Review Article

Chronic Liver Disease and Silymarin: A Biochemical and

Clinical Review
Sean P. Tighe1, Daud Akhtar2, Umair Iqbal*3 and Aijaz Ahmed4
1
Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA; 2Department of
Medicine, University of British Columbia, Vancouver, BC, Canada; 3Department of Gastroenterology and Hepatology, Geisinger
Commonwealth School of Medicine, Danville, PA, USA; 4Division of Gastroenterology and Hepatology, Stanford University School
of Medicine, Stanford, CA, USA

Abstract for affordable and effective treatment modalities to reduce

the morbidity and mortality associated with CLD.4 Certain
Chronic liver disease (CLD) is an under-recognized epidemic medicinal plants, such as Silybum marianum, more com-
that continues to increase in prevalence and is a major health monly known as milk thistle, have historically been used for
concern. Silymarin, the active compound of Silybum maria- the treatment and prevention of liver disorders. Specifically,
num (Milk thistle), has historically been used in CLD. A sig- silymarin has shown promising protective effects in preclinical
nificant barrier to silymarin use is its poor bioavailability. studies using a number of formulations, including Legalon
Attempts at improving the bioavailability of silymarin have which contains the Eurosil 85 formulation.5–8 The aim of this
led to a better understanding of formulation methods, phar- article is elaborate on the biochemistry of silymarin pertaining
macokinetics, dosing, and associated drug interactions. Clin- to its formulation, pharmacokinetics, dosing, drug interac-
ically, silymarin exerts its hepatoprotective effects through tions, mechanism of action, while also reviewing the current
antioxidative, antifibrotic, anti-inflammatory, antitoxin, and evidence of silymarin use in chronic liver disease.
anticancerous mechanisms of actions. Despite the use of si-
lymarin being extensively studied in alcoholic liver disease, Biochemistry
metabolic-associated fatty liver disease, viral hepatitis, and
drug-induced liver injury, the overall efficacy of silymarin re- Formulation
mains unclear and more research is warranted to better elu-
cidate the role of silymarin in CLD, specifically regarding its Silymarin is a complex mixture that includes an array of
anti-inflammatory effects. Here, we review the current bio- different flavonolignan isomers. Silybin, one of these
chemical and clinical evidence regarding silymarin in CLD. isomers, composes up to 50% of the silymarin mixture and
Citation of this article: Tighe SP, Akhtar D, Iqbal U, Ahmed plays an important role in the antioxidative effects of silymarin.
A. Chronic liver disease and silymarin: A biochemical and clin- These antioxidant effects are a result of silybin diastereomers
ical review. J Clin Transl Hepatol 2020;8(4):454–458. doi: that undergo biotransformation, leading to the formation of
10.14218/JCTH.2020.00012. glucuronide derivatives (Fig. 1).9
A significant barrier to the clinical use of silymarin is its poor
bioavailability, due to its lipophilic nature, and subsequent poor
Introduction solubility.9 Attempts at improving the solubility of silymarin
formulations has led to the development of many different
Over the last decade, there has been a significant increase in commercially tested forms of silymarin, which differ in their
the burden of chronic liver disease (CLD) due to the growing composition of silybin. Moreover, approximately 75 silymarin
prevalence of metabolic-associated fatty liver disease brands have been developed in various dosage forms, such as
(MAFLD), with CLD now a major cause of morbidity and tablets like Carsil, syrups like Alrin-B, and capsules like
mortality worldwide.1 The increasing numbers of patients at
risk for cirrhosis and in need of liver transplantation have
become important economic and health concerns, with
studies showing hospitalizations due to CLD having doubled
in number over the last decade.2,3 Therefore, there is a need

Keywords: Silymarin; Chronic liver disease; Silybum marianum; MAFLD; ALD;

Pharmacokinetics.
Abbreviations: ALD, alcoholic liver disease; AST, aspartate aminotransferase;
ALT, alanine aminotransferase; CLD, chronic liver disease; HCC, hepatocellular
carcinoma; HCV, hepatitis C virus; MAFLD, metabolic-associated fatty liver
disease; RCT, randomized control trials.
Received: 27 February 2020; Revised: 20 May 2020; Accepted: 8 September
2020
*Correspondence to: Umair Iqbal, Department of Gastroenterology and Hepa-
tology, Geisinger Commonwealth School of Medicine, Danville, PA 17821, USA.
Tel: +1-570-271-6211, E-mail: [email protected] Fig. 1. Chemical structure of silybin.

454 Journal of Clinical and Translational Hepatology 2020 vol. 8 | 454–458

Copyright: © 2020 Authors. This article has been published under the terms of Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0), which
permits noncommercial unrestricted use, distribution, and reproduction in any medium, provided that the following statement is provided. “This article has been published
in Journal of Clinical and Translational Hepatology at DOI: 10.14218/JCTH.2020.00012 and can also be viewed on the Journal’s website at http://www.jcthnet.com”.
Tighe S.P. et al: Silymarin in chronic liver disease

Legalon.9 Legalon contains Eurosil 85Ò, which is a standardized

preparation method that contains 60% of silybin and has been
used in studies examining the effects of silymarin.
Despite standardized preparation methods, the bioavail-
ability of silymarin can further be affected by genetic poly-
morphisms and the presence of liver disease. Specifically, the
plasma half-life of silybin, the bioactive component in sily-
marin formulations, is 6 hours, while peak plasma concen-
trations are usually reached 2-4 hours after administration.
Genetic polymorphisms, such as ABCB1 C3435T, however,
can affect silybin bioavailability, with one study in healthy
patients illustrating varying peak and half times for oral doses
of 80 mg of silybin equivalents when compared to plain
silymarin capsules.10 In addition to genetic polymorphisms,
the bioavailability of silymarin can also be significantly affected
by the presence of liver disease due to alterations in liver metab-
olism. Studies have also shown that the effectiveness of Fig. 2. Hepatoprotective mechanisms of action of silymarin.
silymarin varies between MAFLD and hepatitis C virus (HCV)-
infected patients. This is a result of higher flavonolignan
plasma concentrations and more extensive enterohepatic Antioxidative effect
cycling.11
The antioxidant properties of silymarin arise from its ability to
utilize scavengers, allowing for the elimination of free radicals.
Dosing
Silymarin’s antioxidant activities have different potential mech-
anisms. These include the inhibition of reactive oxygen species-
Presently, silymarin is available in a variety of different forms,
producing enzymes that prevent free radical formation, scav-
including capsules and tablets of different strength, with a
enging of said free radicals, intestinal ion chelation, promoting
recommended daily dosage between 420 mg to 600 mg. Clinical
protective molecule synthesis, and antioxidant enzyme activa-
studies have been conducted with varying doses, ranging as low
tion.18 The antioxidant properties of silymarin have been dem-
as 80 mg and as high as 1600 mg. One study tested various
onstrated to restore NAD+ homeostasis, sirtuin 1 activity, and
amounts (160, 240, and 360 mg/day) and found statistically
the AMP-activated protein kinase a pathway to improve poly-
significant decreases in liver enzymes in the 240 and 360 mg/
(ADP-ribose)-polymerase function (all-important regulatory
day groups in patients with alcoholic liver disease (ALD) and
pathways linked with oxidative stress).19 Furthermore, the anti-
chronic viral hepatitis.12 Another study on HCV-decompensated
oxidant capabilities of silymarin improve the hepatic lipid
cirrhotic patients concluded that higher doses of silymarin (1.05
homeostasis by decreasing de novo lipogenesis via the down-
g/day) is superior to a standard dose (420 mg/day).13 Although
regulation of peroxisome proliferator-activated receptor g,
the data from some studies point towards a link between higher
acetyl-CoA carboxylase, and fatty acid synthase.19–22
concentrations of silymarin and better treatment results and
patient outcomes, certain patient populations, such as those
with hepatocellular carcinoma (HCC), have not shown the Antifibrotic effect
same signal.14 Dosage adjustments may, therefore, be neces-
sary to exert a similar effect in patients with liver disease. The antifibrotic activity of silymarin is primarily due to its
ability to inhibit the conversion of hepatic stellate cells into
myofibroblasts through the inhibition of fibrogenic pathways,
Drug interactions
such as those implicated in cytoskeletal formation, profibro-
genic collagen, and electron transfer chains. Specifically,
The drug interaction profile of silymarin has been studied
silymarin down-regulates TGF-ß1 mRNA, inhibits NF-kB, and
extensively both in laboratory/animal models and clinical
prevents the stimulation of hepatic stellate cells. These
trials.15,16 Studies with human hepatocytes demonstrate neg-
findings are supported by studies in animal models,
ligible inhibition of CYP450 enzymes at supratherapeutic sily-
whereby silymarin was shown to slow down the progression
marin concentrations, suggesting that at therapeutic doses
of early fibrosis.23,24
silymarin is unlikely to cause hepatocyte related drug-drug
interactions.15 Silymarin may be indirectly implicated in this
reduction, as an additive effect secondary to interactions with Anti-inflammatory effect
antihyperglycemic agents. Furthermore, studies have shown
that silymarin can theoretically interfere and effect the clear- The immunomodulatory activity of silymarin exerts an anti-
ance of other drugs, such as statins, glucorinidated drugs, and inflammatory effect by preventing the activation of the
immunosuppressants, such as sirolimus. inflammasomes, and NF-kB, which are important in regulat-
ing the immune response in inflammatory states.17 Silymarin
can also restore a pathway known as insulin receptor sub-
Mechanism of action strate-1/PI3K/Akt, which can reduce MAFLD-induced insulin
resistance and steatosis, as well as activate the farnesyl X
The hepatoprotective effects of silymarin are due to its receptor, which in turn can diminish hepatic inflamma-
antioxidative, antifibrotic, regenerative, choleretic, immuno- tion.20,25,26 Silymarin’s anti-inflammatory and antioxidant
modulatory, and anti-inflammatory properties, as illustrated capabilities have also been shown to reduce virus-related
in Fig. 2.17 damage to the liver in chronic HCV infection.27

Journal of Clinical and Translational Hepatology 2020 vol. 8 | 454–458 455

 Tighe S.P. et al: Silymarin in chronic liver disease

Antitoxin effect Viral hepatitis

In cases of drug/toxin-related hepatic injury, the primary The advent of antiviral therapy has dramatically changed the
mechanisms by which silymarin protects against further landscape of viral hepatitis management. Despite this, high
damage is through the regulation of membrane permeability treatment costs and issues with accessibility has created a
and the competitive inhibition of toxins at specific binding possible niche for other treatment modalities, such as sily-
sites. This prevents the absorption of these harmful substan- marin. Unfortunately, the efficacy of silymarin when com-
ces, particularly in the hepatic phalloidin-transporting pared to placebo in a well-designed double-blinded trial by
system.28,29 Fried et al.35 did not significantly reduce serum alanine ami-
notransferase (ALT) levels. A systematic meta-analysis
Anticancerous effect further demonstrated slightly reduced ALT and aspartate ami-
notransferase (AST) levels in HCV patients taking silymarin,
Silymarin also demonstrates anticancerous effects believed but these effects were proven to be too variable to provide
to be linked to the inhibition of oxidative stress, promotion of any concrete clinical significance.36
apoptosis, cell cycle arresting, and mitochondrial pathway
inhibition.14 In vitro and in vivo assays, as well as animal Drug-induced liver injury
models with HCC treated with silymarin, have showcased
the antitumoral effects at varying stages of hepatocarcino- Drug- and toxin-induced liver injury can result from harmful
genesis (initiation, promotion, and progression).17 Silymar- increases in oxidative stress from exposure to various
in’s ability to aid in hepatic regeneration is also an important chemicals.37 Normally, a balance exists between free
characteristic that makes it well suited as a potential therapy radical production and the human body’s ability to produce
in patients with CLD. Specifically, there is an association with counter-acting antioxidants as a corresponding defense
ribosomal RNA synthesis, possibly through the stimulation of mechanism. However, in drug- and toxin-induced liver
polymerase I.17 injury, the pathogenesis is associated with an imbalance
between these two, which explains why silymarin, with its
antioxidant effects, is a considerable treatment option for
Current evidence of silymarin in CLD CLDs including jaundice, cirrhosis, and hepatitis.38 Studies
examining CCl4-hepatotoxicity in rats showed the preven-
The clinical applications of silymarin encompass a broad tion of hepatic dysfunction and the restoration of normal
range of CLD. These include ALD, MAFLD, drug-and toxin- liver functionality with silymarin use.39,40–44 Silymarin aids
induced liver disease, cholestasis (both pregnancy and as an antioxidant, not only by scavenging for free radicals
nonpregnancy related), primary liver malignancies (includ- but also by preventing the loss of the antioxidant gluta-
ing both cholangiocarcinoma and HCC), and viral thione.18 One study known as Hep573 demonstrated that
hepatitis.17 an intervention of silymarin and antioxidants in a complex
naturopathic mixture might lead to normal ALT levels in HCV
ALD patients as well as an overall improved quality of life, which
includes treating comorbidities that are not always properly
Alcohol is a key risk factor for liver diseases and is responsible treated with the antiviral ‘cure’.45 These results were mostly
for about half of all liver-related cirrhosis. Significant alcohol found in patients with the specific HCV genotype 1, which
consumption initially leads to a fatty liver, which can progress can be explained by these individuals lacking endogenous
to cirrhosis.30 The use of silymarin in ALD is limited, due to the antioxidants, like glutathione.46 These findings could be
poor design of initial studies. A recent systematic review applied to any of the aforementioned liver diseases that
assessing the role of silymarin in patients with ALD suggested result from antioxidant deficiencies and/or free-radical sur-
that better clinical trials are indicated in order to determine pluses. Although, various studies have shed a positive light
whether or not there is a role for silymarin in ALD on the beneficial effects of silymarin in different liver dis-
management.31 eases, these studies are limited by the volume of data and
thus are not adequate for robust conclusions. This, there-
fore, warrants the need for more quality studies examining
MAFLD
silymarin before it can be used as an official clinical treat-
ment in CLD.
On the contrary, the use of silymarin for MAFLD, appears to
better supported with multiple randomized control trials
(commonly referred to as RCTs) showing benefit from Conclusions
silymarin use.32 MAFLD is a clinical spectrum that can man-
ifest with hepatic fibrosis and inflammation. This is due to Silymarin is a potent inhibitor of inflammation, fibrosis and
the associations between MAFLD and the aforementioned, oxidative stress that is safe and has low risks of drug
“anti-inflammatory, antioxidant, antifibrotic, and pro- interactions. Although some evidence of efficacy exists in a
regenerative effects of silymarin, in conjunction with its subset of patients with CLD, such as those with ALD and
metabolic actions on insulin resistance and hyperlipide- MAFLD, the overall efficacy of silymarin remains unclear, with
mia”.17,33,34 With a recent meta-analysis involving 587 a recent multiple meta-analysis showing no clinically sub-
patients suggesting an improvement in liver function in stantial benefit in the management of CLD. Silymarin may
patients with MAFLD, the use of silymarin for the treatment have a role in combination with antioxidants; however, more
of MAFLD is promising but still requires further analysis with research is warranted to better elucidate the role of silymarin
larger standardized RCTs.32 in the management of CLD.

456 Journal of Clinical and Translational Hepatology 2020 vol. 8 | 454–458

Tighe S.P. et al: Silymarin in chronic liver disease

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