double-blind trial of ursodeoxycholic acid in patients with chronic hepatitis C. Gut. 2007;56:1747–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Manns MP, Wedemeyer H, Singer A, et al. Glycyrrhizin in patients who failed previous interferon alpha-based therapies: biochemical and histological effects after 52 weeks. J Viral Hepat. 2012;19:537–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by Health and Labour Sciences Research Grants (Research on Hepatitis) from the Ministry of Health, Labour and Welfare of Japan.

Author information

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, 4-86 Minaminokawa, Ogaki, Gifu, 503-8502, Japan

    Toshifumi Tada, Takashi Kumada, Hidenori Toyoda, Seiki Kiriyama, Makoto Tanikawa, Yasuhiro Hisanaga, Akira Kanamori, Shusuke Kitabatake & Tsuyoki Yama

  2. Department of Epidemiology, Infectious Disease Control, and Prevention, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan

    Junko Tanaka

Authors
  1. Toshifumi Tada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takashi Kumada
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hidenori Toyoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seiki Kiriyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Makoto Tanikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yasuhiro Hisanaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Akira Kanamori
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shusuke Kitabatake
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tsuyoki Yama
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Junko Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toshifumi Tada.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tada, T., Kumada, T., Toyoda, H. et al. Long-term prognosis of patients with chronic hepatitis C who did not receive interferon-based therapy: causes of death and analysis based on the FIB-4 index. J Gastroenterol 51, 380–389 (2016). https://doi.org/10.1007/s00535-015-1117-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-015-1117-5

Keywords

Search

Navigation