Original Contribution
Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: A randomized controlled trial

https://doi.org/10.1016/j.freeradbiomed.2012.02.008Get rights and content

Abstract

The only currently recommended treatment for nonalcoholic fatty liver disease (NAFLD) is lifestyle modification. Preliminary studies of silybin showed beneficial effects on liver function. Realsil (RA) comprises the silybin phytosome complex (silybin plus phosphatidylcholine) coformulated with vitamin E. We report on a multicenter, phase III, double-blind clinical trial to assess RA in patients with histologically documented NAFLD. Patients were randomized 1:1 to RA or placebo (P) orally twice daily for 12 months. Prespecified primary outcomes were improvement over time in clinical condition, normalization of liver enzyme plasma levels, and improvement of ultrasonographic liver steatosis, homeostatic model assessment (HOMA), and quality of life. Secondary outcomes were improvement in liver histologic score and/or decrease in NAFLD score without worsening of fibrosis and plasma changes in cytokines, ferritin, and liver fibrosis markers. We treated 179 patients with NAFLD; 36 were also HCV positive. Forty-one patients were prematurely withdrawn and 138 patients analyzed per protocol (69 per group). Baseline patient characteristics were generally well balanced between groups, except for steatosis, portal infiltration, and fibrosis. Adverse events (AEs) were generally transient and included diarrhea, dysgeusia, and pruritus; no serious AEs were recorded. Patients receiving RA but not P showed significant improvements in liver enzyme plasma levels, HOMA, and liver histology. Body mass index normalized in 15% of RA patients (2.1% with P). HCV-positive patients in the RA but not the P group showed improvements in fibrogenesis markers. This is the first study to systematically assess silybin in NAFLD patients. Treatment with RA but not P for 12 months was associated with improvement in liver enzymes, insulin resistance, and liver histology, without increases in body weight. These findings warrant further investigation.

Graphical abstract

Research Highlights

► Currently there is no effective therapy for nonalcoholic fatty liver disease, except for lifestyle modification. ► Realsil treatment for 12 months improves liver enzymes, insulin resistance, and liver histology. ► HCV patients in the Realsil group showed improvements in fibrogenesis markers.

Section snippets

Trial design

The trial was conducted at 11 Italian and 2 Romanian centers. Protocol and patient consent forms were designed by the coordinating center and reviewed by all participating centers. The protocol conformed to ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Institutional Review Board at each participating center. All patients gave informed written consent. The trial was registered with the European Clinical Trials Database (EudraCT, Ref. 2005-000860-24). No

Results

The trial took place from 13 June 2005 to 10 October 2008 and enrolled 180 patients with histologically proven NAFLD; 36 were HCV positive. Overall, 91 patients received RA and 88 received P. Forty-one patients were prematurely withdrawn (22 and 19 from the RA and P groups, respectively), with 138 patients available for PP analysis (69 in each group). Reasons for discontinuation were physician's decision (n = 5), patient's decision (n = 21), AEs (n = 10), or other (n = 5). AEs were generally transient

Discussion

This is the first study to systematically assess the effects of silybin in NAFLD patients, with and without HCV infection. Patients treated for 12 months with RA, an oral complex containing silybin, phosphatidylcholine, and vitamin E, exhibited improvements in levels of transaminases and γGT, insulin resistance, and several aspects of liver histology. These improvements were similar to those noted in patients treated with pioglitazone and vitamin E [4], [31]. However, in our study, body weight

Acknowledgments

We thank Gardiner-Caldwell Communications for general editing and styling assistance, which was funded by the Istituto Biochimico Italiano Lorenzini S.p.a, Italy. This study was funded by a grant from the Istituto Biochimico Italiano, Lorenzini S.p.a., Italy. The manuscript was written by the lead and corresponding author and was approved by all authors, who assume responsibility for the completeness of the data and the overall content of the article. This article was approved by the ethics

References (59)

  • J.W. Wu et al.

    Drug–drug interactions of silymarin on the perspective of pharmacokinetics

    J. Ethnopharmacol.

    (2009)
  • C. Loguercio et al.

    Non-alcoholic fatty liver disease: a multicentre clinical study by the Italian Association for the Study of the Liver

    Dig. Liver Dis.

    (2004)
  • S.J. Polyak et al.

    Inhibition of T-cell inflammatory cytokines, hepatocyte NF-κB signaling, and HCV infection by standardized silymarin

    Gastroenterology

    (2007)
  • P. Ferenci et al.

    Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy

    Gastroenterology

    (2008)
  • M. Biermer et al.

    Rapid suppression of hepatitis C viremia induced by intravenous silibinin plus ribavirin

    Gastroenterology

    (2009)
  • A. Ahmed-Belkacem et al.

    Silibinin and related compounds are direct inhibitors of hepatitis C virus RNA-dependent RNA polymerase

    Gastroenterology

    (2010)
  • F. Stickel et al.

    Herbal medicine in the treatment of liver diseases

    Dig. Liver Dis.

    (2007)
  • B.P. Jacobs et al.

    Milk thistle for the treatment of liver disease: a systematic review and meta-analysis

    Am. J. Med.

    (2002)
  • S. Aghazadeh et al.

    Inhibition of JNK along with activation of ERK1/2 MAPK pathways improve steatohepatitis among the rats

    Clin. Nutr.

    (2010)
  • K.K. Kharbanda et al.

    Betaine attenuates alcoholic steatosis by restoring phosphatidylcholine generation via the phosphatidylethanolamine methyltransferase pathway

    J. Hepatol.

    (2007)
  • C.P. Colturato et al.

    Metabolic effects of silibinin in the rat liver

    Chem. Biol. Interact.

    (2012)
  • G. Targher et al.

    Risk of cardiovascular disease in patients with non alcoholic fatty liver disease

    N. Engl. J. Med.

    (2010)
  • A.J. Sanyal et al.

    Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis

    N. Engl. J. Med.

    (2010)
  • G. Musso et al.

    A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease

    Hepatology

    (2010)
  • R. Gazak et al.

    Silybin and silymarin—new and emerging applications in medicine

    Curr. Med. Chem.

    (2007)
  • C. Tamayo et al.

    Review of clinical trials evaluating safety and efficacy of milk thistle (Sylibum marianum [L.] Gaertn.)

    Integr. Cancer Ther.

    (2007)
  • R. Amini et al.

    Anti-apoptotic and anti-inflammatory effects of Silybum marianum in treatment of experimental steatohepatitis

    Exp. Toxicol. Pathol.

    (2011)
  • G. Serviddio et al.

    A silybin–phospholipids complex prevents mitochondrial dysfunction in a rodent model of non-alcoholic steatohepatitis

    J. Pharmacol. Exp. Ther.

    (2010)
  • F. Lirussi et al.

    Silybin-β-cyclodextrin in the treatment of patients with diabetes mellitus and alcoholic liver disease: efficacy study of a new preparation of an anti-oxidant agent

    Diabetes Nutr. Metab.

    (2002)
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