Ursodeoxycholic Acid: Efficacy and Safety in the Treatment of Nonalcoholic Fatty Liver Disease (Meta-Analysis)

Cover Page
  • Authors: Pavlov С.S.1, Varganova D.L.1,2, Semenistaia M.C.1, Kuznetsova E.A.1, Usanova A.A.3, Svistunov A.A.1
  • Affiliations:
    1. First Moscow State Medical University named after I.M.Sechenov (Sechenov University)
    2. Ulyanovsk Regional Clinical Hospital
    3. National Research Mordovian State University named after. N.P. Ogareva
  • Issue: Vol 73, No 5 (2018)
  • Pages: 294-305
  • Section: INTERNAL DISEASES: CURRENT ISSUES
  • URL: https://vestnikramn.spr-journal.ru/jour/article/view/975
  • DOI: https://doi.org/10.15690/vramn975
Open Access Open Access
Restricted Access Subscription or Fee Access

Abstract


Вackground: Non-alcoholic liver disease (NAFLD) is a widely spread disease that needs an effective and safe treatment strategy. One of pharmacological treatments for people with NAFLD is ursodeoxycholic acid (UDCA). The use of UDCA is pathogenetically justified because of its cytoprotective, antiapoptotic, antioxidant, and hypoglycemic properties. Aim: Our meta-analysis (M-A) aimed to assess the benefits and harms of UDCA in people with NAFLD. Material and methods: We identified trials through electronic searches in the Cochrane Hepato-Biliary (CHB) Controlled Trials Register, CENTRAL, MEDLINE, Embase, SCI, LILACS, eLibrary (May 2018). We considered for inclusion randomised clinical trials (RCTs) assessing URSO versus placebo/no intervention in adult participants with NAFLD. We allowed co-interventions in the trial groups if they were similar. We followed Cochrane methodology, CHB Group methodology using Review Manager 5 and Trial Sequential Analysis to perform meta-analysis (M-A), assessed bias risk of the trials, quality of evidence using GRADE. Results: Four RCT, at high bias risk, low quality of evidence, provided data for analysis: 254 participants at different stages of NAFLD received oral UDCA (median of 18 months), 256 ― placebo/no intervention; age 18 to 75 years. We found no evidence of effect on mortality (there were no deaths) and on histological parameters such as steatosis (MD -0.13; CI -0.40−0.13; participants 323; trials 3; I2=43%), fibrosis (MD 0.00; CI -0.00−0.22; participants 323; trials 3; I2=0%), and inflammation (MD -0.05; CI -0.20−0.10; participants 325; trials 3; I2=0%). Also we found no evidence for significant influence of UDCA on occurrence of serious adverse events (RR 1.45, 95% CI 0.65−3.21; participants 292; trials 2; I2=0%), adverse events (RR 1.52, 95% CI 0.73−3.16; participants 510; trials 4; I2=36%) neither with traditional M-A (random-effects), nor with TSA SAE (CI 0.56−2.91; participants 292; trials 2; I2=0%, D2=0%), AE (CI 0.77–2.21; participants 510; trials 4; I2=0%, D2=0%). There was no evidence of effect on cytolysis, but beneficial effect of UDCA on cholestasis (GGTP) (data from two trials only) (р<0.0001). We found no data on quality of life. All the trials were funded by the industry. Conclusion: Based on the small number of trials at high risk of bias, low quality, despite the safety profile observed with our M-A, we can neither recommend nor reject the use of UDCA for people with NAFLD. Further trials with low risk of bias and high quality are required to assess the benefits and harms of UDCA. 


Сhavdar S. Pavlov

First Moscow State Medical University named after I.M.Sechenov (Sechenov University)

Author for correspondence.
Email: chpavlov@mail.ru
ORCID iD: 0000-0001-5031-9798

Russian Federation

MD,PhD.

1 bld. 1, Pogodinskaya street, 119881 Moscow.

SPIN-код: 5052-9020

 

 

Daria L. Varganova

First Moscow State Medical University named after I.M.Sechenov (Sechenov University); Ulyanovsk Regional Clinical Hospital

Email: datich@yandex.ru
ORCID iD: 0000-0002-5745-7605

Russian Federation

MD, gastroenterological department.

SPIN-код: 3689-5602

 

Marianna C. Semenistaia

First Moscow State Medical University named after I.M.Sechenov (Sechenov University)

Email: marianna.semenistaia@yahoo.com
ORCID iD: 0000-0002-1724-4760

Russian Federation

MD.

1 bld. 1, Pogodinskaya street, 119881 Moscow.

SPIN-код: 9357-3700

Ekatherina A. Kuznetsova

First Moscow State Medical University named after I.M.Sechenov (Sechenov University)

Email: fraokat@gmail.com
ORCID iD: 0000-0002-8264-0559

Russian Federation

1 bld. 1, Pogodinskaya street, 119881 Moscow.

SPIN-код: 4830-1668

Anna A. Usanova

National Research Mordovian State University named after. N.P. Ogareva

Email: anna61-u@mail.ru
ORCID iD: 0000-0003-2948-4865

Russian Federation

MD, PhD, Professor.

SPIN-код: 8346-6031

Andrei A. Svistunov

First Moscow State Medical University named after I.M.Sechenov (Sechenov University)

Email: svistunov@sechenov.ru
ORCID iD: 0000-0003-1592-5703

Russian Federation

MD, PhD, Professor.

1 bld. 1, Pogodinskaya street, 119881 Moscow.

SPIN-код: 4042-9063

 

  1. Глобальные практические рекомендации Всемирной гастроэнтерологической организации. Неалкогольная жировая болезнь печени и неалкогольный стеатогепатит [интернет]. World Gastroenterology Organisation; 2012. Доступно по: http://www.worldgastroenterology.org/UserFiles/file/guidelines/nafld-nash-russian-2012.pdf. Ссылка активна на 12.09.2018.
  2. Ивашкин В.Т., Драпкина О.М., Шульпекова Ю.О. Диагностика и лечение неалкогольной жировой болезни печени: методические рекомендации. ― М.: М-Вести; 2009. ― 20 с.
  3. Российское общество по изучению печени. Диагностика и лечение неалкогольной жировой болезни печени (Методические рекомендации для врачей). / Под ред. акад. РАН, проф. В.Т. Ивашкина. ― М.; 2015.
  4. Beuers U. Drug insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat Clin Pract Gastroenterol Hepatol. 2006;3(6):318−328. doi: 10.1038/ncpgasthep0521.
  5. Fickert P, Zollner G, Fuchsbichler A, et al. Effects of ursodeoxycholic and cholic acid feeding on hepatocellular transporter expression in mouse liver. Gastroenterology. 2001;121(1):170–183. doi: 10.1053/gast.2001.25542.
  6. Murakami M, Une N, Nishizawa N, et al. Incretin secretion stimulated by ursodeoxycholic acid in healthy subjects. Springerplus. 2013;2(1):20. doi: 10.1186/2193-1801-2-20.
  7. Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, the Cochrane Collaboration; 2014. Available from: https://community.cochrane.org/help/tools-and-software/revman-5. Accessed September 9, 2018.
  8. Trial Sequential Analysis (TSA) [Computer program]. Version 0.9.5.5 Beta. Copenhagen: the Nordic Cochrane Centre, the Cochrane Collaboration; 2011. Available from: http://www.ctu.dk/tsa/. Accessed September 9, 2018.
  9. Thorlund K, Engstrøm J, Wetterslev J, et al. User manual for Trial Sequential Analysis (TSA) [Internet]. Copenhagen, Denmark: Copenhagen trial unit, Centre for clinical intervention research; 2011. pр. 1–115 [cited 2016 Feb 9]. Available from: http://www.ctu.dk/tsa/files/tsa_manual.pdf.
  10. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539−1558. doi: 10.1002/sim.1186.
  11. Gluud C, Brok J, Gong Y, Koretz RL. Hepatology may have problems with putative surrogate outcome measures. J Hepatol. 2007;46(4):734−742. doi: 10.1016/j.jhep.2007.01.003.
  12. Dufour JF, Oneta CM, Gonvers JJ, et al. Randomized placebo-controlled trial of Ursodeoxycholic acid with vitamin e in non-alcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2006;4(12):1537−1543. doi: 10.1016/j.cgh.2006.09.025.
  13. Leuschner UF, Lindenthal B, Herrmann G, et al. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology. 2010; 52(2):472−479. doi: 10.1002/hep.23727.
  14. Lindor KD, Kowdley KV, Heathcote EJ, et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology. 2004;39(3):770−778. doi: 10.1002/hep.20092.
  15. Ratziu V, De Ledinghen V, Oberti F, et al. A multicentric, double-blind, randomised-controlled trial (RCT) of high dose ursodeoxycholic acid in patients with non-alcoholic steatohepatitis (NASH). J Hepatol. 2009;50:S21. doi: 10.1016/S0168-8278(09)60049-0.
  16. Ratziu V, De Ledinghen V, Oberti F, et al. A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol. 2011;54(5):1011−1019. doi: 10.1016/j.jhep.2010.08.030.
  17. Higgins J, Green S, editors. Cochrane handbook for systematic reviews of interventions [Internet]. Chichester, England: John Wiley & Sons, Ltd; 2008 [cited 2018 Oct 12]. Available from: https://www.radioterapiaitalia.it/wp-content/uploads/2017/01/cochrane-handbook-for-systematic-reviews-of-interventions.pdf.
  18. Bedossa P. Current histological classification of NAFLD: strength and limitations. Hepatol Int. 2013;7 Suppl 2:765−770. doi: 10.1007/s12072-013-9446-z.
  19. Adams LA, Sanderson S, Lindor KD, Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol. 2005;42(1):132−138. doi: 10.1016/j.jhep.2004.09.012.
  20. Balmer ML, Siegrist K, Zimmermann A, Dufour JF. Effects of ursodeoxycholic acid in combination with vitamin E on adipokines and apoptosis in patients with nonalcoholic steatohepatitis. Liver Int. 2009;29(8):1184−1188. doi: 10.1111/j.1478-3231.2009.02037.x.
  21. Balmer M, Schmitter K, Dufour JF. The effect of ursodeoxycholic acid (UCDA) in combination with vitamin E on adipokines in patients with NASH. J Hepatol. 2008;48(Suppl 2):S337. doi: 10.1016/s0168-8278(08)60900-9.
  22. Cicek B, Koksal A, Oguz D, et al. Ursodeoxycholic acid and gemfibrozil in the treatment of non-alcoholic steatohepatitis: a randomized controlled trial. J Hepatol. 2004;40(Suppl 1):169–170. doi: 10.1016/S0168-8278(04)90578-8.
  23. Cruz RD, Mappala HT. The efficacy of ursodeoxycholic acid, probiotics vs. diet and exercise in the treatment of nafld: an open-labelled prospective randomized trial. J Gastroenterol Hepatol. 2012;27(Suppl 5):223.
  24. Ersöz G, Günşar F, Karasu Z, et al. Management of fatty liver disease with vitamin E and C compared to ursodeoxycholic acid treatment. Turk J Gastroenterol. 2005;16(3):124−128. doi: 10.1016/s0168-8278(03)80123-x.
  25. Ji G, Fan JG, Chen JJ, et al. Effectiveness of Danning Tablet in patients with non-alcoholic fatty liver of damp-heat syndrome type: a multicenter randomized controlled trial. Zhong Xi Yi Jie He Xue Bao. 2008; 6(2):128−133. doi: 10.3736/jcim20080205.
  26. Troisi G, Crisciotti F, Gianturco V, et al. The treatment with ursodeoxycholic acid in elderly patients affected by NAFLD and metabolic syndrome: a case-control study. Clin Ter. 2013;164(3):203−207. doi: 10.7417/CT.2013.1550.
  27. Kiyici M, Gulten M, Gurel S, et al. Ursodeoxycholic acid and atorvastatin in the treatment of nonalcoholic steatohepatitis. Can J Gastroenterol. 2003;17(12):713−718. doi: 10.1155/2003/857869.
  28. Кляритская И.Л.,Стилиди Е.И., Максимова Е.В. Сравнение различных схем лечения у больных с неалкогольной жировой болезнью печени // Экспериментальная и клиническая гастроэнтерология. ― 2015. ― №7 ― С. 12–17.
  29. Santos VN, Lanzoni VP, Szejnfeld J, et al. A randomized double-blind study of the short-time treatment of obese patients with nonalcoholic fatty liver disease with ursodeoxycholic acid. Braz J Med Biol Res. 2003;36(6):723−729. doi: 10.1590/s0100-879x2003000600007.
  30. Laurin J, Lindor KD, Crippin JS, et al.Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology. 1996;23(6):1464−1467. doi: 10.1002/hep.510230624.
  31. Lee SH, Cheon GJ, Kim HS, et al. [Comparison on the efficacy and safety of biphenyl dimethyl dicarboxylate and ursodeoxycholic acid in patients with abnormal alanine aminotransferase: multicenter, double-blinded, randomized, active-controlled clinical trial. (In Korean).] Korean J Gastroenterol. 2014;64(1):31−39. doi: 10.4166/kjg.2014.64.1.31.
  32. Marschall HU, Wagner M, Zollner G, et al. Ursodeoxycholic acid for treatment of fatty liver disease and dyslipidemia in morbidly obese patients. Dig Dis. 2011;29(1):117−118. doi: 10.1159/000324146.
  33. Méndez-Sánchez N, González V, Chávez-Tapia N, et al. Weight reduction and ursodeoxycholic acid in subjects with nonalcoholic fatty liver disease. A double-blind, placebo-controlled trial. Ann Hepatol. 2004;3(3):108−112.
  34. Mudaliar S, Henry RR, Sanyal AJ, et al. Efficacy and safety of the farnesoid x receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology. 2013;145(3):574−582. doi: 10.1053/j.gastro.2013.05.042.
  35. Mueller M, Thorell A, Claudel T, et al. Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity. J Hepatol. 2015;62(6):1398−1404. doi: 10.1016/j.jhep.2014.12.034.
  36. Oh B, Choi W, Park SB, et al. Efficacy and safety of ursodeoxycholic acid composite on fatigued patients with elevated liver function and/or fatty liver: a multi-centre, randomised, double-blinded, placebo-controlled trial. Int J Clin Pract. 2016;70(4):302−311. doi: 10.1111/ijcp.12790.
  37. Oliveira C, Cotrim H, Cristina A, et al. Combination of long term N-Acetylcysteine and Ursodeoxycolic Acid in NASH: a multicenter randomized control trial. J Hepatol. 2017;66(1 Suppl):S152−S153. doi: 10.1016/S0168-8278(17)30577-9.
  38. Parikh P, Ingle M, Patel J, et al. An open-label randomized control study to compare the efficacy of vitamin E versus ursodeoxycholic acid in nondiabetic and noncirrhotic indian NAFLD patients. Saudi J Gastroenterol. 2016;22(3):192−197. doi: 10.4103/1319-3767.182451.
  39. Abstracts of the 24th Annual Conference of APASL, March 12−15, 2015, Istanbul, Turkey. Hepatol Int. 2015;9(Suppl 1):1−391. doi: 10.1007/s12072-015-9609-1.
  40. Popescu AM. Pilot study of a new treatment in NAFLD/NASH, interfering intestinal microbiota and bile acids resorption and metabolism. J Hepatol. 2015;62 Suppl 2:S713. doi: 10.1016/s0168-8278(15)31180-6.
  41. Virstyuk N, Deltsova O, Geraschenko S, Kovalchuk L. Effects of ursodeoxycholic acid and pioglitazone long therapy on hepatocytes changes in NASH patients. J Hepatol. 2015;62 Suppl 2:S730. doi: 10.1016/S0168-8278(15)31220-4.
  42. Zhang X, Zhou M, Hu G. Clinical study on nonalcoholic steatohepatitis treated by ursodeoxycholic acid combined with human tablet. Chin J Int Med. 2003;13:8−9.
  43. Haedrich M, Dufour JF. UDCA for NASH: end of the story? J Hepatol. 2011;54(5):856−858. doi: 10.1016/j.jhep.2010.10.009.
  44. Chan AW, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013;158(3):200–207. doi: 10.7326/0003-4819-158-3-201302050-00583.

Views

Abstract - 13

PDF (Russian) - 0

Cited-By


PlumX



Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.