Silymarin as Supportive Treatment in Liver Diseases: A Narrative Review

Abstract

Silymarin, an extract from milk thistle seeds, has been used for centuries to treat hepatic conditions. Preclinical data indicate that silymarin can reduce oxidative stress and consequent cytotoxicity, thereby protecting intact liver cells or cells not yet irreversibly damaged. Eurosil 85^® is a proprietary formulation developed to maximize the oral bioavailability of silymarin. Most of the clinical research on silymarin has used this formulation. Silymarin acts as a free radical scavenger and modulates enzymes associated with the development of cellular damage, fibrosis and cirrhosis. These hepatoprotective effects were observed in clinical studies in patients with alcoholic or non-alcoholic fatty liver disease, including patients with cirrhosis. In a pooled analysis of trials in patients with cirrhosis, silymarin treatment was associated with a significant reduction in liver-related deaths. Moreover, in patients with diabetes and alcoholic cirrhosis, silymarin was also able to improve glycemic parameters. Patients with drug-induced liver injuries were also successfully treated with silymarin. Silymarin is generally very well tolerated, with a low incidence of adverse events and no treatment-related serious adverse events or deaths reported in clinical trials. For maximum benefit, treatment with silymarin should be initiated as early as possible in patients with fatty liver disease and other distinct liver disease manifestations such as acute liver failure, when the regenerative potential of the liver is still high and when removal of oxidative stress, the cause of cytotoxicity, can achieve the best results.

Keywords: Fatty liver disease; Milk thistle; Non-alcoholic fatty liver disease; Silibinin; Silymarin.

Fig. 1

Chemical structure of the silibinin diastereoisomers, silibinin A and silibinin B (C₂₅H₂₁O₁₀)

Fig. 2

Levels of collagen type 1 in hepatic biopsy samples from baboons fed a diet containing 50% alcohol, with or without concomitant silymarin [49]. SEM: standard error of the mean. ^aP < 0.05 vs. alcohol. Reproduced with permission from Lieber et al. [49]

Fig. 3

Effect of silymarin on antioxidant capacity [63]. This was measured by serum levels of free sulfhydryl groups and glutathione peroxidase activity in erythrocytes and lymphocytes in patients with alcohol-induced liver disease receiving silymarin or placebo. SH: sulfhydryl; GSH-Px: glutathione peroxidase. ^aP < 0.05 vs. month 0; ^bP < 0.05 vs. placebo [63]

Fig. 4

Changes in alcoholic liver disease and diabetes parameters in patients with diabetes and alcoholic liver disease receiving standard treatment alone (untreated) or with concomitant silymarin (treated) [59]. a Plasma malondialdehyde levels (a marker of membrane peroxidation); b glycosylated hemoglobin; c average daily insulin dose. ^aP < 0.05 vs. untreated control group; ^bP < 0.01 vs. untreated control group. Reproduced with permission from Velussi et al. [59]

Fig. 5

Effect of 48 weeks’ treatment with silymarin 2100 mg/day in 99 patients with histologically proven non-alcoholic steatohepatitis [79]. A proportion of patients with: a NAS score improvement (defined as ≥ 30% improvement in NAS), fibrosis improvement (defined as a ≥ 1 point improvement in the histologic component of the NAS score), resolution of fibrosis (defined as absence of fibrosis at EOT) or development of cirrhosis [79]. ^aP < 0.05 vs. placebo; ^bline charts illustrating the changes in the (i) APRI, (ii) FIB-4 score and (iii) NAFLD fibrosis scores in the silymarin and placebo groups [79]. APRI aspartate aminotransferase to platelet ratio index, EOT end of treatment, FIB-4 fibrosis-4, NAFLD nonalcoholic fatty liver disease, NAS NASH and NAFLD activity score, NASH non-alcoholic steatohepatitis. Part B of figure reproduced with permission from Wah Kheong et al. [79]

Fig. 6

Changes in liver enzymes, liver-related symptoms and quality of life in patients with non-alcoholic liver disease receiving silymarin for 4 months [92]. a Liver function parameters (all comparisons P < 0.001 baseline vs. 4 months); b signs and symptoms of liver disease; c: quality of life. ALT alanine aminotransferase, AP alkaline phosphatase, AST aspartate aminotransferase, GGT gamma-glutamyl transferase, TBIL total bilirubin. Reproduced with permission from Gillessen et al. [92]

Fig. 7

Preventive effect on DILI by treatment with the combination of silymarin (420 mg/day) plus diammonium glycyrrhizinate compared with diammonium glycyrrhizinate alone in patients with acute lymphoblastic or acute myeloid leukemia undergoing chemotherapy [94]. DILI was measured according to the 1990 Paris International Consensus Conference classification of liver injury. Chemo chemotherapy, DILI drug-induced liver injury, Glyc diammonium glycyrrhizinate, Sil silymarin