Journal Of Herbal Pharmacotherapy

ISSN: 1522-8940 (Print) 1522-9106 (Online) Journal homepage: https://www.tandfonline.com/loi/iher20

The Clinical Utility of Milk Thistle (Silybum

marianum) in Cirrhosis of the Liver

Joel Boerth (Clinical Assistant Professor) (Psychiatric Pharmacy Resident) &

Kathryn M. Strong

To cite this article: Joel Boerth (Clinical Assistant Professor) (Psychiatric Pharmacy Resident) &
Kathryn M. Strong (2002) The Clinical Utility of Milk Thistle (Silybum�marianum) in Cirrhosis of the
Liver, Journal Of Herbal Pharmacotherapy, 2:2, 11-17, DOI: 10.1080/J157v02n02_02

To link to this article: https://doi.org/10.1080/J157v02n02_02

Published online: 20 Aug 2009.

Submit your article to this journal

Article views: 87

View related articles

Citing articles: 10 View citing articles

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=ijds20
 The Clinical Utility
of Milk Thistle (Silybum marianum)
in Cirrhosis of the Liver
Joel Boerth, PharmD
Kathryn M. Strong, PharmD

ABSTRACT. Milk thistle (Silybum marianum) is a flowering herb uti-

lized for its potentially protective effects on the liver. Although the
mechanism of action is not fully understood, one explanation may be that
it concentrates in the hepatocytes and competes with toxins for hepa-
tocyte binding and penetration. Preliminary clinical evaluations of milk
thistle for cirrhosis of the liver indicate potential benefits in healthier pa-
tients with alcoholic cirrhosis. However, major flaws in many of the
studies make it difficult to draw solid conclusions. Milk thistle appears to
be relatively safe, even with long-term use. [Article copies available for a
fee from The Haworth Document Delivery Service: 1-800-HAWORTH. E-mail
address: <getinfo@haworthpressinc.com> Website: <http://www.HaworthPress.
com> 2002 by The Haworth Press, Inc. All rights reserved.]

KEYWORDS. Milk thistle, Silybum marianum, liver, cirrhosis, silybin,

silychristin, silidianin

Milk thistle (Silybum marianum) is an herb that has received much

public attention for its protective effects on the liver. It is a flowering
plant indigenous to the Mediterranean, which can now be found through-
out North America.1 The flowers of the plant hold seeds that contain a

Joel Boerth is Psychiatric Pharmacy Resident, University of Connecticut College of

Pharmacy.
Kathryn M. Strong is Clinical Assistant Professor, University of Rhode Island Col-
lege of Pharmacy, 144 Fogartu Hall, Kingston, RI 02881.
Journal of Herbal Pharmacotherapy, Vol. 2(2) 2002
 2002 by The Haworth Press, Inc. All rights reserved. 11
12 JOURNAL OF HERBAL PHARMACOTHERAPY

biologically active compound called silymarin. Since the oral bioavail-

ability of silymarin is quite low, high concentrations of the extract are
required for all orally administered preparations.1 Silymarin extract is
used to produce a variety of milk thistle products (Table 1). In the
United States milk thistle is available in capsule, tablet, and liquid form.
Most products are standardized by silymarin content. Milk thistle prod-
ucts commonly contain 140 milligrams of silymarin per capsule, but
strengths can vary from one brand to another. Some products even mix
vitamins and other herbs with silymarin.
Silymarin is actually a combination of three flavonolignans (silybin,
silychristin, and silidianin). Of the three flavonolignans, silybin is the
compound most responsible for silymarin’s hepatoprotective proper-
ties.1 Like many biologically active compounds, silymarin’s mecha-
nism for hepatoprotection is not fully understood. It is known that
silymarin stays largely confined to enterohepatic circulation and con-
centrates in hepatocytes.1 Silymarin may compete with toxins for hepato-
cyte binding which blocks the penetration of toxins. It is also considered
to have antioxidant properties.1 Hence, silymarin may act as a scaven-
ger for harmful free radicals. Additionally, silymarin may also stimu-
late nucleolar polymerase A resulting in increased ribosomal protein
synthesis, which can stimulate liver regeneration and the formation of
new hepatocytes, thus augmenting the regenerative capacity of the
liver.

TABLE 1. Examples of Products Containing Milk Thistle (Silybum marianum)

Anti-Ox: Herbal Antioxidant Arthro-Glucosamine

Atri-Oxy C+Herbs
Cat's Claw Defense Complex CleanseSMART I
Complete Cleanse Daily Detox
Dandelion-Milk Thistle Virtue Derma-Klear Akne Treatment Cream
Detox Detox-Support-Now
Detoxinal Detoxygen
Earthrise NutraGreens Enviro-Gard
Female Balance-Enzymatic Therapy Firm Lotion
From the Earth Herbal Liver Complex
Holista Milk Thistle Immumax-Rx
Lipotrope Liv-R-Actin Milk Thistle Blend
Liver Guard Liver Maintenance Formula
Liver Enhancer Livr D-Tox
Livral UnDo
 Joel Boerth and Kathryn M. Strong 13

The positive biological effects of silymarin have lent some hope to a

number of Americans afflicted with cirrhosis of the liver. Despite a de-
cline in the death rate over the last twenty years, cirrhosis continues to
contribute significantly to all-cause mortality in Americans.2 It is known
that there are a host of drug-related, viral, autoimmune, and genetic
causes of cirrhosis. Still, in the United States the most prominent cause
is the chronic consumption of alcohol.2 Cirrhosis is the ultimate result
of any longstanding liver disease. The major complication of cirrhosis
is portal hypertension, which is responsible for further insults such as
ascites, and esophageal varices.2 Hepatic encephalopathy, jaundice,
and coagulopathies are among other complications associated with this
terminal illness. In addition, nutritional status of these patients is typi-
cally quite poor.2 This is due in part to degeneration in liver function,
however alcoholics tend to be malnourished despite changes in liver
function. Treatment of cirrhosis has traditionally been symptomatic and
supportive as the only cure for the disease is through a liver transplant.
As a result, many people seek alternative therapies that can be added to
their conventional treatment. Because milk thistle is thought to have a
positive effect on liver tissue, many cirrhotic patients are using the herb
as a supportive adjunct to conventional therapy.
In a study by Ferenci et al. entitled “Randomized controlled trial of
silymarin treatment in patients with cirrhosis of the liver,” 170 patients
with mixed forms of cirrhosis confirmed on biopsy were randomized to
receive 140 mg of silymarin three times per day or placebo for 2-6 years
duration.3 Both alcoholic and non-alcoholic patients with cirrhosis were
included in the study, and patients had varied ranges of liver disease se-
verity. Child-Turcotte4 criteria were used to classify liver disease sever-
ity (Child A; less severe, Child B; moderate severity, Child C; more
severe). Patients were excluded from the study if they had end-stage
liver failure (ESLF), malignancies, primary biliary cirrhosis, or were
taking immunosuppressive medications. Approximately two-thirds of
patients who entered the study were newly diagnosed with cirrhosis.
Overall, most patients fit the Child class A and B criteria. Very few pa-
tients were classified as Child C. All patients were expected to abstain
from alcohol during the study. To assess abstinence, patients and family
members were questioned about alcohol use. Additionally, serum γ-gluta-
myl-transpeptidase (SGGTP) levels were used to detect alcohol use.
Every three months liver function was assessed using parameters such
as liver enzymes, serum bilirubin, prothrombin time, and serum albu-
min levels. The study was originally scheduled to run for two years,
14 JOURNAL OF HERBAL PHARMACOTHERAPY

however, the recruitment process took more time than anticipated. Con-
sequently, the study was not completed until the last of the new recruits
had participated for a two-year period.
Results of the Ferenci study demonstrated a non-significant differ-
ence in mortality of 33% versus 23% in placebo and silymarin groups
respectively (p = 0.07) during the two-year study period.3 At the
four-year mark cumulative survival rates were significantly different in
the two groups (58% in the silymarin group versus 38% in the placebo
group, p = 0.036). In the alcoholic subgroup there were twice as many
deaths in the placebo group and outcome was better in the silymarin
group (p = 0.01).3 Interestingly, silymarin treatment did not improve
survival rates in the subgroup of patients who were not alcoholics.
Finally, silymarin patients in the Child A subgroup demonstrated sig-
nificantly larger survival rates over placebo (p = 0.03), but silymarin
patients in Child groups B and C did not improve their survival rates.
The adverse effects most commonly experienced in silymarin treated
patients were nausea and mild epigastric discomfort. Overall, silymarin
treatment was well tolerated.
The Ferenci trial contains some significant defects. For example, the
authors gave no indication as to how end-stage liver failure was defined
or how ESLF was different than the Child C classification. The investi-
gators measured serum γ-glutamyl-transpeptidase (SGGTP) levels to
detect alcohol use. Elevations of this enzyme are actually non-specific
and may be related to completely non-hepatic functions, including pan-
creatic, renal, diabetes, and pulmonary diseases. Additionally, the out-
comes being measured were confounded by the heterogeneous nature
of the disease. Furthermore, the trial’s outcomes were poorly defined,
leaving readers the task of postulating which findings were most impor-
tant to the investigators. In the analysis of survival rates in each sub-
group of cirrhosis, it is unclear which time points reached significance
and which did not. Despite these pitfalls, some useful information can
be derived from the trial. For example, it appeared that only the alco-
holic subgroup was able to benefit from the silymarin treatment. Addi-
tionally, patients classed as Child A showed better survival rates than
classes B and C. This information suggests that perhaps silymarin treat-
ment should be considered only in alcoholic patients who present with
mild cirrhosis.
A trial by Parés et al. entitled “Effects of silymarin in alcoholic pa-
tients with cirrhosis of the liver: results of a controlled, double-blind,
randomized and multicenter trial,” was designed to evaluate time to
 Joel Boerth and Kathryn M. Strong 15

death and progression to liver failure as primary and secondary out-

comes, respectively.5 Two hundred patients were enrolled in the study.
All patients were alcoholics with histologically proven cirrhosis of the
liver (laparoscopic exam was used in subjects with delayed prothrom-
bin times). An alcoholic was defined as a male who consumes greater
than 80 g of ethanol per day, or a female who consumes greater than 60
g of ethanol per day.5 Patients were excluded from the trial for: prior use
of colchicine, malotilate, penicillamine, or corticosteroids (all being in-
vestigated in cirrhosis); life expectancy less than six months; addiction
to other drugs; or pregnancy.5 Likewise, patients were excluded for
having forms of cirrhosis caused by hepatitis B, autoimmunity, primary
biliary cirrhosis, or cryptogenic cirrhosis.5 These exclusions served to
provide the investigators with a more homogenous patient base. The pa-
tients were randomly assigned to treatment with 150 mg of silymarin
three times per day or placebo. Subjects were asked to abstain from al-
cohol during the study. Alcohol use was assessed through questioning
of subjects and relatives. Alcohol was also tested in the urine at each
follow-up visit. As in the Ferenci trial, follow-up visits were performed
every three months, and liver function was monitored by changes in
liver enzymes, serum bilirubin, prothrombin time, and serum albu-
min.3,5
The Parés trial could not detect any significant differences in survival
rate at any point in time. Interestingly, both the silymarin group and pla-
cebo group experienced fewer complications of cirrhosis at the conclu-
sion of the study when compared to baseline. Additionally, both groups
experienced improvement in laboratory measures. This implies that re-
moval of the offensive agent (alcohol) has a beneficial effect regardless
of silymarin treatment. Adverse effects documented in both groups in-
clude arthralgias, pruritus, headache, and urticaria. A total of eleven
cases of adverse events were documented in the two groups.
This trial also has its strengths and weaknesses. For example, the in-
vestigators’ attempt at homogenizing the type of cirrhosis under study
was valid because it removed some of the same confounders present in
the Ferenci trial. Additionally, the investigators clearly defined the pri-
mary and secondary outcomes of the study. Nevertheless, this trial had
problems with dropouts. Of the 200 patients entered into the trial, 15
(seven in the treatment group and eight in the placebo group) did not re-
turn after the first visit. Eighteen patients (ten in the treatment and eight
placebo) died. In addition, 42 patients left the trial during the first 2
years, typically due to drug-related adverse effects and non-compliance
or voluntary withdrawal. Overall, there were 46 dropouts in the treat-
16 JOURNAL OF HERBAL PHARMACOTHERAPY

ment group and 29 in the placebo. In trials where sample size is small to
begin with, dropouts have an overwhelming impact on the power of the
study. Therefore, there may have been differences in the two treatment
arms that were not detected due to a loss of power.
It has been difficult to draw solid conclusions based on the clinical
trials assessing silymarin’s efficacy. The problems facing clinicians
have been: small numbers of subjects, heterogeneity of the disease un-
der investigation, variable dosing strategies from one study to another,
and poorly defined study endpoints. In reviewing the Ferenci and Parés
studies, only the Ferenci study detected a decreased mortality in pa-
tients with cirrhosis taking silymarin, but that was only after four years
of treatment. Another interesting point is that the Ferenci study showed
that healthier, alcoholic patients seem to derive more benefit from
silymarin treatment than any other group. Perhaps this observation
should prompt a more refined examination of silymarin’s efficacy in the
healthier patients with alcoholic cirrhosis. Finally, the Parés study dem-
onstrated that simply abstaining from alcohol is enough to improve
liver function. This highlights the intrinsic regenerative capabilities of
the liver upon discontinuation of hepatotoxins (something that many
silymarin studies fail to address).
As seen in the trials, adverse reactions to milk thistle are generally
mild. When taken orally, milk thistle may cause a laxative effect. Also,
allergic reactions may occur in patients sensitive to the Asteraceae/
Compositae family. This includes chrysanthemums, marigolds, rag-
weed, and daisies. Drug interactions are mostly theoretical at this point
and may be related to milk thistle’s inhibition of the cytochrome
P450-3A4 enzyme.8 Drugs that may potentially interact include lova-
statin, ketoconazole, itraconazole, fexofenadine, and triazolam.
Clinical studies of milk thistle’s effectiveness have used the stan-
dardized 70% silymarin extract at a daily dose of 200-400 mg calcu-
lated as silibinin. Alternatively, the typical dose is 12-15 g of the dried
fruit or seed per day.9,10 It is not recommended to administer as a tea as
the active ingredients are not very soluble in water.9 Intravenous silibinin,
typically used in cases of Amanita phalloides mushroom poisoning, is
not available in the United States.
Clearly, more research is needed to determine the role of silymarin in
cirrhosis. On a positive note, silymarin was not shown to cause undue
harm in subjects treated with the herb, and most subjects tolerated treat-
ment quite well.3,5 Additionally, the extended duration of silymarin
used in these studies appears to support safety in long-term use. At the
 Joel Boerth and Kathryn M. Strong 17

very least, this indicates that routine use of this herb probably poses lit-
tle threat to consumers. Health care professionals can support patients
in their decision to use milk thistle products, but patients need to under-
stand that the products may or may not provide the desired benefit.

REFERENCES
1. Hebel, SK (ed.) Facts and Comparisons. The Review of Natural Products. St.
Louis (MO): Wolters Kluwer Company; 1996.
2. Gill MA, Kirchain WR. Portal hypertension and cirrhosis. In: DiPiro JT,
Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy: A
Pathophysiologic Approach. 4th ed. Stamford (CT): Appleton & Lange; 1999,
pp. 614-618.
3. Ferenci P, Dragosics B, Dittrich H, Frank H, Benda L, Lochs H, et al. Random-
ized controlled trial of silymarin treatment in patients with cirrhosis of the liver. Jour-
nal of Hepatology 1989;9:105-113.
4. Child CG, Turcotte JG. Surgery and portal hypertension. In: Child CG, ed. The
Liver and Portal Hypertension. Philadelphia: WB Saunders and Co., 1964; 50-56.
5. Parés A, Planas R, Torres M, Caballería J, Viver JM, Acero D, et al. Effects of
silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, dou-
ble-blind, randomized and multicenter trial. Journal of Hepatology 1998;28:615-621.
6. Flora K, Hahn M, Rosen H, Benner K. Milk thistle (Silybum marianum) for the
therapy of liver disease. The American Journal of Gastroenterology 1998;93(2):139-143.
7. Pepping J. Milk thistle: Silybum marianum. American Journal of Health-Sys-
tem Pharmacy 1999 Jun 15;56:1195-1197.
8. Budzinski JW, Foster BC, Vandenhoek S, et al. An in vitro evaluation of human
cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures.
Phytomedicine 2000;7:273-82.
9. Tyler VE. The Honest Herbal: A Sensible Guide to the Use of Herbs and Re-
lated Remedies. 3rd ed. Binghamton, New York: Pharmaceutical Products Press,
1993.
10. Wichtl MW. Herbal Drugs and Phytopharmaceuticals. Bisset NM, ed. Stuttgart:
Medpharm GmbH Scientific Publishers, 1994.

SUBMITTED: 05/03/01
REVISED: 06/20/01
ACCEPTED: 09/13/01