UDCA for NASH: End of the story?
Authors: Marion Haedrich, Jean-François Dufour
Journal: Journal of Hepatology (2010)

A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitisJournal of HepatologyVol. 54Issue 5PreviewNonalcoholic steatohepatitis (NASH) is a prevalent liver disease associated with increased morbidity and mortality. Ursodeoxycholic acid (UDCA) may have antioxidant, anti-inflammatory, and antifibrotic properties and may reduce liver injury in NASH. To date, no studies have assessed the efficacy and safety of high-dose UDCA (HD-UDCA) in patients with NASH. Full-Text PDF Non-alcoholic steatohepatitis (NASH) is estimated to affect about 1% of the European and North-American population. Longitudinal studies reported that the histological parameters worsen in one third of patients, which carries the risk of progression to cirrhosis [[1]Argo C.K. Northup P.G. Al-Osaimi A.M. Caldwell S.H. Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis.J Hepatol. 2009; 51: 371-379Abstract Full Text Full Text PDF PubMed Scopus (414) Google Scholar]. The most physiological therapy of NASH is physical exercise and weight loss, and is especially indicated in overweight patients with insulin resistance [[2]Neuschwander-Tetri B.A. Lifestyle modification as the primary treatment of NASH.Clin Liver Dis. 2009; 13: 649-665Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar]. However, treatments based on changes in lifestyle often fail, which provides the incentive for the continued exploration of drug therapies. Glitazones, which are PPAR-γ agonists and insulin-sensitizers, have proven promising in randomized clinical trials, but these drugs are associated with weight gain. Moreover, the cardiovascular safety of glitazones has been questioned [[3]Dufour J.F. NASH and thiazolidinediones: not to be taken lightly.J Hepatol. 2007; 47: 451-453Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar]. In 1996, Laurin published a pilot study in which 24 NASH patients were treated with 13–15 mg/kg/day of ursodeoxycholic acid (UDCA) for 12 months [[4]Laurin J. Lindor K.D. Crippin J.S. Gossard A. Gores G.J. Ludwig J. et al.Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study.Hepatology. 1996; 23: 1464-1467Crossref PubMed Scopus (537) Google Scholar]. The result was a significant decrease in mean serum concentrations of alkaline phosphatase (−8%), alanine transaminase (ALT) (−30%), and gamma-glutamyl transpeptidase (γGT) (−45%), as well as a decrease in the histological grade of hepatic steatosis. Why should UDCA be beneficial in NASH? Three non-exclusive mechanisms can explain the benefits of UDCA. First, hepatocyte apoptosis is a pathogenic feature of NASH [[5]Feldstein A.E. Canbay A. Angulo P. Taniai M. Burgart L.J. Lindor K.D. et al.Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis.Gastroenterology. 2003; 125: 437-443Abstract Full Text Full Text PDF PubMed Scopus (831) Google Scholar] and UDCA has well-known anti-apoptotic properties [[6]Amaral J.D. Viana R.J. Ramalho R.M. Steer C.J. Rodrigues C.M. Bile acids: regulation of apoptosis by ursodeoxycholic acid.J Lipid Res. 2009; PubMed Google Scholar]. Second, TNF-α is increased in NASH patients [[7]Kugelmas M. Hill D.B. Vivian B. Marsano L. McClain C.J. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E.Hepatology. 2003; 38: 413-419Crossref PubMed Scopus (448) Google Scholar] and aggravates the insulin resistance. UDCA has been reported to decrease serum TNF-α levels, at least in patients with primary biliary cirrhosis [[8]Neuman M. Angulo P. Malkiewicz I. Jorgensen R. Shear N. Dickson E.R. et al.Tumor necrosis factor-alpha and transforming growth factor-beta reflect severity of liver damage in primary biliary cirrhosis.J Gastroenterol Hepatol. 2002; 17: 196-202Crossref PubMed Scopus (124) Google Scholar]. The third mechanism was deduced from experimental data, which showed that the taurine-conjugated UDCA (TUDCA) decreases endoplasmic reticulum stress [[9]Ozcan U. Yilmaz E. Ozcan L. Furuhashi M. Vaillancourt E. Smith R.O. et al.Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes.Science. 2006; 313: 1137-1140Crossref PubMed Scopus (1970) Google Scholar] and that TUDCA improves muscle and hepatic insulin sensitivity in obese individuals [[10]Kars M. Yang L. Gregor M.F. Mohammed B.S. Pietka T.A. Finck B.N. et al.Tauroursodeoxycholic acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women.Diabetes. 2010; 59: 1899-1905Crossref PubMed Scopus (305) Google Scholar]. When interpreted in light of this background, the results of a randomized controlled trial of UDCA in NASH reported by Lindor and colleagues were disappointing. Lindor enrolled 166 NASH patients, who received either UDCA 13–15 mg/kg/d or placebo for 2 years. Both groups achieved the same decrease in serum ALT concentrations at the end of the study. Similarly, both groups improved their degree of steatosis. Consequently, no measurable benefit could be attributable to UDCA. A smaller Swiss, randomized, controlled study reported no benefit of UDCA over placebo on histology in NASH patients [[11]Dufour J.F. Oneta C.M. Gonvers J.J. Bihl F. Cerny A. Cereda J.M. et al.Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis.Clin Gastroenterol Hepatol. 2006; 4: 1537-1543Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar]. There was a beneficial effect of UDCA on ALT in this trial, which was due to the absence of improvement of serum ALT levels in the placebo arm. These mostly negative results raise the possibility that UDCA was not effective because its dosage was too low. Since the benefits of higher dosage of UDCA were reported for other diseases [12Colombo C. Crosignani A. Assaisso M. Battezzati P.M. Podda M. Giunta A. et al.Ursodeoxycholic acid therapy in cystic fibrosis-associated liver disease: a dose-response study.Hepatology. 1992; 16: 924-930Crossref PubMed Scopus (108) Google Scholar, 13Mitchell S.A. Bansi D.S. Hunt N. Von Bergmann K. Fleming K.A. Chapman R.W. A preliminary trial of high-dose ursodeoxycholic acid in primary sclerosing cholangitis.Gastroenterology. 2001; 121: 900-907Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar], two trials with higher dosage were launched. This issue of the Journal publishes the results of one study conducted by Ratziu et al. [[14]Ratziu V. DeLedinghen V. Oberti F. Mathurin P. Wartelle-Bladou C. Renou C. et al.A randomized controlled trial of high-dosei ursodeoxycholic acid for nonalcoholic steatohepatitis.J Hepatol. 2011; 54: 1011-1019Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar]. One hundred and twenty-six patients with biopsy-proven NASH and elevated ALT levels were randomized to receive either high-dose UDCA (28–35 mg/kg/d) or placebo for 1 year. The reduction of the mean ALT levels was significantly greater in the UDCA group than in the placebo group (see Table 1). High-dose UDCA was associated with a decrease in γGT and a reduction of FibroTest® measures, which has γGT as one of its components and which was used as a surrogate marker for fibrosis instead of histological analysis. Serum glucose concentrations improved as did the insulin resistance (HOMA score) in the group treated with high doses of UDCA. (see Table 1) The adinopectin levels fell in both groups but the decrease was greater in the control (−22%) than in the high-dose UDCA group (−5%, not significant).Table 1Serum glucose concentrations and insulin resistance (HOMA score) improve in the group treated with high doses of UDCA.In red, differences 21Lindor K.D. Kowdley K.V. Heathcote E.J. Harrison M.E. Jorgensen R. Angulo P. et al.Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial.Hepatology. 2004; 39: 770-778Crossref PubMed Scopus (604) Google Scholar, 11Dufour J.F. Oneta C.M. Gonvers J.J. Bihl F. Cerny A. Cereda J.M. et al.Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis.Clin Gastroenterol Hepatol. 2006; 4: 1537-1543Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar, 15Leuschner U.F. Lindenthal B. Herrmann G. Arnold J.C. Rossle M. Cordes H.J. et al.High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial.Hepatology. 2010; 52: 472-479Crossref PubMed Scopus (233) Google Scholar, 16Kleiner D.E. Brunt E.M. Van Natta M. Behling C. Contos M.J. Cummings O.W. et al.Design and validation of a histological scoring system for nonalcoholic fatty liver disease.Hepatology. 2005; 41: 1313-1321Crossref PubMed Scopus (6996) Google Scholar, 17Brunt E.M. Janney C.G. Di Bisceglie A.M. Neuschwander-Tetri B.A. Bacon B.R. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions [In Process Citation].Am J Gastroenterol. 1999; 94: 2467-2474Crossref PubMed Scopus (3105) Google Scholar, 22Promrat K. Kleiner D.E. Niemeier H.M. Jackvony E. Kearns M. Wands J.R. et al.Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis.Hepatology. 2010; 51: 121-129Crossref PubMed Scopus (878) Google Scholar were statistically significant (p <0.05). Open table in a new tab In red, differences 21Lindor K.D. Kowdley K.V. Heathcote E.J. Harrison M.E. Jorgensen R. Angulo P. et al.Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial.Hepatology. 2004; 39: 770-778Crossref PubMed Scopus (604) Google Scholar, 11Dufour J.F. Oneta C.M. Gonvers J.J. Bihl F. Cerny A. Cereda J.M. et al.Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis.Clin Gastroenterol Hepatol. 2006; 4: 1537-1543Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar, 15Leuschner U.F. Lindenthal B. Herrmann G. Arnold J.C. Rossle M. Cordes H.J. et al.High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial.Hepatology. 2010; 52: 472-479Crossref PubMed Scopus (233) Google Scholar, 16Kleiner D.E. Brunt E.M. Van Natta M. Behling C. Contos M.J. Cummings O.W. et al.Design and validation of a histological scoring system for nonalcoholic fatty liver disease.Hepatology. 2005; 41: 1313-1321Crossref PubMed Scopus (6996) Google Scholar, 17Brunt E.M. Janney C.G. Di Bisceglie A.M. Neuschwander-Tetri B.A. Bacon B.R. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions [In Process Citation].Am J Gastroenterol. 1999; 94: 2467-2474Crossref PubMed Scopus (3105) Google Scholar, 22Promrat K. Kleiner D.E. Niemeier H.M. Jackvony E. Kearns M. Wands J.R. et al.Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis.Hepatology. 2010; 51: 121-129Crossref PubMed Scopus (878) Google Scholar were statistically significant (p <0.05). In the second trial, Leuschner et al. assigned 185 patients with biopsy-proven NASH to receive either high-dose UDCA (23–28 mg/kg/d) or placebo for 18 months [[15]Leuschner U.F. Lindenthal B. Herrmann G. Arnold J.C. Rossle M. Cordes H.J. et al.High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial.Hepatology. 2010; 52: 472-479Crossref PubMed Scopus (233) Google Scholar]. High-dose UDCA failed to improve the histological parameters, the primary endpoint. The NASH activity score changed from 5.7 to 4.7 in the placebo group and from 5.6 to 4.3 in the high-dose UDCA group. Only γ-GT levels improved significantly after the high-dose UDCA for 18 months, whereas the ALT levels decreased in a comparable way in both groups (see Table 1). How do these two trials compare? Apart from the ethnic differences in the sample populations, the dose of UDCA was higher in Ratziu’s trial than in Leuschner’s (28–35 vs. 23–28 mg, respectively) and the duration of treatment was longer in Leuschner’s study than in Ratziu’s (18 vs. 12 months, respectively). For the histological inclusion criteria, Riatzu used the score elaborated by Kleiner et al. [[16]Kleiner D.E. Brunt E.M. Van Natta M. Behling C. Contos M.J. Cummings O.W. et al.Design and validation of a histological scoring system for nonalcoholic fatty liver disease.Hepatology. 2005; 41: 1313-1321Crossref PubMed Scopus (6996) Google Scholar], whereas Leuschner chose a modified Brunt score [[17]Brunt E.M. Janney C.G. Di Bisceglie A.M. Neuschwander-Tetri B.A. Bacon B.R. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions [In Process Citation].Am J Gastroenterol. 1999; 94: 2467-2474Crossref PubMed Scopus (3105) Google Scholar]. The mean NASH activity score was higher in Leuschner’s trial than in Ratziu’s (5.6 vs. 5.15 in the high-dose UDCA arm and 5.7 vs. 4.88 in the placebo arm, respectively). The ALT improvement in the placebo group of Leuschner’s trial stands in contrast to that of Ratziu’s trial. Leuschner included patients with elevated ALT levels documented over a period of 3 months whereas Ratziu required documentation of elevated ALT on three occasions over a period of 12 months. This may have excluded patients with fluctuating ALT levels. The fact that more diabetic patients were enrolled in Ratziu’s trial than in Leuschner’s trail (39% in the UDCA arm and 25% in the placebo arm vs. 11% and 12%, respectively) may explain why Ratziu’s trial presented improved metabolic endpoints, albeit given in percentages. A comparison of the absolute numbers (serum glucose decreased from 5.6 to 5.47 with high-dose UDCA and increased from 5.5 to 5.7 with placebo) is less convincing. It is noteworthy that a trend towards lower serum glucose concentrations in the UDCA arm than the control arm was also noted in Leuschner’s trial (5.9–5.71 (−3%) vs. 5.6–5.52 (−1.4%), p = 0.193). What message should be retained from these trials? The first message is that UDCA in monotherapy has no positive effect in NASH with the usual dose, and has only marginal and perhaps clinically irrelevant effects at a higher dose. But the story does not end there for bile acids. In a randomized controlled trial, we reported that vitamin E added to UDCA was better than UDCA monotherapy [[11]Dufour J.F. Oneta C.M. Gonvers J.J. Bihl F. Cerny A. Cereda J.M. et al.Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis.Clin Gastroenterol Hepatol. 2006; 4: 1537-1543Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar]. Since vitamin E has shown impressive effects in monotherapy in the treatment of NASH [[18]Sanyal A.J. Chalasani N. Kowdley K.V. McCullough A. Diehl A.M. Bass N.M. et al.Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.N Engl J Med. 2010; 362: 1675-1685Crossref PubMed Scopus (2203) Google Scholar], a trial comparing vitamin E monotherapy with the vitamin E + UDCA combination is warranted. Bile acids – but not UDCA – regulate metabolism by binding to the nuclear hormone receptor farnesoid X and to a transmembrane bile acid receptor, TGR5. Activation of farnesoid X receptor improves insulin sensitivity and reduces circulating glucose and lipids levels [[19]Zhang Y. Edwards P.A. FXR signaling in metabolic disease.FEBS Lett. 2008; 582: 10-18Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar]. TGR5 is an important regulator of glucose homeostasis and lipid metabolism and its activation stimulates energy expenditure and protects against obesity [[20]Thomas C. Pellicciari R. Pruzanski M. Auwerx J. Schoonjans K. Targeting bile-acid signalling for metabolic diseases.Nat Rev Drug Discov. 2008; 7: 678-693Crossref PubMed Scopus (904) Google Scholar]. These actions of bile acids mimic those of lifestyle changes. The effects of non-UDCA bile acids in NASH should now receive some of the attention that we have, until now, reserved for UDCA. The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.