Milk Thistle: Effects on Liver Disease and Cirrhosis - Parents of Kids ...

Evidence Report/Technology Assessment 

Number 21 

<strong>Milk</strong> <strong>Thistle</strong>: <strong>Effects</strong> on 

Liver Disease and 

Cirrhosis and Clinical 

Adverse <strong>Effects</strong> 

Agency for Healthcare Research and Quality

On December 6, 1999, under Public Law 106-129, the Agency for Health Care Policy and 

Research (AHCPR) was reauthorized and renamed the Agency for Healthcare Research and 

Quality (AHRQ). The law authorizes AHRQ to continue its research on the cost, quality, and 

outcomes of health care and expands its role to improve patient safety and address medical 

errors. 

This report may be used, in whole or in part, as the basis for development of clinical practice 

guidelines and other quality enhancement tools, or a basis for reimbursement and coverage 

policies. AHRQ or U.S. Department of Health and Human Services endorsement of such 

derivative products may not be stated or implied.

Evidence Report/Technology Assessment 

Number 21 

<strong>Milk</strong> <strong>Thistle</strong>: <strong>Effects</strong> on Liver Disease 

and Cirrhosis and Clinical Adverse 

<strong>Effects</strong> 

Prepared for: 

Agency for Healthcare Research and Quality 

U.S. Department of Health and Human Services 

2101 East Jefferson Street 

Rockville, MD 20852 

Contract No. 290-97-0012 

Prepared by: 

San Antonio Evidence-based Practice Center based at The University of Texas Health Science Center 

at San Antonio and The Veterans Evidence-based Research, Dissemination, and Implementation 

Center, a Veterans Affairs Health Services Research and Development Center of Excellence 

Cynthia Mulrow, MD, MSc 

Program Director 

Valerie Lawrence, MD, MSc 

Principal Investigator 

Bradly Jacobs, MD, MPH 

Cathi Dennehy, PharmD 

Jodi Sapp, RN 

Gilbert Ramirez, DrPH 

Christine Aguilar, MD, MPH 

Kelly Montgomery, MPH 

Laura Morbidoni, MD 

Jennifer Moore Arterburn, MTSC 

Elaine Chiquette, PharmD 

Martha Harris, MLS, MA 

David Mullins 

Andrew Vickers, MD 

Kenneth Flora, MD, FACG 

AHRQ Publication No. 01-E025 

October 2000

Preface 

The Agency for Healthcare Research and Quality (AHRQ), formerly the Agency for Health 

Care Policy and Research, through its Evidence-based Practice Centers (EPCs), sponsors the 

development of evidence reports and technology assessments to assist public and private-sector 

organizations in their efforts to improve the quality of health care in the United States. The 

reports and assessments provide organizations with comprehensive, science-based information 

on common, costly medical conditions and new health care technologies. The EPCs 

systematically review the relevant scientific literature on topics assigned to them by AHRQ and 

conduct additional analyses when appropriate prior to developing their reports and assessments. 

To bring the broadest range of experts into the development of evidence reports and health 

technology assessments, AHRQ encourages the EPCs to form partnerships and enter into 

collaborations with other medical and research organizations. The EPCs work with these partner 

organizations to ensure that the evidence reports and technology assessments they produce will 

become building blocks for health care quality improvement projects throughout the Nation. The 

reports undergo peer review prior to their release. 

AHRQ expects that the EPC evidence reports and technology assessments will inform 

individual health plans, providers, and purchasers as well as the health care system as a whole by 

providing important information to help improve health care quality. 

We welcome written comments on this evidence report. They may be sent to: Director, 

Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, 

6010 Executive Blvd., Suite 300, Rockville, MD 20852. 

John M. Eisenberg, M.D. Douglas B. Kamerow, M.D. 

Director Director, Center for Practice and Technology 

Agency for Healthcare Research Assessment 

and Quality Agency for Healthcare Research and Quality 

The authors of this report are responsible for its content. Statements in the report should not be 

construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. 

Department of Health and Human Services of a particular drug, test, treatment, or other clinical 

service. 

iii

Structured Abstract 

Objectives. This evidence report summarizes studies of efficacy and adverse effects of milk 

thistle in humans with alcohol, viral, or toxin-related liver disease. 

Search Strategy. English and non-English citations were identified through December 1999 

from 11 electronic databases, references of pertinent articles and reviews, manufacturers, and 

technical experts. 

Selection Criteria. Selection criteria regarding efficacy were placebo-controlled trials of milk 

thistle. For adverse effects, all studies in humans were used. 

Data Collection and Analysis. Abstractors independently abstracted data from published 

reports. Relationships between clinical outcomes and methodologic characteristics were 

examined in evidence tables and graphic summaries. Exploratory meta-analyses were used to 

examine possible patterns of effects. 

Main Results. 

• Sixteen prospective placebo-controlled trials were identified. 

• Interpreting the evidence was difficult because of inadequate reporting and study design 

regarding severity of liver disease, subject characteristics, and potential confounders. 

Outcome measures, dose, duration, and followup widely varied among studies. 

• Four of six studies of chronic alcoholic liver disease reported significant improvement in at 

least one parameter of liver function or histology with milk thistle. 

• In three of 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. 

• Three studies evaluated the effects of milk thistle on viral hepatitis. The acute hepatitis study 

showed no improvement in liver function. Improvement in aspartate aminotransferase and 

bilirubin was significant in the study of acute hepatitis. Two studies of chronic viral hepatitis 

showed improvement in aminotransferases with milk thistle in one and a trend toward 

histologic improvement in the other. 

• There were two studies of patients with alcoholic or nonalcoholic cirrhosis. In one study, 

milk thistle showed a positive effect, but no data were given. In the other, milk thistle 

showed a trend toward improved survival and significantly improved survival for subgroups 

with alcoholic cirrhosis or Child’s Group A severity. 

• Two trials specifically studied alcoholic cirrhosis. One showed no improvement in liver 

function, hepatomegaly, jaundice, ascites, or survival but did show nonsignificant trends 

v

favoring milk thistle in the incidence of encephalopathy, gastrointestinal bleeding, and death 

in subjects with hepatitis C. The other reported significant improvements in 

aminotransferases with milk thistle. 

• Three trials evaluated thistle as therapy or prophylaxis in the setting of hepatotoxic drugs; 

results were mixed. 

• Meta-analyses generally showed small effect sizes, some statistically significant and some 

not, favoring milk thistle. 

• Available evidence does not define milk thistle’s effectiveness across preparations or doses. 

• Little evidence is available regarding causality, but evidence suggests milk thistle is 

associated with few, generally minor, adverse effects. 

Conclusions. <strong>Milk</strong> thistle’s efficacy is not established. Published evidence is clouded by poor 

design and reporting. Possible benefit has been shown most frequently, but inconsistently, for 

aminotransferases, but laboratory tests are the most common outcome measure studied. Survival 

and other clinical outcomes have been studied less, with mixed results. Future research should 

include definition of multifactorial mechanisms of action, well-designed clinical trials, and 

clarification of adverse effects. 

This document is in the public domain and may be used and reprinted without permission except 

those copyrighted materials noted for which further reproduction is prohibited without the 

specific permission of copyright holders. 

Suggested Citation: 

Mulrow C, Lawrence V, Jacobs B, et al. <strong>Milk</strong> thistle: effects on liver disease and cirrhosis and 

clinical adverse effects. Evidence Report/Technology Assessment No. 21 (Contract 290-97- 

0012 to the San Antonio Evidence-based Practice Center, based at the University of Texas 

Health Science Center at San Antonio, and The Veterans Evidence-based Research, 

Dissemination, and Implementation Center, a Veterans Affairs Services Research and 

Development Center of Excellence). AHRQ Publication No. 01-E025. Rockville, MD: Agency 

for Healthcare Research and Quality. October 2000. 

vi

Contents 

Summary..........................................................................................................................................1 

EVIDENCE REPORT 

Chapter 1. Introduction ...................................................................................................................9 

Scope and Objectives.................................................................................................................9 

<strong>Effects</strong> of <strong>Milk</strong> <strong>Thistle</strong> on Hepatic Disease ...............................................................................9 

Clinical Adverse <strong>Effects</strong> of <strong>Milk</strong> <strong>Thistle</strong>...................................................................................9 

Background................................................................................................................................9 

The Plant ............................................................................................................................11 

Historical Uses of <strong>Milk</strong> <strong>Thistle</strong>..........................................................................................11 

The <strong>Milk</strong> <strong>Thistle</strong> Industry ..................................................................................................12 

Chemistry and Pharmacokinetics of <strong>Milk</strong> <strong>Thistle</strong> ...................................................................13 

Mechanisms of <strong>Milk</strong> <strong>Thistle</strong> ....................................................................................................14 

Antioxidant Activity ..........................................................................................................14 

Toxin Blockade..................................................................................................................15 

Enhanced Protein Synthesis...............................................................................................15 

Antifibrotic Activity...........................................................................................................15 

Other Postulated Mechanisms............................................................................................16 

Current Preparations of <strong>Milk</strong> <strong>Thistle</strong> .......................................................................................16 

Challenges in Interpreting the Evidence..................................................................................16 

Chapter 2. Methodology ...............................................................................................................17 

Expert Input .............................................................................................................................17 

Questions Addressed in Evidence Report................................................................................17 

Literature Search and Selection Methods ................................................................................19 

Sources and Search Methods .............................................................................................19 

Selection Processes ............................................................................................................19 

Data Abstraction Process .........................................................................................................22 

Unpublished Data...............................................................................................................22 

Data Analysis Process........................................................................................................22 

Exploratory Meta-Analysis................................................................................................23 

Chapter 3. Results .........................................................................................................................25 

Overview of the Evidence........................................................................................................25 

<strong>Milk</strong> <strong>Thistle</strong> Preparations and Doses .......................................................................................25 

<strong>Milk</strong> <strong>Thistle</strong> and Liver Disease................................................................................................27 

<strong>Milk</strong> <strong>Thistle</strong> and Alcohol-Related Liver Disease ..............................................................27 

<strong>Milk</strong> <strong>Thistle</strong> and Chronic Liver Disease of Mixed Etiology .............................................27 

<strong>Milk</strong> <strong>Thistle</strong> and Viral Liver Disease.................................................................................28 

<strong>Milk</strong> <strong>Thistle</strong> and Cirrhosis .................................................................................................28 

<strong>Milk</strong> <strong>Thistle</strong> and Toxin-Induced Liver Disease.................................................................29 

<strong>Milk</strong> <strong>Thistle</strong> and Cholestasis..............................................................................................30 

<strong>Milk</strong> <strong>Thistle</strong> and Primary Hepatic Malignancy .................................................................30 

Effectiveness of Different Preparations of <strong>Milk</strong> <strong>Thistle</strong>..........................................................30 

Exploratory Meta-Analyses Results ........................................................................................31 

vii

Adverse <strong>Effects</strong> of <strong>Milk</strong> <strong>Thistle</strong>...............................................................................................38 

Overview of Adverse Effect Literature..............................................................................38 

Common Symptomatic <strong>Effects</strong>..........................................................................................38 

Common and Uncommon Serious Adverse <strong>Effects</strong> ..........................................................38 

Chapter 4. Conclusions .................................................................................................................41 

Chapter 5. Future Research...........................................................................................................43 

Adverse <strong>Effects</strong>........................................................................................................................43 

Beneficial <strong>Effects</strong> Regarding Liver Diseases ..........................................................................43 

Specific Areas of Research ......................................................................................................43 

References......................................................................................................................................45 

Summary Tables ............................................................................................................................53 

Evidence Tables ............................................................................................................................73 

Bibliography ..................................................................................................................................99 

Appendix A. <strong>Milk</strong> <strong>Thistle</strong> Search Strategies ..............................................................................113 

Appendix B. Graphic Summaries ...............................................................................................115 

Appendix C. Contributors...........................................................................................................143 

Appendix D. Acronyms ..............................................................................................................149 

viii

Appendix C. Contributors 

We owe a major debt of gratitude to the following groups of multidisciplinary experts from 

around the world who assisted in preparing this report: 10 national advisory panel members, 3 

technical experts who helped define the scope and shape the content, 14 peer reviewers 

representing a variety of backgrounds and viewpoints, and 5 scientific authors who provided 

additional data from their studies. 

National Advisory Panel 

Marilyn Barrett, PhD 

Owner and Principal 

Pharmacognosy Consulting Services 

Mark Blumenthal 

Executive Director 

American Botanical Council 

David Eisenberg, MD 

Beth Israel Deaconess Medical Center 

Lucinda Miller, PharmD, BCPS 

Editor 

Journal of Herbal Pharmacotherapy 

Richard Nahin, MPH, PhD 

Acting Director 

Division of Extramural Research 

National Center for Complementary and Alternative Medicine 

Mary Ann Richardson, DrPH 

Assistant Professor and Director 

The University of Texas Center for Alternative Medicine Research in Cancer 

The University of Texas - Houston Health Science Center School of Public Health 

Nancy Ridenour, RN, PhD, CS, FNC, FAAN 

Dean 

College of Nursing 

Illinois State University 

David Schardt 

Associate Nutritionist 

Center for Science in the Public Interest 

143

William A. Watson, PharmD, DABAT, FAACT 

Professor (Clinical) and Managing Director 

Department of Surgery 

South Texas Poison Center 

The University of Texas Health Science Center at San Antonio 

Elizabeth Yetley, PhD 

Director 

Office of Special Nutritionals 

Center for Food Safety and Applied Nutrition 

Food and Drug Administration 

Technical Experts 


Senior Clinical Research Fellow 

Osher Center for Integrative Medicine 

Department of Medicine 

University of California - San Francisco/Veterans Affairs Medical Center 


Assistant Clinical Professor 

University of California at San Francisco 


Assistant Professor 

Oregon Health Sciences University 

Peer Reviewers 

Fourteen peer reviewers provided insightful comments and feedback on our draft report. 

Maurizio Bonacini, MD 

Associate Professor 

Hepatitis Research Center 

Division of Gastroenterology and Liver Diseases 


University of Southern California School of Medicine 

Robert Eckel, MD 

Professor 

Division of Endocrinology, Metabolism, and Diabetes 


University of Colorado Health Science Center 

144

Wolfgang Fleig, MD 

Professor and Chair 

First Department of Medicine 

Martin Luther University Halle-Wittenberg 

Halle (Saale), Germany 

Robert Fontana, MD 

Assistant Professor 

Department of Internal Medicine 

University of Michigan Health System 

Alexander Gerbes, MD 


Ludwig-Maximilians-Universitat-München 

Eric Gershwin, MD 

Division Chief 

Division of Rheumatology/Allergy 

Department of Internal Medicine 

University of California at Davis School of Medicine 

Ruth Kava, PhD, RD 

Director of Nutrition 

American Council on Science and Health 

Ronald Koretz, MD 

Professor and Chief 

Division of Gastroenterology 


University of California at Los Angeles 

David Lee, PhD 

Director 

Natural Products Laboratory 

McLean Hospital 

Klaus Linde, MD 

Researcher 

Centre for Complementary Medicine Research 

Department of Internal Medicine II Technichal University 

Tianshu Liu, MD, MSc 

Attending Physician 

Department of Gastroenterology 

Shanghai Medical University 

Zhoug Medical Hospital 

145

Srini Srinivasan, PhD 

Director 

Dietary Supplements Division 

U.S. Pharmacopoeia 

Kathleen Stevens, RN, EdD, FAAN 


Department of Family Nursing 


Wendell Winters, PhD 

Associate Professor 

Department of Microbiology 


Authors Who Provided Additional Data 

Some articles included in this report had relevant data missing from their publications. We 

contacted the authors requesting this information. Our heartfelt thanks to those who responded: 

Dr. Paolo Saba 

Dr. Heikki A. Salmi 

Dr. Gianluigi Vendemiale 

Dr. Peter Ferenci 

Dr. Robert Flisiak 

San Antonio Evidence-based Practice Center and Veterans 

Evidence-based Research, Dissemination and 

Implementation Center Staff 

Project Leaders 


Program Director 


Principal Investigator 

146

Project Investigators 





Jodi Sapp, RN 

Christine Aguilar, MD, MPH 

Kelly Montgomery, MPH 

Laura Morbidoni, MD 

Elaine Chiquette, PharmD 


Meta-Analysts 

Gilbert Ramirez, DrPH 

John E. Cornell, PhD 

Information Specialists 

Andrew Vickers, MD 

Martha Harris, MLS, MA 

Technical Writer and Peer Review Coordinator 

Jennifer Moore Arterburn, MTSC 

Computer Resources 

David Mullins 

Administration 

Annie Almanza 

Sheryl Moore 

Linn Morgan 

147

Summary 

Overview 

This evidence report details a systematic review summarizing clinical studies of milk thistle 

in humans. 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: (1) effects of milk thistle on liver disease of alcohol, viral, toxin, 

cholestatic, and primary malignancy etiologies; and (2) 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 (AHRQ). 

Reporting the Evidence 

Specifically, the report addresses 10 questions regarding whether milk thistle supplements— 

compared with no supplement, placebo, other oral supplements, or drugs—alter the physiological 

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. 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, and 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, 

and 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 nonplacebo controls, the type 

of control varied widely. Therefore, qualitative and quantitative syntheses of data on 

1

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 <strong>Milk</strong> <strong>Thistle</strong> 

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 <strong>Milk</strong> <strong>Thistle</strong> for Liver Disease 

• Sixteen prospective trials were identified. Fourteen were randomized, blinded, placebocontrolled 

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 placebocontrolled 

study was a cohort study with a placebo comparison group. 

• Seventeen additional trials used nonplacebo 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). 

2

• 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. 

3

• 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 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, and 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. 

4

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 compliance and dropouts; systematic standardized surveillance for adverse 

effects; and 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. 

5

Chapter 1. Introduction 

Scope and Objectives 

This evidence report about milk thistle was requested by the National Center for 

Complementary and Alternative Medicine, a component of the National Institutes of Health, and 

was contracted by the Agency for Healthcare Research and Quality. This chapter highlights the 

history of milk thistle, its chemistry, recent research, the variety in available commercial 

preparations, and challenges in conducting research and interpreting the evidence in humans. 

The evidence report is a systematic review that summarizes studies in humans that address the 

effects of milk thistle in treating liver disease of alcohol, viral, toxin, cholestatic, and primary 

malignancy etiologies. Figure 1 shows the evidence model, which was formulated by the 

national advisory and technical expert panels that guided the review. 

<strong>Effects</strong> of <strong>Milk</strong> <strong>Thistle</strong> on Hepatic Disease 

Results of trials comparing milk thistle preparations with placebo or other agents are 

presented. A formal summary of the evidence uses only available placebo controlled trials. 

<strong>Effects</strong> on the following outcomes are addressed: laboratory tests, histologic findings, 

morbidity, and mortality. 

Clinical Adverse <strong>Effects</strong> of <strong>Milk</strong> <strong>Thistle</strong> 

Various reported adverse effects, including dermatologic, gastrointestinal, and anaphylactoid 

reactions, are summarized. 

Background 

<strong>Milk</strong> thistle has been used since the time of ancient physicians and herbalists to treat a range 

of liver and gallbladder disorders, including hepatitis, cirrhosis, and jaundice, and to protect the 

liver against poisoning from chemical and environmental toxins, including snake bites, insect 

stings, mushroom poisoning, and alcohol. 

<strong>Milk</strong> thistle’s history begins with its name. The scientific name for milk thistle is Silybum 

marianum: “Silybum” is the name Dioscorides gave to edible thistles, 1 and “marianum” comes 

from the legend that the white veins running through the plant’s leaves were caused by a drop of 

the Virgin Mary’s milk. 1-4 While looking for a place to nurse the infant Jesus when leaving 

Egypt, Mary could only find shelter in a bower formed by the thorny leaves of the milk thistle. 5 

From this story was born the folk belief that the plant was good for nursing mothers. 6 Other 

names that have been attributed to milk thistle include Marian thistle, Mary thistle, St. Mary’s 

thistle, Lady’s thistle, Holy thistle, sow thistle, thistle of the blessed virgin, Christ’s crown, 

Venus thistle, heal thistle, variegated thistle, and wild artichoke. 

<strong>Milk</strong> thistle is a member of the aster or daisy family (Asteracae), which includes, in addition 

to asters and daisies, a host of other thistles and the artichoke. 7 <strong>Milk</strong> thistle is one of the most 

important medical members of this genus. 8 

9

Figure 1. Evidence model: <strong>Milk</strong> thistle and liver disease 

10

The Plant 

<strong>Milk</strong> thistle is a tall plant that can grow up to 10 feet with thorny stems, dark glossy green 

leaves, and milky-white veins running throughout. Its most distinguishing feature is the large, 

bright purple flower sprouting at the top. 3,7,8 

Historical Uses of <strong>Milk</strong> <strong>Thistle</strong> 

For centuries, nearly every part of the plant—from root to hull—has been used in some 

way. 4,6 In her famous book, Maud Grieve explained several ways the milk thistle can be eaten, 

including the heads like an artichoke, raw stalks (which are considered palatable and nutritious), 

and the leaves as a salad. 8 She also quoted Bryant, who wrote in his Flora Dietetica, “The 

young shoots in the Spring, cut close to the root with part of the stalk on, is one of the best 

boiling salads that is eaten, and surpasses the finest cabbage. They were sometimes baked in 

pies. The roots may be eaten like those of Salsify.” 8 

<strong>Milk</strong> thistle has also historically been used for animal feed. Grieve wrote that in parts of 

England, the leaves are called “pig leaves” because pigs liked them; also, the seeds are a favorite 

food of goldfinches. 8 In Scotland, the leaves were used extensively as food for cattle and horses 

(the leaves were beaten and crushed to rid them of prickles) before the introduction of special 

green crops. 8 The milk thistle prickles have also been used historically as a substitute for barbed 

wire. 9 Despite this wide spectrum of perceived value, farmers considered it and other thistles a 

sign of untidiness and neglect. 8 

Most sources on milk thistle, which is native to southern Europe (specifically Mediterranean 

areas) and Asia, 5 put its beginning at 2,000 years ago. 1,2,6,9 One of the earliest mentions of 

thistles in general is in the Bible (Genesis 3:18). In this verse, God told Adam and Eve when 

they were banished from the Garden of Eden that “thorns also and thistles shall it bring forth to 

thee.” 

Some of the earliest people to use and write about milk thistle were ancient Greek and 

Roman physicians and herbalists, each of whom seemed to have their own name for the herb. 

Dioscorides called it “sillybon,” Pliny the Elder called it “sillybum,” and Theophrastus called it 

“pternix.” 5 Dioscorides’ use of milk thistle is one of the oldest known references to the 

medicinal use of this plant. He suggested preparing it in a tea “for those that be bitten of 

serpents.” 10 Another famous ancient herbalist, Pliny the Elder, wrote that mixing the juice of the 

plant with honey was good for “carrying off bile.” 1,9 

<strong>Milk</strong> thistle is mentioned in several works from the Middle Ages, one of the first being in a 

record of old Saxon remedies, which claimed that “this wort if hung upon a man’s neck it setteth 

snakes to flight.” 8 One of the best known herbalists from this time, John Gerard (1545-1612), 

recommended milk thistle for expelling melancholy and its related diseases (melancholy diseases 

were described in medicine in the Middle Ages as related to the liver and also called “black 

bile”). 8-10 Another well known English herbalist, Nicholas Culpeper (1616-54), recommended 

milk thistle for several maladies: breaking and expelling stones, removing obstructions of the 

liver and spleen, treating jaundice and infections of the plague, and cleansing the blood. 8,9 

Maud Grieve, who compiled her book of herbal information in 1931, quoted several early 

English herbalists on their love for and use of milk thistle. She reports that in 1694 Westmacott 

wrote of milk thistle, “It is a friend to the liver and blood: the prickles cut off, they were 

formerly used to be boiled in the spring and eaten with other herbs; but as the World decays, so 

11

does the use of good old things and other more delicate and less virtuous brought in.” 8 She also 

reports that John Evelyn wrote, “Disarmed of its prickles and boiled it is worthy of esteem, and 

thought to be a great breeder of milk and proper diet for women who are nursing.” 8 

Although milk thistle’s use during the 17th century is most often associated with English 

herbalists, many monasteries cultivated and used the plant for medicinal purposes as well. 

St. Hildegard von Bingen (1098-1179) recommended the roots, herbs, and leaves for swelling 

and erysipelas. 5 

<strong>Milk</strong> thistle was popular with German herbalists and scientists, also. Otto Brunfels (1488- 

1534), Hieronimous Bock (1498-1554), Jacob Theodorus (1520-90), Adam Lonicerus (1528-86), 

and Pietro Andrea Mattioli (1501-77) all recommended milk thistle for treating liver diseases. 5,9 

Another German physician from the 19th century, Johannes Gottfried Rademacher, developed a 

tincture made from milk thistle seeds for his liver patients. 1,4 Rademacher’s Tincture is an 

ethanol extract from the seeds used for hepatosplenic disorders. 9 

In the United States, milk thistle enjoyed popularity in the 19th century with the Eclectics 

movement, an officially recognized branch of North American medicine that predominantly used 

Native American herbs. The Eclectics used milk thistle for varicose veins, menstrual difficulty, 

and congestion of the liver, spleen, and kidneys. 1,7 <strong>Milk</strong> thistle was also used as part of the 

naturopathic medical tradition and Native American medical practices. 10 So popular was milk 

thistle that a tincture of the whole plant was listed in the first United States Homeopathic 

Pharmacopoeia. 1,2 

Available history does not seem to tell us how (i.e., by what anecdotal or empirical evidence) 

milk thistle came to be advised for liver and gallbladder problems. Although milk thistle is most 

often associated with treating liver disorders, physicians have tried to apply its curative 

properties to other ailments, including stimulating breast-milk production and bile secretion, 

treating depression, and protecting against the poisonous mushroom Amanita phalliodes and 

other environmental toxins. 4 

The <strong>Milk</strong> <strong>Thistle</strong> Industry 

<strong>Milk</strong> thistle enjoys significant popularity in the current herbal industry. The World Health 

Organization estimates that 4 billion people (nearly two-thirds of persons in developing 

countries) use herbal medicine for some aspect of health care. Herbal medicine is a major 

component in all indigenous peoples’ traditional medicine and a common element in Ayurvedic, 

homeopathic, naturopathic, traditional oriental, Chinese, and Native American Indian medicine. 11 

<strong>Milk</strong> thistle has been available in Europe since 1969, and more than $180 million worth of 

products were sold in one recent year. 10 In Germany alone, milk thistle was the 11th most 

frequently prescribed monopreparation herbal, with $16 million (U.S. dollars) in sales in 1996. 12 

In the United States, the herbal market was estimated at about $1.6 billion in 1994 with some 

projections reaching about $3.5 billion in 1997. Of the 14 top-selling herbal supplements in the 

United States in 1997 in food, drug, and mass-market retail outlets, milk thistle ranked 13th 

(more than $3 million). 12 However, it is difficult to determine the actual size of the herbal 

market because herbal products were formerly sold mostly through channels of distribution 

normally not subject to econometric tracking services (e.g., health food stores, mail order, 

multilevel marketing organizations). 12 

Attesting to milk thistle’s popularity in this country, a recent poll of patients attending a 

hepatology clinic at Oregon Health Sciences University found that 31 percent of patients were 

12

using over-the-counter “alternative agents” for the therapy of their liver disease. The most 

commonly used nontraditional therapy was milk thistle, and over 50 percent of those patients felt 

they had experienced subjective improvement in their symptoms. 13 In the United States, milk 

thistle is now being tested for safety by the U.S. National Toxicology Program, along with aloe 

vera, ginseng, and kava. 14 

Chemistry and Pharmacokinetics of <strong>Milk</strong> <strong>Thistle</strong> 

Flavonoids, of bioflavonoids, are a ubiquitous group of polyphenolic substances that are 

present in most plants and concentrated in seeds, fruit skin or peel, bark, and flowers. A great 

number of plant medicines contain flavonoids, which have been reported as having antibacterial, 

anti-inflammatory, antiallergic, antimutagenic, antiviral, antineoplastic, antithrombotic, and 

vasodilatory actions. The structural components common to these molecules include two 

benzene rings on either side of a three-carbon ring. Multiple combinations of hydroxyl groups, 

sugars, oxygens, and methyl groups attached to these structures create the various classes of 

flavonoids: flavanols, flavanones, flavones, flavan-3-ols (catechins), anthocyanins, and 

isoflavones. Flavonoids have been shown in a number of studies to be potent antioxidants, 

capable of scavenging hydroxyl radicals, superoxide anions, and lipid oxygen radicals due to 

lipid peroxidation. 15 

As reviewed by Bindole, et al., in 1968 Wagner isolated and called the flavonoid complex in 

milk thistle “silymarin.” Silymarin, the active component of milk thistle responsible for its 

putative hepatoprotective actions, is a mixture of silybin (also known as silybinin or silibinin), 

silychristin (or silicristin), and silydianin (also silidianin). 16 Silybin is the most prevalent of the 

three (about 50 percent of silymarin) and the most biologically active. 9,17 Silydianin is very 

heavily metabolized, whereas silycristin is only absorbed to a very slight extent in the 

gastrointestinal tract. 18 Silymarin is found throughout the entire plant, but concentrations of 

silymarin are highest in the seeds and leaves. 3 It is typically extracted with 95 percent ethyl 

alcohol, yielding a bright yellow fluid (“flavonoids” is derived from “flavus,” meaning yellow) 

or acetone. 9 However, the leading manufacturer of milk thistle, (Madaus, a German company) 

prepares its product Legalon ® with ethylacetate as the primary solvent. 19 Subsequent research in 

Germany has revealed other constituents in milk thistle, including dehydrosilybin, 

desoxysilydianin (silymonin), silandrin, and silybinomer. 20 

German research initially led to a standardized milk thistle extract of 70 percent silymarin. 1 

Standardized silymarin extract now contains 70 to 80 percent silymarin. Madaus’ Legalon ® is 

sold in tablets containing 70 or 140 milligrams (mg) silymarin and is given in a dose of one to 

two tablets up to three times daily, with a maximum dosage of 420 mg. Madaus now outsources 

production of crude silymarin to the Italian firm Indena in Milan. This crude extract is made 

exclusively for Madaus according to their standards, cannot be sold to other companies, and is 

further processed back in Madaus’ facilities to produce the extract sold as Legalon ® . 21,22 

Silymarin preparations, although standardized on silymarin content, differ regarding the in vitro 

release of silymarin or silybin; as a result, the availability of silybin for absorption differs also. 

In two studies of nine and six silymarin preparations, respectively, release of silybin from 

Legalon ® was more rapid and higher compared with other preparations. 23 

From standardized silymarin, silybin can be isolated and complexed with 

phosphatidylcholine. 24 This formulation, called IdB 1016, is now sold as Silipide ® (Inverni, 

Italy) and is expressed as silybin equivalents. Silipide ® has been shown to be more bioavailable 

13

than standardized silymarin after oral ingestion in normal volunteers, cirrhotics, and patients 

after cholecystectomy. 9,25-28 The bioavailability of silybin in Silipide ® is approximately tenfold 

greater than the silybin content of standard milk thistle preparations. 5 

Various methods have been developed to identify the constituents of silymarin, including 

thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), 

colorimetry, and electrophoresis. 18,29-34 There are two species of the silymarin plant: S. 

marianum (L.) Gaertn. and S. eburneum Coss. Dur. Of the S. marianum species, there are two 

varieties: the common purple flower and the much less common white flower. HPLC can 

distinguish between the two species. 28 There are also two chemotypes for the purple variety, 

which can be distinguished by TLC and HPLC. One has a relatively high silybin content and a 

high silybin:silydianin ratio. The other has a relatively high silydianin content and low 

silybin:silydianin ratio. They appear to be stable chemotypes with characteristic silybin and 

silydianin contents and proportions for several generations under the same field conditions. 28 In 

summary, chromatography can thus far distinguish four biochemical profiles: three for S. 

marianum and one for S. eburneum. Differences are smaller between S. marianum and S. 

eburneum than between the white and purple varieties of S. marianum. 

Mechanisms of <strong>Milk</strong> <strong>Thistle</strong> 

Currently, milk thistle (silymarin, silybin, and Silipide ® ) is primarily advocated as a 

therapeutic and hepatoprotective agent, especially in the settings of cirrhosis, chronic hepatitis, 

alcohol consumption, and environmental toxin exposure. Silymarin, silybin, and Silipide ® have 

multiple mechanisms of action that may be hepatoprotective, including antioxidant activity, toxin 

blockade, enhanced protein synthesis, and antifibrotic activity. 

Antioxidant Activity 

Silymarin is thought to have antioxidant activity in the liver, as well as the small intestine 

and stomach. As an antioxidant, this compound may reduce free radical production and lipid 

peroxidation in the setting of hepatotoxicity. Lipid peroxidation is the end result of unstable free 

radicals’ damage to membrane lipids. These membranes contain fatty acids that are transformed 

to lipoperoxidases, peroxides, and lipidic hydroperoxides. Malondialdehyde is a biproduct of 

phospholipid turnover and linoleic acid and is frequently used in clinical and in vitro studies as a 

surrogate marker for oxidation activity. Multiple in vitro studies have demonstrated lipid 

peroxidation inhibition using malondialdehyde as a marker in rat hepatic microsomes and 

mitochondria. 35-38 Furthermore, the phenolic conformation of silymarin is thought to permit the 

formation of stable compounds from hydroxylic and oxygen radicals. 39,40 Primary defenses 

against oxidation or free radical production include glutathione, catalase, and superoxide 

dismutase. In the setting of an acute toxic event, if stores of these compounds are depleted in 

intracellular or extracellular (sinusoidal) compartments, oxidative injury is unimpeded. 41-43 

The phenol structure of silymarin led investigators to postulate that silymarin might have 

potential activity as an antioxidant. In vivo studies in rats indicate that silymarin can reduce the 

free radical load. One study exposed rats to acetaminophen at toxic doses, and then measured 

levels of reduced glutathione and superoxide dismutase in experimental and control rats. In 

another study, mice exposed to acetaminophen at toxic doses had increased levels of reduced 

glutathione and superoxide dismutase when treated with silymarin compared with the levels in 

14

controls. 41,42 Another study demonstrated preserved hepatic glutathione stores and improved 

reduced:oxidized glutathione ratios in rats exposed to acetaminophen and ethyl alcohol at high 

doses when compared with those in controls. 42 Similarly, in humans, investigators have 

demonstrated increases in serum glutathione peroxidase and erythrocyte and lymphocyte 

superoxide dismutase. 44 

Silymarin may also protect hepatocyte-lipid membranes. Studies demonstrated that 

silymarin can inhibit cell lysis as measured by changes in alanine aminotransferase levels when 

exposing isolated hepatocytes to carbon tetrachloride and galactosamine. 45 

Toxin Blockade 

Studies demonstrated improvements in cytosol liver and histologic markers in animals 

receiving silymarin compared with those in controls for an array of hepatotoxins including 

carbon tetrachloride, galactosamine, thioacetamide, ethanol, and acetaminophen. 5 The 

mechanism of action is thought to be mediated by competitive inhibition, membrane 

stabilization, and antioxidant activity. However, in many studies the mechanism was not clearly 

identified. Silymarin can bind to liver cell membrane receptors to protect cells from toxins. One 

study demonstrated this effect using the death cap mushroom, Amanita phalloides. The toxins in 

this fungus are amanititin and phalloidin. Several studies showed that silymarin competes with 

the toxin for cell membrane receptor sites, thus reducing the effect of the toxin. 46,47 

Enhanced Protein Synthesis 

Regeneration of hepatocytes is necessary for hepatic recovery from acute or chronic insults. 

In chronic injury, fibrosis occurs simultaneously with regeneration; the ultimate outcome is 

determined by which process dominates. Several studies identified mechanisms through which 

silybin may facilitate hepatocyte regeneration. In several rat studies, silybin appeared to 

stimulate ribonucleic acid (RNA) polymerase I and ribosomal RNA. 48,49 This effect leads to 

more rapid formation of ribosomes, which in turn increases protein synthesis. The exact 

mechanism of how RNA polymerase I is stimulated is unclear. One study demonstrated that 

silymarin binds to a steroid receptor, 48 and it is hypothesized that structural similarity with 

steroids permits binding. Silymarin then, like steroids, may be able to modulate RNA synthesis. 

Additionally, one study in rats suggested that silymarin can also enhance deoxyribonucleic acid 

synthesis and, therefore, possibly enhance hepatocyte regeneration. 50 Thus far, one study 

demonstrated hepatocyte regeneration in rats with silymarin. 49 

Antifibrotic Activity 

To date, the evidence for antifibrotic activity comes largely from animal studies. Reportedly, 

human trials are in progress with Legalon ® that are examining antifibrotic activity. According to 

Madaus, Legalon ® administered orally in a rat biliary fibrosis model reduced hepatic collagen 

accumulation and levels of a serum marker for fibrosis. Another study reportedly slowed down 

regeneration of procollagen RNA by silymarin in rat livers. 51 

15

Other Postulated Mechanisms 

<strong>Milk</strong> thistle reportedly reduced leukotriene formation through noncompetitive inhibition of 

lipoxygenase, thereby suggesting possible anti-inflammatory effects. 52 

Current Preparations of <strong>Milk</strong> <strong>Thistle</strong> 

Because silymarin is poorly soluble in water, teas are considered to have a less than 10 

percent bioavailability. Since absorption of silymarin from the gastrointestinal tract is only 20 to 

50 percent, oral tinctures, or alcohol-extracted preparations, are considered suboptimal, and 

effective oral therapy is assumed to require concentrated products. A water-soluble derivative of 

silybinin (silybinin dihemisccinate disodium) is available from Madaus, Germany, and is used 

parenterally in Europe for deathcap mushroom (Amanita phalloides) poisoning. 53 

The most common oral formulation is capsules containing powdered seeds or a seed extract. 

Formulation includes extraction with alcohol, filtration, and evaporation and may also include 

pressing, heat drying, and blending with other compounds. Some brands may add choline, 

inositol, tumeric extract, artichoke extract, whole herb powders, dandelion, licorice, curcuma, 

boldo, iron, or Vitamins A and C. One formulation is combined with kutkin, the roots and 

rhizome of Picrorhize kurroa, a perennial herb found only in the higher mountains of the 

northwestern Himalayas. Other concentrated oral formulations include tablets and softgel 

capsules. Silipide ® is the complex of one part silybin and two parts phosphatidycholine from 

soybean phopholipids (lecithin), for which standardization is expressed as silybin equivalents. 

Challenges in Interpreting the Evidence 

The primary difficulty in interpreting the available evidence is the quality of study designs 

and the quality of published reports. 9,54 Quality of trials is hampered by heterogeneity in 

etiologies, chronicity, and severity of liver disease both within and between trials; adequacy of 

randomization; amount and duration silymarin dosing; assessment of alcohol use during trials; 

types of controls; and recruitment and sampling strategies. Only placebo-controlled trials permit 

assessment of the liver’s intrinsic regenerative capacity when the source of injury is removed 

(e.g., alcohol and resolution of hepatitis). In addition, even if investigators attended to these 

important issues of study design and methods, there is a very problematic lack of information in 

many published reports. Much information is lacking on type and homogeneity of liver disease, 

recruitment settings and methods for study subjects, chronicity and severity of liver disease, dose 

and duration of treatment with silymarin, whether statistical comparisons are within or between 

intervention and control groups, exactly what statistical comparisons were done, and the actual 

results. Few studies report screening subjects for human immunodeficiency virus (HIV), 

hepatitis B virus (HBV), or hepatitis C virus (HCV), and screening and systematic monitoring 

for alcohol intake. Few trials adjust for these and other potential confounders; most trials are 

small, and randomization sometimes did not adequately balance known potential cofounders. 

Little information is available regarding compliance with milk thistle and placebo and adequacy 

of blinding. Many of the trials are small, and Type II errors cannot be excluded. Much of the 

trial data are in languages other than English, raising problems with retrieving the evidence, 

identifying peer-reviewed journals, and the potential risks of error in translating the information 

and interpreting the data. 9,54 

16

Figure 1. Evidence model: <strong>Milk</strong> thistle and liver disease 

Toxin- and drug- 

Alcoholic liver 

Individuals with: Viral hepatitis 

induced liver 

Cholestasis 

disease 

disease 

Other health 

promoting actions 

Acute 

Hep A 

Hep B 

Hep C 

Chronic 

Hep A 

Hep B 

Hep C 

Cirrhosis 

Silybum marianum 

Silybum marianum 

constituents 

Mechanisms 

<strong>Effects</strong> on 

pathology and 

physiology 

Clinical outcomes 

Liver 

failure 

Powdered 

seeds 

Silymarin complex 

(silybin + silydianin + 

silychristin) 

Antioxidant 

Biochemical markers 

Overall 

mortality and 

morbidity 

Acute 




failure 

Seeds mash/ 

liquid 

Protein 

synthesis 


mortality and 

morbidity 

10 

Acute 




failure 

Other 

preparations 

Single agent silybin 

Toxin blockade through 

membrane stabilization 

Structural changes: 

Cirrhosis, fatty 

infiltration 

Quality of life 

Pregnancy 

related 

Not 

pregnancy 

related 

Combined with other 

compounds (e.g., 

phosphatidylcholine) 

Other activities (e.g., 

antifibrotic and 

antiinflammatory) 

Enzyme failure: 

Toxemia 

Other 

unexpected 

beneficial 

effects 

Clinical 

adverse 

effects 

Primary hepatic 

malignancy 

Hepatoma 

Cholangiocarcinoma

Chapter 2. Methodology 

This section describes methods used to identify key questions; literature search, retrieval, and 

selection strategies; and processes used for abstracting and analyzing studies. 

Expert Input 

We owe a major debt of gratitude to the following groups of multidisciplinary experts from 

around the world who assisted in preparing this report: 10 national advisory panel members and 

3 technical experts who helped define the scope and shape the content, 14 peer reviewers 

representing a variety of backgrounds and viewpoints, 5 scientific authors who provided 

additional data from their studies, and 12 staff members of the San Antonio Evidence-based 

Practice Center and the San Antonio Veterans Evidence-based Research, Dissemination, and 

Implementation Center, a Veterans Affairs Health Service Research and Development Center of 

Excellence. Their names are listed in the “Appendix C. Contributors” section of this report. 

Questions Addressed in Evidence Report 

The national advisory and technical expert panels used the evidence model (Figure 1) and a 

modified Delphi process to identify clinically important questions that the evidence report should 

address (Table 1). Per the evidence model (see Figure 1), liver disease could be of viral, alcohol, 

toxin, or malignancy etiologies. The spectrum of level of disease included acute, chronic, 

cirrhosis (compensated), and liver failure (decompensated cirrhosis or fulminant toxic or viral 

disease). 

Cholestatic liver disease and primary malignancy were included in the evidence model and 

questions to be addressed because, a priori, we did not know if there would be evidence available 

for review. The final questions and types of studies deemed appropriate to answer the questions 

(selection criteria) are given in Table 1. 

17

Table 1. Key questions and selection criteria for evidence 

18

Literature Search and Selection Methods 

Sources and Search Methods 

English and non-English citations were identified to July 1999 from the electronic databases 

cited in Table 2; references of pertinent articles and reviews; Madaus, Germany; and technical 

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

searching used maximally sensitive strategies to identify all papers on milk thistle and treatment 

or prevention of liver disease. Titles, abstracts, and keyword lists of the 11 sources in Table 2 

were searched using the following terms that include Latin names for milk thistle and its 

constituents (“.tw” indicates text word searches, “/” indicates key word searches, and “$” 

indicates a truncation within a text word). Search strategies are included in Appendix A. 

carduus marianus.tw. 

legalon$.tw. 

mariendistel.tw. 

milk thistle$.tw. 

milk-thistle$.tw. 

milk-thistle$.tw. 

milkthistle$.tw. 

sily$.tw. 

silybin$.tw. 

silybum marianum.tw. 

silybum$.tw. 

silychristin$.tw. 

silydianin$.tw. 

silymarin$.tw. 

silymarin$/ 

silymarin.tw. 

silymarin/ 

After these materials were reviewed and relevant studies obtained and abstracted, an updated 

search to November 1, 1999, was conducted using MEDLINE and EMBASE. 

Selection Processes 

At least two independent reviewers scanned the titles and abstracts of all records identified 

from the search using the selection criteria given in Table 1. For each formulated question, 

selection criteria specified the types of participants, interventions, control groups, outcomes, and 

study designs that were deemed appropriate. Figure 2 schematically presents the selection 

process. Of 1,727 records, reviewers excluded 1,505 with certainty when screening titles and 

abstracts. Most of these were in vitro studies, involved animals, did not provide primary data 

regarding effectiveness, were duplicate reports, or did not meet design inclusion criteria. When 

the full texts of the remaining 215 (7 were unobtainable) were screened, 164 more were excluded 

for the same reasons. Of the 51 records meeting selection criteria, 33 were prospective trials, 

and 18 were reports of adverse effects. 

19

Table 2. Electronic sources searched 

20

Figure 2. Selection process 

21

Initially, we planned to limit efficacy evidence to randomized controlled trials (RCTs) 

comparing milk thistle with placebo, no milk thistle, or another active agent. Ultimately, we 

included evidence from prospective placebo-controlled trials or cohort studies for several 

reasons. First, there were scant data, and it was thought that evidence from studies other than 

randomized trials might provide useful preliminary information. Second, several reportedly 

“randomized” trials had dissimilar numbers of subjects among the study arms, raising the 

possibility that they were not randomized and not of significantly different quality than other 

prospective controlled studies. The search for evidence was not repeated at the point that 

selection criteria were broadened, because the search had been designed to detect all studies of 

milk thistle regardless of their design. 

Data Abstraction Process 

Two independent persons with clinical and methodologic expertise abstracted data; they were 

not blinded either to study titles or to authors’names. Previous research indicates such blinding 

does not enhance validity of results, and it is time and labor intensive to prepare fully masked 

publications. 55 Items related to the internal validity of studies that were assessed included 

whether the trial was randomized, adequacy of randomization (method and concealment of 

assignment), whether the trial was single or double blind, whether intervention and control 

groups were adequately matched, identification of cointerventions such as diet or other 

medications, and the number of dropouts. Disagreements in abstractions were resolved by 

consensus. Formal quality scores were not done because of controversy as to how to handle and 

weight such scores statistically. Elements of study quality are given in the evidence tables. If 

not known, then no information or “not given” is noted in the evidence tables. After the 

abstraction training phase, no further reliability assessment was conducted. 

One research nurse and one physician with expertise in methodology abstracted studies 

addressing adverse effects. Items addressing adverse effects that were abstracted included study 

design (case report, case series, case control, cohort, controlled trial) and type of specific adverse 

effect. Several explicit criteria aimed at assessing drug adverse effect causality were assessed, 

including appropriate temporal relationship, lack of apparent alternative causes, known toxic 

concentrations of the drug at the time of the appearance of the symptom, disappearance of the 

symptom with drug discontinuation, dose-response relationship, and reappearance of the 

symptom if the drug was readministered. 56 

Unpublished Data 

For reports published as abstracts, we excluded those for which we were unable to identify a 

complete subsequent publication by a repeat search of MEDLINE and EMBASE for any of the 

abstract authors. When published studies met selection criteria but did not report important 

design features or outcome data, this unpublished information was requested from the authors. 

Data Analysis Process 

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 

22

outcome assessment or intervention administration, and study designs. Relationships between 

clinical outcomes, participant characteristics, and methodologic characteristics are presented in 

evidence tables and graphic summaries such as forest plots. 

Primary outcomes in studies were measured with continuous rather than categorical 

variables. We used the standardized mean differences between treatment and comparison group 

scores as the effect size measure for each study. Hedges’ g was used to compute the 

standardized mean difference for each trial: 

g 

i 

x − x 

= 

s 

T C 

where, for a given trial i, x T and x C are the mean clinical outcome scores for the treatment 

group and comparison group, respectively; spooled is the pooled standard deviation for the 

difference between the two means. 57 These estimates were adjusted for between-group 

differences at baseline and for small sample bias. 57 Adjustment for baseline differences was 

accomplished by calculating an “effect size” at baseline; by definition, it should be zero if study 

groups were well matched. When a nonzero “effect size” at baseline was found, outcome effect 

sizes were adjusted by subtracting the baseline effect size. 

Published reports seldom provided estimates of spooled. One of three strategies was used to 

estimate spooled when the authors did not directly provide it. First, the individual group variances 

were used to estimate spooled. If these data were not reported, the pooled variance was backcalculated 

from either the test statistic or the p value for differences at followup. 58 If neither was 

possible, a mean variance derived from studies of similar size was used. Studies in which the 

pooled variance was calculated using either of the two latter methods were flagged in the event 

the magnitude of the effect size resulted in the study being identified as a potential outlier in the 

analysis of heterogeneity. 

Exploratory Meta-Analysis 

Meta-analysis was used as an exploratory tool to help identify patterns of findings. 

Prospective placebo-controlled randomized trials using albumin, bilirubin, aspartate 

aminotransferase (AST), alanine aminotransferase (ALT), gammaglutamyl transpeptidase 

(GGTP), malondialdehyde (MDA), alkaline phosphatase (alk phos), prothrombin time (PT), 

Child’s score (a score or classification system for chronic liver disease), and histologic and 

survival outcomes were quantitatively pooled by clinical outcome using meta-analysis. 

Subgroup analyses were conducted for trials that included patients with the following: chronic 

alcoholic liver disease, acute viral liver disease, chronic viral liver disease, mixed liver disease 

(all chronic), cirrhosis, and alcoholic cirrhosis. 

We adopted the DerSimonian and Laird random-effects model to estimate the pooled 

measures of treatment efficacy. 59,60 If there is no substantial heterogeneity among the trials, the 

random-effects estimator reduces to the classical fixed-effects estimate. When significant 

heterogeneity exists, the random-effects model incorporates the statistical heterogeneity into the 

summary estimate and confidence interval. The random-effects model confidence interval is 

wider than the fixed-effect model confidence interval, when substantial heterogeneity exists, 

making the random-effects model more conservative. 

23 

pooled

Heterogeneity among trials was tested with a standard chi-square test (using a p value greater 

than 0.1 as evidence of heterogeneity), Galbraith plots, and funnel plots. A Galbraith plot is a 

graphic method used to complement the statistical assessment of heterogeneity and is particularly 

useful when the number of studies is small. 60 The position of each study along the two axes 

gives an indication of the weight allocated in the meta-analysis. The vertical axis (a Z statistic 

equal to the effect size divided by its standard error) gives the contribution of each study to the Q 

(heterogeneity) statistic. Points outside the confidence bounds are those studies that have a 

major contribution to heterogeneity; in the absence of heterogeneity, all points would be 

expected to be within the confidence bounds. Funnel plots used Begg’s rank order correlation 

test. 61 STATA 6.0 ® (STATA Corporation ® ) was used to perform all analyses and produce the 

graphic output. 62 Specifically, the meta command was used to compute and graph the randomeffects 

model estimates, 63 the “galbr” command to assess heterogeneity and produce Galbraith 

plots, 62 and the metabias command to examine publication bias. 64 

Effect sizes were converted to clinical laboratory units to aid in interpreting effect-size 

standard deviation units. As noted above, the effect-size statistic is calculated by dividing the 

between-group difference by the pooled standard deviation of the two groups. Since both 

numerator and denominator are expressed in the original laboratory units (e.g., milligrams per 

deciliter [mg/dL]), the units cancel out, and the effect size statistic is therefore “unitless.” Effect 

sizes can be back-converted to a clinical laboratory value expressed in the original unit (e.g., 

mg/dL) by multiplying the effect-size value by a standard-deviation value. The statistical 

significance of the values (effect sizes or converted values) does not change; however, the 

magnitude of the “converted effect” will vary up or down depending on the magnitude of the 

standard deviation used. 

Conversion of effect sizes to clinical laboratory units should not be interpreted as “true” 

values; conversions are presented for the single purpose of enhancing the interpretation of effectsize 

standard-deviation units. 

Lacking population standard-deviation values (if available, they could be used), the 

investigator chose to use the “average” standard-deviation value for the pooled studies within 

each group. Two “averages” were examined: a weighted pooled standard deviation across 

studies (weighted by sample size) and the median pooled standard deviation. When the two 

values were substantially different (representing skewness), the median value was chosen. When 

the values were similar (or when only two studies provided pooled standard deviation estimates), 

the weighted pooled standard deviation value was used to convert effect sizes. Weighted 

average standard deviations that were used to convert effect sizes to clinical laboratory units 

were: albumin (0.74 grams per deciliter [g/dL]), bilirubin (0.32 g/dL), aspartate aminotransferase 

(44.77 units per liter [U/L]), alanine aminotransferase (36.02 U/L), gammaglutamyl 

transpeptidase (153.94 U/L), malondialdehyde (6.65 millimoles per milliliter [mmol/mL]), 

alkaline phosphatase (101.01 U/L), prothrombin time (17.40 seconds), and Child’s score (2.55 

units). 

24

Table 1. Key questions and selection criteria for evidence 

Questions About Efficacy Selection Criteria 

1. In adults with alcohol-related liver disease (acute, chronic, 

cirrhosis, or liver failure), does oral ingestion of milk thistle 

supplements compared with no supplement, placebo, other oral 

supplements, or drugs alter physiologic markers of liver function, 

reduce mortality or morbidity, or improve quality of life? 

2. In adults with viral hepatitis or its sequel (acute viral hepatitis, 

chronic active viral hepatitis, cirrhosis, or liver failure), does oral 

ingestion of milk thistle supplements compared with no 

supplement, placebo, other oral supplements, or drugs alter 

physiologic markers of liver function, reduce mortality or 

morbidity, or improve quality of life? 

3. In adults with toxin- or drug-induced (other than alcohol) liver 

disease (acute, chronic, cirrhosis, or liver failure), does oral 

ingestion of milk thistle supplements compared with no 

supplement, placebo, other oral supplements, or drugs alter 

physiologic markers of liver function, reduce mortality or 


4. In adults with cholestasis (pregnancy-related or not pregnancyrelated), 

does oral ingestion of milk thistle supplements compared 

with no supplement, placebo, other oral supplements, or drugs 

alter physiologic markers of liver function, reduce mortality or 


5. In adults with primary hepatic malignancy (hepatoma or 

cholangiocarcinoma), does oral ingestion of milk thistle 

supplements compared with no supplement, placebo, other oral 

supplements, or drugs alter physiologic markers of liver function, 

reduce mortality or morbidity, or improve quality of life? 

6. Do different preparations vary in effectiveness regarding the 

above disease states and outcomes? 

Study type: Initially, randomized controlled trial, 

then changed to any prospective controlled trial. 

Participants: Humans 

Intervention group: Supplemental milk thistle 

Control group: Placebo, no supplement, other oral 

supplements, drugs 

Outcomes (physiologic): Laboratory or histologic 

assessment of in vivo liver function 

Outcomes (clinical): Morbidity, mortality, 

hospitalization, quality of life, symptoms, Child’s 

score (a score or classification system for chronic 

liver disease) 

Questions About Chemical Profiling Selection Criteria 

1. What are the constituents of commonly available preparations of 

silymarin that have been used in studies? 

Study type: Chemical profiling 

Questions About Harms Selection Criteria 

1. What are the common symptomatic adverse effects of milk thistle, 

and what is their frequency? 

2. What common serious adverse effects of milk thistle have been 

established for standard doses or large single doses, and what is 

their frequency? 

3. What uncommon serious adverse effects of milk thistle have been 

established for standard doses or large single doses, and what is 

their frequency? 

18 

Study type: Randomized controlled trial, cohort 

study, case series study, or case report 

Participants: Humans 

Intervention group: Supplemental milk thistle 

Control group: Not required 

Outcomes: Any reported adverse effect 

Outcomes (clinical): Morbidity, mortality, 

hospitalization, quality of life, symptoms, Child’s 

score

Table 2. Electronic sources searched 

Electronic Database Description 

AMED (Alternative and Allied Medicine Database) 

Searched from 1985 to October 1998 

CINAHL (Cumulative Index to Nursing and Allied 

Health Literature) 

Searched from 1984 to July 1999 

CISCOM (Centralised Information Service for 

Complementary Medicine) 

Searched 1968 to July 1999 

Cochrane Library (http://www.cochrane.org) 

DARE (Database of Reviews of Effectiveness) 

(http://www.york.ac.uk/inst/crd/ ) 

The Cochrane Controlled Trials Registry 

Searched Issue 2 1999 

Dissertation Abstracts 

Searched from 1961 to December 1998 

EMBASE 


MEDLINE (PubMed) 


PubMed searched July 1999 to November 1999 

MICROMEDEX contains: 

DRUGDEX Product Index (drug ingredients) 

POISONDEX/IDENTIDEX (toxicology) 

DRUG-REAX (interactive drug interactions) 

Searched July 1999 

NAPRALERT (Natural Products Alert) 

Searched September 1999 

PHYTODOK (German Database) 

Searched 1995 to July 1999 

Science Citation Index 

Searched from January 1990 to March 1999 

This database contains 100,000 references from 400 journals 

on alternative and complementary medicine going back to 

1985. 

This database includes citations from over 500 biomedical and 

popular sources, including National League of Nursing and 

American Nurses Association publications, covers publications 

from 1982 to the present, and is considered the premier nursing 

database. 

This database contains over 34,000 references and combines 

data from MEDLINE, AMED, and other specialist European 

databases. 

These databases contain references of randomized controlled 

trials and systematic reviews identified from electronic 

bibliographic sources and hand searching of multiple journals 

and symposia or meeting proceedings. 

This library indexes doctoral dissertations and masters 

abstracts from more than 1,000 institutions. 

This database contains biomedical and pharmaceutical citations 

and is considered the premier biomedical database in Europe. 

These databases (MEDLINE and PubMed) index almost 4,000 

international biomedical journals from 1966 to the present, 

includes references from Index Medicus, International Nursing 

Index, and Index to Dental Literature, and is considered the 

premiere biomedical database in the United States. 

This database provides a major source for drug, poison, and 

acute care information. 

This database contains records from 1650 to the present on 

natural products, including the pharmacology, biologic activity, 

taxonomic distribution, ethno-medicine and chemistry of plant, 

microbial, and animal extracts. 

This database contains 8,800 references from approximately 

300 journals worldwide on toxicology, pharmacology, and 

therapeutic uses for natural compounds and on isolation of 

natural compounds from plant material. 

This index covers 4,400 scientific and 1,400 social science 

journals worldwide, together with selected coverage of related 

material. 

20

Figure 2. Selection process 

18 studies of 

adverse effects 

1,727 total 

records 

215 records 

retrieved 

51 records of 

primary data 

included 

33 trials 

1,505 records 

excluded 

7 unobtainable 

records 

164 records 

excluded 

21

Chapter 3. Results 

Overview of the Evidence 

Sixteen prospective trials were identified. Fourteen were placebo-controlled, randomized, 

and single- or double-blind trials (Evidence Table 1). Two were placebo-controlled prospective 

studies (randomized trial and cohort) with unclear blinding (Evidence Table 2). 

In addition, 16 reports of 17 trials were identified that used nonplacebo controls (Evidence 

Table 3). The study by Flisiak and Prokopowicz (1997) 65 is described in Evidence Table 3 as 

two separate trials for convenience because it compared silymarin with two different controls 

(misoprostol and no treatment) and because reported methods did not seem consistent for the two 

“substudies.” Nonplacebo-controlled trials are not considered further or discussed in detail in 

evaluating milk thistle’s efficacy because control interventions were diverse and spanned “other 

hepatoprotective medications,” misoprostol, ursodeoxycholic acid, comparisons with different 

doses or formulations of silymarin, “traditional therapy and diet,” multivitamins, a 12-component 

cocktail that included steroids, and no treatment. 

Finally, two trials evaluated milk thistle as prophylaxis against hepatotoxic effects of 

antituberculosis drugs or tacrine (Evidence Table 4). These trials did not meet selection criteria 

for evaluating milk thistle’s efficacy because patients did not have liver disease at baseline. 

However, their results are provocative, and they are discussed in this report. 

The term “liver function tests,” when used most precisely, refers to laboratory tests of liver 

function (e.g., bilirubin, albumin, and prothrombin time) and does not include aminotransferases. 

However, for this report, we will use the more common vernacular interpretation that includes all 

tests referent to liver status. 

Again, interpreting available evidence and meta-analysis is compromised by poor study 

design and poor reporting of published studies. Across the trials there is heterogeneity in, and 

lack of information about, the spectrum of liver disease, etiology, severity, and chronicity; 

preparations and doses of milk thistle; duration of intervention; assessment of compliance; 

effectiveness of blinding; followups; dropouts; and statistical analyses (see Evidence Tables 1 

through 4). Information is scant about screening for alcohol intake, HBV, HCV, and HIV status 

at baseline, as well as explicit monitoring of alcohol intake during studies. All of these factors 

can affect the course of liver disease and potential efficacy of milk thistle. 

Information on other potential confounders (e.g., comorbidities and severity of liver disease 

at baseline) is also rarely reported. No information was given regarding whether oral solid 

dosage formulation used in the trial met any criteria for in vitro dissolution standards. The 

precision of the available evidence did not measure up to the precision regarding etiology, 

severity, and chronicity in the a priori evidence questions. 

<strong>Milk</strong> <strong>Thistle</strong> Preparations and Doses 

We will use the term “milk thistle” loosely for summarizing results. By “silymarin,” we 

mean the extract of seeds, containing silybin, silychristin, and silydianin, which may or may not 

have been standardized to percent silymarin in the reports of published trials and for which 

silybin is the primary component. By Silipide ® , we mean a silybin-phosphatidylcholine 

complex, but again studies may not have reported standardization results. Among the 16 

25

placebo-controlled studies, Legalon ® (Madaus) was used in 12. Of these 12 studies, the dose 

varied from 240 to 800 milligrams per day (mg/d) in 8 trials, duration varied from 7 days to 6 

years, and neither dose nor duration of Legalon ® was given for 4 trials (Figures 3 and 4). Of the 

remaining 4 of 16 placebo-controlled studies, 2 used silymarin (no further characterization 

regarding preparation) in doses of 210 and 800 mg, and two used Silipide ® at 240 mg/d. 

Treatment duration for these four trials was 7 to 446 days for three and not given for one (see 

Figures 3 and 4). 

Figure 3. Distribution of durations of therapy for 16 blinded, placebo-controlled studies 

Number of Studies 

5 

4 

3 

2 

1 

0 

0-14 15-30 31-60 61-90 90+ Unclear/ 

not given 

Study Duration (days) 

Figure 4. Distribution of doses for 16 placebo-controlled trials 

Number of Studies 

10 

9 

8 

7 

6 

5 

4 

3 

2 

1 

0 

Legalon Legalon Legalon Legalon Silymarin Silipide Silybin 

280 mg daily 420 mg daily 450 mg daily unclear dose 800 mg daily 240 mg daily 210 mg daily 

<strong>Milk</strong> <strong>Thistle</strong> Dose 

26

Among the 17 nonplacebo-controlled trials (Evidence Table 3), five used 420 mg/d of 

Legalon ® , one used 600 mg/d, and two studies used variable dosing from 210 mg/d to 420 mg/d. 

Preparations for the other nine studies included silymarin, silybin, Silipide ® , and Silimarol ® . No 

further information was given, and doses ranged from 140 to 600 mg of silymarin and 10 to 360 

mg of silybin; no standardized dose was given for Silimarol ® . Over all 17 studies, intervention 

duration ranged from 14 days to 1 year for 13 and was “variable” or not given for 4 studies. 

In the two studies of prophylactic silymarin in conjunction with potentially hepatatoxic 

antituberculosis drugs or tacrine, an unknown formulation (unknown dose) and silymarin (not 

further characterized) at 420 mg/d were used. Intervention duration was 56 days and 84 days, 

respectively (Evidence Table 4). 

<strong>Milk</strong> <strong>Thistle</strong> and Liver Disease 

<strong>Milk</strong> <strong>Thistle</strong> and Alcohol-Related Liver Disease 

No placebo-controlled studies clearly evaluated subjects with purely acute alcoholic 

hepatitis. Six randomized, blinded, placebo-controlled studies appear to have evaluated chronic 

alcoholic liver disease, but the spectrum of disease chronicity and severity varied among the 

studies or was not clear; two merely described subjects as having “alcoholic liver disease.” 66-72 

Summary Table 1 summarizes these six studies and is from Evidence Tables 1 and 2. 

Across these trials, results varied and may be generally confounded by the question of 

abstinence from alcohol. In one, there was significant improvement in liver function with 

abstinence from alcohol for patients given silymarin or placebo. However, between silymarin 

and placebo, there was no difference in the course of liver function as measured by prothrombin 

time (PT), albumin, bilirubin, gammaglutamyl transpeptidase (GGTP), aspartate 

aminotransferase (AST), or degree of hepatitis or fibrosis on biopsy. 67 In four trials, at least one 

parameter of liver function improved significantly with silymarin compared with placebo, but the 

courses of an equal number or more parameters were not significantly different between 

silymarin and placebo. 66,69-71 One study showed no improvement in overall survival with 

silymarin but marginally significantly improved survival (p=0.059 by univariate analysis) in 

HCV-positive patients given silymarin versus placebo. 68 Qualitatively, there does not appear to 

be a relationship between duration of therapy and improvement in liver function. 

<strong>Milk</strong> <strong>Thistle</strong> and Chronic Liver Disease of Mixed Etiology 

The available evidence did not provide sufficient information to put six studies into any of 

our a priori etiologic categories of disease. These studies could be characterized as only 

addressing chronic liver disease of mixed etiologies, including both alcoholic and nonalcoholic 

disease and without further clarification. 73-77,72 Summary Table 2, extracted from Evidence 

Tables 1 and 2, summarizes these six studies. 

Across three studies, at least one parameter showed significant improvement with silymarin 

compared with placebo, and there was no difference between silymarin and placebo for as many 

or more parameters. Two studies indicated a possible survival benefit: In one study, survival 

was significantly improved for patients with Child’s A alcoholic liver disease with silymarin 

compared with placebo, and in the other study, there was a trend toward improved overall 

27

survival. 75,76 Again, there is no apparent qualitative relationship between duration of therapy and 

efficacy of silymarin, but duration was not given or unclear for three of the trials. 

In one study, 65 subjects with “chronic persistent hepatitis, etiology unknown” were 

randomized to receive either Silipide ® at 240 mg/d for 3 months or placebo. 77 AST improved 

significantly in subjects receiving silymarin, but there were no significant differences between 

the two study groups in the course of alanine aminotransferase (ALT), bilirubin, albumin, and 

PT. 

<strong>Milk</strong> <strong>Thistle</strong> and Viral Liver Disease 

One study evaluated silymarin in the setting of acute viral hepatitis. Summary Table 3 

summarizes this study and is extracted from Evidence Table 1. 

In a blinded study, 59 patients with acute hepatitis A and B were randomized to silymarin at 

420 mg/d for 25 days or placebo. 78 No further information on inclusion/exclusion criteria, 

acuity, or severity was given. The mean age was 37, and 22 percent of subjects were men. 

Compared with that seen with placebo, improvement in AST and bilirubin was significantly 

better with silymarin, with a nonsignificant trend toward improvement in ALT. There was no 

significant difference in the course of alkaline phosphatase. 

Two placebo-controlled studies evaluated the efficacy of silymarin in the setting of chronic 

viral hepatitis (Summary Table 4). <strong>Milk</strong> thistle was given as Silipide ® at 240 mg/d and as 

Legalon ® at 420 mg/d; duration of treatment was 1 week for Silipide ® and 1 year for Legalon ® . 

Summary Table 4 summarizes these studies, which are extracted from Evidence Tables 1 and 2. 

One randomized, blinded, placebo-controlled trial included 20 patients with biopsy-proven 

chronic viral hepatitis or with AST and ALT levels greater than twice normal for more than 12 

months due to HBV and/or HCV. 79 Patients with portal hypertension, hepatic encephalopathy, 

ascites, bilirubin or alkaline phosphatase more than twice the normal limit, alcohol consumption 

exceeding 30 grams per day (g/d), hepatocellular carcinoma, or liver disease associated with 

collagen vascular disease were excluded. Subjects received placebo or Silipide ® at 240 mg/d for 

7 days. AST, ALT, and GGTP significantly improved in patients receiving Silipide ® compared 

with placebo. There was no difference between groups in bilirubin, alkaline phosphatase, 

malondialdehyde (MDA), or albumin. 

In the other trial, 24 subjects with chronic viral hepatitis for more than 6 months were 

randomized to silymarin at 420 mg/d or placebo for 1 year. 80 Exclusion criteria were prior 

treatment with silymarin, steroids or other toxic drugs, alcohol consumption of more than 80 g/d, 

or other comorbidities requiring medication. There was a trend toward histologic improvement 

by liver biopsy in those receiving silymarin compared with placebo. 

<strong>Milk</strong> <strong>Thistle</strong> and Cirrhosis 

Five randomized and placebo-controlled trials included patients with cirrhosis along with 

patients with a mixed spectrum of types and severity of liver disease. Four are discussed in the 

section on chronic alcoholic liver disease, 66,67,70,72 and one is discussed in the section on chronic 

liver disease of mixed etiologies. 74 Across three trials, at least one parameter of liver function 

improved in those taking silymarin compared with placebo. 66,70,72 Most parameters, however, 

did not improve. Specifically, none improved in one study, 74 results were not separately 

28

presented for cirrhotic patients in a third study, and in another study, liver function improved 

equally in placebo and milk thistle arms with abstinence from alcohol. 67 

Two randomized, blinded, placebo-controlled trials studied patients with alcoholic or 

nonalcoholic cirrhosis. 75,76 Summary Table 5, extracted from Evidence Tables 1 and 2, 

summarizes these studies. In both studies, silymarin dose was 420 mg/d, but duration of therapy 

was variable or unclear. The two studies are nearly identical in sample size (n=172, n=170) and 

relatively similar in exclusion criteria. One showed a nonsignificant trend toward improved 

survival overall with silymarin, and the other found significantly improved survival in the 

subgroups with alcoholic liver disease and in patients initially rated as Child’s score A in 

severity. 75,76 

Only two randomized, placebo-controlled, blinded trials specifically studied patients with 

alcoholic cirrhosis. 68,71 These studies are summarized in Summary Table 6, which is extracted 

from Evidence Tables 1 and 2. In these studies, the dose of silymarin was similar (450 mg/d of 

Legalon ® and 420 mg/d of Legalon ® ); duration of therapy was unclear in one study and 30 days 

in the other. One reported nonsignificant trends favoring silymarin, compared with placebo, in 

rates of encephalopathy and upper gastrointestinal bleeding. There was a trend (p=0.059) toward 

improved survival, compared with placebo, in the subgroup of patients who also had HCV. 

However, HCV status was determined retrospectively on frozen sera from a convenience sample 

of patients. There was no apparent benefit of silymarin in aminotransferases, PT, bilirubin, 

alkaline phosphatase, survival, or rates of other clinical syndromes (i.e., hepatomegaly, 

splenomegaly, jaundice, and ascites). 68 Again, duration of treatment with silymarin was unclear. 

In the other study, when silymarin was given for 30 days, there was a significant improvement in 

aminotransferases for patients taking silymarin compared with placebo, but no improvement in 

bilirubin. 71 

<strong>Milk</strong> <strong>Thistle</strong> and Toxin-Induced Liver Disease 

Only one study met criteria for evaluating milk thistle’s efficacy in the setting of nonalcohol 

toxin-induced liver disease. 81 Summary Table 7 summarizes this study and is extracted from 

Evidence Table 1. In randomized, placebo-controlled, blinded trial with factorial design, 60 

women were studied who were 40 to 60 years old, had been receiving phenothiazines and/or 

butyrophenones for 5 or more years, and had increased aminotransferases to more than twice the 

normal limit. Exclusion criteria included current therapy with other potentially hepatotoxic 

drugs or other etiologies of liver disease, compromised renal function (blood urea nitrogen 

exceeding 60 mg/dL or creatinine exceeding 2.5 mg/dL), “cardiac or circulatory insufficiency,” 

diabetes mellitus, “other important extrahepatic disease,” pregnancy, and alcohol (more than 30 

g/d) or opiate abuse. Subjects were treated for 90 days after randomization to the following: 

(1) placebo and continued psychotropic drugs; (2) silymarin at 800 mg/d and continued 

psychotropic drugs; (3) silymarin at 800 mg/d and psychotropic drugs discontinued; or (4) 

placebo and psychotropic drugs discontinued. MDA significantly improved in patients on 

silymarin and psychotropic drugs compared with women on placebo and psychotropic drugs. 

However, no difference was found in the course of liver function tests for AST, ALT, or MDA 

between patients taken off psychotropic drugs and given silymarin or placebo. 

Two blinded studies evaluated prophylactic milk thistle in conjunction with hepatotoxic 

medications—drugs for treating tuberculosis and tacrine for treating Alzheimer’s disease. 82,83 

Summary Table 8 summarizes these studies and is extracted from Evidence Table 4. 

29

In the study of prophylactic milk thistle during treatment for tuberculosis, 29 subjects with 

normal liver function tests received antituberculosis drugs plus Hepabene ® , a mixture of 

silymarin and Fumaria officinalis alkaloids (two capsules daily, no other information given), and 

93 subjects received antituberculosis drugs alone. 82 Proportions receiving various 

antituberculosis drugs, in the control and silymarin groups respectively, were the following: 

rifampin (98 percent and 100 percent); isoniazid (99 percent and 97 percent); pyrazinamide 

(84 percent and 100 percent); ethambutol (50 percent and 38 percent); and streptomycin 

(37 percent and 14 percent). Initially, AST increased in 49 percent of control subjects and 

38 percent of subjects receiving Hepabene ® . Similarly, ALT increased in 48 percent of control 

and 31 percent of those receiving Hepabene ® . These differences were statistically significant 

over the course of 8 weeks; AST then fell in 40 percent of subjects receiving Hepabene ® , 

compared with 19 percent of controls. Similarly, ALT fell in 48 percent of those receiving 

Hepabene ® , compared with 22 percent in controls. Again, these differences were statistically 

significant. 

The second study of prophylatic milk thistle was a randomized, double-blind trial in which 

222 patients meeting a priori criteria for Alzheimer’s dementia were randomized to tacrine and 

silymarin or tacrine with placebo. 83 Patients with prior liver disease were excluded. Silymarin 

(420 mg/d) was given for 1 week, and then tacrine was added, first at 40 mg/d for 6 weeks, then 

at 80 mg/d for 6 additional weeks. (Note: Published report 83 states that silymarin [Legalon ® ] 

dose was 420 mg/d, but an internal study summary reportedly states dose was 140 mg/d from 

Madaus. 84 ) There were no significant differences in the courses of AST or ALT levels or the 

rate of side effects during the study. There was no significant difference even though rates 

appeared lower. 

<strong>Milk</strong> <strong>Thistle</strong> and Cholestasis 

No studies met criteria for evaluating efficacy of milk thistle in treating cholestatic liver 

disease, pregnancy-related or not. 

<strong>Milk</strong> <strong>Thistle</strong> and Primary Hepatic Malignancy 

No studies met criteria for evaluating milk thistle efficacy in treating or preventing primary 

hepatic malignancy (hepatocellular carcinoma or cholangiocarcinoma). 

Effectiveness of Different Preparations of <strong>Milk</strong> <strong>Thistle</strong> 

Pharmacokinetic studies indicate that one preparation of oral Silipide ® (silybinphosphatidylcholine 

complex) has better absorption from the gastrointestinal tract and, as a 

result, is more bioavailable than a particular preparation of oral silymarin. However, because of 

variability in different preparations, differences in bioavailability may not be generalizable. No 

randomized, placebo-controlled trials directly compared a standardized silymarin extract with 

Silipide ® for effectiveness in treating liver disease. One Phase II, dose-response study compared 

different doses of Silipide ® with no treatment, and one nonrandomized study compared 

silymarin, Silipide ® , and “no treatment or placebo control.” 85 Summary Table 9 summarizes the 

Phase II study of Silipide ® and is extracted from Evidence Table 3. 

30

In the Phase II study, 60 subjects with chronic viral or alcoholic hepatitis were randomized to 

14 days of Silipide ® at 160 mg/d, 240 mg/d, or 360 mg/d or no treatment. AST, GGTP, and 

bilirubin improved significantly more in subjects receiving 240 mg/d or 360 mg/d, compared 

with those receiving 160 mg/d. 85 No comparative data and data specific to the control group (no 

treatment) versus any dose of Silipide ® were reported. 

Exploratory Meta-Analyses Results 

Exploratory meta-analyses proceeded in the following sequence: (1) all 16 placebocontrolled 

studies (studies in Evidence Tables 1 and 2); (2) the 14 randomized, placebocontrolled 

trials in Evidence Table 1; and (3) subgroup analyses by etiology of liver disease and 

duration of followup (≤45 days or 46 to 90 days). Relevant funnel plots, Galbraith plots, and 

forest plots are given in Appendix B. 

Summary Table 10 shows the results for pooling all 16 placebo-controlled trials. Effect size 

is given both as the standardized mean difference, in standard deviation units, and in converted 

laboratory values (see preceding Data Analysis Process section). Statistical significance is 

expressed as the probability that the effect of silymarin is not zero. When one outlier study was 

removed, there was no significant heterogeneity. Most effect sizes favored silymarin, but effect 

sizes were small or not statistically significant. Results were similar for pooling only the 14 

higher quality trials in Evidence Table 1 (Summary Table 11). 

Table 3 shows the variables for which data were available in etiologic subgroups. Tables 4, 

5, and 6 show results of these subgroup analyses. Results are similar throughout: Silymarin was 

generally associated with small favorable, but not statistically significant, effect sizes. 

In summary, results of multiple exploratory meta-analyses show either nonsignificant effects 

or a few statistically significant effects that are small in magnitude. There is no obvious 

relationship between observed effectiveness and etiology of liver disease or duration of 

followup. It is possible that clinical heterogeneity in subject populations and small sample sizes 

may have masked statistically significant effects of milk thistle in different clinical groups. As 

we conducted multiple exploratory analyses, it is also possible that some of the statistically 

significant findings occurred by chance. 

31

Insert Table 3 Here 

32

Insert Table 3 Here. 

33


34


35


36


37

Adverse <strong>Effects</strong> of <strong>Milk</strong> <strong>Thistle</strong> 

Overview of Adverse Effect Literature 

The adverse effect literature regarding milk thistle is difficult to interpret for many reasons. 

First, searching for studies that report adverse effects is difficult and, given current indexing 

systems for electronic databases, probably incomplete. Many studies may mention adverse 

effects in passing, but they do not use adverse effects as a key index word or in their abstracts. If 

these studies do not otherwise meet selection criteria in a review, they will be missed. Second, 

information is frequently missing on whether adverse effects were elicited by voluntary selfreport 

or standardized probes. Third, in some case reports and case series, adverse effects cannot 

be directly attributed to milk thistle because chance, coincidence, or confounding factors could 

have been responsible. Fourth, case reports and case series may miss delayed adverse reactions 

because such associations are more difficult to make than those that occur immediately after 

administration of an agent. Fifth, although case reports and case series can provide qualitative 

information about the nature of an adverse effect, they cannot generate estimates of incidence. 86 

Based on identified reports, milk thistle appears to be safe for most people. Seventeen 

reports of adverse effects possibly due or attributed to milk thistle oral supplements were 

identified (Evidence Table 5). Data were abstracted from seven randomized clinical 

trials, 66,68,75,77,83,85,87 six cohort studies, 88-93 and five case reports. 94-98 Besides study 

characteristics, we attempted to abstract data regarding evidence for causality: (1) 

documentation of improved adverse effect after the milk thistle supplement was discontinued, 

(2) adverse effect recurrence when rechallenged with the milk thistle formulation, (3) careful 

search for other causes of the adverse effect, and (4) documentation of a dose-response 

relationship. 56 None of the 17 reports provided information regarding a possible dose-response 

relationship. Detailed data are shown in Evidence Table 5. An overall summary of reported 

adverse effects, by level of evidence, is shown in Summary Table 12. 

Common Symptomatic <strong>Effects</strong> 

Gastrointestinal side effects are the most commonly reported adverse effects, in both 

randomized clinical trials and prospective cohort studies. 75,77,83,85,88-93,98 Overall incidence 

appears relatively low, and in RCTs there is no apparent difference between treatment and 

control groups. 66,68,77 Skin manifestations of adverse drug effects are also fairly commonly 

reported, but again overall incidence appears low and no more frequent in groups receiving milk 

thistle than in control groups. 66,68,77 Incidence of headaches also appears low and no different 

between silymarin and control groups in RCTs. 66,68 

Common and Uncommon Serious Adverse <strong>Effects</strong> 

Serious adverse effects identified in available evidence for this systematic review were 

anaphylactoid reactions or anaphylaxis. Available evidence was limited to three case reports. In 

one case report, a variety of symptoms plus “collapse” was associated with milk thistle, 

improved after discontinuation of milk thistle, reappeared on rechallenge, but was also associated 

with potential alternative etiologies. 98 In a second case report of anaphylactic shock, no 

information was given about associated evidence of causality. 94 A third case report of an 

38

apparent anaphylactoid reaction improved with prednisone and discontinuing silymarin, and 

there were no apparent alternative possible etiologies. 95 

39

Table 3. Outcome measures and followup times for trials of chronic liver disease, chronic liver disease of mixed etiology, and viral liver 

disease 

Study Outcomes Measures Time Point(s) a,b 

Chronic drug 

Palasciano81 Chronic alcoholic liver disease 

AST ALT 30, 90 days 

Salmi69 AST ALT Alk phos Histology 28 days 

Lang71 Bili AST ALT GGTP 30 days 

Trinchet67 Alb Bili AST GGTP PT Histology 90 days 

Feher70 Alb Bili AST ALT Alk phos GGTP PT MDA 

(180 only) 

90, 180 days 

Bunout66 Alb Bili AST Alk phos GGTP PT Child’s 

score 

15 months 

Pares68 Alb Bili AST ALT Alk phos GGTP PT Child’s 

score 

2 years 

Chronic liver disease, mixed etiologies (alcohol, viral, toxin assumed) 

Fintelmann73 AST ALT GGPT 1, 3, 7, 10, 14, 21, 

28 daysa Tanasescu74 : Data 

separately reported for CAH, 

CPH, HCV 

Bili ALT Alk phos GGTP PT 40 days 

Fintelmann72 AST ALT Alk phos 42 days 

Marcelli77 Alb Bili AST ALT PT 90 days 

Ferenci75 : No numerical data 

for chemistries 

Survival 41 months 

Benda76 : No numerical data 

for chemistries 

Acute viral hepatitis 

Survival 48 months 

Magliulo78 Bili AST ALT Alk phos GGTP 1, 3, 5, 7, 9, 14, 21, 

28 daysa

Table 3. Outcome measures and followup times for trials of chronic liver disease, chronic liver disease of mixed etiology, and viral liver 

disease (continued) 

Study Outcomes Measures Time Point(s) a,b 

Chronic viral hepatitis 

Buzelli 79 Bili AST ALT Alk phos GGTP MDA 7 days 

Kiesewetter 80 : Reported as 

improvement, no change, 

worse 

Histologic 

change 

90 days; 360 days 

combined 

Note: When there was more than one study, effect sizes were pooled. 

a 

The last time point (7 to 45 days) was selected for pooling as “≤45 day” time point. 

b 

Time points for pooling included ≤45 days and 90 days. 

Abbreviations Used: alb = albumin; alk phos = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; bili = bilirubin; 

CAH = chronic active hepatitis; CPH = chronic persistence hepatitis; GGTP = gammaglutamyl transpeptidase; HCV = hepatitis C virus; MDA = malondialdehyde; 

PT = prothrombin time.

Table 4. Effect sizes and meta-analysis for chronic alcoholic liver disease (6 studies) 

Outcome a 

AST 

44.77 U/L a 

ALT 

36.02 U/L a 

GGTP 

153.94 U/L a 

Time of 

Followup 

No. of 

Studies 

Effect Size (SD units) 

95% CI 

Effect Size, 

Clinical Units b 95% CI 

p Value c 

(ES ≠ 0) 

Q p Value c 

(homogeneity) 

≤45 days 2 -0.24 (-0.58 to 0.10) -10.7 (-26.0 to 4.5) 0.16 0.61 

90 days 2 -0.02 (-0.76 to 0.72) -0.9 (-34.0 to 32.2) 0.96 0.06 

180 days 1 -0.37 (-1.03 to 0.29) -16.6 (-46.1 to 13.0) 0.27 – 

15 months 1 0.37 (-0.21 to 0.95) 17.5 (-9.4 to 42.5) 0.21 – 

2 years 1 0.28 (-0.07 to 0.64) 12.5 (-3.1 to 28.7) 0.12 – 

≤45 days 2 -0.33 (-0.67 to 0.004) -11.9 (-24.1 to 0.1) 0.05 0.83 

90 days 1 -0.39 (-1.05 to 0.27) -14.0 (-37.8 to 9.7) 0.24 – 

180 days 1 -0.28 (-0.93 to 0.38) -10.1 (-33.5 to 13.7) 0.41 – 

2 years 1 0.33 (-0.03 to 0.68) 11.9 (-1.1 to 24.5) 0.07 – 

≤45 days 1 -0.71 (-1.34 to –0.08) -109.3 (-206.3 to -12.3) 0.03 – 

90 days 2 -0.04 (-0.41 to 0.32) -6.2 (-63.1 to 49.3) 0.81 0.93 

180 days 1 -0.64 (-1.30 to 0.03) -98.5 (-200.1 to 4.6) 0.06 – 

15 months 1 -0.26 (-0.84 to 0.32) -40.0 (-129.3 to 49.3) 0.38 – 

2 years 1 0.38 (0.02 to 0.73) 58.5 (3.1 to 112.4) 0.04 – 

MDA 

6.65 nmol/ml a 180 days 1 -0.81 (-1.49 to -0.13) -5.4 (-9.9 to -0.9) 0.02 – 

Alkaline 

Phosphate 

101.01 U/L a 

Bilirubin 

0.32 g/dL a 

Albumin 

0.74 g/dL a 

PT 

17.39 a 

seconds 

≤45 days 1 0.19 (-0.21 to 0.59) 19.2 (-21.2 to 59.6) 0.35 – 

90 days 1 0.10 (-0.55 to 0.76) 10.1 (-55.6 to 76.8) 0.76 – 

180 days 1 -0.34 (-1.00 to 0.31) -34.3 (-101.0 to 31.3) 0.31 – 


2 years 1 -0.08 (-0.43 to 0.27) -8.1 (-43.3 to 27.3) 0.65 – 

≤45 days 1 -0.30 (-0.92 to 0.32) -0.1 (-0.3 to 0.1) 0.35 – 

90 days 2 -0.10 (-0.70 to 0.49) -0.03 (-0.2 to 0.2) 0.73 0.13 

180 days 1 -0.49 (-1.16 to 0.17) -0.2 (-0.4 to 0.05) 0.14 – 

15 months 1 -0.16 (-0.74 to 0.43) -0.05 (-0.2 to 0.1 0.60 – 

2 years 1 0.004 (-0.35 to 0.36) 0.001 (-0.1 to 0.1) 0.98 – 

90 days 2 -0.13 (-0.87 to 0.60) -0.1(-0.6 to 0.4) 0.72 0.06 

180 days 1 0.19 (-0.47 to 0.84) 0.1 (-0.3 to 0.6) 0.58 – 

15 months 1 0.25 (-0.35 to 0.85) 0.2 (-0.2 to 0.6) 0.42 – 

2 years 1 -0.23 (-0.59 to 0.12) -0.2 (-0.4 to 0.09) 0.20 – 

90 days 2 -0.30 (-1.00 to 0.40) -5.2 (-17.4 to 7.0) 0.40 0.08 

180 days 1 0.47 (-0.20 to 1.13) 8.2 (-3.5 to 19.7) 0.17 – 


2 years 1 -0.18 (-0.53 to 0.17) -3.1 (-9.2 to 3.0) 0.32 – 

34

Table 4. Effect sizes and meta-analysis for chronic alcoholic liver disease (6 studies) (continued) 

Outcome a 


Follow-Up 


Studies 


95% CI 

Effect Size, 


p-Value c 

(ES ≠ 0) 

Q p-Value c 

(Homogeneity) 

Child’s 15 months 1 -0.09 (-0.68 to 0.50) -0.2 (-1.7 to 1.3) 0.78 – 

2.55 score 2 years 1 0.27 (-0.08 to 0.62) 0.7 (-0.2 to 1.6) 0.13 

Note: When there was more than one study, effect sizes were pooled. 

a Mean pooled standard deviations. 

b Standard deviation effect size units are back-converted to clinical effect sizes by standard deviation x effect size. 

c All studies refer to combination of chronic alcohol, chronic and acute viral, and chronic mixed etiology unless 

otherwise noted (the inclusion of one drug study, factorial design); values reported for meta-analytic results; N/A for 

single study estimates. 

Abbreviations Used: ALT = alanine aminotranferase; AST = aspartase aminotranferase; CI = 95% confidence 

interval; ES = effect size; GGTP = gammaglutamyl transpeptidase; g/dL = grams per deciliter; 

MDA = malondialdehyde; nmol/ml = nanomoles per milliliter; PT = prothrombin time; SD = standard deviation; 

U/L = units per liter. 

35

Table 5. Effect sizes and meta-analysis for chronic liver disease of mixed etiologies (6 studies) 

Outcome a 

AST 

44.77 U/L a 

ALT 


Followup 


Studies 


95% CI 

Effect Size, 


p Value c 

(ES ≠ 0) 

Q p Value c 

(homogeneity) 

≤45 days 2 -0.30 (-0.67 to 0.08) -13.4 (-30.0 to 3.6) 0.12 0.41 

90 days 1 -0.73 (-1.22 to -0.24) -32.7 (-54.6 to -10.7)

Table 6. Effect sizes and meta-analysis for viral liver disease, acute and chronic (3 studies) 

Outcome a 


Followup 


Studies 

Effect Size 

(SD units) 95% CI 

Effect Size, 


p Value c 

(ES ≠ 0) 

Q p Value c 

(homogeneity) 

AST 

44.77 U/L a ≤45 days 2 -0.17 (-0.70 to 0.36) -7.6 (-31.3 to 16.1) 0.53 0.31 

ALT 

36.02 U/L a ≤45 days 2 0.25 (-1.46 to 1.96) 9.0 (-52.6 to 70.6) 0.77

Chapter 4. Conclusions 

The effectiveness of milk thistle in human liver disease has not been established. This may 

be because of the scientific quality of study methods or published reports or both. Possible 

benefit has been shown most frequently, but not consistently, for improvement in 

aminotransferases, but 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. Mechanisms of action, disease populations likely to 

benefit, the optimal formulations of milk thistle, and duration of therapy are undefined. Also, 

little about adverse effects is known. Further study of mechanisms of action and well-designed 

clinical trials, with detailed reporting of adverse effects and components of potential causality, 

are needed. 

41

Chapter 5. 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. The most serious 

potential adverse effects of milk thistle reported thus far are anaphylactoid reactions and 

anaphylaxis, and available data are extremely limited regarding causality. 

Beneficial <strong>Effects</strong> Regarding Liver Diseases 

Studies in humans with physiologic outcomes are limited by unclear study populations, 

randomization procedures, small sample sizes, variable and sometimes short duration of 

treatment, unclear blinding for outcome assessment, and unclear or inadequate information about 

potential confounders. Characteristics of future studies should include longer and larger 

randomized trials; clinical, as well as physiologic, outcome measures; histologic outcomes; 

adequate blinding; detailed data about compliance and dropouts; systematic standardized 

surveillance for adverse effects; and sophisticated considerations regarding study populations 

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). 

There are several important considerations for study populations and confounders. After 

correction for baseline risk differences, our meta-analyses found generally adequate statistical 

homogeneity, despite poorly defined and heterogeneous study populations. Yet, clinical 

heterogeneity in study populations regarding etiology, chronicity, and severity of liver disease 

might have masked subgroup differences in outcomes. There are numerous important potential 

confounders and combinations of confounders that might affect outcomes in individual subjects. 

These include the following: comorbidities, baseline and ongoing use of alcohol, various 

combinations of alcoholic and viral liver disease in individual patients, various etiologies of 

concomitant fatty liver disease, coinfection with HIV and HBV and/or HCV, treatment with 

antiviral medications for HIV, and use of interferon for HCV. Thus, future research should 

assess baseline status regarding alcohol, HBV, HCV, and HIV, as well as systematic surveillance 

for these factors through the duration of studies. 

Specific Areas of Research 

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. Several specific research directions appear 

especially relevant at this time. The high prevalence of alcoholic liver disease and the increasing 

prevalence of HCV liver disease in the United States and high prevalence of HBV infection in 

43

intravenous drug users and in developing countries warrant research focusing on these 

populations. Effectiveness of milk thistle in cholesetatic disease and nonalcohol steatohepatitis 

has not been studied. Because of provocative data from two small trials, further research is 

needed regarding prophylactic use of milk thistle in the setting of potentially hepatotoxic 

medications or as treatment for iatrogenic liver dysfunction. 

More information is needed about effectiveness of milk thistle for severe acute ingestion of 

hepatotoxins, such as occupational exposures, acetaminophen overdose, and amanita poisoning. 

The available data are limited to case reports and small case series in Europe for amanita 

poisoning and occupational exposures to hepatotoxins. We identified no trials of milk thistle for 

acetaminophen hepatoxicity. Because of the low incidence and ethical issues, it is premature to 

consider randomized clinical trials. However, a systematic review of the evidence at hand and 

then careful consideration of the feasibility and utility of well-designed case-control or cohortcomparison 

studies would be useful. Such data could inform the decision regarding trials of 

n-acetylcysteine with and without milk thistle or treatment for other acute toxic exposures. 

44

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Summary Table 1. Placebo-controlled studies of milk thistle for chronic alcoholic liver disease (n = 6) 

Subject Outcomes (favoring silymarin 

Study 

Design Liver Disease 

Characteristics unless otherwise noted) 

Author: 

Bunout66 Study type: RCT/blind 

Year: 1992 

Country: 

Chile 

Language: 

Spanish 

Intervention/dose/duration: Silymarin 

(Legalon ® )/280 mg daily/446 days 

Control: Placebo 

Outcome measuresa Type: Alcoholic liver disease (inactive cirrhosis, active N: 59 

Significant: Albumin 

: AST, GGTP, alk 

phos, bilirubin, albumin, PT 

Followup interval: Monthly for an 

average of 15 months 

cirrhosis, cirrhosis with alcoholic hepatitis, alcoholic 

hepatitis, fibrosis) 

Include: Positive for alcohol history and symptoms of 

icterus edema, ascites, or encepholopathy or bilirubin 

exceeding 2 mg/dL; PT exceeding 75 percent control; 

albumin less than 3 mg/dL 

Exclude: HBV antigen; renal failure; cardiac failure; 

terminal liver disease 

Mean age: 50 

Percent male: 86 

Setting: Specialty 

clinic 

Not significant: Child’s score, 

bilirubin, AST, GGTP, alk phos, 

PT, survival 

Assessment time points with results 

reported: Mean of 15 months 

Acuity/severity: Chronic, cirrhosis, no other information 

Baseline group similarity: Demos, LFTs appear similar 

Author: 

Feher70,99,100 Study type: RCT/blind 


Year: 

1989/1990 

Country: 

Hungary 

(Legalon 

Language: 

Hungarian 

® )/420 mg daily/180 days 


Outcome measuresa Type: Chronic alcoholic liver disease (cirrhosis, reactive N: 36 

Significant: AST, GGTP, MDA 

fibrosis, fatty degeneration) 

Mean age: 46 Not significant: (assumed for all) 

: AST, ALT, 

GGTP, alk phos, bilirubin, albumin 

Include: Alcohol intake exceeding 60 g/d in men and 

30 g/d in women for 8 + 4 years; chronic liver disease; no 

previous corticosteroid or immunosuppressive treatment 

Exclude: Not given 


Setting: Unclear 

ALT, alk phos, albumin, PT, 

survival 

Followup interval: 90 and 180 days 


reported: 90 and 180 days 

Acuity/severity: Chronic, no other information 


Author: 

Lang71 Study type: RCT/blind/three arms 

Interventions/dose/duration: Silymarin 

Year: 1990 

Country: 

Hungary 

Language: 

English 


AICA-P/600 mg daily/30 days 


Outcome measuresa Type: Alcoholic cirrhosis 

N: 60 

Significant: AST, ALT, GGTP 

Include: Alcohol intake exceeding 60 g/d in men and Mean age: 45 Not significant: Bilirubin 

: AST, ALT, 

GGTP, alk phos, albumin 

30 g/d women for more than 6 years; histologic diagnosis 

of micronodular cirrhosis 

Exclude: Vascular and/or parenchymal decompensation; 

+HBsAg 




Followup interval: 28 days 


reported: Weekly for 1 month 

Baseline group similarity: LFTs appear similar

Summary Table 1. Placebo-controlled studies of milk thistle for chronic alcoholic liver disease (n = 6) (continued) 

Subject Outcomes (favoring silymarin 

Study Design Liver Disease 

Characteristics unless otherwise noted) 

Author: 

Pares68 Study type: RCT/blind 


Year: 1998 

Country: 

Spain 

Language: 

English 

(Legalon ® )/450 mg daily/unclear 


Outcome measuresa Type: Alcoholic cirrhosis (24 percent had superimposed N: 200 

Significant: 

alcohol hepatitis) 

Mean age: 50 + Trend: Encephalopathy, UGIB, 

: AST, ALT, 

GGTP, alk phos, bilirubin, albumin, PT 

Followup interval: Every 3 months for 

2 years 


Include: Chronic alcoholism defined as alcohol 

exceeding 80 g/d men and 60 g/d women for more than 5 

years; biopsy or laparoscopic proven alcoholic cirrhosis 

Exclude: If ever received colchicine, malotilate, 

penicillamine, or corticosteroids; life expectancy less than 

6 months; drug addicted or pregnant; other known 

etiologies for cirrhosis (i.e., HBV, autoimmunity, primary 

biliary cirrhosis, or cryptogenic cirrhosis) 


Setting: Diagnosis in 

hospital then 

outpatient followup. 

survival for HCV-positive patients 

Not significant: AST, ALT, 

GGTP, PT, bilirubin, alk phos, 

hepatomegaly, splenomegaly, 

jaundice, ascites, survival 

Note: Trend was assessed 

qualitatively only for this review. 

reported: Survival at 5 years; all others 

at 2 years (assumed) 

Acuity/severity: Chronic, all cirrhosis, Child’s score 

A/B/C/ 63/114/14 


Author: 

Salmi69 Study type: RCT/blind 


Year: 1982 (Legalon 

Country: 

Finland 

Language: 

English 

® )/420 mg daily/28 days 


Outcome measuresa Type: Alcoholic liver disease 

N: 97 

Significant: AST, ALT, histology 

Include: Increased AST and ALT for more than 1 month Mean age: 37 Not significant: Alk phos, 

despite order to abstain from alcohol 


bilirubin 

: AST, ALT, alk 


Acuity/severity: No other information 

Setting: Hospital 

phos, bilirubin, histology 

Followup interval: Day 28 


reported: 28 days 

Baseline group similarity: Aminotransferase levels 

reported as similar but lower in controls 

Author: 

Trinchet67 Study type: RCT/blind 

Year: 1989 

Country: 

France 

Language: 

French 


(Legalon ® )/420 mg daily/ 90 days 


Outcome measuresa Type: Alcoholic hepatitis (50 percent with cirrhosis) N: 116 

Significant: Both silymarin and 

: AST, GGTP, 

bilirubin, albumin, PT, histology 




Include: Biopsy-proven alcoholic hepatitis with or without 

cirrhosis 

Exclude: Hepatic encephalopathy; contraindications to 

liver biopsy; hepatocellular cancer; ascites resistant to 

diuretics; platelets less than 100,000 per mm; PT less 

than 50 percent; other diseases limiting survival 

Acuity/severity: 58/116 with cirrhosis; no other 

information 


Mean age: 51 

Percent male: 67% 


placebo better with alcohol 

abstinence 

Not significant: PT, albumin, 

bilirubin, GGTP, AST, histology 

(hepatitis, fibrosis) 

a 

Results not necessarily reported for all. 

Abbreviations Used: AICA-P = amino imidazol carboxamial phosphate; alk phos = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartase 

aminotransferase; demos = demographic variables; GGTP = gammaglutamyl transpeptidase; HbsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = 

hepatitis C virus; LFT = liver function test; MDA = malondialdehyde; PT = prothrombin time; RCT = randomized controlled trial; UGIB = upper gastrointestinal bleed.

Summary Table 2. Placebo-controlled studies of milk thistle for chronic liver disease, mixed etiologies (n = 6) 

Subject Outcomes (favoring silymarin unless 

Study 


Characteristics 

otherwise noted) 

Author: 

Fintelmann73 Study type: RCT/blind 

Intervention/dose/duration: 

Year: 1980 Silymarin(Legalon 

Country: 

Germany 

Language: 

German 

® )/not given/not given 


Outcome measuresa Type: Toxic liver disease, any etiology N: 66 

Significant: ALT, GGTP 

(usually alcohol) 

Mean age: Not Not significant: AST, bilirubin, alk phos 

Include: Clinical and laboratory evidence of given 

toxic liver damage 

Percent male: 

: AST, ALT, 


Not given 

GGTP, alk phos, bilirubin 

Acuity/severity: No other information Setting: Unclear 

Followup interval: Days 1, 3, 7, 10, Baseline group similarity: No information 

14, 21, 28 


reported: Had to read off graphs, but 

all followups 

except age and gender “similar” 

Author: 

Fintelmann72 Study type: Cohort with comparison 

Year: 1970 

Country: 

Germany 

Language: 

German 

group/blinding unclear 


(Legalon ® )/6 tablets daily/42 days 


Outcome measuresa Type: Alcoholic liver disease, also other N: 50 

Significant: AST (categorical) 

: Bilirubin, alk 

phos, AST, ALT 

causes of fatty liver (pure parenchymal fatty 

degeneration, fatty degeneration and reactive 

inflammation, cirrhosis transformation in 

progress) 

Include: Biopsy-proven fatty liver, including 

early cirrhosis without portal hypertension, 

assignment stratified by diabetes mellitus, 

Mean age: Not 

given 

Percent male: 

Not given 


Not significant: AST (continuous), ALT, alk phos 


obesity, alcohol intake 

Assessment time points with results Exclude: Not given 


Acuity/severity: All degrees of fatty liver 

including early cirrhosis without portal 

hypertension 

Baseline group similarity: LFTs appear 

similar

Summary Table 2. Placebo-controlled studies of milk thistle for chronic liver disease, mixed etiologies (n = 6) (continued) 


Author: 

Tanasescu74 Year: 1988 

Country: 

Romania 

Language: 

English 

Author: 

Ferenci75 Year: 1989 

Country: 

Austria 

Language: 

English 

Author: 

Benda76 Year: 1980 

Country: 

Germany 

Language: 

German 

Study type: RCT, randomization 

stratified by type of disease: CPH, CAH, 

HCV/blind 


(Silimarina ® )/210 mg silybin equivalents 

daily/ 40 days 


Outcome measuresa : ALT, GGTP, 

bilirubin, alk phos, PT 




Study type: RCT/blind 


(Legalon ® )/420 mg daily/ mean 41 

months, range 2 to 6 years 


Outcome measuresa : AST, ALT, 

GGTP, alk phos, bilirubin, albumin, PT 

Followup interval: 4 years 


reported: 2 and 4 to 5.5 years for 

survival 



(Legalon ® )/420 mg daily/ Unclear 

Control: Placebo MVI 

Outcome measuresa : Survival 



reported: 4 years 

Type: CPH, CAH, hepatic cirrhosis, etiology 

not given 

Include: Diagnosis based on hepatic biopsy; 

clinical and laboratory data on CAH and CPH 

patients; some hepatic cirrhosis patients did 

not have hepatic biopsy; medium forms of 

disease; both sexes; 20 to 60 years old; basic 

disease from 1 to 10 years 


Acuity/severity: Chronic, no other 


Baseline group similarity: Age, LFTs appear 

similar 

Type: Alcoholic and nonalcoholic cirrhosis; 

cirrhosis with alcoholic hepatitis 

Include: Diagnosis of cirrhosis within 2 years 

before entering study 

Exclude: End-stage liver disease; known 

malignancies; primary biliary cirrhosis; 

immunosuppressive therapy 

Acuity/severity: Chronic, cirrhosis, Child’s 

score A/B/C 89/69/12 

Baseline group similarity: Demos, LFTs 

appear similar 

Subject 


N: 177 

Mean age: 53 

Percent male: 

47 


N: 170 

Mean age: 57 

Percent male: 

72 

Setting: Primary 

care/community 

clinic, specialty 

clinic, hospital 

Type: Alcoholic and nonalcoholic cirrhosis N: 172 

Include: Biopsy-proven cirrhosis 

Mean age: Not 

Exclude: Moribund; poor compliance; given 

immunosuppressive treatment in the past Percent male: 

year; prednisone in past 6 months; D- Not given 

penicillamine in past 3 months; primary biliary 

cirrhosis; Wilson’s disease 

Acuity/severity: Chronic, cirrhosis, no other 


Baseline group similarity: No information 


Significant: 

+ Trend: 

Not 

significant: 

Outcomes (favoring silymarin unless 


CAH 

ALT, GGTP, 

bilirubin, alk 

phos, PT 

CPH HCV 

ALT 

GGTP, 


phos, PT 

ALT, GGTP, 


phos, PT 

Note: Trend was assessed qualitatively only for 

this review. 

Significant: Survival (alcohol disease, Child’s 

score A) 

Not significant: (No data given; reported only as 

not significant) AST, ALT, GGTP, bilirubin, 

survival (nonalcohol disease, Child’s score B and 

C) 

Correspondence from Ferenci, Oct. 10, 1999: 

Length of treatment was variable. All patients 

were treated for 2 years (original primary 

endpoint) and were continued on the same 

therapy until the last patient that entered 

completed 2 years of therapy. Mortality was 27/83 

in placebo group and 20/83 in silymarin group. 

Significant: 

+ Trend: Survival 

Not significant: 

Note: Trend was assessed qualitatively only for 

this review.

Summary Table 2. Placebo-controlled studies of milk thistle for chronic liver disease, mixed etiologies (n = 6) (continued) 





Author: 

Marcelli77 Study type: RCT/blinding unclear 


Year: 1992 

Country: Italy 

Silipide 

Language: 

English 

® /240 mg daily/90 days 


Outcome measuresa Type: CPH, etiology unknown 

Include: Biopsy confirmed CPH, ALT, or AST 

1.5 or greater than 2 times normal limits in 

past year 

: AST, ALT, 

bilirubin, albumin, PT 


Exclude: Other forms of liver disease (non- 

CPH) or decompensated disease; treatment 

with interferon antivirals, 

immunosuppressants, or immunomodulators 

Assessment time points with results within past 6 months 




Baseline group similarity: Demos appear 

similar; higher AST and ALT in Silipide ® 

N: 65 

Significant: AST, ALT 

Mean age: 48 Not significant: Bilirubin, albumin, PT 

Percent male: 

71 

Setting: 

Specialty clinic 

group 

a 

Results not necessarily reported for all. Abbreviations used: alk phos = alkaline phosphatase; ALT = alanine aminotranferase; AST = aspartase aminotranferase; 

CAH = chronic active hepatitis; CPH = chronic persistent hepatitis; demos = demographic variables; GGTP = gammaglutamyl transpeptidase; HCV = hepatitis C 

virus; LFT = liver function test; MVI = multivitamin; PT = prothrombin time; RCT = randomized controlled trial.

Summary Table 3. Placebo-controlled studies of milk thistle for acute viral hepatitis 

Study 

Author: 

Magliulo78 Year: 1978 


Language: 

German 






Outcome measuresa Type: Viral HAV and HBV 

Include: Acute HAV and HBV patients 


Acuity/severity: Acute, no other information 

: AST, ALT, GGTP, alk phos, 

bilirubin, PT 

Followup interval: 1, 3, 5, 7, 9, 14, 21, 28 days 

Assessment time points with results reported: 

All followup 

Baseline group similarity: LFTs appear similar 

Subject 


N: 59 

Mean age: 37 



Outcomes 

(favoring silymarin 

unless otherwise noted) 

Significant: AST, bilirubin 

+ Trend: ALT 

Not significant: Alk phos 


qualitatively only for this 

review. 

a Results not necessarily reported for all. Abbreviations used: alk phos = alkaline phosphatase; ALT = alanine aminotranferase; AST = aspartase aminotranferase; 

GGTP = gammaglutamyl transpeptidase; HAV = hepatitis A virus; HBV = hepatitis B virus; LFT = liver function test; PT = prothrombin time; RCT = randomized 

controlled trial.

Summary Table 4. Placebo-controlled studies of milk thistle for chronic viral hepatitis 

Study 

Author: 

Buzelli79 Year: 1993 


Language: 

English 

Author: 

Kiesewetter80 Year: 1977 

Country: 

Austria 

Language: 

German 


Subject 




Silipide ® /240 mg silybin equivalents 

daily/7 days 


Outcome measuresa Type: Chronic active hepatitis due to HBV and/or HCV 

N: 20 

Include: Biopsy-proven CAH, AST, and/or ALT greater than twice Mean age: 53 

normal limits for more than 12 months; age 30 to 70 years old 

Exclude: Portal hypertension; hepatic encephalopathy, ascites, 

Percent male: 

30 

: AST, ALT, 

GGTP, MDA, alk phos, bilirubin, 

albumin 


Assessment time points with 

results reported: 7 days 

hepatocellular cancer, pruritus, icterus bilirubin, and alk phos more than 

twofold reference values; drug addiction and ANA, AMA, and ASMA; 

alcohol exceeding 30 g/d; malabsorption syndromes; cardiovascular, 

renal, or endocrine disorders; pregnancy; any drug treatment 3 months 

before beginning trial 

Acuity/severity: Chronic, AST or ALT greater than twice normal limits 



Study type: RCT/quasi 


Silymarin (Legalon ® )/420 mg 

daily/365 days 


Outcome measuresa Type: Viral hepatitis (CPH and CAH) 

N: 24 

Include: CPH or CAH for more than 6 months; other medications for Mean age: 53 

liver discontinued for 2 weeks or more 

Exclude: Disease less than 6 months; previous treatment with 

Percent male: 

50 

: Histology 

Followup interval: 14, 30, 60 days 

then every 90 days to 1 year 

silymarin, steroids, or other cytotoxic drugs; alcohol exceeding 80 g/d or 

exceeding alcohol intake by laboratory values than patients’ statement; 

other comorbidities requiring medications 




results reported: One, 

combined/90 to 360 days 

Baseline group similarity: Demos, similar, no information on LFTs 

Outcomes (favoring 

silymarin unless 


Significant: AST, ALT, 

GGTP 

Not significant: Bilirubin, 

alk phos, MDA, albumin 

Significant: 

+ Trend: Improvement in 

liver biopsy 




review. 

a Results not necessarily reported for all. Abbreviations used: alk phos = alkaline phosphatase; ALT = alanine aminotranferase; AMA = antimitochondrial 

antibody; ANA = antinuclear antibody; ASMA = antismooth muscle antibody; AST = aspartase aminotranferase; CAH = chronic active hepatitis; CPH = chronic 

persistent hepatitis; demos = demographic variables; GGTP = gammaglutamyl transpeptidase; HBV = hepatitis B virus; HCV = hepatitis C virus; LFT = liver 

function test; MDA = malondialdehyde; RCT = randomized controlled trial.

Summary Table 5. Placebo-controlled studies of milk thistle and cirrhosis due to alcohol or other etiologies 


Study 




Author: 

Benda76 Study type: RCT/blind 


Year: 1980 

Country: 

Germany 

Language: 

Silymarin (Legalon 

German 

® )/420 mg daily/ 

Unclear 


Outcome measuresa Type: Alcoholic and nonalcoholic cirrhosis 

N: 172 

Significant: 


Mean age: Not + Trend: Survival 

: Survival 

Exclude: Moribund; poor compliance; 

immunosuppressive treatment in the past year; 

Prednisone in past 6 months; D-Penicillamine in past 

3 months; primary biliary cirrhosis; Wilson’s disease 

given 

Percent male: 

Not given 



Note: Trend was assessed qualitatively only 

for this review. 



results reported: 4 years 

Acuity/severity: Chronic, cirrhosis, no other 


Baseline group similarity: No information 

Author: 

Ferenci75 Study type: RCT/blind 


Year: 1989 

Country: 

Austria 

Language: 

English 

Silymarin (Legalon ® )/420 mg daily/ 

mean 41 months, range 2 to 6 years 


Outcome measuresa Type: Alcoholic and nonalcoholic cirrhosis; cirrhosis N: 170 

Significant: Survival (alcohol disease, Child’s 

with alcoholic hepatitis 

Mean age: 57 

score A) 

: AST, ALT, 

GGTP, alk phos, bilirubin, albumin, 

PT 



results reported: 2 and 4 to 5.5 

Include: Diagnosis of cirrhosis within 2 years before 

entering study 

Exclude: End-stage liver disease; known 

malignancies; primary biliary cirrhosis; 


Acuity/severity: Chronic, cirrhosis, Child’s score 

A/B/C 89/69/12 

Baseline group similarity: Demos, LFTs appear 

similar 

Percent male: 

72 

Setting: Primary 




Not significant: (No data given; reported only 

as not significant) AST, ALT, GGTP, bilirubin, 

survival (nonalcohol disease, Child’s score B 

and C) 

Correspondence from Ferenci, Oct. 10, 

1999: Length of treatment was variable. All 

patients were treated for 2 years (original 

primary endpoint) and were continued on the 

same therapy until the last patient that 

entered completed 2 years of therapy. 

years for survival 

Mortality was 27/83 in placebo group and 

20/83 in silymarin group. 

a Results not necessarily reported for all. Abbreviations used: alk phos = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartase 

aminotransferase; demos = demographic variables; GGTP = gammaglutamyl transpeptidase; LFT = liver function test; MVI = multivitamin; PT = prothrombin time; 

RCT = randomized controlled trial.

Summary Table 6. Placebo-controlled studies of milk thistle and alcoholic cirrhosis (other etiologies of cirrhosis excluded) 


Subject 


Study 


Characteristics otherwise noted) 

Author: 

Pares68 Study type: RCT/blind 


Year: 1998 

Country: 

Spain 

Language: 

English 

(Legalon ® )/450 mg daily/unclear 


Outcome measuresa Type: Alcoholic cirrhosis (24 percent had superimposed N: 200 

Significant: 


Mean age: 50 + Trend: Encephalopathy, 

: AST, ALT, GGTP, alk 

phos, bilirubin, albumin, PT 

Followup interval: Every 3 months for 2 years 

Include: Chronic alcoholism defined as alcohol 

exceeding 80 g/d men and 60 g/d women for more than 5 

years; biopsy or laparoscopic proven alcoholic cirrhosis 

Exclude: If ever received colchicine, malotilate, 

penicillamine, or corticosteroids; life expectancy less than 

6 months; drug addicted or pregnant; other known 


Setting: Diagnosis 

in hospital then 

outpatient followup. 

UGIB, survival for HCVpositive 

patients 


GGTP, PT, bilirubin, alk 

phos, hepatomegaly, 

splenomegaly, jaundice, 

Assessment time points with results reported: etiologies for cirrhosis (i.e., HBV, autoimmunity, primary 

ascites, survival 

Survival at 5 years; all others at 2 years 

(assumed) 

biliary cirrhosis, or cryptogenic cirrhosis) 

Acuity/severity: Chronic, all cirrhosis, Child’s score 



A/B/C/ 63/114/14 


review. 

Author: 

Lang71 Study type: RCT/blind/three arms 

Interventions/dose/duration: Silymarin 

Year: 1990 

Country: 

Hungary 

Language: 

English 




Outcome measuresa Type: Alcoholic cirrhosis 

N: 60 

Significant: AST, ALT, 

Include: Alcohol intake exceeding 60 g/d in men and 30 Mean age: 45 GGTP 

: AST, ALT, GGTP, alk 

phos, albumin 

g/d women for more than 6 years; histologic diagnosis of 

micronodular cirrhosis 

Exclude: Vascular and/or parenchymal decompensation; 

+HBsAg 




Not significant: Bilirubin 



Weekly for 1 month 

Baseline group similarity: LFTs appear similar 

a Results not necessarily reported for all. Abbreviations used: AICA-P = amino imidazol carboxamial phosphate; alk phos = alkaline phosphatase; ALT = alanine 

aminotransferase; AST = aspartase aminotransferase; demos = demographic variables; GGTP = gammaglutamyl transpeptidase; HBV = hepatitis B virus; 

HCV = hepatitis C virus; LFT = liver function test; PT = prothrombin time; RCT = randomized controlled trial; UGIB = upper gastrointestinal bleed.

Summary Table 7. Placebo-controlled study of milk thistle and toxin-induced liver disease 

Study 


Author: 

Palasciano81 Study type: RCT/blind, factorial design 

Intervention/dose/duration: Silymarin and 

Year: 1994 psychotropic drugs/800 mg silymarin daily/ 90 days 


Language: 

English 

Silymarin and psychotropic drugs discontinued/800 

mg daily/90 days 

Control: Placebo and no psychotropic drugs 

discontinued 

Placebo and psychotropic drugs/ not given/90 days 

Outcome measuresa Type: Drug-induced liver disease (some patients 

were HBV-positive) 

Include: Women 40 to 60 years old; hospitalized; 

phenothiazines and/or butyrophenones for 5 years; 

AST or ALT greater than twice normal limits 

Exclude: Current therapy with other drugs that 

could influence progress of hepatopathy; other 

hepatopathies (alcohol, viral, autoimmune, 

hemochromatosis, Wilson’s disease, porphyria 

: AST, ALT, MDA 

cutanea tarda, primary or secondary hepatic 

Followup interval: Day 15, 30, 60, 90, 120 


30, 60, 90, and 120 days for MDA; 30 and 90 for 

AST and ALT 

neoplasia); BUN exceeding 60 mg/dL and/or 

creatinine exceeding 2.5 mg/dL; cardiac and 

circulatory insufficiency; diabetes mellitus; other 

important extrahepatic diseases; verified or 

presumed pregnancy; alcohol (more than 30 g/d) 

or opiate abuse 

Acuity/severity: Chronic; AST or ALT greater than 

two times the normal limit 

Baseline group similarity: Demos similar; LFTs 

variable 

Subject 


N: 60 

Mean age: 52 




silymarin unless otherwise 

noted) 

Significant: MDA for 

psychotropic drugs with 

silymarin versus placebo 


MDA for psychotropic drugs 

discontinued, silymarin versus 

placebo 

a Results not necessarily reported for all. Abbreviations used: ALT = alanine aminotranferase; AST = aspartase aminotranferase; BUN = blood urea nitrogen; 

demos = demographic variables; HBV = hepatitis B virus; LFT = liver function test; MDA = malondialdehyde; RCT = randomized controlled trial.

Summary Table 8. Prophylactic milk thistle with hepatotoxic drugs 

Study 

Author: 

Magula82 Year: 1996 

Country: 

Language: 

Slovak 

Author: 

Allain83 Year: 1999 

Country: 

France 

Language: 

English 


Study type: RCT/not blinded/prophylaxis 

Intervention/dose/duration tuberculosis treatment 

and Hepabene ® (Silymarin and Fumaria officinalis 

alkaloids)/2 capsules daily/ 8 weeks 

Control: Tuberculosis medications alone 

Outcome measuresa Type: Drug-induced liver disease 

Include: Patients requiring tuberculosis 

treatment; normal LFTs at baseline 


: AST, ALT, bilirubin, “liver 

injury,” interruption of tuberculosis medications 

Followup interval: Every 2 weeks for 8 weeks 


8 weeks (56 days) 

Acuity/severity: No disease at baseline 

Study type: RCT/blind/prophylaxis 

Intervention/dose/duration: Silymarin/420 mg 

daily/84 days 


Outcome measuresa Type: Drug- (Tacrine-) induced liver disease 

Include: Patient over 50 years old; mild to 

moderate Alzheimer’s disease; Tacrine treatment 

Exclude: Past history hepatic disorder (cirrhosis, 

: AST, ALT 

increased bilirubin, AST, and/or ALT) 

Followup interval: 8 times over 15 weeks 


8 times over 15 weeks 

Acuity/severity: No disease at baseline 

Subject 


N: 172 (92 

tuberculosis 

medications alone; 

29 tuberculosis 

medications plus 

silymarin) 

Mean age: 50 



N: 222 

Mean age: 

Approximately 74 



clinic 



noted) 



Significant: 

Not significant: AST, ALT 

a 

Results not necessarily reported for all. Abbreviations used: ALT = alanine aminotransferase; AST = aspartase aminotransferase; LFT = liver function test; 


Summary Table 9. Phase II study of Silipide ® 

Study 


Author: 

Vailati85 Study type: RCT/not blind/Phase II study 


Year: 1993 (Silipide 


Language: 

English 

® )/160 mg silybin equivalents daily/14 days 

Silymarin (Silipide ® )/240 mg silybin equivalents 

daily/14 days 

Silymarin (Silipide ® )/360 mg silybin equivalents 

daily/14 days 

Control: No treatment 

Outcome measuresa Type: Viral and alcoholic hepatitis 

Include: Biopsy-proven chronic hepatitis (viral or 

alcoholic); AST and ALT 1.5 or greater than 2 

times normal limits and biopsy within 1 year 

: AST, GGTP, bilirubin 

Followup interval: 7, 14 days 


7, 14 days 

Exclude: Other forms of liver disease; 

decompensated liver disease; treatment with 

interferon, antivirals, immunosuppressants, or 

immunodulators for 6 months or less 


Subject 


N: 60 

Mean age: 50 


Setting: Outpatient 

clinic 



noted) 

Significant: AST, GGTP, 

bilirubin for 240 or 360 mg 

versus 160 mg 


a 

Results not necessarily reported for all. Abbreviations used: ALT = alanine aminotransferase; AST = aspartase aminotransferase; GGTP = gammaglutamyl 

transpeptidase; RCT = randomized controlled trial.

Summary Table 10. Effect sizes and meta-analyses of 16 placebo-controlled trials (Evidence 

Tables 1 and 2) 

Outcomea Time of No. of Effect Size (SD units) Effect Size, Clinical 

Followup Studies 95% CI 

Unitsb p Value 

95% CI 

c Q p Value 

(ES ≠ 0) 

c 

(homogeneity) 

≤45 days 6 –0.25 (–0.47 to –0.02) –11.2 (–21.0 to –0.9) 0.03 0.83 

90 days 3 –0.27 (–0.96 to 0.42) –12.1 (–4.30 to 89.5) 0.44 0.014 

AST without 

drug study 

44.77 U/L 

90 days 

without 

outlier 

180 days 

2 

1 

–0.02 (–0.76 to 0.72) 

–0.37 (–1.03 to 0.29) 

–0.9 (–34.0 to 32.2) 

–16.6 (–46.1 to 13.0) 

0.96 

0.27 

0.06 

– 

15 months 1 0.37 (–0.21 to 0.95) 17.5 (–9.4 to 42.5) 0.21 – 

a 

2 years 1 0.28 (–0.07 to 0.63) 12.5 (–3.1 to 28.2) 0.12 – 

≤45 days 8 –0.21 (–0.42 to –0.004) –9.4 (–18.8 to –0.2) 0.046 0.90 

AST with 90 days 5 –0.30 (–0.73 to 0.13) –13.4 (–32.7 to 5.8) 0.17 0.03 

drug study 

44.77 U/La 90 days 

without 

outlier 

4 –0.53 (–0.85 to –0.22) –23.7 (–38.0 to –9.8) 0.001 0.79 

≤45 days 

≤45 days 

7 –0.09 (–0.45 to 0.28) –3.2 (–16.2 to 10.1) 0.64 0.004 

ALT without 

drug study 

without 

outlier 

6 –0.22 (–0.42 to –0.03) –7.9 (–15.1 to –1.1) 0.03 0.51 

36.02 U/L 90 days 2 –0.65 (–1.15 to –0.15) –23.4 (–41.4 to –5.4) 0.01 0.28 

180 days 1 –0.28 (–0.94 to 0.38) –10.1 (–33.9 to 13.7) 0.41 – 

a 

2 years 1 0.33 (–0.02 to 0.68) 11.9 (–0.7 to 24.5) 0.07 – 

≤45 days 9 –0.07 (–0.37 to 0.23) –2.5 (–13.3 to 8.3) 0.66 0.01 

ALT with ≤45 days 

drug study without 8 –0.19 (–0.37 to –0.01) –6.8 (–13.3 to –0.4) 0.04 0.63 

36.02 U/L outlier 

a 

90 days 4 –0.48 (–0.83 to –0.14) –17.3 (–29.9 to –5.0) 0.01 0.53 

≤45 days 5 –0.21 (–0.45 to 0.02) –32.3 (–69.3 to 3.1) 0.08 0.35 

GGTP 

153.94 U/L 

90 days 

180 days 

2 

1 

–0.04 (–0.41 to 0.32) 

–0.64 (–1.30 to 0.02) 

–6.2 (–63.1 to 49.3) 

–98.5 (–200.1 to 3.1) 

0.81 

0.06 

0.93 

– 

15 months 1 –0.26 (–0.84 to 0.32) –40.0 (–129.3 to 49.3) 0.38 – 

a 

2 years 1 0.38 (0.02 to 0.73) 58.5 (3.1 to 112.4) 0.04 – 

MDA 6.65 ≤45 days 1 –0.09 (–0.96 to 0.79) –0.6 (–6.4 to 5.3) 0.85 – 

nmol/mla 180 days 1 –0.81 (–1.49 to –1.13) –5.3 (–9.9 to –7.5) 0.02 – 

≤45 days 5 –0.04 (–0.25 to 0.16) –4.0 (–25.3 to 16.2) 0.68 0.61 

Alkaline 90 days 1 0.10 (–0.55 to 0.76) 10.1 (–55.6 to 76.8) 0.76 – 

phosphate 180 days 1 –0.34 (–1.00 to 0.34) –34.3 (–101.0 to 34.3) 0.31 – 

101.01 U/L 


a 

2 years 1 –0.08 (–0.43 to 0.27) –8.1 (–43.4 to 27.3) 0.66 –

Summary Table 10. Effect sizes and meta-analyses of 16 placebo-controlled trials (Evidence 

Tables 1 and 2) (continued) 




95% CI 

c Q p Value 

(ES ≠ 0) 

c 

(homogeneity) 

≤45 days 4 –0.28 (–0.52 to –0.03) –0.1 (–0.2 to –0.01) 0.03 1.00 

Bilirubin 

0.32 g/dL 

90 days 

180 days 

3 

1 

0.02 (–0.33 to 0.37) 

–0.49 (–1.15 to 0.17) 

0.01(–0.1 to 0.1) 

–0.2 (–0.4 to 0.05) 

0.91 

0.15 

0.25 

– 

15 months 1 –0.16 (–0.74 to 0.43) –0.05 (–0.2 to 0.1 0.60 – 

a 

2 years 1 0.00 (–0.35 to 0.36) 0.0 (–0.1 to 0.1) 1.00 – 

90 days 3 –0.08 (–0.53 to 0.38) –0.05 (–0.4 to 0.3) 0.74 0.10 

Albumin 180 days 1 0.19 (–0.46 to 0.84) 0.1 (–0.3 to 0.6) 0.57 – 

0.74 g/dL 15 months 1 0.25 (–0.35 to 0.85) 0.2 (–0.2 to 0.6) 0.42 – 

a 

2 years 1 –0.23 (–0.58 to 0.12) –0.2 (–0.4 to 0.1) 0.20 – 

≤45 days 1 0.14 (–0.16 to 0.44) 2.4 (–2.8 to 7.7) 0.35 – 

PT 90 days 3 –0.19 (–0.67 to 0.28) –3.3 (–11.6 to 4.9) 0.42 0.08 

17.39 180 days 1 0.47 (–0.20 to 1.14) 8.2 (–3.5 to 19.8) 0.17 – 


a 


2 years 1 –0.18 (–0.53 to 0.17) –3.1 (–9.2 to 3.0) 0.31 – 

Child’s 15 months 1 –0.09 (–0.68 to 0.50) –0.2 (–1.7 to 1.3) 0.78 – 

2.55 score 2 years 1 0.27 (–0.08 to 0.62) 0.7 (–0.2 to 1.6) 0.13 – 

When there was more than one study, effect sizes were pooled. 

a 

Mean pooled standard deviations. 

b 

Standard deviation effect size units are back-converted to clinical effect sizes by standard deviation x effect size. 

c 

All studies refer to combination of chronic alcohol, chronic and acute viral, and chronic mixed etiology unless 



Abbreviations used: ALT = alanine aminotranferase; AST = aspartase aminotranferase; CI = 95% confidence 

interval; ES = effect size; GGTP = gammaglutamyl transpeptidase; MDA = malondialdehyde; PT = prothrombin time; 

SD = standard deviation; U/L = units per liter.

Summary Table 11. Effect sizes and meta-analyses of 14 randomized, placebo-controlled trials of 

higher methodological quality (Evidence Table 1) 




95% CI 

c Q p Value 

(ES ≠ 0) 

c 

(Homogeneity) 

≤45 days 5 –0.27 (–0.52 to –0.03) –12.1 (–23.3 to –1.3) 0.03 0.76 

AST without 90 days 2 –0.02 (–0.76 to 0.72) –0.9 (–34.0 to 32.2) 0.96 0.06 

drug study 180 days 1 –0.37 (–1.03 to 0.29) –16.6 (–46.1 to 13.0) 0.27 – 

44.77 U/L 

15 months 1 0.37 (–0.21 to 0.95) 17.5 (–9.4 to 42.5) 0.21 – 

a 

2 years 1 0.28 (–0.07 to 0.63) 12.5 (–3.1 to 28.2) 0.12 – 

AST with ≤45 days 7 –0.23 (–0.46 to –0.004) –10.3 (–20.6 to –0.2) 0.046 0.85 

drug study 

44.77 U/La 90 days 4 –0.15(–0.58 to 0.27) –1.8 (–18.4 to 14.8) 0.48 0.14 

≤45 days 

≤45 days 

6 –0.14 (–0.55 to 0.28) –5.0 (–19.8 to 10.1) 0.52 0.003 

ALT without 

drug study 

without 

outlier 

5 –0.27 (–0.48 to –0.07) –9.7 (–17.3 to –2.5) 0.01 0.71 

36.02 U/L 90 days 1 –0.39 (–1.05 to 0.27) –14.0 (–37.8 to 9.7) 0.24 – 

180 days 1 –0.28 (–0.94 to 0.38) –10.1 (–33.9 to 13.7) 0.41 – 

a 

2 years 1 0.33 (–0.02 to 0.68) 11.9 (–0.7 to 24.5) 0.07 – 

≤45 days 8 –0.10 (–0.43 to 0.23) –3.6 (–15.5 to 8.3) 0.54 0.01 

ALT with ≤45 days 

drug study without 7 –0.23 (–0.42 to –0.04) –8.3 (–15.1 to –1.4) 0.02 0.76 

36.02 U/L outlier 

a 

90 days 3 –0.33 (–0.73 to 0.08) –11.9 (–26.3 to 2.9) 0.11 0.96 

≤45 days 5 –0.21 (–0.45 to 0.02) –32.3 (–69.3 to 3.1) 0.08 0.35 

GGTP 

153.94 U/L 

90 days 

180 days 

2 

1 

–0.04 (–0.41 to 0.32) 

–0.64 (–1.30 to 0.02) 

–6.2 (–63.1 to 49.3) 

–98.5 (–200.1 to 3.1) 

0.81 

0.06 

0.93 

– 


a 

2 years 1 0.38 (0.02 to 0.73) 58.5 (3.1 to 112.4) 0.04 – 

MDA 

6.65 nmol/ml a 

Alkaline 

Phosphate 

101.01 U/L a 

Bilirubin 

0.32 g/dL a 

≤45 days 1 –0.09 (–0.96 to 0.79) –0.6 (–6.4 to 5.3) 0.85 – 

180 days 1 –0.81 (–01.49 to –1.13) –5.4 (–9.9 to –7.5) 0.02 – 

≤45 days 4 –0.04 (–0.26 to 0.17) –4.0 (–26.3 to 17.2) 0.70 0.44 

90 days 1 0.10 (–0.55 to 0.76) 10.1 (–55.6 to 76.8) 0.76 – 

180 days 1 –0.34 (–1.00 to 0.34) –34.3 (–101.0 to 34.3) 0.31 – 


2 years 1 –0.08 (–0.43 to 0.27) –8.1 (–43.4 to 27.3) 0.66 – 

≤45 days 4 –0.28 (–0.52 to –0.03) –0.1 (–0.2 to –0.01) 0.03 1.0 

90 days 2 –0.10 (–0.70 to 0.49) –0.03 (–0.2 to 0.2) 0.73 0.13 

180 days 1 –0.49 (–1.15 to 0.17) –0.2 (–0.4 to 0.05) 0.15 – 

15 months 1 –0.16 (–0.74 to 0.43) –0.05 (–0.2 to 0.1 0.60 – 

2 years 1 0.00 (–0.35 to 0.36) 0.0 (–0.1 to 0.1) 1.00 –

Summary Table 11. Effect sizes and meta-analyses of 14 randomized, placebo-controlled trials of 

higher methodological quality (Evidence Table 1) (continued) 

Outcomea Time of No. of Effect Size Effect Size, Clinical 

Followup Studies (SD units) 95% CI Unitsb p Value 

95% CI 

c Q p Value 

(ES ≠ 0) 

c 

(Homogeneity) 

90 days 2 –0.13 (–0.87 to 0.60) –0.1(–0.6 to 0.4) 0.72 0.06 

Albumin 180 days 1 0.19 (–0.46 to 0.84) 0.1 (–0.3 to 0.6) 0.57 – 

0.74 g/dL 15 months 1 0.25 (–0.35 to 0.85) 0.2 (–0.2 to 0.6) 0.42 – 

a 

2 years 1 –0.23 (–0.58 to 0.12) –0.2 (–0.4 to 0.1) 0.20 – 

≤45 days 1 0.14 (–0.16 to 0.44) 2.4 (–2.8 to 7.7) 0.35 – 

PT 17.39 

90 days 

180 days 

2 

1 

–0.30 (–1.00 to 0.40) 

0.47 (–0.20 to 1.14) 

–5.2 (–17.4 to 7.0) 

8.2 (–3.5 to 19.8) 

0.40 

0.17 

0.08 

– 


a 


2 years 1 –0.18 (–0.53 to 0.17) –3.1(–9.2 to 3.0) 0.31 – 

Child’s 15 months 1 –0.09 (–0.68 to 0.50) –0.2 (–1.7 to 1.3) 0.76 – 

2.55 score 2 years 1 0.27 (–0.08 to 0.62) 0.7 (–0.2 to 1.6) 0.13 – 

When there was more than one study, effect sizes were pooled. 

a 

Mean pooled standard deviations. 

b 

Standard deviation effect size units are back-converted to clinical effect sizes by standard deviation x effect size. 

c 

All studies refer to combination of chronic alcohol, chronic and acute viral, and chronic mixed etiology unless 



Abbreviations used: ALT = alanine aminotranferase; AST = aspartase aminotranferase; CI = 95% confidence 

interval; ES = effect size; GGTP = gammaglutamyl transpeptidase; MDA = malondialdehyde; PT = prothrombin time; 

SD = standard deviation; U/L = units per liter.

Summary Table 12. Adverse effects of oral use of milk thistle, silymarin, or Silipide ® 

Adverse <strong>Effects</strong> Level of Evidence 

Possible/probable anaphylaxis Three case reports 

Gastrointestinal 

Four RCTs: silymarin ≤ control 

Nausea, diarrhea, upset stomach, epigastric 

Five cohort studies: 0.3%, ≤2%, 5%, 6%, 8% 

discomfort, heartburn, dyspepsia, flatulence, 

meteorism, “uneasiness” of stomach, vomiting, 

anorexia, change in bowel movement, “gastric 

intolerance,” abdominal fullness or pain 

11 occurrences/975 patients 

9 occurrences/2,169 patients 

Headache Three RCTs: silymarin ≤ control 

Two cohort studies: 0.04%, 0.04% 

Skin: 

Two RCTs: silymarin ≤ control 

Itching, pruritus 

Three cohort studies: 




Exanthem, urticaria, skin rash, eczema Two RCTs: silymarin ≤ control 

Two cohort studies: 


1 occurrence/2,169 patients 

Other: 

Cohort study: 0.3% 

Decreased energy, discomfort, indisposition, 

1 occurrence/975 patients 

decreased energy, restlessness 

1 occurrence/2,169 patients 

Asthenia, malaise, irritability 

One RCT: silymarin ≤ control 

Insomnia 

Arthalgia 

Rhinoconjunctivitis 

Impotence 



One case report 

One RCT: 1/29 silymarin, 0/31 control 

Frequency of adverse effects was sometimes reported as the following: (1) percent of subjects, (2) number of 

subjects, or (3) number of occurrences of adverse effects in a group of subjects without detail about subjects who 

may have had more than one adverse effect. 


Evidence Table 1. <strong>Milk</strong> thistle for treatment of liver disease: Placebo-controlled, randomized, blinded trials 

Study 

Author: 

Benda 76 

Year: 1980 

Country: 

Germany 

Language: 

German 

Author: 

Bunout 66 

Year: 1992 

Country: 

Chile 

Language: 

Spanish 





daily/ Unclear 


Outcome measures a : 

Survival 


Assessment time points 

with results reported: 4 

years 






Outcome measures a : AST, 

GGTP, alk phos, bilirubin, 

albumin, PT 

Followup interval: Monthly 

for an average of 15 months 


with results reported: Mean 

of 15 months 

Type: Alcoholic and 

nonalcoholic cirrhosis 


Exclude: Moribund; poor 

compliance; immunosuppressive 

treatment in the past year; 

Prednisone in past 6 months; D- 

Penicillamine in past 3 months; 

primary biliary cirrhosis; Wilson’s 

disease 

Acuity/severity: Chronic, 

cirrhosis, no other information 

Baseline group similarity: No 


Type: Alcoholic liver disease 

(inactive cirrhosis, active 

cirrhosis, cirrhosis with alcoholic 

hepatitis, alcoholic hepatitis, 

fibrosis) 

Include: Positive for alcohol 

history and symptoms of icterus 

edema, ascites, or 

encepholopathy or total bilirubin 

exceeding 2 mg/dL; PT 

exceeding 75 percent control; 

albumin less than 3 mg/dL 

Exclude: HBV antigen; renal 

failure; cardiac failure; terminal 

liver disease 



Baseline group similarity: 

Demos, LFTs appear similar 

Subject 


N: 172 

Mean age: Not 

given 

Percent male: 

Not given 

Setting: 

Unclear 

N: 59 

Mean age: 50 

Percent male: 

86 

Setting: 

Specialty clinic 

Outcomes (favoring silymarin unless otherwise 

noted) 

Significant: 

+ Trend: Survival 


Note: Trend was assessed qualitatively only for this 

review. 

Significant: Albumin 

Not significant: Child’s score, bilirubin, AST, GGTP, 

alk phos, PT

Evidence Table 1. <strong>Milk</strong> thistle for treatment of liver disease: Placebo-controlled, randomized, blinded trials (continued) 


Author: 

Buzelli 79 

Year: 1993 


Language: 

English 



Silipide ® /240 mg silybin 

equivalents daily/7 days 



ALT, GGTP, MDA, alk phos, 

bilirubin, albumin 




days 

Type: Chronic active hepatitis 

due to HBV and/or HCV 

Include: Biopsy-proven CAH, 

AST, and/or ALT greater than 

twice normal limits for more than 

12 months; age 30 to 70 years 

old 

Exclude: Portal hypertension; 

hepatic encephalopathy, ascites, 

hepatocellular cancer, pruritus, 

icterus bilirubin, and alk phos 

more than two-fold reference 

values; drug addiction and ANA, 

AMA, and ASMA; alcohol 

exceeding 30 g/d; malabsorption 

syndromes; cardiovascular, 

renal, or endocrine disorders; 

pregnancy; any drug treatment 3 

months before beginning trial 

Acuity/severity: Chronic, AST 

or ALT greater than twice normal 

limits 



Subject 


N: 20 

Mean age: 53 

Percent male: 

30 

Setting: 

Hospital 


noted) 


Not significant: Bilirubin, alk phos, MDA, albumin



Author: 

Feher 70,99,100 

Year: 

1989/1990 

Country: 

Hungary 

Language: 

Hungarian 

Author: 

Ferenci 75 

Year: 1989 

Country: 

Austria 

Language: 

English 







ALT, GGTP, alk phos, 

bilirubin, albumin 

Followup interval: 90 and 

180 days 



and 180 days 




daily/ mean 41 months, range 

2 to 6 years 







with results reported: 2 and 

4 to 5.5 years for survival 

Type: Chronic alcoholic liver 

disease (cirrhosis, reactive 

fibrosis, fatty degeneration) 

Include: Alcohol intake 

exceeding 60 g/d in men and 30 

g/d in women for 8 ± 4 years; 

chronic liver disease; no 

previous corticosteroid or 

immunosuppressive treatment 


Acuity/severity: Chronic, no 

other information 



Type: Alcoholic and 

nonalcoholic cirrhosis; cirrhosis 

with alcoholic hepatitis 

Include: Diagnosis of cirrhosis 

within 2 years before entering 

study 

Exclude: End-stage liver 

disease; known malignancies; 

primary biliary cirrhosis; 



cirrhosis, Child’s score A/B/C 

89/69/12 



Subject 


N: 36 

Mean age: 46 

Percent male: 

75 

Setting: 

Unclear 

N: 170 

Mean age: 57 

Percent male: 

72 

Setting: 

Primary 





noted) 

Significant: AST, GGTP, MDA 

Not significant: (Assumed for all) ALT, alk phos, 

albumin, PT 

Significant: Survival (alcohol disease, Child’s score 

A) 

Not significant: (No data given; reported only as not 

significant) AST, ALT, GGTP, bilirubin, survival (nonalcohol 

disease, Child’s score B and C) 

Correspondence from Ferenci, October 10, 1999: 

Length of treatment was variable. All patients were 

treated for 2 years (original primary end point) and 

were continued on the same therapy until the last 

patient that entered completed 2 years of therapy. 

Mortality was 27/83 in placebo group and 20/83 in 

silymarin group.



Author: 

Fintelmann 73 

Year: 1980 

Country: 

Germany 

Language: 

German 

Author: 

Kiesewetter 80 

Year: 1977 

Country: 

Austria 

Language: 

German 



Silymarin(Legalon ® )/not 

given/not given 




bilirubin 

Followup interval: Days 1, 

3, 7, 10, 14, 21, 28 


with results reported: Had 

to read off graphs, but all 

followups 

Study type: RCT/quasi 






Histologic findings 

Followup interval: 14, 30, 

60 days then every 90 days 

to 1 year 


with results reported: One, 

combined/90 to 360 days 

Type: Toxic liver disease, any 

etiology (usually alcohol) 

Include: Clinical and laboratory 

evidence of toxic liver damage 


Acuity/severity: No other 


Baseline group similarity: No 

information except age and 

gender “similar” 

Type: Viral hepatitis (CPH and 

CAH) 

Include: CPH or CAH for more 

than 6 months; other 

medications for liver 

discontinued for 2 weeks or 

more 

Exclude: Disease less than 

6 months; previous treatment 

with silymarin, steroids, or other 

cytotoxic drugs; alcohol 

exceeding 80 g/d or exceeding 

alcohol intake by laboratory 

values than patients’ statement; 

other comorbidities requiring 

medications 




Demos, similar, no information 

on LFTs 

Subject 


N: 66 

Mean age: Not 

given 

Percent male: 

Not given 

Setting: 

Unclear 

N: 24 

Mean age: 53 

Percent male: 

50 

Setting: 

Hospital 


noted) 

Significant: ALT, GGTP 

Not significant: AST, bilirubin, alk phos 

Significant: 

+ Trend: Improvement in liver biopsy 



review.



Author: 

Lang 71 

Study type: RCT/blind/three Type: Alcoholic cirrhosis 

arms 

Include: Alcohol intake 

Year: 1990 

exceeding 60 g/d in men and 30 

Country: 

Hungary 

Language: 

English 

g/d women for more than 

6 years; histologic diagnosis of 

micronodular cirrhosis 

Exclude: Vascular and/or 

parenchymal decompensation; 

+HBsAg 




LFTs appear similar 

Author: 

Magliulo 78 

Year: 1978 


Language: 

German 

Interventions/dose/duration 

: Silymarin 

(Legalon ® )/420 mg daily/30 

days 





albumin 



with results reported: 

Weekly for 1 month 




daily/25 days 




bilirubin, PT 

Followup interval: 1, 3, 5, 7, 

9, 14, 21, 28 days 


with results reported: All 

followup 

Subject 


N: 60 

Mean age: 45 

Percent male: 

68 

Setting: 

Unclear 

Type: Viral HAV and HBV N: 59 

Include: Acute HAV and HBV Mean age: 37 

patients 

Percent male: 


22 

Acuity/severity: Acute, no other Setting: 




Hospital 


noted) 



Significant: AST, bilirubin 

+ Trend: ALT 

Not significant: Alk phos 


review.



Author: 

Palasciano 81 

Year: 1994 


Language: 

English 

Study type: RCT/blind, 

factorial design 


Silymarin and psychotropic 

drugs/800 mg silymarin daily/ 

90 days 

Silymarin and psychotropic 

drugs discontinued/800 mg 

daily/90 days 

Control: Placebo and no 

psychotropic drugs 


Placebo and psychotropic 

drugs/ not given/90 days 


ALT, MDA 

Followup interval: Day 15, 

30, 60, 90, 120 


with results reported: 30, 

60, 90, and 120 days for 

MDA; 30 and 90 for AST and 

ALT 

Type: Drug-induced liver 

disease (some patients were 

HBV-positive) 

Include: Women 40 to 60 years 

old; hospitalized; phenothiazines 

and/or butyrophenones for 5 

years; AST or ALT greater than 

twice normal limits 

Exclude: Current therapy with 

other drugs that could influence 

progress of hepatopathy; other 

hepatopathies (alcohol, viral, 

autoimmune, hemochromatosis, 

Wilson’s disease, porphyria 

cutanea tarda, primary or 

secondary hepatic neoplasia); 

BUN exceeding 60 mg/dL and/or 

creatinine exceeding 2.5 mg/dL; 

cardiac and circulatory 

insufficiency; diabetes mellitus; 

other important extrahepatic 

diseases; verified or presumed 

pregnancy; alcohol (more than 

30 g/d) or opiate abuse 

Acuity/severity: Chronic; AST 

or ALT greater than two times 

the normal limit 


Demos similar; LFTs variable 

Subject 


N: 60 

Mean age: 52 

Percent male: 

0 

Setting: 

Hospital 


noted) 

Significant: MDA for psychotropic drugs with 

silymarin versus placebo 

Not significant: AST, ALT, MDA for psychotropic 

drugs discontinued, silymarin versus placebo


Author: 

Pares 68 


Year: 1998 

Country: 

Spain 

Language: 

English 




daily/unclear 





Followup interval: Every 3 

months for 2 years 



Survival at 5 years; all others 

at 2 years (assumed) 

Type: Alcoholic cirrhosis (24 

percent had superimposed 


Include: Chronic alcoholism 

defined as alcohol exceeding 80 

g/d men and 60 g/d women for 

more than 5 years; biopsy or 

laparoscopic proven alcoholic 

cirrhosis 

Exclude: If ever received 

colchicine, malotilate, 

penicillamine, or corticosteroids; 

life expectancy less than 6 

months; drug addicted or 

pregnant; other known etiologies 

for cirrhosis (i.e., HBV, 

autoimmunity, primary biliary 

cirrhosis, or cryptogenic 

cirrhosis) 

Acuity/severity: Chronic, all 

cirrhosis, Child’s score A/B/C/ 

63/114/14 



Subject 


N: 200 

Mean age: 50 

Percent male: 

79 

Setting: 

Diagnosis in 

hospital then 

outpatient 

followup. 


noted) 

Significant: 

+ Trend: Encephalopathy, UGIB, survival for HCVpositive 

patients 

Not significant: AST, ALT, GGTP, PT, bilirubin, alk 

phos, hepatomegaly, splenomegaly, jaundice, 

ascites, survival 


review.



Author: 

Salmi 69 

Year: 1982 



Silymarin (Legalon 

Country: 

Finland 

Language: 

English 

® )/420 mg 


Include: Increased AST and 

ALT for more than 1 month 

daily/28 days 


despite order to abstain from 

alcohol 





Aminotransferase levels 

reported as similar but lower in 

controls 

Author: 

Tanasescu 74 

Year: 1988 

Country: 

Romania 

Language: 

English 


ALT, alk phos, bilirubin, 

histologic findings 

Followup interval: Day 28 



days 

Study type: RCT, 

randomization stratified by 

type of disease: CPH, CAH, 

HCV/blind 


Silymarin 

(Silimarina ® )/210 mg silybin 

equivalents daily/40 days 


Outcome measures a : ALT, 

GGTP, bilirubin, alk phos, PT 




days 

Type: CPH, CAH, hepatic 

cirrhosis, etiology not given 

Include: Diagnosis based on 

hepatic biopsy; clinical and 

laboratory data on CAH and 

CPH patients; some hepatic 

cirrhosis patients did not have 

hepatic biopsy; medium forms of 

disease; both sexes; 20 to 60 

years old; basic disease from 1 

to 10 years 




Baseline group similarity: Age, 


Subject 


N: 97 

Mean age: 37 

Percent male: 

86 

Setting: 

Hospital 

N: 177 

Mean age: 53 

Percent male: 

47 

Setting: 

Hospital 


noted) 

Significant: AST, ALT, histology 

Not significant: Alk phos, bilirubin 

Significant: 

+ Trend: 

Not 

significant: 

CAH 

ALT, GGTP, 


phos, PT 

CPH HCV 

ALT 

GGTP, 

bilirubin, 

alk phos, 

PT 

ALT, 

GGTP, 

bilirubin, 

alk phos, 

PT 


review.



Author: 

Trinchet 67 

Year: 1989 

Country: 

France 

Language: 

French 




daily/90 days 



GGTP, bilirubin, albumin, PT, 

histology 




days 

Type: Alcoholic hepatitis 

(50 percent with cirrhosis) 

Include: Biopsy-proven 

alcoholic hepatitis with or without 

cirrhosis 

Exclude: Hepatic 

encephalopathy; 

contraindications to liver biopsy; 

hepatocellular cancer; ascites 

resistant to diuretics; platelets 

less than 100,000 per mm; PT 

less than 50 percent; other 

diseases limiting survival 

Acuity/severity: 58/116 with 

cirrhosis; no other information 



Subject 


N: 116 

Mean age: 51 

Percent male: 

67% 

Setting: 

Unclear 


noted) 

Significant: Both silymarin and placebo better with 

alcohol abstinence 

Not significant: PT, albumin, bilirubin, GGTP, AST, 

histologic findings (hepatitis, fibrosis) 

a Results not necessarily reported for all. 

Alk phos = alkaline phosphatase; ALT = alanine aminotranferase; AMA = antimitochondrial antibody; ANA = antinuclear antibody; 

ASMA = antismooth muscle antibody; AST = aspartase aminotranferase; BUN = blood urea nitrogen; CAH = chronic active hepatitis; 

CPH = chronic persistent hepatitis; demos = demographic variables; GGTP = gammaglutamyl transpeptidase; HAV = hepatitis A virus; HbsAg = Hepatitis B 

surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; LFT = liver function test; MDA = malondialdehyde; MVI = multivitamin; PT = prothrombin time; 

RCT = randomized controlled trial; UGIB = upper gastrointestinal bleed.

Evidence Table 2. <strong>Milk</strong> thistle for treatment of liver disease: Placebo-controlled, prospective trials with unclear blinding 

Study 

Author: 

Fintelmann 72 

Year: 1970 

Country: 

Germany 

Language: 

German 

Author: 

Marcelli 77 

Year: 1992 


Language: 

English 


Study type: Cohort with 

comparison group/blinding unclear 


Silymarin (Legalon ® )/6 tablets 

daily/42 days 


Outcome measures a : Bilirubin, alk 

phos, AST, ALT 




Study type: RCT/blinding unclear 


Silipide ® /240 mg daily/90 days 


Outcome measures a : AST, ALT, 





Type: Alcoholic liver disease, also other 

causes of fatty liver (pure parenchymal fatty 

degeneration, fatty degeneration and reactive 

inflammation, cirrhosis transformation in 

progress) 

Include: Biopsy-proven fatty liver, including 

early cirrhosis without portal hypertension, 

assignment stratified by diabetes mellitus, 

obesity, alcohol intake 


Acuity/severity: All degrees of fatty liver 

including early cirrhosis without portal 

hypertension 

Baseline group similarity: LFTs appear 

similar 

Type: CPH, etiology unknown 

Include: Biopsy confirmed CPH, ALT, or AST 

1.5 or greater than 2 times normal limits in 

past year 

Exclude: Other forms of liver disease (non- 

CPH) or decompensated disease; treatment 

with interferon antivirals, 

immunosuppressants, or immunomodulators 

within past 6 months 



Patient 


N: 50 

Mean age: Not given 

Percent male: Not 

given 





Significant: AST 

(categorical) 

Not significant: AST 

(continuous), ALT, 

alk phos 

Baseline group similarity: Demos appear 

similar; higher AST and ALT in Silipide ® group 

a 


alk phos = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartase aminotransferase; CPH = chronic persistent hepatitis; Demos = demographic 

variables; LFT = liver function test; PT = prothrombin time; RCT = randomized controlled trial. 

N: 65 

Mean age: 48 



clinic 

Significant: AST, 

ALT 


Bilirubin, albumin, PT

Evidence Table 3. <strong>Milk</strong> thistle for treatment of liver disease: Studies without placebo controls 

Study 

Author: 

Boari 101 

Year: 1981 

Country: 

Italy 

Language: 

Italian 

Author: 

Bode 102 

Year: 1977 

Country: 

Germany 

Language: 

German 


Study type: RCT 

unclear/blinding unclear 


Silymarin/420 mg daily/15 to 

20 days 

Control: Vitamin B 

complex/not given/15 to 20 

days 



bilirubin 




days 

Study type: RCT (quasi/oddeven 

birthdate)/not blind 



daily/35 days 




bilirubin, PT 


35 days 



days 

Type: Toxic hepatopathy 

caused by various substances 

(mostly solvents, paints, and 

glues); mostly suffering from 

chronic or subacute forms 

Include: Not given 


Acuity/severity: ? Chronic, 

0 cirrhosis, 11 liver failure, 29 

other, no other information 

Type: Viral hepatitis 

Include: Patients with viral 

hepatitis 

Exclude: Jaundice exceeding 

8 days 

Acuity/severity: Acute, no 


Patient 


N: 55 

Mean age: 36 



N: 151 

Mean age: Not 

given 




noted) 

Significant: AST, ALT, GGTP, alk phos 


Significant: 

Not significant: AST, bilirubin, ALT, alk phos

Evidence Table 3. <strong>Milk</strong> thistle for treatment of liver disease: Studies without placebo controls (continued) 


Author: 

Cavalieri 103 

Year: 1974 

Country: 

Italy 

Language: 

Italian 

Author: Del 

Dotto 104 

Year: 1982 

Country: 

Italy 

Language: 

Italian 




Silymarin (Legalon ® )/ 420 mg 

daily/variable 

Control: “Traditional 

treatment”: a 12-component 

cocktail including vitamin and 

steroids 



bilirubin, PT 

Followup interval: 7, 14, 28 

days 


with results reported: 7, 14, 

28 days 





daily/90 days 

Control: Vitamin B complex 


ALT, GGTP, PT, bilirubin, 

albumin, alk phos 


90 days 



60, 90 days 

Type: Acute hepatitis 

(posttransfusion, contagious, 

presumably parenteral, and 

sporadic) 






Include: Patients with alcoholic 

liver disease 




Patient 


N: 40 

Mean age: 29 



N: 42 

Mean age: 53 



clinic 


noted) 

Significant: AST at weeks 1, 2, and 3; ALT at week 

2; alk phos at week 1; albumin at week 1 

Not significant: AST at week 4; ALT at weeks 1, 3, 

and 4; PT and albumin at weeks 2 and 3 

Significant: 

Not significant: AST, ALT, GGTP, PT, bilirubin, 

albumin, alk phos



Author: 

DeMartiis 105 

Year: 1980 

Country: 

Italy 

Language: 

Italian 




Silymarin, traditional therapy, 

and diet/400 mg daily/45 to 

90 days 

Control: Traditional therapy 

+ diet 


Bilirubin 




days 

Type: Chronic hepatitis and 

cirrhosis 

Include: Macrocytic anemia 

and hemolytic syndrome 

Exclude: Lab values indicating 

the presence of cholestasis (alk 

phos, GGTP) dyslipidemia, or 

diabetes 



Patient 


N: 45 

Mean age: Not 

given 


given 



noted) 

Significant: 

Not significant: Indirect bilirubin



Author: 

DeMartiis 106 

Year: 1980 

Country: 

Italy 

Language: 

Italian 

Author: 

Fintelmann 107 

Year: 1973 

Country: 

Germany 

Language: 

German 




Vitamin B12, folic acid, uridin- 

5, difosfoglucose, and 

silymarin/ 600 mg daily/not 

given 

Vitamin B12, folic acid, uridin- 

5, and difosfoglucose/not 

given/not given 

Control: Vitamin B12, folic 

acid, uridin-5, and 

difosfoglucose/not given/not 

given 

Outcome measures a : Alk 

phos, bilirubin 

Followup interval: Unclear 



Unclear 




Silymarin (Legalon ® )/210 or 

420 mg daily/preoperative 

and 8 days postoperative 



ALT, alk phos, bilirubin 

Followup interval: 1, 2, 3 

days 


with results reported: 1, 2, 

3 days 

Type: Chronic hepatopathies 

(diagnoses include chronic 

hepatitis, hepatic cirrhosis, and 

hepatic neoplasm) 

Include: Hepatic disease 


Acuity/severity: 0 acute, 21 

chronic, 61 cirrhosis, no other 


Type: Cholestasis, not 

pregnancy related 

Include: Consecutive patients 

for cholecystectomy with 

cholelithiasis with or without 

cholecystitis 

Exclude: Obstructive jaundice 



Patient 


N: 91 

Mean age: 56 


Setting: Not given 

N: 63 

Mean age: Not 

given 




noted) 

All 

Patients 

CE or 

EC 

Significant: Alk phos Alk phos, 

bilirubin 

CE 

Bilirubin, 

alk phos 

Not significant: All others All others All 

EC 

Significant: 

+ Trend: Less increase in AST, ALT on postoperative 

day 1 

Not significant: AST, ALT, bilirubin, alk phos 


review.


Patient Outcomes (favoring silymarin unless otherwise 

Study Design Liver Disease Characteristics 

noted) 

Author: 

Flisiak 65 

Study type: RCT/not blind 


Year: 1997 

Country: 

Poland 

Language: 

English 

Silymarin/210 mg daily/28 

days 

Control: Misoprostol 

Outcome measures a Type: Viral HBV 

Include: Viral HBV by HBsAg 

N: 52 

Mean age: 46 

Significant: Misoprostol better than silymarin for 

hepatomegaly bilirubin, alk phos 

: AST, 


bilirubin, jaundice, 

hepatomegaly 

detection; male patients 

admitted; endoscopically 

confirmed stomach mucosal 

injury; comparable age and 

duration of jaundice 

(approximately 2 to 9 days); 

severe hepatocellular 

dysfunction with marked 


Not significant: GGTP, AST, ALT 

Setting: Hospital Correspondence from Flisiak, November 2,1999: 

Study was not placebo controlled; subjects were 

blinded, but providers and outcome assessors were 

not blinded 

Followup interval: 7, 14, 21, increases in bilirubin, AST, and 

28 days 

ALT 

Assessment time points Exclude: Female patients; 

with results reported: 7, 14, concomitant alcoholism, HCV 

21, 28 days 

or HDV infections and chronic 

diseases (e.g., diabetes) 

Acuity/severity: Acute 

Author: 

Flisiak 65 

Study type: Cohort with 

comparison group/not blind 

Year: 1997 

Country: 


Language: 

English 


Silymarin/210 mg daily/28 

days 


Outcome measures a Type: Viral HBV 

N: 52 

Significant: Alk phos 

Include: Viral HBV by HBsAg; Mean age: 46 Not significant: AST, ALT, GGTP, bilirubin, 

male patients admitted; 


hepatomegaly 

endoscopically confirmed 

stomach mucosal injury; Setting: Hospital Correspondence from Flisiak, November 2, 1999: 

Study was not placebo controlled; subjects were 

comparable age and duration 

blinded, but providers and outcome assessors were 

of jaundice (approximately 2 to 

: AST, 

not blinded 

9 days), severe hepatocellular 

ALT, GGTP, alk phos, dysfunction with marked 

bilirubin, jaundice, 

increases in bilirubin, AST, and 

hepatomegaly 

ALT 

Followup interval: 7, 14, 21, Exclude: Female patients, 

28 days 

concomitant alcoholism, HCV 

Assessment time points or HDV infections and chronic 

with results reported: 7, 14, disease (e.g., diabetes) 

21, 28 days 


other information



Author: 

Lirussi 108 

Year: 1995 

Country: 

Italy 

Language: 

English 

Author: 

Roveda 109 

Year: 1991 

Country: 

Italy 

Language: 

Italian 

Study type: RCT/blinding 

unclear 


UDCA/600 mg daily/180 days 

Silymarin (Legalon ® )/420 

mg/180 days 

Combination therapy UDCA 

and silymarin/600 mg UDCA 

and 420 mg silymarin/6 

months 


ALT GGTP, alk phos, 

bilirubin 


210, 300, 395 days 



180 days 




Silymarin/140 or 280 mg daily 

or silybin/70 or 140 mg 

daily/90 days 



bilirubin 




days 

Type: Compensated active 

cirrhosis (HCV, alcoholic with 

or without HCV, HBsAg) 

Include: Biopsy-proven 

compensated cirrhosis; AST 

and ALT 2 to 10 times normal 

limits 




Type: Organic and functional 

diseases of liver parenchyma 





Patient 


N: 23 

Mean age: 58 



Phase 1: Crossover 

Phase 2: UDCA 

and silymarin 

versus no 

treatment 


noted) 

Significant: 

Not significant: AST, ALT, GGTP, bilirubin, alk phos 

N: 51 

Significant: 

Mean age: 55 Not significant: Hepatomegaly, gastric burning, pain 



on palpation



Author: 

Saba 110 

Study type: RCT/blinding Type: Acute viral hepatitis 

unclear 

Include: Onset in 15 days or 

Year: 1979 

fewer; hospitalized 4 days or 

Country: 

Italy 

fewer of onset of jaundice; no 

previous episodes of jaundice 

Language: 

Italian 

Exclude: More than 100 g of 

alcohol per day for 15 days or 

fewer of disease onset 



Author: 

Schopen 111 

Year: 1970 

Country: 

Germany 

Language: 

German 


Silymarin/420 mg daily/not 

given 

Control: MVI + choline + 

methionin 


ALT, alk phos, bilirubin 

Followup interval: Unclear 



Unclear 

Study type: RCT/blinding 

unclear 


Silymarin (Legalon ® )/1 tablet 

= 35 mg (dose varied from 6 

tablets daily to 9 tablets daily 

and, in rare cases, 12 tablets 

daily/mean 45 days 

Control: Other 

hepatoprotective medicines 

but not silymarin 


ALT, alk phos, bilirubin, 

albumin, PT 



with results reported: Mean 

45 days 

Type: Alcoholic-, toxin-, and 

drug-induced liver disease and 

fatty liver secondary to diabetes 

mellitus; cholestasis (not 

pregnancy related) 

Include: Patients with 

microscopic changes of 

moderately severe to severe 

localized fatty deposits or 

diffuse steatosis; 51 toxic 

metabolic changes with fatty 

liver and some with cholestasis 

(patients with alcohol abuse, 

some diabetes mellitus); 13 

diabetes mellitus; 8 poisoning; 

2 aflatoxin; 1 mercury; 5 

chronic barbiturate abuse 




Patient 


N: 38 

Mean age: 36 



N: 72 

Mean age: Not 

given 


given 



noted) 

Significant: Time to normalization for direct bilirubin, 

AST, ALT, alk phos 

Not significant: Time to normalization for total 

bilirubin 


Not significant:



Author: 

Szilard 112 

Year: 1988 

Country: 

Hungary 

Language: 

English 

Author: 

Tkacz 113 

Year: 1983 

Country: 


Language: 

Polish 

Study type: Cohort/not blind 


Silymarin (Legalon ® ) 420 mg 

daily/30 days 



ALT, GGTP 




days 




Silimarol ® (and vitamins B 

and C)/6 pills daily/21 days 

Control: Vitamins B and C 

and cocarboxylase 

Outcome measures a : ALT, 

alk phos, bilirubin, PT 




days 

Type: Toxic hepatopathy 

caused by organic solvents 

(toluene and xylene) 

Include: Hepatomegaly, 

increased AST and ALT levels, 

lymphocytosis, decreased 

platelet counts attributable to 

toluene and/or xylene 

Exlcude: Alcoholics 

Acuity/Severity: No other 



Demos, LFTs, appear similar 

except higher GGTP in 

treatment group 

Type: Viral hepatitis 

Include: Abnormal LFTs 




Patient 


N: 49 (Legalon ® = 

30; no treatment = 

19) 

Mean age: Not 

given 


Setting: 

Workplace 


noted) 


Not significant: GGTP 

N: 87 

Significant: 

Mean age: Not Not significant: ALT, PT, bilirubin, length of stay 

given 


given 

Setting: Unclear



Author: 

Vailati 85 

Year: 1993 

Country: 

Italy 

Language: 

English 

Study type: RCT/not 

blind/phase 2 study 


Silymarin (Silipide ® )/160 mg 

silybin equivalents daily/14 

days 


silybin equivalents 

daily/14days 


silybin equivalents daily/14 

days 



GGTP, bilirubin 

Followup interval: 7, 14 

days 


with results reported: 7, 14 

days 

Type: Viral and alcoholic 

hepatitis 

Include: Biopsy-proven chronic 

hepatitis (viral or alcoholic); 

AST and ALT 1.5 or greater 

than 2 times normal limits and 

biopsy within 1 year 

Exclude: Other forms of liver 

disease; decompensated liver 

disease; treatment with 

interferon, antivirals, 

immunosuppressants, or 

immunodulators for 6 months 

or fewer 



Patient 


N: 60 

Mean age: 50 


Setting: Outpatient 

clinic 


noted) 

Significant: AST, GGTP, bilirubin for 240 or 360 mg 

versus 160 mg 

Not significant:



Author: 

Velussi 114,115 

Year: 1993, 

1997 

Country: 

Italy 

Language: 

English 

Study type: RCT/not blind 





Outcome measures a : MDA, 

AST, ALT GGTP, alk phos, 

bilirubin 


270, 365 days 



180, 270, 365 days 

Type: Diabetics with alcoholic 

cirrhosis 

Include: Age 45 to 70 years; 

NIDDM with alcoholic liver 

cirrhosis; BMI more than 29 

kg/m 2 ; diabetes for 5 or more 

years treated with insulin only; 

stable insulin therapy for 2 or 

more years; increased 

endogenous insulin secretion; 

negative for HAV, HBV, and 

HCV; not addicted to alcohol 

for 2 or more years before 

study; no variceal esophagus 

bleeding; positive liver biopsy 

for cirrhosis 4 or fewer years 

before enrollment 




Patient 


N: 60 

Mean age: Not 

given 


given 


clinic 


noted) 

Significant: MDA 

Not significant: GGTP, bilirubin, alk phos 

a Results not necessarily reported for all. 

alk phos = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartase aminotransferase; BMI = body mass index; CE = cirrosi epatica; 

Demos = demographic variables; EC = epatite cronica; GGTP = gammaglutamyl transpeptidase; HAV = hepatitis A virus; HbsAg = hepatitis B surface antigen; 

HBV = hepatitis B virus; HCV = hepatitis C virus; HDV = hepatitis D virus; LFT = liver function test; MDA = malondialdehyde; MVI = multivitamin; 

NIDDM = noninsulin dependent diabetes; PT = prothrombin time; RCT = randomized controlled trial; UDCA = ursodeoxycholic acid.

Evidence Table 4. <strong>Milk</strong> thistle for prophylaxis against liver disease: Ineligible (normal liver function at study entry) but provocative 

studies 


Patient 


Author 


Characteristics otherwise noted) 

Author: Allain 83 

Study type: RCT/blind/prophylaxis 

Year: 1999 Intervention/dose/duration: 

Country: 

France 

Language: 

English 

Silymarin/420 mg daily/84 days 


Outcome measures a Type: Drug- (Tacrine-)induced liver N: 222 

Significant: 

disease 

Mean age: 

Not significant: AST, 

: AST, ALT 

Followup interval: 8 times over 15 

weeks 

Include: Patient over 50 years old; 

mild to moderate Alzheimer’s 

disease; Tacrine treatment 

Exclude: Past history hepatic 

disorder (cirrhosis, increased 

bilirubin, AST, and/or ALT) 

Acuity/severity: No disease at 

baseline 

Approximately 74 



clinic 

ALT 

Author: 

Magula 82 

Year: 1996 

Country: 

Language: 

Slovak 


results reported: 8 times over 15 

weeks 

Study type: RCT/not 

blinded/prophylaxis 


Tuberculosis treatment and 

Hepabene ® (Silymarin and Fumaria 

officinalis alkaloids)/2 capsules 

daily/8 weeks 

Control: Tuberculosis medications 

alone 

Outcome measures a : AST, ALT, 

bilirubin, “liver injury,” interruption of 

tuberculosis medications 

Followup interval: Every 2 weeks 

for 8 weeks 


results reported: 8 weeks (56 days) 

Type: Drug-induced liver disease 

Include: Patients requiring 

tuberculosis treatment; normal LFTs 

at baseline 


Acuity/severity: No disease at 

baseline 

N: 172 (92 

tuberculosis 

medications alone; 29 

tuberculosis 

medications plus 

silymarin) 

Mean age: 50 



a 


ALT = alanine aminotransferase; AST = aspartase aminotransferase; LFT = liver function test; RCT = randomized controlled trial. 

Significant: AST, 

ALT 

Not significant:

Evidence Table 5. <strong>Milk</strong> thistle for treatment of liver disease: Adverse effects 

Author, 

Year Adverse Effect Study N 

Bunout, 

1992 66 

Ferenci, 

1989 75 

Pares, 

1998 68 

Vailati, 

1993 85 

Control: 

Pruritus 

Headache 

Treatment: 

Pruritus 

Headache 

Control: Nausea, 

epigastric discomfort 

Treatment: Nausea, 

epigastric discomfort 

Control: 4 

Urticaria, pruritus, 

arthralgia, headache 

Treatment: 7 

Urticaria, pruritus, 

arthralgia, headache 


heartburn 

Dyspepsia 

Postprandial nausea, 

meteorism 

11/34 

4/34 

4/25 

3/24 

2/83 

2/87 

Total n: 

11/200 

3/20 

1/20 

2/20 

Study 

Design Type 

RCT 

RCT 

RCT 

RCT 

<strong>Milk</strong> <strong>Thistle</strong> Exposure Questions 

Placebo 

Silymarin 

(Legalon ® ) 

Placebo 

Silymarin 


Placebo 

Silymarin 


Silipide ® 

Silipide ® 

d after 

discontinued? Amount Improve 

280 mg/d 

420 mg/d 

450 mg/d 

160 mg/d 

240 mg/d 

360mg/d 

Yes, in one 

patient 

Not 


Yes 

Yes 

Yes, 2 

patients 

in treatment 

and 1 patient 

in control 

Yes 

Yes 

Rechallenged? 

No 

No 

No 

No 

Alternative causes 

possible? 

Not given 

Not given 

Not given 

Not given 

Dose-response? 

Not given 

Not given 

Not given 

Not given 

No Not given Not given 

No 

No 

Not given 

Not given 

Not given 

Not given 

Not given

Evidence Table 5. <strong>Milk</strong> thistle for treatment of liver disease: Adverse effects (continued) 

Author, 


Andrade, 

1998 87 

Marcelli, 

1992 77 

Allain, 

1999 83 


after 

Study 

Design Type Amount Improved 

Control: 0/31 RCT 

Not given Not given 

Treatment: Impotence 

Control: Nausea, 

dyspepsia, heartburn, skin 

rash 


heartburn, transient 

headache 

Control: Frequency ADE 

occurred b : 

Diarrhea 5 (10.1%) 

Vomiting 10 (8.2%) 

Nausea 10 (6.3%) 

Anorexia 7 (5.7%) 

Irritability 6 (5.1%) 

Insomnia 6 (4.4%) 

Asthenia 5 (3.8%) 

Malaise 3 (3.2%) 

Bronchitis 7 (5.1%) 

Treatment: Frequency 

ADE occurred b : 

Diarrhea 8 (8.1%) 

Vomiting 6 (4.8%) 

Nausea 10 (10.5%) 

Anorexia 9 (8.2%) 

Irritability 5 (4.8%) 

Insomnia 5 (4.8%) 

Bronchitis 7 (5.6%) 

1/29 

5/34 

3/31 

112 

110 

RCT 

RCT 

Silymarin 

Placebo 

Silipide ® 

Placebo and 

Tacrine 

Silymarin 

and Tacrine 

450 mg/d 

240 mg/d 

420 mg/d 

discontinued? 

Not 


Not given 

Not given 

Rechallenged? 


possible? 


Not given Not given 

Not given Not given Not given 

Not given 

Not given 

Not given 

Not given 

Not given 

Not given


Author, 


Studlar, 

1985 90 

Albrecht, a 

1992 88 

Marena, 

1991 93 

Grungreiff, 

1995 89 

Temporary uneasiness of 

stomach 

Treatment: (in 0.8% of 

patients): 

Mild diarrhea 

Nausea 

Upset stomach 

Itching 

Exanthem 

Headache 

Decreased energy and 

discomfort NOS 

Gastrointestinal: 

Mostly upset stomach 

Control: 

Silipide ® 

Frequency ADE occurred b : 

Changes in BM 4 

Diarrhea 

Dizziness/circulatory 

4 

problems 4 

Nausea/vomiting 2 

Itching 2 

Eczemas 2 

Indisposition 1 

Flatulence 1 

2/34 

4/2,637 

3/2,637 

2/2,637 

2/2,637 

1/2,637 

1/2,637 

7/2,637 

6/117 


after 

Study 


Prospective 

cohort 

Prospective 

cohort 

Cohort c 

12/232 

16/975 Cohort 

(12 

patients 

reported 1 

adverse 

effect and 

4 patients 

reported 2 

adverse 

effects) 

c 

Silibene ® 

(a silymarincontaining 

drug) 

Silymarin 


70 mg 

Placebo 


280 mg/d Not 


3.8±1.48 tablets 

per day 

267.4±103.6 mg 

1 to 9 tablets 55.2 

percent 1 tablet tid 

28.3 percent 

2 tablets tid 

Rechallenged? 


possible? 


Not given Not given Not given 

Not given Not given Not given Not given 


Commercial 

extract 

Silipide ® 

280 to 420 mg/d 

Silymarin 280 to 420 mg/d Not given Not given Not given Not given


Author, 


Frerick, a 

1990 91 

Schuppan, 

1998 92 

Anonymous, 

1972 98 

Geier, 

1990 94 

Mironets, 

1990 95 

Wollemann, 

1987 97 

Frequency ADE occurred b : 

Mild diarrhea 4 

Nausea 3 

Gastric intolerance 2 

Itching 2 

Eczema 1 

Diffuse headaches 1 

Decreased energy/ 

restlessness 1 

No specifics 7 

12 ADEs occurred, but not 

specifically noted; 

examples were diarrhea, 

flatulence, abdominal 

fullness or pain, nausea, 

vomiting, and dizziness 

Sweating, nausea, colicky 

abdominal pain, fluid 

diarrhea, weakness, and 

collapse 

Anaphylactic shock: facial 

edema, oral mucosa 

swelling, marked 

respiratory distress, 

bronchospasm, and 

decrease blood pressure 

Urticaria, fever, laryngeal 

edema 

Rhinoconjunctivitis 

2,169 


after 

Study 


Cohort c 

20/998 Cohort c 

1 

Case report Microgenics 

Herbals 

M.T. 

Silymarin 1,210 patients 

received 210 mg/d 

583 patients 

received 420 mg/d 

376 patients 

received 70 to 630 

mg/d 


Rechallenged? 


possible? 



Silymarin 280 to 420 mg/d Not given Not given Not given Not given 

Vegicaps ® 

1 Case report Silybum 

marianum 

tea 

1 Case report Carsil ® 3 pills per day, no 

dosage given 

1 Case report Silybum Contact with 

marianum seeds 

1 capsule Yes Yes Yes, 

due to 

multiherbal 

capsule 

Not given 

Not given Not given Not given Not given Not given 

Yes, and Tx 

Prednisone 

No Not given Not given 

Not given Yes Not given Not given


Author, 


DeSmet, 

1996 96 

Jaundice, increase LFTs 1 Case report Multiherbal 

tablets with 

unknown 

amount of 

milk thistle 


after 

Study 


a The study by Albrecht is an extension of the study by Frerick and includes the same patients. 19 

6 to 15 tablets 

per day 


Yes 

Rechallenged? 


possible? 

Yes Yes, due 

to 

multiherbal 

tablet 

b Unit of reporting was ADE, not patient. 

c Unclear if cohort was prospective or retrospective. 

ADE = adverse drug effects; BM = bowel movement; LFT = liver function test; NOS = not otherwise specified; RCT = randomized controlled trial; tid = three times daily. 


Not given

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109

Appendix A. <strong>Milk</strong> <strong>Thistle</strong> Search Strategies 

All papers MEDLINE 

Date: 18-Jun-1999 

Name: sily1, sily2, sily3, sily3a, sily4 (SAVED AS SILYMEDL) 

Database: Medline 

Set Search Results 

001 exp liver diseases/ 201649 

002 exp medicine, herbal/ 1079 

003 1 and 2 36 

004 legalon.tw. 34 

005 silymarin.tw. 277 

006 silybin.tw. 120 

007 mariendistel.tw. 0 

008 carduus marianus.tw. 5 

009 milk thistle.tw. 19 

010 milkthistle.tw. 0 

011 silybum marianum.tw. 46 

012 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 441 

013 limit 12 to french 17 

014 limit 12 to german 87 

015 limit 12 to italian 15 

016 silymarin$/ 393 

017 16 or 12 530 

018 silydianin.tw. 13 

019 silychristin.tw. 9 

020 17 or 18 or 19 530 

021 silybum.tw. 49 

022 silymarin$.tw. 289 

023 silybin$.tw. 128 

024 milk thistle$.tw. 19 

025 milk-thistle$.tw. 19 

026 20 or 21 or 22 or 23 or 24 or 25 537 

027 sily$.tw. not 26 587 


029 liver.tw. 285638 



032 31 or 26 555 

033 amanita phalloides.tw. 323 


035 32 555 

113

All papers EMBASE 

Date: 18-Jun-1999 

Name: silyem1 

Database: EMBASE 

Set Search Results 

001 exp clinical trials/ 152066 

002 (clin$ adj25 trial$).ti,ab. 41418 

003 (((singl$ or doubl$ or trebl$ or tripl$) adj25 blind$) or ma 46401 

sk$).ti,ab. 

004 placebo$.ti,ab. 40081 

005 random$.ti,ab. 121458 

006 or/1-5 281333 

007 (animal not human).sh. 643 

008 6 not 7 281326 

009 comparative study.sh. 2801 

010 exp evaluation studies/ 88844 

011 (control$ or prospectiv$ or volunteer$).ti,ab. 597231 

012 or/9-11 669129 

013 12 not 7 669060 

014 12 not 8 557713 

015 8 or 14 839039 

016 silymarin$.tw. 184 

017 legalon$.tw. 69 

018 silymarin/ 353 

019 silybin$.tw. 75 

020 silydianin$.tw. 3 

021 silychristin$.tw. 1 

022 silybum$.tw. 37 

023 milk--thistle$.tw. 16 

024 milkthistle$.tw. 0 

025 milk thistle$.tw. 16 

026 exp herbal medicine/ 2179 

027 exp liver disease/ 93302 



030 or/16-25 431 

031 30 or 29 464 

032 31 464 

114

Z Statistic 

Effect Size 

-3.2 

-1 

2 

0 

-2 

1 

0 

Figure 1-1. Aspartate aminotransferase, less drug study,

Buzelli 1993 

telmann 1970 

telmann 1980 

Lang 1990 

Magliulo 1978 

Salmi 1982 

Combined 

Effect Size 

0.5 

0 

-0.5 

-1 

Figure 1-3. Aspartate aminotransferase, less drug study,

Feher 1990 

Marcelli 1992 

Trinchet 1989 

Combined 

Z Statistic 

-2 

-2.9 

2 

0 

Figure 1-5. Aspartate aminotransferase, less drug study, 90 days 

Figure 1-6a. Aspartate aminotransferase, less drug study, 90 days 

Marcelli 1992 

0 2 4 

Inverse of Standard Error 

-1.5 -1 -0.5 0 0.5 1 

Effect Size 

119 

Trinchet 1989

Feher 1990 

Marcelli 1992 

Combined 

Effect Size 

1 

0 

-1 

Figure 1-6b. Aspartate aminotransferase, less drug study, less outlier, 90 days 

-1.5 -1 -0.5 0 0.5 1 

Effect Size 

Figure 1-7. Aspartate aminotransferase, < 45 days 

Begg's funnel plot with pseudo 95% confidence limits 

0 0.2 0.4 0.6 

Standard Error 

120

Z Statistic 

-3.0 

Buzelli 1993 

2 

0 

-2 



Lang 1990 

Magliulo 1978 

Palasciano 1994 


Salmi 1982 

Combined 

Figure 1-8. Aspartate aminotransferase, < 45 days 

0 2 4 6 


Figure 1-9. Aspartate aminotransferase,

Z Statistic 

Effect Size 

-3.1 

0.5 

-0.5 

2 

0 

-2 

0 

-1 

Figure 1-10. Aspartate aminotransferase, 90 days 


Trinchet 1989 

Marcelli 1992 

0 0.1 0.2 


0.3 0.4 

Figure 1-11. Aspartate aminotransferase, 90 days 

0 2 4 


122 

Marcelli 1992 

Trinchet 1989

Feher 1990 

Marcelli 1992 

Palasciano 

1994 

Palasciano 

1994 

Trinchet 

1989 

Combined 

Feher 1990 

Marcelli 1992 

Palasciano 

1994 

Palasciano 

1994 

Combined 

Figure 1-12a. Aspartate aminotransferase, 90 days 

-1.5 -1 -0.5 0 0.5 0 

Effect Size 

Figure 1-12b. Aspartate aminotransferase, less outlier, 90 days 

-1.5 -1 -0.5 0 0.5 1 

Effect Size 

123

Z Statistic 

Effect Size 

-2.7 

-0.5 

2 

0 

-2 

1 

0.5 

0 

-1 

Figure 1-13. Alanine aminotransferase, less drug study,

Buzelli 1993 

Fintelmann 

1970 

Fintelmann 

1980 

Lang 1990 

Magliulo 1978 

Salmi 1982 

Tanasescu 

1988 

Combined 

Buzelli 1993 



Lang 1990 

Salmi 1982 

Tanasescu 1988 

Combined 

Figure 1-15a. Alanine aminotransferase, less drug study,

Z Statistic 

Effect Size 

0 

-0.5 

-1 

-1.5 

2 

0 

-2 

-3.9 

Figure 1-16. Alanine aminotransferase, less drug study, 90 days 


0 0.1 0.2 0.3 0.4 



0 1 2 3 


126

Feher 1990 

Marcelli 1992 

Combined 

Effect Size 

1 

0.5 

0 

-0.5 

-1 


-1.5 -1 -0.5 0 0.5 1 1.5 

Effect Size 

Figure 1-19. Alanine aminotransferase,

Z Statistic 

-2.6 

Buzelli 1993 



Lang 1990 

Magliulo 1978 



Salmi 1982 


Combined 

2 

0 

-2 

Figure 1-20. Alanine aminotransferase,

Buzelli 1993 



Lang 1990 



Salmi 1982 


Effect Size 

Combined 

0.5 

0 

-0.5 

-1 

-1.5 

Figure 1-21b. Alanine aminotransferase, less outlier,

Z Statistic 

2 

0 

-2 

-3.4 

Feher 1990 

Marcelli 1992 



Combined 

Figure 1-23. Alanine aminotransferase, 90 days 

0 1 2 3 


Figure 1-24. Alanine aminotransferase, 90 days 

-1.5 -1 -0.5 0 0.5 1 1.5 

Effect Size 

130

Z Statistic 

Effect Size 

-1 

2 

0 

-2 

-3.3 

1 

0 

Figure 1-25. Gammaglutamyl transpeptidase,

Buzelli 1993 


Lang 1990 

Magliulo 1978 


Effect Size 

Combined 

0.5 

0 

-0.5 

-1 

Figure 1-27. Gammaglutamyl transpeptidase,

Z Statistic 

-2 

-2.2 

Feher 1990 

Trinchet 1989 

Combined 

2 

0 

Figure 1-29. Gammaglutamyl transpeptidase, 90 days 

0 2 4 


Figure 1-30. Gammaglutamyl transpeptidase, 90 days 

-1.5 -1 -0.5 0 0.5 1 

Effect Size 

133

Z Statistic 

Effect Size 

-0.5 

2 

0 

-2 

-2.3 

1 

0.5 

0 

-1 

Figure 1-31. Alkaline phosphatase,

Buzelli 1993 


Magliulo 1978 

Salmi 1982 


Combined 

Effect Size 

1 

0 

-1 

Figure 1-33. Alkaline phosphatase,

Z Statistic 

-2 

-3.8 

Buzelli 1993 

Lang 1990 

Magliulo 1978 


Combined 

2 

0 

Figure 1-35. Bilirubin,

Z Statistic 

Effect Size 

2.2 

2 

1 

0.5 

0 

-0.5 

0 

-2 

Figure 1-37. Bilirubin, 90 days 


0 0.1 0.2 0.3 0.4 



0 2 4 


137

Feher 1990 

Marcelli 1992 

Trinchet 1989 

Combined 

Effect Size 

0.5 

0 

-0.5 

-1 


-1.5 -1 -0.5 0 0.5 1 

Effect Size 

Figure 1-40. Albumin, 90 days 


0 0.1 0.2 0.3 0.4 


138

Z Statistic 

-2.6 

Feher 1990 

Marcelli 1992 

Trinchet 1989 

Combined 

2 

0 

-2 


0 2 4 



-1 -0.5 0 0.5 1 

Effect Size 

139

Z Statistic 

Effect Size 

-0.5 

2 

0 

-2 

-3.1 

0.5 

0 

-1 

Figure 1-43. Prothrombin time, 90 days 


0 0.1 0.2 0.3 0.4 



0 2 4 


140

Feher 1990 

Marcelli 1992 

Trinchet 1989 

Combined 


-1 -0.5 0 0.5 1 

Effect Size 

141

Appendix D. Acronyms 

ALT alanine aminotransferase 

AST aspartate aminotransferase 

GGTP gammaglutamyl transpeptidase 

HBV hepatitis B virus 

HCV hepatitis C virus 

HIV human immunodeficiency virus 

HPLC high performance liquid chromatography 

MDA malondialdehyde 

PT prothrombin time 

RCT randomized controlled trial 

RNA ribonucleic acid 

TLC thin-layer chromatography 

149

Milk Thistle: Effects on Liver Disease and Cirrhosis - Parents of Kids ...

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