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VOLUME 14 , ISSUE 1 ( January-June, 2024 ) > List of Articles


Ursodeoxycholic Acid's Effectiveness in the Management of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis

Vaibhavi S Patel, Safa F Mahmood, Kunal H Bhatt, Richisha M Khemkar, Devanshi R Jariwala, Bilal Harris, Mirna M George, Reuel A Kurudamannil, Onyekachi E Anyagwa, Rajeeka S Tak, Maha Kassem

Keywords : Meta-analysis, Nonalcoholic fatty liver disease, Systematic review, Ursodeoxycholic acid

Citation Information : Patel VS, Mahmood SF, Bhatt KH, Khemkar RM, Jariwala DR, Harris B, George MM, Kurudamannil RA, Anyagwa OE, Tak RS, Kassem M. Ursodeoxycholic Acid's Effectiveness in the Management of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis. Euroasian J Hepatogastroenterol 2024; 14 (1):92-98.

DOI: 10.5005/jp-journals-10018-1434

License: CC BY-NC 4.0

Published Online: 12-06-2024

Copyright Statement:  Copyright © 2024; The Author(s).


Aim: This meta-analysis's objective was to assess the effectiveness of ursodeoxycholic acid (UDCA) in the management of nonalcoholic fatty liver disease (NAFLD). Methods: Electronic databases like PubMed, Embase, Scopus, and Cochrane Library were thoroughly looked for randomized controlled trials determining ursodeoxycholic acid's (UDCAs) effectiveness on the serum liver function tests in NAFLD patients. After screening, seven randomized controlled trials were incorporated overall. Utilizing a fixed effects model, quantitative data synthesis was performed in R version 4.3.1. Results: The meta-analysis showed significant reductions in alanine transaminase (ALT) (p ≤ 0.0001), aspartate transaminase (p = 0.0009), and gamma-glutamyl transferase (GGT) (p ≤ 0.0001) after UDCA therapy. However, significant reductions in bilirubin (p = 0.6989) and alkaline phosphatase (ALP) (p = 0.1172) levels were not noted. Sensitivity analysis by removing the studies with some concerns of bias was successful in demonstrating a remarkable reduction in heterogeneity for aspartate transaminase and ALP, which was also observed while performing the subgroup analyses via dosage. Conclusion: Ursodeoxycholic acid was beneficial in patients diagnosed with NAFLD as it significantly reduced aspartate transaminase, ALT and GGT levels. However, more randomized controlled trials are required to be conducted in the future to increase the certainty of the evident findings. Clinical significance: This meta-analysis strengthens the evidence about the reductions in AST, ALT, and GGT levels observed with ursodeoxycholic acid therapy in NAFLD patients by pooling the data together from the latest RCTs thus proving its hepatoprotective effects which can be beneficial in preventing the associated complications.

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  1. Maurice J, Manousou P. Non-alcoholic fatty liver disease. Clinical Medicine (London, England) 2018;18(3):245–250. PMID: 29858436.
  2. Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64(1):73–84. DOI: 10.1002/hep.28431.
  3. Kanwal F, Kramer JR, Mapakshi S, et al. Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease. Gastroenterology 2018;155(6):1828–1837.e2. DOI: 10.1053/j.gastro.2018.08.024.
  4. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 2015:149(2):389–397.e10. DOI: 10.1053/j.gastro.2015.04.043.
  5. Dulai PS, Singh S, Patel J, et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis. Hepatology 2017;65(5):1557–1565. DOI: 10.1002/hep. 29085.
  6. Hofmann AF. Pharmacology of ursodeoxycholic acid, an enterohepatic drug. Scand J Gastroenterol Suppl 1994;204:1–15. DOI: 10.3109/00365529409103618.
  7. Floreani A, Mangini C. Primary biliary cholangitis: Old and novel therapy. Eur J Intern Med 2018;47:1–5. DOI: 10.1016/j.ejim.2017.06.020.
  8. Di Ciaula A, Wang DQ, Wang HH, et al. Targets for current pharmacologic therapy in cholesterol gallstone disease. Gastroenterol Clin North Am 2010;39(2):245–264, viii-ix. DOI: 10.1016/j.gtc.2010.02.005.
  9. Rubin RA, Kowalski TE, Khandelwal M, et al. Ursodiol for hepatobiliary disorders. Ann Intern Med 1994;121(3):207–218. DOI: 10.7326/0003-4819-121-3-199408010-00009.
  10. Chen W, Liu J, Gluud C. Bile acids for viral hepatitis. Cochrane Database Syst Rev 2007;2007(4):CD003181. DOI: 10.1002/14651858.CD003181.pub2.
  11. Kotb MA. Review of historical cohort: ursodeoxycholic acid in extrahepatic biliary atresia. J Pediatr Surg 2008;43(7):1321–1327. DOI: 10.1016/j.jpedsurg.2007.11.043.
  12. Feldstein AE, Perrault J, El-Youssif M, et al. Primary sclerosing cholangitis in children: A long-term follow-up study. Hepatology 2003;38(1):210–217. DOI: 10.1053/jhep.2003.50289.
  13. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. DOI: 10.1136/bmj.n71.
  14. Higgins JPT, Savović J, Page MJ, et al. Chapter 8: Assessing risk of bias in a randomized trial. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.4 (updated August 2023). Cochrane, 2023.
  15. Higgins JPT, Li T, Deeks JJ (editors). Chapter 6: Choosing effect measures and computing estimates of effect. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.4 (updated August 2023). Cochrane, 2023.
  16. Deeks JJ, Higgins JPT, Altman DG (editors). Chapter 10: Analysing data and undertaking meta-analyses. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.4 (updated August 2023). Cochrane, 2023.
  17. 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.
  18. Leuschner UF, Lindenthal B, Herrmann G, et al. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: A double-blind, randomized, placebo-controlled trial. Hepatology (Baltimore, Md.) 2010;52(2):472–479. DOI: 10.1002/hep.23727.
  19. 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.
  20. University A, Mojtahedi K, Joukar F, et al. (n.d.). Bull Pharm Sci Assiut University 2023;46(1):347–360.
  21. Elhini SH, Wahsh EA, Elberry AA, et al. The impact of an SGLT2 Inhibitor versus ursodeoxycholic acid on liver steatosis in diabetic patients. Pharmaceuticals (basel) 2022;15(12):1516. DOI: 10.3390/ph15121516.
  22. 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.
  23. 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. PMID: 15505596.
  24. von Hippel PT. The heterogeneity statistic I(2) can be biased in small meta-analyses. BMC Med Res Methodol 2015;15:35. DOI: 10.1186/s12874-015-0024-z.
  25. Sterne JA, Sutton AJ, Ioannidis JP, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 2011;343:d4002. DOI: 10.1136/bmj.d4002.
  26. Araújo AR, Rosso N, Bedogni G, et al. Global epidemiology of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: What we need in the future. Liver Int 2018;38 Suppl 1:47–151. DOI: 10.1111/liv.13643.
  27. Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med 2000;342(17):1266–1271. DOI: 10.1056/NEJM200004273421707.
  28. Siller AF, Whyte MP. Alkaline phosphatase: Discovery and naming of our favorite enzyme. J Bone Miner Res 2018;33(2):362–364. DOI: 10.1002/jbmr.3225.
  29. Beckingham IJ, Ryder SD. ABC of diseases of liver, pancreas, and biliary system. Investigation of liver and biliary disease. BMJ 2001;322(7277):33–36. DOI: 10.1136/bmj.322.7277.33.
  30. Xiang Z, Chen YP, Ma KF, et al. The role of ursodeoxycholic acid in non-alcoholic steatohepatitis: A systematic review. Medscape.
  31. Ishizaki K, Imada T, Tsurufuji M. Hepatoprotective bile acid ‘ursodeoxycholic acid (UDCA)’ Property and difference as bile acids. Hepatol Res 2005;33(2):174–177. DOI: 10.1016/j.hepres.2005.09.029.
  32. Simental-Mendía LE, Simental-Mendía M, Sánchez-García A, et al. Impact of ursodeoxycholic acid on circulating lipid concentrations: A systematic review and meta-analysis of randomized placebo-controlled trials. Lipids Health Dis 2019;18(1):88. DOI: 10.1186/s12944-019-1041-4.
  33. 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(4):561–566. DOI: 10.1016/s0168-8278(00)80216-0.
  34. Poupon RE, Eschwège E, Poupon R. Ursodeoxycholic acid for the treatment of primary biliary cirrhosis. Interim analysis of a double-blind multicentre randomized trial. The UDCA-PBC Study Group. J Hepatol 1990;11(1):16–21. DOI: 10.1016/0168-8278(90)90265-s.
  35. Poupon RE, Balkau B, Eschwège E, et al. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group. N Engl J Med 1991;324(22):1548–1554. DOI: 10.1056/NEJM199105303242204.
  36. Gianturco V, Troisi G, Bellomo A, et al. Impact of combined therapy with alpha-lipoic and ursodeoxycolic acid on nonalcoholic fatty liver disease: Double-blind, randomized clinical trial of efficacy and safety. Hepatol Int 2013;7(2):570–576. DOI: 10.1007/s12072-012- 9387-y.
  37. 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.
  38. Kotb MA. Molecular mechanisms of ursodeoxycholic acid toxicity & side effects: Ursodeoxycholic acid freezes regeneration & induces hibernation mode. Int J Mol Sci 2012;13(7):8882–8914. DOI: 10.3390/ijms13078882.
  39. Ishizaki K, Iwaki T, Kinoshita S, et al. Ursodeoxycholic acid protects concanavalin A-induced mouse liver injury through inhibition of intrahepatic tumor necrosis factor-alpha and macrophage inflammatory protein-2 production. Eur J Pharmacol 2008;578(1):57–64. DOI: 10.1016/j.ejphar.2007.08.031.
  40. Heuman DM, Pandak WM, Hylemon PB, et al. Conjugates of ursodeoxycholate protect against cytotoxicity of more hydrophobic bile salts: in vitro studies in rat hepatocytes and human erythrocytes. Hepatology 1991;14(5):920–926. DOI: 10.1002/hep.1840140527.
  41. Mitsuyoshi H, Nakashima T, Sumida Y, et al. Ursodeoxycholic acid protects hepatocytes against oxidative injury via induction of antioxidants. Biochem Biophys Res Commun 1999;263(2):537–542. DOI: 10.1006/bbrc.1999.1403.
  42. Rodrigues CM, Ma X, Linehan-Stieers C, et al. Ursodeoxycholic acid prevents cytochrome c release in apoptosis by inhibiting mitochondrial membrane depolarization and channel formation. Cell Death Differ 1999;6(9):842–854. DOI: 10.1038/sj.cdd.4400560.
  43. Miura T, Ouchida R, Yoshikawa N, et al. Functional modulation of the glucocorticoid receptor and suppression of NF-kappaB-dependent transcription by ursodeoxycholic acid. J Biol Chem 2001;276(50):47371–47378. DOI: 10.1074/jbc.M107098200.
  44. Poupon RE, Chrétien Y, Poupon R, et al. Serum bile acids in primary biliary cirrhosis: Effect of ursodeoxycholic acid therapy. Hepatology. 1993;17(4):599–604. DOI: 10.1002/hep.1840170412.
  45. Calmus Y, Gane P, Rouger P, et al. Hepatic expression of class I and class II major histocompatibility complex molecules in primary biliary cirrhosis: Effect of ursodeoxycholic acid. Hepatology 1990;11(1):12–15. DOI: 10.1002/hep.1840110104.
  46. Stiehl A, Rudolph G, Sauer P, et al. Efficacy of ursodeoxycholic acid treatment and endoscopic dilation of major duct stenoses in primary sclerosing cholangitis. An 8-year prospective study. J Hepatol 1997;26(3):560–566. DOI: 10.1016/s0168-8278(97)80421-7.
  47. Saksena S, Tandon RK. Ursodeoxycholic acid in the treatment of liver diseases. Postgrad Med J 1997;73(856):75–80. DOI: 10.1136/pgmj.73.856.75.
  48. Lin X, Mai M, He T, et al. Efficiency of ursodeoxycholic acid for the treatment of nonalcoholic steatohepatitis: A systematic review and meta-analysis. Expert Rev Gastroenterol Hepatol 2022;16(6):537–545. DOI: 10.1080/17474124.2022.2083605.
  49. Zhang W, Tang Y, Huang J, et al. Efficacy of ursodeoxycholic acid in nonalcoholic fatty liver disease: An updated meta-analysis of randomized controlled trials. Asia Pac J Clin Nutr 2020;29(4):696–705. DOI: 10.6133/apjcn.202012_29(4).0004.
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