Effect of Silymarin Treatment on Circulating Bilirubin and Cardiovascular Disease Risk Factors in Healthy Men: A Single‐Blind, Randomized Crossover Trial

Abstract

This clinical trial (ACTRN12619001296123) investigated the impact of silymarin (Legalon®) on circulating bilirubin concentration, lipid status, systemic inflammation, and antioxidant status. The study design was a randomized, placebo‐controlled, single‐blind crossover trial of healthy men (18‐65 years), conducted at Griffith University, Gold Coast, Australia. Participants were recruited from Griffith University and were randomized to silymarin (140 mg silymarin capsules thrice daily) or placebo (3 capsules containing mannitol taken daily) for 14 days followed by a ≥4‐week washout and crossover to the other arm. The main outcomes were whether silymarin treatment would increase serum bilirubin concentration by >0.29 mg/dL, change serum lipid status (cholesterol and triglycerides), inflammation (c‐reactive protein), and antioxidant capacity (ferric reducing ability of plasma) compared with baseline. Silymarin consumption (n = 17) did not affect serum concentrations of unconjugated bilirubin (0.73 versus 0.67 mg/dL, P = .79), cholesterol (185 versus 189 mg/dL, P = .19), triglycerides (94.2 versus 92.3 mg/dL, P = .79), c‐reactive protein (0.17 versus 0.09 mg/dL, P = .23), or antioxidant status (6.61 versus 6.67 mg Fe2+/dL, P = .40). These findings challenge previous reports and manufacturer claims of hyperbilirubinemia following silymarin treatment and are critical to guiding researchers toward an effective means to mildly elevate bilirubin, which evidence suggests could protect from cardiovascular disease.

The effects of Silymarin on the features of cardiometabolic syndrome in adults: A systematic review and meta‐analysis

“…(c) Inhibitory effects on adipogenesis factors, such as CCAAT enhancer-binding protein α (C/EBPα), peroxisome proliferatoractivated receptor γ (PPARγ) and fatty acid-binding protein 4 (FABP4) that could decrease lipid accumulation and normalize serum lipids (Ji, 2017;Suh, Cho, Kim, & Choi, 2015); (d) reducing liver synthesis of cholesterol and biliary cholesterol concentrations by Silybin (one of silymarin constituents) (Vidimce et al, 2021); (e) inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase as a main enzyme of cholesterol synthesis in dose-dependent manner (Federico, Dallio, & Loguercio, 2017;Mahdavi, Bagherniya, & Fakheran, 2020). (c) reducing advanced glycation end products (AGEs) formation (Wu, Huang, & Yen, 2011).…”

“…Beneficial effects of silymarin on blood lipids can be partly explained by the following potential mechanisms: (a) Prohibition of intestine cholesterol absorption with prohibition of acyl‐CoA like cholesterol acyltransferase as a main pathway of lipid metabolism (Orolin et al, 2007; Sobolová, Škottová, Večeřa, & Urbánek, 2006; Tajmohammadi, Razavi, & Hosseinzadeh, 2018); (b) Activating beta‐oxidation of fatty acids in mitochondria (Škottová et al, 2004); (c) Inhibitory effects on adipogenesis factors, such as CCAAT enhancer‐binding protein α (C/EBPα), peroxisome proliferator‐activated receptor γ (PPARγ) and fatty acid‐binding protein 4 (FABP4) that could decrease lipid accumulation and normalize serum lipids (Ji, 2017; Suh, Cho, Kim, & Choi, 2015); (d) reducing liver synthesis of cholesterol and biliary cholesterol concentrations by Silybin (one of silymarin constituents) (Vidimce et al, 2021); (e) inhibiting 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase as a main enzyme of cholesterol synthesis in dose‐dependent manner (Federico, Dallio, & Loguercio, 2017; Mahdavi, Bagherniya, & Fakheran, 2020).…”

Hepatoprotective effects of silymarin in management of liver injury caused by tuberculosis treatment

“…Of note, this reduction in bilirubin levels is in contrast with previous clinical studies, which reported inconsistent effects of silymarin treatment on serum bilirubin levels, with some studies reporting no effects and others reporting increased bilirubin concentrations. 9 In this case report, reduction in serum bilirubin levels following silymarin treatment may be linked to its anti-inflammatory and antioxidant properties.…”

Milk Thistle (Silybum Marianum L.) as a Novel Multipurpose Crop for Agriculture in Marginal Environments: A Review

“…Medical applications of milk thistle have been thoroughly demonstrated by many experiments for more than 50 years [5][6][7][8]12,[14][15][16]19,20,116,[130][131][132][133][134][135], and interest in silymarin has increased in the fields of medical, pharmaceutical, and veterinary sciences due to its wide use in various therapies and medical applications [18,101,136,137]. However, the yield potential and the chemical composition of milk thistle fruits and vegetative biomass have suggested a variety of additional uses, ranging from livestock feeding to human consumption and industrial exploitation, and involving several plant parts, derivatives, and extracts (Tables 1-3).…”