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Journal of Clinical Gastroenterology 2003; 37(4):278-279
Is Silymarin Hepatoprotective in Alcoholic Liver Disease?
Jose Berger, MF; Kris V. Kowdley, MD
Division of Gastroenterology, University of Washington Medical
Center Seattle, Washington.
Reprints: Kris V. Kowdley, MD, University of Washington,
1959 N.E. Pacific Street, Seattle, WA 98195-6174. E-mail:
kkowdley@u.washington.edu
Silymarin is the main active complex extracted from the milk
thistle (Silybum marianum L.), an annual plant that
has been used by herbalists since antiquity. Pharmacologic
evidence from numerous studies in the last few decades supports
potential therapeutic benefits of milk thistle and silymarin
in liver necroinflammation and fibrogenesis given its free-radical
scavenging, antioxidant, anti-inflammatory, immunomodulatory,
iron chelating, and membrane stabilizing properties as well
as its purported ability to selectively stimulate hepatocyte
proliferation.1
Current knowledge of the role of oxidative stress in the pathogenesis
of alcohol liver disease (ALD), suggests that silymarin's
pharmacological properties may have potential therapeutic
value in ALD.2
This is a top medical journal for gastroenterologists
acknowledging the therapeutic effect of milk thistle.
Since the 1960s, milk thistle products
have been prescribed by physicians in Europe for ALD as well
as other liver-related conditions. Several European manufacturers
have developed pharmaceutical grade milk thistle products
standardized to a higher content of silymarin (70%-80%) than
in non-standardized herbal preparations ([ap]5%)3,
mainly because of silymarin's poor oral bioavailability.4
As part of pharmaceutical development, several clinical studies
have been conducted in Europe to assess the efficacy of oral
milk thistle products in liver diseases of diverse etiology.
Two key points here. 1.) Milk thistle
is prescribed by doctors in other leading industrial countries.
2.) Milk thistle itself is hard to absorb, which is a key
reason to choose Maximum Milk Thistle -- proven superior absorption.
Recently, a systematic review sponsored by the Agency for
Healthcare Research and Quality (AHRQ) selectively analyzed
16 prospective randomized placebo-controlled European trials
in terms of the efficacy and safety of milk thistle products
in alcohol, viral or toxin-related liver diseases.5
Six of the selected trials evaluated ALD using various doses
of Legalon, a milk thistle product standardized to 80% silymarin
manufactured in by Madhaus AG (Cologne, Germany). The reviewers
found these trials difficult to interpret due to unclear and
variable definitions of disease chronicity and severity. Some
of the studies included liver diseases of various etiologies.
None of the studies stratified patients by presence or absence
of ongoing alcohol consumption or chronic hepatitis C infection
as potential confounders. All 6 studies
on silymarin and ALD found at least 1 biochemical parameter
of liver function or liver histology that improved significantly
with silymarin compared with placebo. The parameters that
were significant varied from study to study.6-12
Importantly, 1 of the 6 studies showed significant improvement
in overall survival among cirrhotic patients treated with
silymarin,10
a second study showed a non-statistical trend toward improved
survival9
and yet another study showed no improvement in overall survival
in silymarin compared with placebo.8
No relationship was found between duration of therapy and
improvement in liver function, although 3 of the reports did
not clearly describe the duration of therapy.
Here they are acknowledging the consistent
proof that milk thistle helps protect and support diseased
livers.
The previous data on silymarin in ALD along with current
evidence on the potential benefit of antioxidant therapies
in ALD,13
justify a more systematic assessment of silymarin in ALD.
Furthermore, an evidence-based approach to the evaluation
of the safety and efficacy is crucial because at
least 1 multicenter survey has shown that milk thistle is
the most frequently used supplement in patients with liver
disease.14
In 2001, milk thistle products ranked 12th in the list of
supplements sold in the US surpassing 7 million dollars.15
It is the most used because it is the
best -- and because of its improved absorption, MMT is the
best of the best.
In the current issue, Lieber and colleagues report their
preliminary findings on the effect of chronic treatment with
a standardized silymarin extract in an experimental baboon
model that has been extensively validated in ALD by the lead
author.16
The silymarin product was provided by Madhaus AG, the manufacturer
of Legalon. The primary aim is to determine whether silymarin
co-administration with toxic levels of alcohol prevents development
of ALD in this animal model. The authors' rationale for using
an animal model was to control for alcohol intake and treatment
compliance. The authors also state that their study design
differs from previous clinical studies that examined the effects
of silymarin in patients with established ALD and often consisted
of compensated or end-stage cirrhotics. Regardless of the
proven validity of the baboon model, this difference in experimental
design does place a limitation on our ability to compare results
from this study with previous clinical trials. Additionally,
the findings of the present study would be difficult to test
in humans, given the ethical issues involving the recruitment
of patients with ALD who continue to consume significant amounts
of alcohol.
According to the authors, silymarin dosing was calculated
based on the manufacturer's previous pharmacokinetic studies
in humans and on the faster metabolism of silymarin in baboons.
However, it is unclear how dosing was calculated in terms
of maximizing hepatoprotective effects of silymarin. It is
also unclear how the sample size was determined (6 animals
in the treatment and control groups) since no power calculations
are given in terms of silymarin's effect size.
As in previous clinical studies in ALD, the results obtained
by Lieber et al are equivocal with regard to a potential clinical
benefit from silymarin as preventive therapy in chronic alcohol
use or ALD, at least at the dose used in the current study
(39.8 1 5.2 mg/kg/d). The authors report that hepatic histology
improved in the silymarin compared with the control group
after 3 years. However, the small sample size and lack of
statistical comparison limits the interpretation of these
data. Nevertheless, the authors should be congratulated for
attempting to study the effect of silymarin for ALD in a scientific
manner. We hope that future studies would be adequately powered
to compare the effect of silymarin using semi-quantitative
histopathologic findings as primary endpoints.
There were, however, several favorable
changes in the secondary endpoints in the silymarin treated
group. Plasma levels of ALT, 4-hydroxynonenal (a marker of
lipid peroxidation), procollagen type I and mRNA of[alpha](I)
procollagen (2 markers of fibrogenesis) and hepatic total
triglycerides were all significantly lower in the silymarin
group, thus providing indirect evidence that silymarin is
hepatoprotective and may potentially retard progression in
ALD. Based on the interesting findings in the current study,
additional studies are warranted to determine the optimal
dose of silymarin followed by carefully designed clinical
trials in ALD.
Note well: They are suggesting subsequent
studies to determine optimum dose. Clearly they accept the
usefulness of milk thistle for patients with liver disease
-- they are treating that as a given. They just want to know
how much is best! In the meantime, I recommend you at least
take the recommended dose of MMT every day.
REFERENCES
1. Saller R, Meier R, Brignoli R. The use of
silymarin in the treatment of liver diseases. Drugs. 2001;
61:2035-2063.
PubMed
Abstract
2. Arteel GE. Oxidants and antioxidants in
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PubMed
Abstract
3. Flora K, Hahn M, Rosen H, et al. Milk thistle
(Silybum marianum) for the therapy of liver disease. Am J
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PubMed
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PubMed
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and Implementation Center, a Veterans Affairs Services Research
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01-E025. Rockville, Maryland: Agency for Healthcare Research
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action of silymarin therapy in chronic alcoholic liver diseases
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PubMed
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PubMed
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9. Benda L, Dittrich H, Ferenzi P, et al. The
influence of therapy with silymarin on the survival rate of
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Wochenschr. 1980; 92:678-683.
PubMed
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Randomized controlled trial of silymarin treatment in patients
with cirrhosis of the liver. J Hepatol. 1989; 9:105-113.
PubMed
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11. Salmi HA, Sarna S. Effect of silymarin on
chemical, functional, and morphological alterations of the
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study in 116 patients. Gastroenterol Clin Biol. 1989; 13:120-124.
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13. Arteel GE. Oxidants and antioxidants in alcohol-induced
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PubMed
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15. Blumenthal M. Herb sales down 15 percent
in mainstream market. HerbalGram. 2001; 51:69.
16. Lieber CS, De Carli LM. Animal models of
chronic ethanol toxicity. In Packer L, ed. Methods in Enzymology:
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Journal of Clinical Gastroenterology 2003; 37(4):278-279
Copyright ) 2003 Lippincott Williams & Wilkins
All rights reserved
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