THE AMERICAN JOURNAL OF G.

4sTRoENTERoLoGY
Copyright
0 1998 by Am. Coll. of Gastmenterology
Published
by Elsevier Science Inc.

Vol. 93. No. 2, 1998

ISSN 0002-9270/98/$19.00
I11 SooO2-9270(97)00082-8

Clinical reviews

Milk Thistle (Silybum matinum)

for the Theraply of
Liver Disease
Kenneth Flora, M.D., Martin

Hahn, M.D., Hugo Rosen, M.D., and Kent Benner, M.D.

Division of Gastroenterology,

Oregon Health Sciences University, Portland,

Silymarin, derived from the milk thistle plant, Silybum mariunum, has been used for centuries as a natural
remedy for diseases of the liver and biliary tract. As
interest in alternative therapy has emerged in the United
States, gastroenterologists have encountered increasing
numbers of patients taking silymarin with little understanding of its purported properties. Silymarin and its
active constituent, silybin, have been reported to work as
antioxldants scavenging free radicals and inhibiting lipid
peroxidation.
Studies also suggest that they protect
against genomic injury, increase hepatocyte protein synthesis, decrease the activity of tumor promoters, stabilize
mast cells, chelate iron, and slow calcium metabolism. In
this article we review silymarins history, pharmacology,
and properties, and the clinical trials pertaining to patients with acute and chronic liver disease. (Am J Gastroenterol 1998;93:139-143.
0 1998 by Am. Coll. of
Gastroenterology)

Oregon

improvement in their symptoms, yet the data was insufficient to analyze for objective improvement.
Silybum marianum
is a member of the aster family (Asteruceae or Compositae),
which encompassesdaisies and
thistles, including the common thistle and artichoke. Milk
thistle, distributed widely throughout Europe, was first introduced to North America by European colonists early in
their migration, and now is establishedin the easternUnited
States, California, and South America (3). The name milk
thistle derives from its characteristic spiked leaves with
white veins, which, according to legend, were believed to
carry the milk of the Virgin Mary (4). The Latin name
derives from the sametradition. The mamreplant haslarge,
bright purple flowers and an abundanceof stout spines.This
latter characteristic lends to its use in some locales as a
substitute for barbed wire. Milk thistle is grown commercially throughout the United States, preferring sunny locations and well drained soil.
HISTORY

INTRODUCTION

Extracts of milk thistle have been used as medical remediessince the time of ancient Greece, when Dioscorides, a
Greek herbalist, wrote that a tea of milk thistle seedscould
cure the bite of a poisonoussnake(4). Pliney The Elder (AD
23-79) noted that a mixture of plant juice and honey was
excellent for carrying off bile (5). In 1596, Gerarde stated
that milk thistle was the best remedy against melancholy
or black bile (3). Milk thistle was touted for the treatment of
liver diseasesby Otto Brunfels (1534), Hieronimus Bock
(1595), Jacobus Theodorus (1664), and Adam Lonicerus
(1679) (6). In the late sixteenth century Culpepper (1787)
noted that it was an excellent remedy for obstructions of the
liver and the spleen,and that infusions from fresh root and
seedswere curative for jaundice and for breaking and expelling stones (4). Between 1772 and 1850, Rademacher
popularized the RademachersTincture, an ethanol extract
from the seedsused for hepatosplenicdisorders (7). In this
tradition, at the turn of the 20th century, a school of medical

Derivatives of milk thistle (Silybum marianum) have been

used as herbal remedies for almost 2000 years. They are
currently enjoying a reemergencefor the therapy of liver
disease,asother natural remedieshave becomeincreasingly
popular in the United States.Their usehasbeen widespread
throughout Europe since preparations became officially
available for clinical use there in 1969. At present, milk
thistle extracts account for over $180 million in salesannually in Germany and natural remediesin general for $1.6
billion annually in the United States (1). In a recent poll of
patients attending our Hepatology clinic (2) we found that
31% were using over-the-counter alternative agents for
the therapy of their liver diseases.The most commonly used
nontraditional therapy was milk thistle (silymarin). Over
50% of our patients felt they had experienced subjective
Received

Mar.

26, 1997: accepted

Oct. 13, 1997.

139

FLORA

140

Srudy Findings

Absorption
T,,, (hr)
Elimination
T1,* (hr)
Time to maximum
concentration
(hr)
Maximum
concentration

AJG - Vol. 93, No. 2, 1998

et al.
TABLE 1
on Pharmacokinetics

of Silymarin

Lorenz
(11)

Barzaghi

Healthy
Volunteers,
60 mg

Healthy
Volunteers,
360 mg

(12)

Orlando
(13)
Cirrhotic
Patients,
360 mg

0.17
6.32
1.32

1.4

2.6

0.34

0.2

0.12

&d/ml)
Data taken from Lorenz et al. (ref. ll), Barzaghi et al. (ref. 12), and
Orlando
et al. (ref. 13). Data reported reflect plasma levels after the
specified oral doses.

herbalists called the Eclectics

were using milk thistle
extracts for liver congestion, varicose veins, menstrual
disorders, and abnormalities of the spleen and kidneys (3).
The herbal industry in the U.S. has emerged over the past 2.5
years, as interest in natural remedies and fitness has increased. Annual sales of herbal products were estimated to
be $1.6 billion in 1994 (1). In that same year, Congress
passed the Dietary Supplement Health and Education Act of
1994 (DSHAE) classifying vitamins, minerals, and herbs as
dietary supplements rather than drugs. As such, the Food
and Drug Administration (FDA) has little control over their
manufacture and sales as long as the product labels do not
specify particular medical indications, recommended dosages, or contraindications (8, 9). This has allowed widespread marketing of herbal products and a 300% increase in
the market since 1992 (1).
PHARMACOLOGY
The active extract of milk thistle is silymarin, a mixture
of the flavonolignans, silydianin, silychristine, and silybin,
with the latter being the most biologically active. The flavonoids appear to be active as free radical scavengers and
stabilizers of plasma membranes. Concentrations of silymatin are highest in the fruit of the plant, as well as in the seeds
and leaves (3, 6), from which it is typically extracted with
95% ethyl alcohol, yielding a bright yellow fluid. The term
flavonoid is derived from flavus, meaning yellow.
A standard silymarin extract contains 70% silymarin (10);
however, with the lack of FDA regulation, it is unclear that
most products are assayed for content of active compounds.
Pharmacokinetic
studies have shown that there is rapid
absorption of silybin into the bloodstream after an oral dose.
Peak plasma concentrations are reached after 2 h and the
elimination T,,* is 6 h (11, 12, 13) (Table 1). From 3 to 8%
of an oral dose is excreted in the urine (12, 15, 16); 20-40%
is recovered from the bile as glucuronide and sulfate conjugates (15, 16, 18, 19). Silybin levels in bile peak within 2
to 9 h (15) and biliary excretion continues for 24 h after a

single dose. Efforts to increase intestinal absorption have

included combining the silybin with phosphatidylcholine
(compound dB 1016), which results in an increase in biliary
silybin concentrations from 3 to 11% (12). An enterohepatic
circulation of silymarin has been suggested (3, 20).
PROPERTIES
It is hypothesized that silybin functions as an antioxidant,
reacting rapidly with oxygen free radicals as demonstrated
in vitro with hydroxyl anions (OH-) and hypochlorous acid
(HOCL) (21). Reported activities include inhibition of lipid
peroxidation of hepatocyte, microsomal (22,23), and erythrocyte (24) membranes in rats, and protection against
genomic injury by suppression of hydrogen peroxide and
super oxide anions and of lipoxygenase. Silybin is also
thought to increase hepatocyte protein synthesis by stimulating the activity of ribosomal RNA polymerase (25). Furthermore, it decreases hepatic and mitochondrial glutathione
oxidation induced by iron overload and is a mild chelator of
iron (26). It decreases the activity of tumor promoters (27),
stabilizes mast cells (28), protects against radiation-induced
suppression of hepatic and splenic DNA and RNA synthesis
(29), and may slow calcium metabolism.
HUMAN

CLINICAL

TRIALS

Most of the clinical trials designed to assess the efficacy

of silymarin are difficult to interpret, as they are flawed by
the small numbers of subjects, variability in etiologies, and
severity of the liver diseases studied, as well as inconsistencies in alcohol usage by patients, heterogeneous dosing,
inconsistent use of control groups, and inadequately defined
endpoints. Demonstration of statistically significant biochemical or histological improvement in liver injury has
been the exception. In addition, the intrinsic ability of liver
injury to improve upon removal of hepatotoxins, i.e., discontinuation of alcohol use or resolution of acute hepatitis,
has usually not been taken into account in these studies.
Acute viral hepatitis
Double blind studies on humans with acute viral hepatitis
generally suggest that therapy with silymarin decreases
complications (30), hastens recovery. and shortens hospital
stays. In a study by Magliulo et al., 57 patients with acute
hepatitis A or B were randomized in a double blind fashion
to receive silymarin 140 mg t.i.d. for at least 3 wk (28
patients, mean treatment duration 26.6 days) or a placebo
(31). Presence of underlying liver disease or alcohol use was
not commented on. After 5 days, mean levels of AST and
ALT and total bilirubin were significantly lower in the
treated group than in the placebo group. Significantly more
patients had normalization of bilirubin (40 vs 11%) and AST
(82 vs 52%) within 3 wk. There was no difference in the
number of patients who developed immunity. A second
controlled trial showed a significantly shorter length of

AJG - February

1998

inpatient care (23.3 vs 30.4 days) in patients treated with

silymarin when compared with patients who received supportive care only (32). Moreover, among the patients with
hepatitis B, a shorter interval to the development of immunity (30.4 vs 41.2 days, respectively) was demonstrable in
the silymarin group. Patients who exhibited increases in
AST or ALT levels after initiation of therapy were removed
from analysis, perhaps inappropriately, as this type of response is desirable in patients undergoing therapy with
interferon.
Toxin and drug-induced hepatitis
Silymarin therapy has been studied for both natural and
industrial toxin exposure. It has been evaluated most extensively for its role in acute poisoning with the Amanita
phalloides mushroom. In early studies, isolated livers from
dogs, rabbits, rats, mice, and pigs were exposed to high
doses of phalloidin. Silymarin administered before sacrifice
was effective in diminishing histologic injury (33, 34, 35).
Lyophilized Amanita phalloides was administered to 23
beagles, resulting in vomiting and diarrhea after a mean of
16 h (36). Twelve of the dogs received only supportive care
and four died after developing coma within 35-54 h. Among
the I I dogs who received silybin 50 mg/kg at 5 h and 24 h
after poisoning, none died. Liver function tests peaked at
lower levels, prothrombin time prolongation was less, and
histologic evidence of hemorrhagic necrosis was markedly
reduced. Silymarin has also been reported to be effective
against Amanita poisoning in humans. In an uncontrolled
study, 60 consecutive patients were treated with silybin 20
mg/kg/day, which was initiated 24 h to 36 h after Amanita
ingestion. The survival rate was 100% (37). A second European trial involving 220 patients resulted in a mortality
rate of 12.8%, versus a 22.4% rate in patients who had not
received silymarin therapy (38, 39).
Fourteen persons chronically exposed to organophosphates (malathion) and treated with silymarin for 1 month
did not show improvement in liver function tests when
compared with 10 matched controls. Serum pseudocholinesterase levels rose significantly, however, perhaps reflecting blockade of an anticholinesterase activity of the
toxin by the silymarin (40). Silymarin therapy for exposure
to many solvents, paints, and glues resulting in subacute or
chronic liver disease has not led to significant improvement
in AST and ALT levels. Conversely, Szilard treated 30
patients exposed to toluene and/or xylene for over 5 yr and
found that AST, ALT, and platelet counts all improved (41).
Although the published trials of silymarin for drug-induced hepatitis were small and therefore not reliable, the
results reported are positive. Sixty patients receiving treatment with psychotropic medications (phenothiazines or butyrophenones) were divided into two groups and their medication was either discontinued or the dose left unchanged
(42). Both groups were divided again with half of each
receiving silymarin 800 mg/day, the other a placebo for 90
days. Silymarin therapy resulted in improved liver function

MILK

THISTLE

FOR LIVER

DISEASE

141

tests regardless of whether or not the psychotropic drugs

were discontinued. Improvement in biochemical parameters
was also found by Saba in 19 patients or psychotropic drugs
after 6 months of silymarin treatment (43). Martines et al.
noted that silymarin protected against histologic changes
found in the livers of women who were pregnant or on birth
control pills (44). Silymarin also seems to reduce the toxic
hepatic injury caused by halothane (451.
Alcoholic liver disease
A 6-month, double blind trial of patients who chronically
abused alcohol and had histologic documentation of chronic
alcoholic hepatitis was reported in a series of papers (46). In
17 patients on silymarin 140 mg b.i.d. for 6 months, total
bilirubin, AST, and ALT levels normalized and GGT and
procollagen III levels decreased significantly, as compared
with levels in 19 placebo patients. Pod.tive effects of silymarin on histology, lymphocyte proliferation, and lipid peroxidation were also described.
Ninety-seven patients with persistent liver function test
abnormalities after abstinence for over 1 month from alcohol were randomized to 4 months of silymarin versus placebo (47). At the end of therapy, mean serum AST levels
had fallen by 30% compared with a 5% increase in the
placebo group. ALT levels fell by 41% with silymarin
compared with a 3% increase with placebo. There was no
significant difference in bilirubin levels, Significantly more
patients returned to a normal bromophthalein retention with
treatment and there was significantly more reversal of histological injury. Abstinence from alcohol during the study
period was advised but not monitored.
A double blind, randomized, placebo-controlled trial of
patients who met biochemical and histological criteria for
acute alcoholic hepatitis divided 66 patients into two
groups: 31 who received silymarin (dose unspecified) and
35 who received placebo (48). Mean AST, ALT, and GGT
levels normalized sooner (13 vs 24 day.s), and significantly
more often in the treated over those in the placebo group. A
higher number of silymarin patients had normalization of all
three parameters versus those in the placebo patients. Significant differences between the groups were noted by day
7.
Chronic hepatitis/cirrhosis
(undifferent,!ated)
Ferenci asked 170 patients with biopsy-confirmed cirrhosis (92 alcoholic, 78 nonalcoholic) to abstain from alcohol,
then treated 87 with silymarin 140 mg t.i.d. and 83 with
placebo for a period of 2-6 years (mean follow-up 41
months) (49). A total of 105 patients completed the follow-up period. Biochemical parameters did not change significantly. However, survival did improve in the treated
group (77 1~s67% overall, and 82 vs 68,s at 2 yr). Survival
was higher in patients who had abused alcohol @ = 0.01).
In nonalcoholics, only Childs A patients benefited. There
was no survival change in Childs classes B and C.
A total of 2637 patients with chronic liver disease were

142

FLORA

et al.

treated with high dose silymarin (560 mg/day) for 8 wk.

Resolution of subjective symptoms occurred in 63%. The
mean AST fell by 36%, the mean ALT by 34%, and the
mean GGT by 46%. There was also a decrease in the
frequency of palpable hepatomegaly reported by the examining physicians (50).
JSiesewetter performed a 12-month study combining two
double blind trials assessing histologically how silymarin
affected patients with chronic persistent or aggressive
hepatitis with or without cirrhosis (51). All patients with a
duration of disease of <6 months, alcohol intake >80 g/day,
or previous therapy with silymarin or steroids, or on other
medication, were excluded. Over an observation period of
3-12 months, no differences in improvement in liver function tests were noted between the two groups. There was a
trend toward improvement in portal inflammation, parenchymal alteration, and piecemeal necrosis. Incomplete follow-up resulted in reporting the outcomes of only 36 of the
60 patients enrolled.
In summary, silymarin has been used for the treatment of
liver diseases for centuries. It may be effective in improving
the clinical courses of both acute and chronic viral, drug-,
and toxin-induced and alcoholic hepatitis. Reported trials of
the compound must be interpreted with care, however, because of the small number of patients enrolled, the heterogeneity of diagnoses within the same study, the lack of
standardization of silymarin preparations, dosing, and outcome parameters, and the inconsistent presence or absence
of alcohol. Clearly, silymarin has not been shown to have
any adverse side effects. Because the popularity of treatment
with this and other herbs for a variety of medical maladies
is increasing, well-designed,
double blind, placebo-controlled studies for specified diagnoses are necessary.
Reprint requests and correspondence:
Ken Flora, M.D., Assistant Professor of Medicine, Division of Gastroenterology,
Oregon Health Sciences
University,
3181 SW Sam Jackson Park Rd; PV310, Portland, OR 972013098.

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