Skip to main content
SpringerLink
Log in

Response to Ursodeoxycholic Acid May Be Assessed Earlier to Allow Second-Line Therapy in Patients with Unresponsive Primary Biliary Cholangitis

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

Abstract

Background

Response to ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) has been traditionally assessed 1 to 2 years after treatment initiation. With the development of new drugs, some patients may benefit from an earlier introduction of second-line therapies.

Aims

This study aims to identify whether well-validated response criteria could correctly identify individuals likely to benefit from add-on second-line therapy at 6 months.

Methods

Analysis of a multicenter retrospective cohort which included only patients with clear-cut PBC.

Results

206 patients with PBC (96.6% women; mean age 54 ± 12 years) were included. Kappa concordance was substantial for Toronto (0.67), Rotterdam (0.65), Paris 1 (0.63) and 2 (0.63) criteria at 6 and 12 months, whereas Barcelona (0.47) and POISE trial (0.59) criteria exhibited moderate agreement. Non-response rates to UDCA was not statistically different when assessed either at 6 or 12 months using Toronto, Rotterdam or Paris 2 criteria. Those differences were even smaller or absent in those subjects with advanced PBC. Mean baseline alkaline phosphatase was 2.73 ± 1.95 times the upper limit of normal (× ULN) among responders versus 5.05 ± 3.08 × ULN in non-responders (p < 0.001).

Conclusions

After 6 months of treatment with UDCA, the absence of response by different criteria could properly identify patients who could benefit from early addition of second-line therapies, especially in patients with advanced disease or high baseline liver enzymes levels.

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

Similar content being viewed by others

Data availability

Data is available upon request to corresponding author.

Abbreviations

UDCA:

Ursodeoxycholic acid

PBC:

Primary biliary cholangitis

ULN:

Upper limit of normal

BCSG:

Brazilian Cholestasis Study Group

AMA:

Anti-mitochondrial antibodies

ALP:

Alkaline phosphatase

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

GGT:

Gamma-glutamyl transferase

IQR:

Interquartile range

ANA:

Antinuclear antibodies

SD:

Standard deviation

References

  1. Corpechot C, Carrat F, Bonnand AM et al. The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis. Hepatology. 2000;32:1196–1199.

    Article  CAS  Google Scholar 

  2. Corpechot C, Abenavoli L, Rabahi N et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology. 2008;48:871–877.

    Article  CAS  Google Scholar 

  3. Harms MH, van Buuren HR, Corpechot C et al. Ursodeoxycholic acid therapy and liver transplant-free survival in patients with primary biliary cholangitis. J Hepatol. 2019;71:357–365.

    Article  CAS  Google Scholar 

  4. Lammers WJ, van Buuren HR, Hirschfield GM et al. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study. Gastroenterology. 2014;147:1338-1349.e5.

    Article  CAS  Google Scholar 

  5. Itakura J, Izumi N, Nishimura Y et al. Prospective randomized crossover trial of combination therapy with bezafibrate and UDCA for primary biliary cirrhosis. Hepatol Res. 2004;29:216–222.

    Article  CAS  Google Scholar 

  6. Lens S, Leoz M, Nazal L et al. Bezafibrate normalizes alkaline phosphatase in primary biliary cirrhosis patients with incomplete response to ursodeoxycholic acid. Liver Int. 2014;34:197–203.

    Article  CAS  Google Scholar 

  7. Corpechot C, Chazouillères O, Rousseau A et al. A placebo-controlled trial of bezafibrate in primary biliary cholangitis. N Engl J Med. 2018;378:2171–2181.

    Article  CAS  Google Scholar 

  8. Nevens F, Andreone P, Mazzella G et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016;375:631–643.

    Article  CAS  Google Scholar 

  9. Trauner M, Nevens F, Shiffman ML et al. Long-term efficacy and safety of obeticholic acid for patients with primary biliary cholangitis: 3-year results of an international open-label extension study. Lancet Gastroenterol Hepatol. 2019;4:445–453.

    Article  Google Scholar 

  10. Tanaka A, Hirohara J, Nakano T et al. Association of bezafibrate with transplant-free survival in patients with primary biliary cholangitis. J Hepatol. 2021;75:565–571.

    Article  CAS  Google Scholar 

  11. Lindor KD, Bowlus CL, Boyer J et al. Primary biliary cholangitis: 2018 Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2019;69:394–419.

    Google Scholar 

  12. Ludwig J, Dickson ER, McDonald GSA. Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis). Virchows Arch A Pathol Anat Histol. 1978;379:103–112.

    Article  CAS  Google Scholar 

  13. Parés A, Caballería L, Rodés J. Excellent long-term Survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid. Gastroenterology. 2006;130:715–720.

    Article  Google Scholar 

  14. Corpechot C, Chazouillères O, Poupon R. Early primary biliary cirrhosis: Biochemical response to treatment and prediction of long-term outcome. J Hepatol. 2011;55:1361–1367.

    Article  CAS  Google Scholar 

  15. Kumagi T, Guindi M, Fischer SE et al. Baseline Ductopenia and treatment response predict long-term histological progression in primary biliary cirrhosis. Am J Gastroenterol. 2010;105:2186–2194.

    Article  CAS  Google Scholar 

  16. Haynes R. Determinants of compliance: The disease and the mechanics of treatment. Compliance in health care. 1979.

  17. Cançado GGL, Braga MH, Ferraz MLG et al. Clinical features and treatment outcomes of primary biliary cholangitis in a highly admixed population. Ann Hepatol. 2022;27:100546.

    Article  Google Scholar 

  18. Carey EJ, Ali AH, Lindor KD. Primary biliary cirrhosis. Lancet (London, England). 2015;386:1565–1575.

    Article  CAS  Google Scholar 

  19. Corpechot C, Carrat F, Bahr A et al. The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Gastroenterology. 2005;128:297–303.

    Article  CAS  Google Scholar 

  20. Lammert C, Juran BD, Schlicht E et al. Biochemical response to ursodeoxycholic acid predicts survival in a North American cohort of primary biliary cirrhosis patients. J Gastroenterol. 2014;49:1414–1420.

    Article  CAS  Google Scholar 

  21. Angulo P, Lindor KD, Therneau TM et al. Utilization of the Mayo risk score in patients with primary biliary cirrhosis receiving ursodeoxycholic acid. Liver. 1999;19:115–121.

    Article  CAS  Google Scholar 

  22. Perez CFM, Harms MH, Lindor KD et al. Goals of treatment for improved survival in primary biliary cholangitis: treatment target should be bilirubin within the normal range and normalization of alkaline phosphatase. Am J Gastroenterol. 2020;115:1066–1074.

    Article  Google Scholar 

Download references

Funding

This work was supported by Brazilian Society of Hepatology and Instituto Brasileiro do Fígado – IBRAFIG.

Author information

Authors and Affiliations

  1. Instituto Alfa de Gastroenterologia, Hospital das Clínicas da Universidade Federal de Minas Gerais, Av. Professor Alfredo Balena 110, Belo Horizonte, Minas Gerais, 30130-100, Brazil

    Guilherme Grossi Lopes Cançado, Cláudia Alves Couto, Mateus Jorge Nardelli & Luciana Costa Faria

  2. Hospital da Polícia Militar de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

    Guilherme Grossi Lopes Cançado

  3. Departamento de Gastroenterologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil

    Debora Raquel Benedita Terrabuio, Eduardo Luiz Rachid Cançado, Michelle Harriz Braga, Mario Guimarães Pessoa & Laura Vilar Guedes

  4. Hospital Universitário Clementino Fraga Filho e Departamento de Clínica Médica da Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil

    Cristiane Alves Villela-Nogueira & Vivian Rotman

  5. Disciplina de Gastroenterologia, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil

    Maria Lucia Gomes Ferraz & Nathalia Mota de Faria Gomes

  6. Centro Universitário Lusíada - UNILUS, Santos, São Paulo, Brazil

    Elze Maria Gomes Oliveira

  7. Ambulatório Municipal de Hepatites Virais de São José dos Campos, São José dos Campos, São Paulo, Brazil

    Maria Beatriz Oliveira

  8. Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Bahia, Brazil

    Simone Muniz Carvalho Fernandes da Cunha & Liana Codes

  9. Divisão de Gastroenterologia (Gastrocentro), Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil

    Marlone Cunha-Silva

  10. Hospital de Base do Distrito Federal, Brasília, Distrito Federal, Brazil

    Liliana Sampaio Costa Mendes

  11. Serviço de Gastroenterologia, Hepatologia e Transplante Hepático, Hospital Nossa Senhora das Graças, Curitiba, Paraná, Brazil

    Claudia Alexandra Pontes Ivantes

  12. Hospital Português, Salvador, Bahia, Brazil

    Liana Codes & Paulo Lisboa Bittencourt

  13. Instituto de Gastroenterologia, Endoscopia e Proctologia, Uberlândia, Minas Gerais, Brazil

    Valéria Ferreira de Almeida e Borges

  14. Universidade Federal de Uberlândia, Uberlândia, Minas Gerais, Brazil

    Valéria Ferreira de Almeida e Borges

  15. Serviço de Gastroenterologia e Hepatologia, Universidade Federal de Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil

    Fabio Heleno de Lima Pace

  16. Hospital Universitário Cassiano Antônio Moraes, Universidade Federal do Espírito Santo, Vitoria, Espírito Santo, Brazil

    Izabelle Venturini Signorelli

  17. Irmandade da Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil

    Gabriela Perdomo Coral

  18. Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, FL, USA

    Cynthia Levy

  19. Escola Bahiana de Medicina e Saúde Pública, Salvador, Bahia, Brazil

    Paulo Lisboa Bittencourt

Authors
  1. Guilherme Grossi Lopes Cançado
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cláudia Alves Couto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Debora Raquel Benedita Terrabuio
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eduardo Luiz Rachid Cançado
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cristiane Alves Villela-Nogueira
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maria Lucia Gomes Ferraz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michelle Harriz Braga
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mateus Jorge Nardelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Luciana Costa Faria
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Nathalia Mota de Faria Gomes
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Elze Maria Gomes Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Vivian Rotman
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Maria Beatriz Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Simone Muniz Carvalho Fernandes da Cunha
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Marlone Cunha-Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Liliana Sampaio Costa Mendes
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Claudia Alexandra Pontes Ivantes
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Liana Codes
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Valéria Ferreira de Almeida e Borges
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Fabio Heleno de Lima Pace
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Mario Guimarães Pessoa
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Laura Vilar Guedes
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Izabelle Venturini Signorelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Gabriela Perdomo Coral
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Cynthia Levy
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Paulo Lisboa Bittencourt
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

Members of the Brazilian Cholestasis Study Group Consortium

Corresponding author

Correspondence to Guilherme Grossi Lopes Cançado.

Ethics declarations

Conflict of interest

None declared.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 13 kb)

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cançado, G.G.L., Couto, C.A., Terrabuio, D.R.B. et al. Response to Ursodeoxycholic Acid May Be Assessed Earlier to Allow Second-Line Therapy in Patients with Unresponsive Primary Biliary Cholangitis. Dig Dis Sci 68, 514–520 (2023). https://doi.org/10.1007/s10620-022-07654-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-022-07654-x

Keywords

Search

Navigation