Journal of Gastroenterology

, Volume 50, Issue 6, pp 675–682 | Cite as

Biochemical responses to bezafibrate improve long-term outcome in asymptomatic patients with primary biliary cirrhosis refractory to UDCA

  • Atsushi Tanaka
  • Junko Hirohara
  • Yasuni Nakanuma
  • Hirohito Tsubouchi
  • Hajime Takikawa
Original Article—Liver, Pancreas, and Biliary Tract
First Online:
Received:
Accepted:

Abstract

Background

Bezafibrate is reported to have biochemical efficacy for patients with primary biliary cirrhosis (PBC) refractory to ursodeoxycholic acid (UDCA), yet the long-term effect is still unknown. In Japan, nationwide surveys of PBC have been performed since 1980. In the current study, we retrospectively examined whether response to bezafibrate treatment is associated with the long-term outcomes using this large-scale database.

Methods

Among 7,376 patients in the database, we enrolled patients who were treated with UDCA at 13–15 mg/kg per day and followed up for at least 2 years after diagnosis. Bezafibrate (400 mg/day) was administered in addition to UDCA when biochemical response to UDCA was not optimal. Response to bezafibrate treatment was determined by serum alanine transaminase (ALT) levels within 2–3 years or at the earliest point thereafter from the commencement of bezafibrate treatment.

Results

We enrolled 1,121 PBC patients, and the observational period was 6.1 ± 3.4 years. Among the PBC patients, 835 were asymptomatic, defined as no liver-related symptoms at the baseline. In asymptomatic PBC patients, multivariate analysis indicated that ALT response to bezafibrate treatment was significantly associated with the presence of liver-related symptoms at the end of observation [hazard ratio 1.46 (95 % confidence interval 1.01–2.13), P = 0.048]. The cumulative liver-related-symptoms-free rate of patients treated with bezafibrate and who had a normal ALT level was significantly higher than that of those treated with bezafibrate and who had an elevated ALT level (P < 0.001), and was comparable to that of those who received UDCA monotherapy.

Conclusion

These results suggested that normalization of ALT levels with additional bezafibrate treatment significantly decreased the rate of occurrence of liver-related symptoms in asymptomatic PBC patients with suboptimal response to UDCA.

Keywords

Bezafibrate Ursodeoxycholic acid Outcome Liver enzymes 

Abbreviations

ALP

Alkaline phosphatase

ALT

Alanine transaminase

aPBC

Asymptomatic primary biliary cirrhosis

AST

Aspartate transaminase

GGT

γ-Glutamyltransferase

LT

Liver transplantation

PBC

Primary biliary cirrhosis

sPBC

Symptomatic primary biliary cirrhosis

UDCA

Ursodeoxycholic acid

ULN

Upper limit of normal

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Notes

Acknowledgment

This study was conducted and supported by Health and Labor Sciences Research Grants from Research on Measures for Intractable Diseases, the Japanese Intractable Hepatobiliary Disease Study Group.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ, et al. Primary biliary cirrhosis. Hepatology. 2009;50:291–308.PubMedCrossRefGoogle Scholar
  2. 2.
    European Association for the Study of the Liver. EASL clinical practice guidelines: management of cholestatic liver diseases. J Hepatol. 2009;51:237–67.CrossRefGoogle Scholar
  3. 3.
    Working Subgroup (English Version) for Clinical Practice Guidelines for Primary Biliary Cirrhosis. Guidelines for the management of primary biliary cirrhosis. The Intractable Hepatobiliary Disease Study Group supported by the Ministry of Health, Labour and Welfare of Japan. Hepatol Res. 2014;44(Suppl S1):71–90.CrossRefGoogle Scholar
  4. 4.
    Poupon R. Primary biliary cirrhosis: a 2010 update. J Hepatol. 2010;52:745–58.PubMedCrossRefGoogle Scholar
  5. 5.
    Corpechot C, Abenavoli L, Rabahi N, Chretien Y, Andreani T, Johanet C, et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology. 2008;48:871–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Kuiper EM, Hansen BE, de Vries RA, den Ouden-Muller JW, van Ditzhuijsen TJ, Haagsma EB, et al. Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid. Gastroenterology. 2009;136:1281–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Pares A, Caballeria L, Rodes J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid. Gastroenterology. 2006;130:715–20.PubMedCrossRefGoogle Scholar
  8. 8.
    Willson TM, Brown PJ, Sternbach DD, Henke BR. The PPARs: from orphan receptors to drug discovery. J Med Chem. 2000;43:527–50.PubMedCrossRefGoogle Scholar
  9. 9.
    Iwasaki S, Tsuda K, Ueta H, Aono R, Ono M, Saibara T, et al. Bezafibrate may have a beneficial effect in pre-cirrhotic primary biliary cirrhosis. Hepatol Res. 1999;16:12–8.CrossRefGoogle Scholar
  10. 10.
    Hazzan R, Tur-Kaspa R. Bezafibrate treatment of primary biliary cirrhosis following incomplete response to ursodeoxycholic acid. J Clin Gastroenterol. 2010;44:371–3.PubMedGoogle Scholar
  11. 11.
    Kanda T, Yokosuka O, Imazeki F, Saisho H. Bezafibrate treatment: a new medical approach for PBC patients? J Gastroenterol. 2003;38:573–8.PubMedGoogle Scholar
  12. 12.
    Kita R, Takamatsu S, Kimura T, Kokuryu H, Osaki Y, Tomono N. Bezafibrate may attenuate biliary damage associated with chronic liver diseases accompanied by high serum biliary enzyme levels. J Gastroenterol. 2006;41:686–92.PubMedCrossRefGoogle Scholar
  13. 13.
    Kurihara T, Niimi A, Maeda A, Shigemoto M, Yamashita K. Bezafibrate in the treatment of primary biliary cirrhosis: comparison with ursodeoxycholic acid. Am J Gastroenterol. 2000;95:2990–2.PubMedCrossRefGoogle Scholar
  14. 14.
    Lens S, Leoz M, Nazal L, Bruguera M, Pares A. Bezafibrate normalizes alkaline phosphatase in primary biliary cirrhosis patients with incomplete response to ursodeoxycholic acid. Liver Int. 2014;34:197–203.PubMedCrossRefGoogle Scholar
  15. 15.
    Miyaguchi S, Ebinuma H, Imaeda H, Nitta Y, Watanabe T, Saito H, et al. A novel treatment for refractory primary biliary cirrhosis? Hepatogastroenterology. 2000;47:1518–21.PubMedGoogle Scholar
  16. 16.
    Nakai S, Masaki T, Kurokohchi K, Deguchi A, Nishioka M. Combination therapy of bezafibrate and ursodeoxycholic acid in primary biliary cirrhosis: a preliminary study. Am J Gastroenterol. 2000;95:326–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Ohmoto K, Mitsui Y, Yamamoto S. Effect of bezafibrate in primary biliary cirrhosis: a pilot study. Liver. 2001;21:223–4.PubMedCrossRefGoogle Scholar
  18. 18.
    Ohmoto K, Yoshioka N, Yamamoto S. Long-term effect of bezafibrate on parameters of hepatic fibrosis in primary biliary cirrhosis. J Gastroenterol. 2006;41:502–3.PubMedCrossRefGoogle Scholar
  19. 19.
    Takeuchi Y, Ikeda F, Fujioka S, Takaki T, Osawa T, Yasunaka T, et al. Additive improvement induced by bezafibrate in patients with primary biliary cirrhosis showing refractory response to ursodeoxycholic acid. J Gastroenterol Hepatol. 2011;26:1395–401.PubMedGoogle Scholar
  20. 20.
    Yano K, Kato H, Morita S, Takahara O, Ishibashi H, Furukawa R. Is bezafibrate histologically effective for primary biliary cirrhosis? Am J Gastroenterol. 2002;97:1075–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Itakura J, Izumi N, Nishimura Y, Inoue K, Ueda K, Nakanishi H, et al. Prospective randomized crossover trial of combination therapy with bezafibrate and UDCA for primary biliary cirrhosis. Hepatol Res. 2004;29:216–22.PubMedCrossRefGoogle Scholar
  22. 22.
    Iwasaki S, Ohira H, Nishiguchi S, Zeniya M, Kaneko S, Onji M, et al. The efficacy of ursodeoxycholic acid and bezafibrate combination therapy for primary biliary cirrhosis: a prospective, multicenter study. Hepatol Res. 2008;38:557–64.PubMedCrossRefGoogle Scholar
  23. 23.
    Invernizzi P, Gershwin ME. New therapeutics in primary biliary cirrhosis: will there ever be light? Liver Int. 2014;34:167–70.PubMedCrossRefGoogle Scholar
  24. 24.
    Nakano T, Inoue K, Hirohara J, Arita S, Higuchi K, Omata M, et al. Long-term prognosis of primary biliary cirrhosis (PBC) in Japan and analysis of the factors of stage progression in asymptomatic PBC (a-PBC). Hepatol Res. 2002;22:250–60.PubMedCrossRefGoogle Scholar
  25. 25.
    Harada K, Hirohara J, Ueno Y, Nakano T, Kakuda Y, Tsubouchi H, et al. Incidence of and risk factors for hepatocellular carcinoma in primary biliary cirrhosis: national data from Japan. Hepatology. 2013;57:1942–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Tanaka A. Management of PBC cases failing to respond to UDCA. Nihon Shokakibyo Gakkai Zasshi. 2013;110:16–21.PubMedGoogle Scholar
  27. 27.
    Drafting Committee for Hepatitis Management Guidelines, Japan Society of Hepatology. JSH guidelines for the management of hepatitis B virus infection. Hepatol Res. 2014;44(Suppl S1):1–58.CrossRefGoogle Scholar
  28. 28.
    Drafting Committee for Hepatitis Management Guidelines, Japan Society of Hepatology. JSH guidelines for the management of hepatitis C virus infection: a 2014 update for genotype 1. Hepatol Res. 2014;44(Suppl S1):59–70.CrossRefGoogle Scholar
  29. 29.
    Marschall HU, Wagner M, Zollner G, Fickert P, Diczfalusy U, Gumhold J, et al. Complementary stimulation of hepatobiliary transport and detoxification systems by rifampicin and ursodeoxycholic acid in humans. Gastroenterology. 2005;129:476–85.PubMedCrossRefGoogle Scholar
  30. 30.
    Honda A, Ikegami T, Nakamuta M, Miyazaki T, Iwamoto J, Hirayama T, et al. Anticholestatic effects of bezafibrate in patients with primary biliary cirrhosis treated with ursodeoxycholic acid. Hepatology. 2013;57:1931–41.PubMedCrossRefGoogle Scholar
  31. 31.
    Azemoto N, Abe M, Murata Y, Hiasa Y, Hamada M, Matsuura B, et al. Early biochemical response to ursodeoxycholic acid predicts symptom development in patients with asymptomatic primary biliary cirrhosis. J Gastroenterol. 2009;44:630–4.PubMedCrossRefGoogle Scholar
  32. 32.
    Corpechot C, Chazouilleres O, Poupon R. Early primary biliary cirrhosis: biochemical response to treatment and prediction of long-term outcome. J Hepatol. 2011;55:1361–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Kumagi T, Guindi M, Fischer SE, Arenovich T, Abdalian R, Coltescu C, et al. Baseline ductopenia and treatment response predict long-term histological progression in primary biliary cirrhosis. Am J Gastroenterol. 2010;105:2186–94.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2014

Authors and Affiliations

  • Atsushi Tanaka
    • 1
  • Junko Hirohara
    • 2
  • Yasuni Nakanuma
    • 3
  • Hirohito Tsubouchi
    • 4
  • Hajime Takikawa
    • 1
  1. 1.Department of MedicineTeikyo University School of MedicineTokyoJapan
  2. 2.The Third Department of Internal MedicineKansai Medical UniversityOsakaJapan
  3. 3.Department of Human PathologyKanazawa University Graduate School of MedicineKanazawaJapan
  4. 4.Kagoshima City HospitalKagashimaJapan

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