Milk Thistle: Effects on Liver Disease and Cirrhosis and Clinical Adverse Effect

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Milk Thistle: Effects on Liver Disease and Cirrhosis and Clinical

Adverse Effects

Under its Evidence-based Practice Program, the Agency for Healthcare

Research and Quality (AHRQ) is developing scientific information for

other agencies and organizations on which to base clinical

guidelines, performance measures, and other quality improvement

tools. Contractor institutions review all relevant scientific

literature on assigned clinical care topics and produce evidence

reports and technology assessments, conduct research on methodologies

and the effectiveness of their implementation, and participate in

technical assistance activities. This evidence report details a

systematic review summarizing clinical studies of milk thistle in

humans.

Overview

The scientific name for milk thistle is Silybum marianum. It is a

member of the aster or daisy family and has been used by ancient

physicians and herbalists to treat a range of liver and gallbladder

diseases and to protect the liver against a variety of poisons.

Two areas are addressed in the report:

· Effects of milk thistle on liver disease of alcohol, viral, toxin,

cholestatic, and primary malignancy etiologies.

· Clinical adverse effects associated with milk thistle ingestion or

contact.

The report was requested by the National Center for Complementary and

Alternative Medicine, a component of the National Institutes of

Health, and sponsored by the Agency for Healthcare Research and

Quality.

Reporting the Evidence

Specifically, the report addresses 10 questions regarding whether

milk thistle supplements (when compared with no supplement, placebo,

other oral supplements, or drugs):

· Alter the physiologic markers of liver function.

· Reduce mortality or morbidity, or improve the quality of life in

adults with alcohol-related, toxin-induced, or drug-induced liver

disease, viral hepatitis, cholestasis, or primary hepatic malignancy

(hepatocellular carcinoma).

One question addresses the constituents of commonly available milk

thistle preparations, and three questions address the common and

uncommon symptomatic adverse effects of milk thistle.

Methodology

Search Strategy

Eleven electronic databases, including AMED, CISCOM, the Cochrane

Library (including DARE and the Cochrane Controlled Trials Registry),

EMBASE, MEDLINE, and NAPRALERT, were searched through July 1999 using

the following terms:

· Carduus marianus.

· Legalon.

· Mariendistel.

· Milk thistle.

· Silybin.

· Silybum marianum.

· Silybum.

· Silychristin.

· Silydianin.

· Silymarin.

An update search limited to PubMed was conducted in December 1999.

English and non-English citations were identified from these

electronic databases, references in pertinent articles and reviews,

drug manufacturers, and technical experts.

Selection Criteria

Preliminary selection criteria regarding efficacy were reports on

liver disease and clinical and physiologic outcomes from randomized

controlled trials (RCTs) in humans comparing milk thistle with

placebo, no milk thistle, or another active agent. Several of these

randomized trials had dissimilar numbers of subjects in study arms,

raising the question that these were not actually RCTs but cohort

studies. In addition, among studies using non placebo controls, the

type of control varied widely. Therefore, qualitative and

quantitative syntheses of data on effectiveness were limited to

placebo-controlled studies. For adverse effects, all types of studies

in humans were used to assess adverse clinical effects.

Data Collection and Analysis

Abstractors (physicians, methodologists, pharmacists, and a nurse)

independently abstracted data from trials; a nurse and physician

abstracted data about adverse effects. Data were synthesized

descriptively, emphasizing methodologic characteristics of the

studies, such as populations enrolled, definitions of selection and

outcome criteria, sample sizes, adequacy of randomization process,

interventions and comparisons, cointerventions, biases in outcome

assessment, and study designs.

Evidence tables and graphic summaries, such as funnel plots,

Galbraith plots, and forest plots, were used to examine relationships

between clinical outcomes, participant characteristics, and

methodologic characteristics. Trial outcomes were examined

quantitatively in exploratory meta-analyses that used standardized

mean differences between mean change scores as the effect size

measure.

Findings

Mechanisms of Action

Evidence exists that milk thistle may be hepatoprotective through a

number of mechanisms: antioxidant activity, toxin blockade at the

membrane level, enhanced protein synthesis, antifibriotic activity,

and possible anti-inflammatory or immunomodulating effects.

Preparations of Milk Thistle

The largest producer of milk thistle is Madaus (Germany), which makes

an extract of concentrated silymarin. However, numerous other

extracts exist, and more information is needed on comparability of

formulations, standardization, and bioavailability for studies of

mechanisms of action and clinical trials.

Benefit of Milk Thistle for Liver Disease

· Sixteen prospective trials were identified. Fourteen were

randomized, blinded, placebo-controlled studies of milk thistle's

effectiveness in a variety of liver diseases. In one additional

placebo-controlled trial, blinding or randomization was not clear,

and one placebo-controlled study was a cohort study with a placebo

comparison group.

· Seventeen additional trials used non placebo controls; two other

trials studied milk thistle as prophylaxis in patients with no known

liver disease who were starting potentially hepatotoxic drugs. The

identified studies addressed alcohol-related liver disease, toxin-

induced liver disease, and viral liver disease. No studies were found

that evaluated milk thistle for cholestatic liver disease or primary

hepatic malignancy (hepatocellular carcinoma, cholangiocarcinoma).

· There were problems in assessing the evidence because of

incomplete information about multiple methodologic issues, including

etiology and severity of liver disease, study design, subject

characteristics, and potential confounders. It is difficult to say if

the lack of information reflects poor scientific quality of study

methods or poor reporting quality or both.

· Detailed data evaluation and syntheses were limited to the 16

placebo-controlled studies. Distribution of durations of therapy

across trials was wide (7 days to 2 years), inconsistent, and

sometimes not given. Eleven studies used Legalon®, and eight of those

used the same dose. Outcome measures varied among studies, as did

duration of therapy and the followup for which outcome measures were

reported.

· Among six studies of milk thistle and chronic alcoholic liver

disease, four reported significant improvement in at least one

measurement of liver function (i.e., aminotransferases, albumin,

and/or malondialdehyde) or histologic findings with milk thistle

compared with placebo, but also reported no difference between groups

for other outcome measures.

· Available data were insufficient to sort six studies into

specific etiologic categories; these were grouped as chronic liver

disease of mixed etiologies. In three of the six studies that

reported multiple outcome measures, at least one outcome measure

improved significantly with milk thistle compared with placebo, but

there were no differences between milk thistle and placebo for one or

more of the other outcome measures in each study. Two studies

indicated a possible survival benefit.

· Three placebo-controlled studies evaluated milk thistle for viral

hepatitis. The one acute viral hepatitis study reported latest

outcome measures at 28 days and showed significant improvement in

aspartate aminotransferase and bilirubin. The two studies of chronic

viral hepatitis differed markedly in duration of therapy (7 days and

1 year). The shorter study showed improvement in aminotransferases

for milk thistle compared with placebo but not other laboratory

measures. In the longer study, milk thistle was associated with a

nonsignificant trend toward histologic improvement, the only outcome

measure reported.

· Two trials included patients with alcoholic or nonalcoholic

cirrhosis. The milk thistle arms showed a trend toward improved

survival in one trial and significantly improved survival for

subgroups with alcoholic cirrhosis or Child's Group A severity. The

second study reported no significant improvement in laboratory

measures and survival for other clinical subgroups, but no data were

given.

· Two trials specifically studied patients with alcoholic cirrhosis.

Duration of therapy was unclear in the first, which reported no

improvement in laboratory measures of liver function, hepatomegaly,

jaundice, ascites, or survival. However, there were nonsignificant

trends favoring milk thistle in incidence of encephalopathy and

gastrointestinal bleeding and in survival for subjects with

concomitant hepatitis C. The second study, after treatment for 30

days, reported significant improvements in aminotransferases but not

bilirubin for milk thistle compared with placebo.

· Three trials evaluated milk thistle in the setting of hepatotoxic

drugs: one for therapeutic use and two for prophylaxis with milk

thistle. Results were mixed among the three trials.

· Exploratory meta-analyses generally showed positive but small and

nonsignificant effect sizes and a sprinkling of significant positive

effects.

· No studies were identified regarding milk thistle and cholestatic

liver disease or primary hepatic malignancy.

· Available evidence does not establish whether effectiveness of

milk thistle varies across preparations. One Phase II trial suggested

that effectiveness may vary with dose of milk thistle.

Adverse Effects

Adverse effects associated with oral ingestion of milk thistle

include:

· Gastrointestinal problems (e.g., nausea, diarrhea, dyspepsia,

flatulence, abdominal bloating, abdominal fullness or pain, anorexia,

and changes in bowel habits).

· Headache.

· Skin reactions (pruritus, rash, urticaria, and eczema).

· Neuropsychological events (e.g., asthenia, malaise, and insomnia).

· Arthralgia.

· Rhinoconjunctivitis.

· Impotence.

· Anaphylaxis.

However, causality is rarely addressed in available reports. For

randomized trials reporting adverse effects, incidence was

approximately equal in milk thistle and control groups.

Conclusions

Clinical efficacy of milk thistle is not clearly established.

Interpretation of the evidence is hampered by poor study methods

and/or poor quality of reporting in publications. Problems in study

design include heterogeneity in etiology and extent of liver disease,

small sample sizes, and variation in formulation, dosing, and

duration of milk thistle therapy.

Possible benefit has been shown most frequently, but not

consistently, for improvement in aminotransferases and liver function

tests are overwhelmingly the most common outcome measure studied.

Survival and other clinical outcome measures have been studied least

often, with both positive and negative findings. Available evidence

is not sufficient to suggest whether milk thistle may be more

effective for some liver diseases than others or if effectiveness

might be related to duration of therapy or chronicity and severity of

liver disease.

Regarding adverse effects, little evidence is available regarding

causality, but available evidence does suggest that milk thistle is

associated with few, and generally minor, adverse effects.

Despite substantial in vitro and animal research, the mechanism of

action of milk thistle is not fully defined and may be

multifactorial. A systematic review of this evidence to clarify what

is known and identify gaps in knowledge would be important to guide

design of future studies of the mechanisms of milk thistle and

clinical trials.

Future Research

The type, frequency, and severity of adverse effects related to milk

thistle preparations should be quantified. Whether adverse effects

are specific to dose, particular preparations, or additional herbal

ingredients needs elucidation, especially in light of equivalent

frequencies of adverse effects in available randomized trials. When

adverse effects are reported, concomitant use of other medications

and product content analysis should also be reported so that other

drugs, excipients, or contaminants may be scrutinized as potential

causal factors.

Characteristics of future studies in humans should include:

· Longer and larger randomized trials.

· Clinical as well as physiologic outcome measures.

· Histologic outcomes.

· Adequate blinding.

· Detailed data about Systematic standardized surveillance for

adverse effects.

· Attention to specific study populations (e.g., patients with

hepatitis B virus [HBV], or hepatitis C virus [HCV], or mixed

infection or coinfection with human immunodeficiency virus [HIV]),

comorbidities, alcohol consumption, and potential confounders.

There also should be detailed attention to preparation,

standardization, and bioavailability of different formulations of

milk thistle (e.g., standardized silymarin extract and silybin-

phosphatidylcholine complex).

Precise mechanisms of action specific to different etiologies and

stages of liver disease need explication. Further mechanistic

investigations are needed and should be considered before, or in

concert with, studies of clinical effectiveness. More information is

needed about effectiveness of milk thistle for severe acute ingestion

of hepatotoxins, such as occupational exposures, acetaminophen

overdose, and amanita poisoning.