The role of Ursodeoxycholic acid in non-alcoholic steatohepatitis: a systematic review

BMC Gastroenterology

Xi Jin²  You-ming Li²  Yi-da Yang³  Lin Zheng³  Yue-fang Ye⁴  Kui-fen Ma¹  Yi-peng Chen²  Zun Xiang² 

[1] Department of Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang, China;Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang, China;Department of Infectious Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang, China;Department of Gastroenterology, The Affiliated Hospital, College of Medicine, Hangzhou Normal University, Hangzhou, China

关键词: Clinical trial;    NASH;    Non-alcoholic steatohepatitis;    UDCA;    Ursodeoxycholic acid;   

Others  :  857595
DOI  :  10.1186/1471-230X-13-140

 received in 2012-11-09, accepted in 2013-09-17,  发布年份 2013

【 摘 要 】

Background

Non-alcoholic steatohepatitis (NASH) is a condition that occurs during the progression of non-alcoholic fatty liver disease. Effective therapy for NASH is still lacking. In this study, we investigated the effects of Ursodeoxycholic acid (UDCA) in the treatment of NASH.

Methods

Western and Chinese databases were searched by independent investigators using appropriate MESH headings to identify randomized, controlled Western and Chinese clinical trials, published between January 1990 and October 2012, testing the effects of UDCA in patients with NASH. Patient characteristics and trial endpoints were analyzed, with quality assessment according to widely acknowledged criteria. P < 0.05 was defined as statistically significant in all trials.

Results

Twelve qualified randomized clinical trials, including six from China and involving 1160 subjects, were selected. Seven of these trials assessed the effects of UDCA Monotherapy, with the other five testing combinations of UDCA with vitamin E, polyene phosphatidylcholine, silymarin, glycyrrhizin and tiopronin. The duration of therapy ranged from 3 to 24 months, with two studies using high doses of UDCA (23–35 mg/kg/d). The average quality point was 2.69, and was significantly lower in articles from China than in those from Western countries (2.2 ± 0.4 vs. 3.8 ± 1.1, respectively, p < 0.05). UDCA Monotherapy significantly improved liver function in five studies and improved steatosis and fibrosis in two studies. All five studies assessing UDCA combination therapy showed significant improvements liver function, while two studies also improved steatosis and inflammation. One study of high-dose UDCA showed significant improvements in ALT, γGT and liver fibrosis, whereas the other study showed no significant change in ALT and liver pathology.

Conclusions

UDCA therapy is effective in NASH, especially when combined with other drugs. However, the low quality of these studies and the heterogeneity of their results precluded further meta-analysis. Additional carefully designed clinical trials are needed, especially in China.

【 授权许可】

   
2013 Xiang et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Marignani M, Angeletti S: Non-alcoholic fatty liver disease. New Engl J Med 2002, 347(10):768-769. author reply 768–769
• [2]Adams LA, Lindor KD: Non-alcoholic fatty liver disease. Ann Epidemiol 2007, 17(11):863-869.
• [3]Ekstedt M, Franzen LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, Kechagias S: Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatol 2006, 44(4):865-873.
• [4]Ong JP, Younossi ZM: Epidemiology and natural history of NAFLD and NASH. Clin Liver Dis 2007, 11(1):1-16. vii
• [5]Day CP, James OF: Steatohepatitis: a tale of two: “hits”? Gastroenterol 1998, 114(4):842-845.
• [6]Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G: A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol 2010, 53(2):372-384.
• [7]Neuschwander-Tetri BA: Lifestyle modification as the primary treatment of NASH. Clin Liver Dis 2009, 13(4):649-665.
• [8]Haukeland JW, Konopski Z, Eggesbo HB, von Volkmann HL, Raschpichler G, Bjoro K, Haaland T, Loberg EM, Birkeland K: Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol 2009, 44(7):853-860.
• [9]Nobili V, Manco M, Ciampalini P, Alisi A, Devito R, Bugianesi E, Marcellini M, Marchesini G: Metformin use in children with non-alcoholic fatty liver disease: an open-label, 24-month, observational pilot study. Clin Therapeut 2008, 30(6):1168-1176.
• [10]Mahady SE, Webster AC, Walker S, Sanyal A, George J: The role of thiazolidinediones in non-alcoholic steatohepatitis - a systematic review and Meta analysis. J Hepatol 2011, 55(6):1383-1390.
• [11]Dufour JF: NASH and thiazolidinediones: not to be taken lightly. J Hepatol 2007, 47(4):451-453.
• [12]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.
• [13]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.
• [14]Haedrich M, Dufour JF: UDCA for NASH: end of the story? J Hepatol 2011, 54(5):856-858.
• [15]Moher D, Liberati A, Tetzlaff J, Altman DG: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Bmj 2009, 339:b2535.
• [16]Kjaergard LL, Villumsen J, Gluud C: Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Int Med 2001, 135(11):982-989.
• [17]Bernal-Reyes R, Escudero RB: Treatment of non-alcoholic steatohepatitis (NASH). A comparative study of Ursodeoxycholic acid and alpha-tocopherol. A preliminary report. Revista de gastroenterologia de Mexico 2002, 67(2):70-75.
• [18]Copaci I, Mindrut E, Micu L, Hortopan M, Voiculescu M: Can disease progression in non-alcoholic steatohepatitis be stopped? J Hepatol 2009, 50:S150.
• [19]Cicek B, Koksal A, Oguz D, Erden E, Sahin T: Ursodeoxycholic acid and gemfibrozil in the treatment of non-alcoholic steatohepatitis: a randomized controlled trial [EASL abstract]. J Hepatol 2004, 40:169-170.
• [20]Dufour JF, Oneta CM, Gonvers JJ, Bihl F, Cerny A, Cereda JM, Zala JF, Helbling B, Steuerwald M, Zimmermann A: Randomized placebo-controlled trial of Ursodeoxycholic acid with vitamin e in non-alcoholic steatohepatitis. Clin Gastroenterol Hepatol 2006, 4(12):1537-1543.
• [21]Balmer ML, Siegrist K, Zimmermann A, Dufour JF: Effects of Ursodeoxycholic acid in combination with vitamin E on adipokines and apoptosis in patients with non-alcoholic steatohepatitis. Liver Int 2009, 29(8):1184-1188.
• [22]Pietu F, Guillaud O, Walter T, Vallin M, Hervieu V, Scoazec JY, Dumortier J: Ursodeoxycholic acid with vitamin E in patients with non-alcoholic steatohepatitis: long-term results. Clin Res Hepatol Gastroenterol 2012, 36(2):146-155.
• [23]Madan K, Batra Y, Gupta DS, Chander B, Anand Rajan KD, Singh R, Panda SK, Acharya SK: Vitamin E-based therapy is effective in ameliorating transaminasemia in non-alcoholic fatty liver disease. Indian J Gastroenterol 2005, 24(6):251-255.
• [24]Laurin J, Lindor KD, Crippin JS, Gossard A, Gores GJ, Ludwig J, Rakela J, McGill DB: Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatol 1996, 23(6):1464-1467.
• [25]Lindor KD, Kowdley KV, Heathcote EJ, Harrison ME, Jorgensen R, Angulo P, Lymp JF, Burgart L, Colin P: Ursodeoxycholic acid for treatment of non-alcoholic steatohepatitis: results of a randomized trial. Hepatol 2004, 39(3):770-778.
• [26]Kiyici M, Gulten M, Gurel S, Nak SG, Dolar E, Savci G, Adim SB, Yerci O, Memik F: Ursodeoxycholic acid and atorvastatin in the treatment of non-alcoholic steatohepatitis. Canad J Gastroenterol 2003, 17(12):713-718.
• [27]Hong-juan Z: Effect of Ursodeoxycholic acid in non-alcoholic steatohepatitis. Med Innov China 2010, 7(32):85-86.
• [28]Ratziu V, de Ledinghen V, Oberti F, Mathurin P, Wartelle-Bladou C, Renou C, Sogni P, Maynard M, Larrey D, Serfaty L, et al.: A randomized controlled trial of high-dose Ursodeoxycholic acid for non-alcoholic steatohepatitis. J Hepatol 2011, 54(5):1011-1019.
• [29]Leuschner UF, Lindenthal B, Herrmann G, Arnold JC, Rossle M, Cordes HJ, Zeuzem S, Hein J, Berg T: High-dose Ursodeoxycholic acid therapy for non-alcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatol 2010, 52(2):472-479.
• [30]Zhuang Xue-shan ZZ-j: Study of Ursodeoxycholic acid (UDCA) combined with polyene phosphatidylcholin in the treatment of non-alcoholic steatohepatitis. China Pract Med 2009, 4(10):11-12.
• [31]Yan S: Ursodeoxycholic acid in nonalcoholic steatohepatitis: a short term abservation. Med Inn Res 2007, 4(9):46-47.
• [32]Hong Qian ZS-y, Li B-d, Guo-wei C, Zhi-hua C, Qiao-ling C: Study of Ursodeoxycholic acid (UDCA) and Essentiale Forte N in the treatment of non-alcoholic steatohepatitis. J Gangdong Med College 2007, 25(5):528-529.
• [33]Hong L: Therapeutic effect of Glycyrrhizin with Ursodeoxycholic acid on patients with non-alcoholic steatohepatitis. Hebei Med 2005, 11(5):439-440.
• [34]Zhi-ye L, YL-q: The combined use of Tiopronin tablets and Ursodeoxycholic acid in treating non-alcoholic steatohepatitis. J Shandong Med College 2006, 28(1):59-60.
• [35]Ludwig J, Viggiano TR, McGill DB, Oh BJ: Non-alcoholic steatohepatitis: mayo clinic experiences with a hitherto unnamed disease. Mayo Clin Proc Mayo Clin 1980, 55(7):434-438.
• [36]Farrell GC, Larter CZ: Non-alcoholic fatty liver disease: from steatosis to cirrhosis. Hepatol 2006, 43(2 Suppl 1):S99-S112.
• [37]Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P: The natural history of non-alcoholic fatty liver disease: a population-based cohort study. Gastroenterol 2005, 129(1):113-121.
• [38]Pathil A, Mueller J, Warth A, Chamulitrat W, Stremmel W: Ursodeoxycholic lysophosphatidylethanolamide improves steatosis and inflammation in murine models of non-alcoholic fatty liver disease. Hepatol 2012, 55(5):1369-1378.
• [39]Buko VU, Kuzmitskaya-Nikolaeva IA, Naruta EE, Lukivskaya OY, Kirko SN, Tauschel HD: Ursodeoxycholic acid dose-dependently improves liver injury in rats fed a methionine- and choline-deficient diet. Hepatol Res 2011, 41(7):647-659.
• [40]Castro RE, Ferreira DM, Afonso MB, Borralho PM, Machado MV, Cortez-Pinto H, Rodrigues CM: miR-34a/SIRT1/p53 is suppressed by Ursodeoxycholic acid in Rat liver and activated by disease severity in human Non-alcoholic fatty liver disease. J Hepatol 2012, 58(1):199-25.
• [41]Beuers U: Drug insight: mechanisms and sites of action of Ursodeoxycholic acid in cholestasis. Nat Clin Pract Gastroenterol Hepatol 2006, 3(6):318-328.
• [42]Sokolovic D, Nikolic J, Kocic G, Jevtovic-Stoimenov T, Veljkovic A, Stojanovic M, Stanojkovic Z, Sokolovic DM, Jelic M: The effect of Ursodeoxycholic acid on oxidative stress level and DNase activity in rat liver after bile duct ligation. Drug Chem Toxicol 2012, 36(2):141-148.
• [43]Bellentani S: Immunomodulating and anti-apoptotic action of Ursodeoxycholic acid: where are we and where should we go? Eur J Gastroenterol Hepatol 2005, 17(2):137-140.
• [44]Tanaka H, Makino Y, Miura T, Hirano F, Okamoto K, Komura K, Sato Y, Makino I: Ligand-independent activation of the glucocorticoid receptor by Ursodeoxycholic acid. Repression of IFN-gamma-induced MHC class II gene expression via a glucocorticoid receptor-dependent pathway. J Immunol (Baltimore, Md: 1950) 1996, 156(4):1601-1608.
• [45]Chun HS, Low WC: Ursodeoxycholic acid suppresses mitochondria-dependent programmed cell death induced by sodium Nitroprusside in SH-SY5Y cells. Toxicology 2012, 292(2–3):105-112.