Placebo in Nonalcoholic Steatohepatitis: Insight Into Natural History and Implications for Future Clinical Trials

      Background & Aims

      Changes in biochemical and histologic parameters related to nonalcoholic steatohepatitis (NASH) in placebo-treated patients may provide an insight into the natural history and help in defining treatment end points in NASH. The aim of our study was to assess the biochemical and histologic changes seen in the placebo arm of the randomized, placebo-controlled trials in adult patients with NASH.


      Medline was searched (through May 2008) for studies published in the English language. Randomized, placebo-controlled trials of at least 6 months' duration in patients with NASH that provided biochemical and/or histologic data of the placebo arm were included. One investigator performed the literature search and data extraction. Two investigators independently confirmed that the studies met prespecified criteria. Pooled estimates of biochemical and histologic parameters associated with NASH were calculated.


      Five randomized controlled trials met the predefined criteria and included 162 placebo-treated and 189 active-treatment patients. The mean serum alanine and aspartate aminotransferase levels decreased on placebo. A 1-point improvement in steatosis, ballooning degeneration, lobular inflammation, NASH fibrosis, and combined inflammation scores was seen in 31%, 15%, 33%, 22%, and 32% of patients, respectively. A 2-point improvement in NASH histologic scores is rarely seen.


      Serum alanine aminotransferase levels may decrease on placebo and is not a reliable measure of treatment response. Although a 1-point improvement is seen in a third of patients, a 2-point improvement in histologic parameters is rarely seen in the placebo arm and may be more reliable in assessing treatment response. These data may have important implications in designing future clinical trials in NASH.

      Abbreviations used in this paper:

      ALT (alanine aminotransferase), AST (aspartate aminotransferase), NASH (nonalcoholic steatohepatitis)
      To read this article in full you will need to make a payment
      AGA Member Login
      Login with your AGA username and password.
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Greenfield S.
        • Kravitz R.
        • Duan N.
        • et al.
        Heterogeneity of treatment effects: implications for guidelines, payment, and quality assessment.
        Am J Med. 2007; 120: S3-S9
        • Hrobjartsson A.
        • Gotzsche P.C.
        Is the placebo powerless?.
        N Engl J Med. 2001; 344: 1594-1602
        • Su C.
        • Lewis J.D.
        • Goldberg B.
        • et al.
        A meta-analysis of the placebo rates of remission and response in clinical trials of active ulcerative colitis.
        Gastroenterology. 2007; 132: 516-526
        • Su C.
        • Lichtenstein G.R.
        • Krok K.
        • et al.
        A meta-analysis of the placebo rates of remission and response in clinical trials of active Crohn's disease.
        Gastroenterology. 2004; 126: 1257-1269
        • Kleiner D.E.
        • Brunt E.M.
        • Van Natta M.
        • et al.
        Design and validation of a histological scoring system for nonalcoholic fatty liver disease.
        Hepatology. 2005; 41: 1313-1321
        • Promrat K.
        • Lutchman G.
        • Uwaifo G.I.
        • et al.
        A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis.
        Hepatology. 2004; 39: 188-196
        • Brunt E.M.
        • Janney C.G.
        • Di Bisceglie A.M.
        • et al.
        Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions.
        Am J Gastroenterol. 1999; 94: 2467-2474
        • Neuschwander-Tetri B.A.
        • Caldwell S.H.
        Nonalcoholic steatohepatitis: summary of an AASLD single topic conference.
        Hepatology. 2003; 37: 1202-1219
        • Suzuki A.
        • Lymp J.
        • Sauver J.S.
        • et al.
        Values and limitations of serum aminotransferases in clinical trials of nonalcoholic steatohepatitis.
        Liver Int. 2006; 26: 1209-1216
        • Littell R.F.J.
        Asymptotic optimality of Fisher's method of combining independent tests.
        J Am Stat Assoc. 1971; 66: 802-806
        • Chande N.
        • Laidlaw M.
        • Adams P.
        • et al.
        Yo Jyo Hen Shi Ko (YHK) improves transaminases in nonalcoholic steatohepatitis (NASH): a randomized pilot study.
        Dig Dis Sci. 2006; 51: 1183-1189
        • Zelber-Sagi S.
        • Kessler A.
        • Brazowsky E.
        • et al.
        A double-blind randomized placebo-controlled trial of orlistat for the treatment of nonalcoholic fatty liver disease.
        Clin Gastroenterol Hepatol. 2006; 4: 639-644
        • Lindor K.D.
        • Kowdley K.V.
        • Heathcote E.J.
        • et al.
        Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial.
        Hepatology. 2004; 39: 770-778
        • Belfort R.
        • Harrison S.A.
        • Brown K.
        • et al.
        A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis.
        N Engl J Med. 2006; 355: 2297-2307
        • Dufour J.F.
        • Oneta C.M.
        • Gonvers J.J.
        • et al.
        Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin E in nonalcoholic steatohepatitis.
        Clin Gastroenterol Hepatol. 2006; 4: 1537-1543
        • Merat S.
        • Malekzadeh R.
        • Sohrabi M.R.
        • et al.
        Probucol in the treatment of non-alcoholic steatohepatitis: a double-blind randomized controlled study.
        J Hepatol. 2003; 38: 414-418
        • Ratziu V.
        • Giral P.
        • Jacqueminet S.
        • et al.
        Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement With Rosiglitazone Therapy (FLIRT) Trial.
        Gastroenterology. 2008; 135: 100-110