Skip to main content
SpringerLink
Log in

Treatment of Fatigue in Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis

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

Abstract

Background and Aims

Fatigue is the most common complication of primary biliary cholangitis (PBC) and can be debilitating. Numerous interventions have been trialed targeting several proposed mechanisms of PBC-associated fatigue. We sought to summarize and perform a meta-analysis to determine the efficacy of these interventions.

Methods

A comprehensive database search was conducted from inception through March 27, 2018. The primary outcome was proportion of fatigued patients or reduction in degree of fatigue. Adverse events were a secondary outcome. We assessed studies for risk of bias, graded quality of evidence, and used meta-analysis to obtain overall effect by pooling studies of the same class.

Results

We identified 16 studies evaluating ursodeoxycholic acid (UDCA) (7), liver transplantation (2), serotonin reuptake inhibitors (2), colchicine (1), methotrexate (1), cyclosporine (1), modafinil (1), and obeticholic acid (1). On meta-analysis, UDCA was not associated with a reduction in risk of fatigue (RR = 0.86, 95% CI 0.69–1.08, p = 0.19, I2 = 56.2%). While liver transplantation did reduce degree of fatigue (SMD − 0.57, 95% CI − 0.89 to − 0.24, p = 0.001, I2 = 67.3%), fatigue did not return to baseline indicating the underlying cause may not be addressed.

Conclusions

While there is some improvement in fatigue with liver transplantation, there is a lack of high-quality evidence supporting the efficacy of any other intervention in the treatment of PBC-related fatigue. Further research into the underlying pathophysiology may help guide future trials.

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
Fig. 5

Similar content being viewed by others

References

  1. Boonstra K, Beuers U, Ponsioen CY. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review. J Hepatol. 2012;56:1181–1188. https://doi.org/10.1016/j.jhep.2011.10.025.

    Article  PubMed  Google Scholar 

  2. Witt-Sullivan H, Heathcote J, Cauch K, et al. The demography of primary biliary cirrhosis in Ontario, Canada. Hepatology. 1990;12:98–105.

    Article  CAS  PubMed  Google Scholar 

  3. Goldblatt J, Taylor PJS, Lipman T, et al. The true impact of fatigue in primary biliary cirrhosis: a population study. Gastroenterology. 2002;122:1235–1241. https://doi.org/10.1053/gast.2002.32993.

    Article  PubMed  Google Scholar 

  4. Poupon RE, Chrétien Y, Chazouillères O, Poupon R, Chwalow J. Quality of life in patients with primary biliary cirrhosis. Hepatology. 2014;40:489–494. https://doi.org/10.1002/hep.20276.

    Article  Google Scholar 

  5. Mells GF, Pells G, Newton JL, et al. Impact of primary biliary cirrhosis on perceived quality of life: the UK-PBC national study. Hepatology. 2013;58:273–283. https://doi.org/10.1002/hep.26365.

    Article  PubMed  Google Scholar 

  6. Al-Harthy N, Kumagi T, Coltescu C, Hirschfield GM. The specificity of fatigue in primary biliary cirrhosis: evaluation of a large clinic practice. Hepatology. 2010;52:562–570. https://doi.org/10.1002/hep.23683.

    Article  PubMed  Google Scholar 

  7. Newton JL, Gibson GJ, Tomlinson M, Wilton K, Jones D. Fatigue in primary biliary cirrhosis is associated with excessive daytime somnolence. Hepatology. 2006;44:91–98. https://doi.org/10.1002/hep.21230.

    Article  PubMed  Google Scholar 

  8. Selmi C, Gershwin ME, Lindor KD, et al. Quality of life and everyday activities in patients with primary biliary cirrhosis. Hepatology. 2007;46:1836–1843. https://doi.org/10.1002/hep.21953.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Jones DEJ, Bhala N, Burt J, Goldblatt J, Prince M, Newton JL. Four year follow up of fatigue in a geographically defined primary biliary cirrhosis patient cohort. Gut. 2006;55:536–541. https://doi.org/10.1136/gut.2005.080317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Jones DE, Al-Rifai A, Frith J, Patanwala I, Newton JL. The independent effects of fatigue and UDCA therapy on mortality in primary biliary cirrhosis: results of a 9 year follow-up. J Hepatol. 2010;53:911–917. https://doi.org/10.1016/j.jhep.2010.05.026.

    Article  CAS  PubMed  Google Scholar 

  11. Jopson L, Jones DEJ. Fatigue in primary biliary cirrhosis: prevalence, pathogenesis and management. Dig Dis. 2015;33:109–114. https://doi.org/10.1159/000440757.

    Article  PubMed  Google Scholar 

  12. Jopson L, Hegade V, Mells G, Sandford R, Jones DE. P1197: natural history of fatigue and pruritus in primary biliary cirrhosis: implications for the role of pruritus in the aetiology and treatment of fatigue. J Hepatol. 2015;62:S804–S805. https://doi.org/10.1016/S0168-8278(15)31393-3.

    Article  Google Scholar 

  13. Griffiths L, Jones DE. Pathogenesis of primary biliary cirrhosis and its fatigue. Dig Dis. 2014;32:615–625. https://doi.org/10.1159/000360515.

    Article  PubMed  Google Scholar 

  14. Stanca CM, Bach N, Krause C, et al. Evaluation of fatigue in U.S. patients with primary biliary cirrhosis. Am J Gastroenterol. 2005;100:1104–1109. https://doi.org/10.1111/j.1572-0241.2005.41315.x.

    Article  PubMed  Google Scholar 

  15. Jacoby A, Rannard A, Buck D, et al. Development, validation, and evaluation of the PBC-40, a disease specific health related quality of life measure for primary biliary cirrhosis. Gut. 2005;54:1622–1629. https://doi.org/10.1136/gut.2005.065862.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. 2011. http://handbook.cochrane.org.

  17. Wells G, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2013. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed October 6, 2018.

  18. Guyatt GH, Oxman AD, Vist G, et al. GRADE guidelines: 4. Rating the quality of evidence–study limitations (risk of bias). J Clin Epidemiol. 2011;64:407–415. https://doi.org/10.1016/j.jclinepi.2010.07.017.

    Article  Google Scholar 

  19. Combes B, Carithers RL, Maddrey WC, et al. A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology. 1995;22:759–766.

    CAS  PubMed  Google Scholar 

  20. Lindor KD, Dickson ER, Baldus WP, et al. Ursodeoxycholic acid in the treatment of primary biliary cirrhosis. Gastroenterology. 1994;106:1284–1290.

    Article  CAS  PubMed  Google Scholar 

  21. Vuoristo M, Färkkilä M, Karvonen AL, et al. A placebo-controlled trial of primary biliary cirrhosis treatment with colchicine and ursodeoxycholic acid. Gastroenterology. 1995;108:1470–1478.

    Article  CAS  PubMed  Google Scholar 

  22. Poupon RE, Balkau B, Eschwège E, Poupon R. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group. N Engl J Med. 1991;324:1548–1554. https://doi.org/10.1056/nejm199105303242204.

    Article  CAS  PubMed  Google Scholar 

  23. Heathcote EJ, Cauch-Dudek K, Walker V, et al. The Canadian Multicenter Double-blind Randomized Controlled Trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology. 1994;19:1149–1156.

    Article  CAS  PubMed  Google Scholar 

  24. Parés A, Caballería L, Rodés J, et al. Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the Spanish Association for the Study of the Liver. J Hepatol. 2000;32:561–566.

    Article  PubMed  Google Scholar 

  25. Chan CW, Gunsar F, Feudjo M, et al. Long-term ursodeoxycholic acid therapy for primary biliary cirrhosis: a follow-up to 12 years. Aliment Pharmacol Ther. 2005;21:217–226. https://doi.org/10.1111/j.1365-2036.2005.02318.x.

    Article  CAS  PubMed  Google Scholar 

  26. Carbone M, Bufton S, Monaco A, Griffiths L, Jones DE, Neuberger JM. The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: a prospective study. J Hepatol. 2013;59:490–494. https://doi.org/10.1016/j.jhep.2013.04.017.

    Article  PubMed  Google Scholar 

  27. Pells G, Mells GF, Carbone M, et al. The impact of liver transplantation on the phenotype of primary biliary cirrhosis patients in the UK-PBC cohort. J Hepatol. 2013;59:67–73. https://doi.org/10.1016/j.jhep.2013.02.019.

    Article  PubMed  Google Scholar 

  28. Talwalkar JA, Donlinger JJ, Gossard AA, et al. Fluoxetine for the treatment of fatigue in primary biliary cirrhosis: a randomized, double-blind controlled trial. Dig Dis Sci. 2006;51:1985–1991. https://doi.org/10.1007/s10620-006-9397-5.

    Article  CAS  PubMed  Google Scholar 

  29. ter Borg PCJ, van Os E, van den Broek WW, Hansen BE, van Buuren HR. Fluvoxamine for fatigue in primary biliary cirrhosis and primary sclerosing cholangitis: a randomised controlled trial [ISRCTN88246634]. BMC Gastroenterol. 2004;4:13. https://doi.org/10.1186/1471-230X-4-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. González-Koch A, Brahm J, Antezana C, Smok G, Cumsille MA. The combination of ursodeoxycholic acid and methotrexate for primary biliary cirrhosis is not better than ursodeoxycholic acid alone. J Hepatol. 1997;27:143–149.

    Article  PubMed  Google Scholar 

  31. Wiesner RH, Ludwig J, Lindor KD, et al. A controlled trial of cyclosporine in the treatment of primary biliary cirrhosis. N Engl J Med. 1990;322:1419–1424. https://doi.org/10.1056/NEJM199005173222003.

    Article  CAS  PubMed  Google Scholar 

  32. Silveira MG, Gossard AA, Stahler AC, et al. A randomized, placebo-controlled clinical trial of efficacy and safety: modafinil in the treatment of fatigue in patients with primary biliary cirrhosis. Am J Ther. 2017;24:e167–e176. https://doi.org/10.1097/MJT.0000000000000387.

    Article  PubMed  Google Scholar 

  33. 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. https://doi.org/10.1056/NEJMoa1509840.

    Article  CAS  PubMed  Google Scholar 

  34. Mayo MJ, Handem I, Saldana S, Jacobe H, Getachew Y, Rush AJ. Sertraline as a first-line treatment for cholestatic pruritus. Hepatology. 2007;45:666–674. https://doi.org/10.1002/hep.21553.

    Article  CAS  PubMed  Google Scholar 

  35. Hegade VS, Kendrick SFW, Dobbins RL, et al. Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study. Lancet. 2017;389:1114–1123. https://doi.org/10.1016/S0140-6736(17)30319-7.

    Article  CAS  PubMed  Google Scholar 

  36. Theal JJ, Toosi MN, Girlan L, et al. A randomized, controlled crossover trial of ondansetron in patients with primary biliary cirrhosis and fatigue. Hepatology. 2005;41:1305–1312. https://doi.org/10.1002/hep.20698.

    Article  CAS  PubMed  Google Scholar 

  37. Prince MI, Mitchison HC, Ashley D, et al. Oral antioxidant supplementation for fatigue associated with primary biliary cirrhosis: results of a multicentre, randomized, placebo-controlled, cross-over trial. Aliment Pharmacol Ther. 2003;17:137–143.

    Article  CAS  PubMed  Google Scholar 

  38. Jones DEJ, Newton JL. An open study of modafinil for the treatment of daytime somnolence and fatigue in primary biliary cirrhosis. Aliment Pharmacol Ther. 2007;25:471–476. https://doi.org/10.1111/j.1365-2036.2006.03223.x.

    Article  CAS  PubMed  Google Scholar 

  39. Ian Gan S, de Jongh M, Kaplan MM. Modafinil in the treatment of debilitating fatigue in primary biliary cirrhosis: a clinical experience. Dig Dis Sci. 2009;54:2242–2246. https://doi.org/10.1007/s10620-008-0613-3.

    Article  CAS  PubMed  Google Scholar 

  40. Poupon RE, Poupon R, Balkau B. Ursodiol for the long-term treatment of primary biliary cirrhosis. The UDCA-PBC study group. N Engl J Med. 1994;330:1342–1347. https://doi.org/10.1056/nejm199405123301903.

    Article  CAS  PubMed  Google Scholar 

  41. 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. https://doi.org/10.1053/j.gastro.2005.12.029.

    Article  CAS  PubMed  Google Scholar 

  42. Cauch-Dudek K, Abbey S, Stewart DE, Heathcote EJ. Fatigue in primary biliary cirrhosis. Gut. 1998;43:705–710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Floreani A, Franceschet I, Cazzagon N. Primary biliary cirrhosis: overlaps with other autoimmune disorders. Semin Liver Dis. 2014;34:352–360. https://doi.org/10.1055/s-0034-1383734.

    Article  PubMed  Google Scholar 

  44. Overman CL, Kool MB, Da Silva JAP, Geenen R. The prevalence of severe fatigue in rheumatic diseases: an international study. Clin Rheumatol. 2016;35:409–415. https://doi.org/10.1007/s10067-015-3035-6.

    Article  PubMed  Google Scholar 

  45. Hardy T, MacDonald C, Jones DEJ, Newton JL. A follow-up study of modafinil for the treatment of daytime somnolence and fatigue in primary biliary cirrhosis. Liver Int. 2010;30:1551–1552. https://doi.org/10.1111/j.1478-3231.2010.02288.x.

    Article  PubMed  Google Scholar 

  46. Khanna A, Jopson L, Howel D, et al. Rituximab is ineffective for treatment of fatigue in primary biliary cholangitis: a phase 2 randomized controlled trial. Hepatology. 2018;. https://doi.org/10.1002/hep.30099.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Hollingsworth KG, Newton JL, Robinson L, Taylor R, Blamire AM, Jones DEJ. Loss of capacity to recover from acidosis in repeat exercise is strongly associated with fatigue in primary biliary cirrhosis. J Hepatol. 2010;53:155–161. https://doi.org/10.1016/j.jhep.2010.02.022.

    Article  CAS  PubMed  Google Scholar 

  48. Hollingsworth KG, Newton JL, Taylor R, et al. Pilot study of peripheral muscle function in primary biliary cirrhosis: potential implications for fatigue pathogenesis. Clin Gastroenterol Hepatol. 2008;6:1041–1048. https://doi.org/10.1016/j.cgh.2008.04.013.

    Article  PubMed  Google Scholar 

  49. Myers RP, Swain MG, Lee SS, Shaheen AAM, Burak KW. B-cell depletion with rituximab in patients with primary biliary cirrhosis refractory to ursodeoxycholic acid. Am J Gastroenterol. 2013;108:933–941. https://doi.org/10.1038/ajg.2013.51.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA, 02215, USA

    Jennifer Y. Lee

  2. Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Dana 603, Boston, MA, 02215, USA

    Christopher J. Danford & Hirsh D. Trivedi

  3. Liver Center, Autoimmune and Cholestatic Liver Disease Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA

    Vilas R. Patwardhan & Alan Bonder

  4. Division of Gastroenterology and Hepatology, University Hospital, University of Michigan, Floor 2, Room 2B353, 1500 E. Medical Center Dr SPC 5051, Ann Arbor, MI, 48109-5051, USA

    Elliot B. Tapper

Authors
  1. Jennifer Y. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christopher J. Danford
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hirsh D. Trivedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Elliot B. Tapper
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vilas R. Patwardhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alan Bonder
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alan Bonder.

Ethics declarations

Conflict of interest

No outside funding or grant support was involved in the production of this manuscript. The authors have no pertinent conflicts of interest.

Additional information

Jennifer Y. Lee and Christopher J. Danford are co-first authors.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 45 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, J.Y., Danford, C.J., Trivedi, H.D. et al. Treatment of Fatigue in Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis. Dig Dis Sci 64, 2338–2350 (2019). https://doi.org/10.1007/s10620-019-5457-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-019-5457-5

Keywords

Search

Navigation