Original article
Pancreas, biliary tract, and liver
A Randomized Trial of Silymarin for the Treatment of Nonalcoholic Steatohepatitis

https://doi.org/10.1016/j.cgh.2017.04.016Get rights and content

Background & Aims

Silymarin is a complex mixture of 6 major flavonolignans and other minor polyphenolic compounds derived from the milk thistle plant Silybum marianum; it has shown antioxidant, anti-inflammatory and antifibrotic effects, and may be useful in patients with nonalcoholic fatty liver disease (NAFLD). We aimed to study the efficacy of silymarin in patients with nonalcoholic steatohepatitis (NASH)—the more severe form of NAFLD.

Methods

We performed a randomized, double-blind, placebo-controlled trial of consecutive adults with biopsy-proven NASH and a NAFLD activity score (NAS) of 4 or more at a tertiary care hospital in Kuala Lumpur, Malaysia, from November 2012 through August 2014. Patients were randomly assigned to groups given silymarin (700 mg; n = 49 patients) or placebo (n = 50 patients) 3 times daily for 48 weeks. After this 48-week period, liver biopsies were repeated. The primary efficacy outcome was a decrease of 30% or more in NAS; findings from 48-week liver biopsies were compared with those from the baseline biopsy. Secondary outcomes included changes in steatosis, lobular inflammation, hepatocyte ballooning, NAS and fibrosis score, and anthropometric measurements, as well as glycemic, lipid, and liver profiles and liver stiffness measurements.

Results

The percentage of patients achieving the primary efficacy outcome did not differ significantly between the groups (32.7% in the silymarin group vs 26.0% in the placebo group; P = .467). A significantly higher proportion of patients in the silymarin group had reductions in fibrosis based on histology (reductions of 1 point or more; 22.4%) than did the placebo group (6.0%; P = .023), and based on liver stiffness measurements (decrease of 30% or more; 24.2%) than did the placebo group (2.3%; P = .002). The silymarin group also had significant reductions in mean aspartate aminotransferase to platelet ratio index (reduction of 0.14, P = .011 compared with baseline), fibrosis-4 score (reduction of 0.20, P = .041 compared with baseline), and NAFLD fibrosis score (reduction of 0.30, P < .001 compared with baseline); these changes were not observed in the placebo group (reduction of 0.07, P = .154; increase of 0.18, P = .389; and reduction of 0.05, P = .845, respectively). There was no significant difference between groups in number of adverse events; adverse events that occurred were not attributed to silymarin.

Conclusions

In a randomized trial of 99 patients, we found that silymarin (700 mg, given 3 times daily for 48 weeks) did not reduce NAS scores by 30% or more in a significantly larger proportion of patients with NASH than placebo. Silymarin may reduce liver fibrosis but this remains to be confirmed in a larger trial. It appears to be safe and well tolerated. ClinicalTrials.gov: NCT02006498.

Section snippets

Methods

The study conformed to the ethical guidelines of the 1975 Declaration of Helsinki and ethical approval was obtained from our institutional review board prior to the commencement of the study (Approval Date: May 25, 2011; Reference No.: 853.1). All subjects who participated in the study provided written informed consent. The study was registered at ClinicalTrials.gov (NCT02006498). All authors had access to the study data and had reviewed and approved the final manuscript.

Consecutive adult NAFLD

Study Subjects and Compliance

Screening began in November 2012 and ended in August 2014 when a sufficient number of subjects have been enrolled. Of the 148 subjects who underwent screening, 99 subjects were eligible for the study and underwent randomization. There were 49 subjects in the silymarin group and 50 subjects in the placebo group (Supplementary Figure 1). The baseline characteristics were comparable between the groups except the serum triglyceride and total cholesterol levels, and the controlled attenuation

Discussion

This is the first study on the use of silymarin for the treatment of NASH that utilized paired liver biopsies and provides histological confirmation of previous observations that silymarin may be useful for the treatment of NAFLD. Furthermore, the randomized, double-blinded, placebo-controlled design eliminates the potential of confounding by lifestyle modifications and the potential biases that may be seen in open-labeled, uncontrolled studies. Treatment with silymarin for 48 weeks did not

References (40)

  • G. Musso et al.

    Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity

    Ann Med

    (2011)
  • P. Zezos et al.

    Liver transplantation and non-alcoholic fatty liver disease

    World J Gastroenterol

    (2014)
  • A.J. Sanyal et al.

    Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis

    N Engl J Med

    (2010)
  • C. Loguercio et al.

    Silybin and the liver: from basic research to clinical practice

    World J Gastroenterol

    (2011)
  • E. Bosisio et al.

    Effect of the flavanolignans of Silybum marianum L. on lipid peroxidation in rat liver microsomes and freshly isolated hepatocytes

    Pharmacol Res

    (1992)
  • F. Cacciapuoti et al.

    Silymarin in non alcoholic fatty liver disease

    World J Hepatol

    (2013)
  • S.J. Hashemi et al.

    A placebo-controlled trial of silymarin in patients with nonalcoholic fatty liver disease

    Hepat Mon

    (2009)
  • A.A. Hajiaghamohammadi et al.

    Effects of metformin, pioglitazone, and silymarin treatment on non-alcoholic Fatty liver disease: a randomized controlled pilot study

    Hepat Mon

    (2012)
  • H. Solhi et al.

    Silymarin in treatment of non-alcoholic steatohepatitis: A randomized clinical trial

    Caspian J Intern Med

    (2014)
  • R. Aller et al.

    Effect of silymarin plus vitamin E in patients with non-alcoholic fatty liver disease. A randomized clinical pilot study

    Eur Rev Med Pharmacol Sci

    (2015)
  • Cited by (162)

    View all citing articles on Scopus

    Conflicts of interest The authors disclose no conflicts.

    Funding This study was funded by the University of Malaya Research Grant (Project Number: RG536-13HTM) and Meda Group. University of Malaya and Meda Group were not involved in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

    View full text