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A Randomized Trial of Silymarin for the Treatment of Nonalcoholic Steatohepatitis
Abstract
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.
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“Silymarin treatment resulted in a significantly greater improvement in liver fibrosis compared with placebo, as assessed by histology and supported by reductions in liver stiffness measured by Fibroscan and other non-invasive fibrosis markers. Notably, these antifibrotic effects occurred in the absence of significant improvements in other key histological features of the disease.”
From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [216]
In the citing paper
“Silymarin (an extract of milk thistle) may improve liver enzymes but the few, small, RCTs available 395,396 did not document histological improvement.”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [395]
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Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis
Sanyal, A. J., Chalasani, N., Kowdley, K. V., McCullough, A., Diehl, A. M., Bass, N. M., Neuschwander-Tetri, B. A., Lavine, J. E., Tonascia, J., Unalp, A., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0907929 · Cited by 3,327
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Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis
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Research works printed but not linked: 1
- Loomba, 2016, GS-4997, an inhibitor of apoptosis signal-regulating kinase (ASK1), alone or in combination with simtuzumab for the treatment of nonalcoholic steatohepatitis (NASH): a randomized phase 2 trial, Hepatology, 64, 1119A
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Rinella, M. E., Neuschwander-Tetri, B. A., Siddiqui, M. S., Abdelmalek, M. F., Caldwell, S., Barb, D., Kleiner, D. E., & Loomba, R. (2023) · Hepatology · doi:10.1097/hep.0000000000000323 · Cited by 2,667
Tacke, F., Horn, P., Wai-Sun Wong, V., Ratziu, V., Bugianesi, E., Francque, S., Zelber-Sagi, S., Valenti, L., Roden, M., Schick, F., et al. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.04.031 · Cited by 2,210
Leoni, S., Tovoli, F., Napoli, L., Serio, I., Ferri, S., & Bolondi, L. (2018) · World Journal of Gastroenterology · doi:10.3748/wjg.v24.i30.3361 · Cited by 560
Silymarin as Supportive Treatment in Liver Diseases: A Narrative Review
Gillessen, A., & Schmidt, H. (2020) · Advances in Therapy · doi:10.1007/s12325-020-01251-y · Cited by 521
(2024) · Obesity Facts · doi:10.1159/000539371 · Cited by 545
Metadata
- Authors
- Wah Kheong, C., Nik Mustapha, N. R., & Mahadeva, S.
- Affiliations
- University of Malaya (MY)
- ORCID
- Mahadeva, Sanjiv
- Venue
- Clinical Gastroenterology and Hepatology
- Publisher
- Elsevier BV
- Published
- 2017-12
- Volume
- 15
- Issue
- 12
- Pages
- 1940-1949.e8
- ISSN
- 1542-3565 (ISSN-L)
- OpenAlex
- W2607263910
- Cited by
- 264
- References
- 39
- Citations by year
- 2026: 27 · 2025: 38 · 2024: 44 · 2023: 34 · 2022: 25 · 2021: 30 · 2020: 23 · 2019: 23 · 2018: 16 · 2017: 2
- FWCI
- 14.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Gastroenterology and Hepatology (publishedVersion)
- PubMed (publishedVersion)
- The University of Malaya Research Repository (University of Malaya) (submittedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Silymarin and Mushroom Poisoning
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Complementary and alternative medicine › Nigella sativa pharmacological applications
- Keywords
- silymarin, nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, Silybum marianum, flavonolignans, liver fibrosis, liver stiffness, NAFLD activity score, hepatocyte ballooning, steatosis, lobular inflammation, antifibrotic therapy, liver biopsy histology, Fibrosis-4 score, aspartate aminotransferase to platelet ratio index, hepatoprotection
- MeSH terms
- Adult, Aged, Antioxidants, Double-Blind Method, Female, Gastrointestinal Agents, Humans, Malaysia, Male, Middle Aged, Placebos, Silymarin, Treatment Outcome, Non-alcoholic Fatty Liver Disease
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