milk thistle: effects on liver disease and cirrhosis …mulrow c, lawrence v, jacobs b, et al. milk...

Evidence Report/Technology Assessment Number 21

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

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

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

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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.

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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

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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. Milk 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. Milk 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.

Contents

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

EVIDENCE REPORT

Chapter 1. Introduction ...................................................................................................................9 Scope and Objectives.................................................................................................................9 Effects of Milk Thistle on Hepatic Disease ...............................................................................9 Clinical Adverse Effects of Milk Thistle ...................................................................................9 Background................................................................................................................................9

The Plant ............................................................................................................................11 Historical Uses of Milk Thistle..........................................................................................11 The Milk Thistle Industry ..................................................................................................12

Chemistry and Pharmacokinetics of Milk Thistle ...................................................................13 Mechanisms of Milk Thistle ....................................................................................................14

Antioxidant Activity ..........................................................................................................14 Toxin Blockade..................................................................................................................15 Enhanced Protein Synthesis...............................................................................................15 Antifibrotic Activity...........................................................................................................15 Other Postulated Mechanisms............................................................................................16

Current Preparations of Milk Thistle .......................................................................................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 Milk Thistle Preparations and Doses .......................................................................................25 Milk Thistle and Liver Disease................................................................................................27

Milk Thistle and Alcohol-Related Liver Disease ..............................................................27 Milk Thistle and Chronic Liver Disease of Mixed Etiology .............................................27 Milk Thistle and Viral Liver Disease.................................................................................28 Milk Thistle and Cirrhosis .................................................................................................28 Milk Thistle and Toxin-Induced Liver Disease .................................................................29 Milk Thistle and Cholestasis..............................................................................................30 Milk Thistle and Primary Hepatic Malignancy .................................................................30

Effectiveness of Different Preparations of Milk Thistle..........................................................30 Exploratory Meta-Analyses Results ........................................................................................31

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Adverse Effects of Milk Thistle...............................................................................................38 Overview of Adverse Effect Literature..............................................................................38 Common Symptomatic Effects ..........................................................................................38 Common and Uncommon Serious Adverse Effects ..........................................................38

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

Chapter 5. Future Research...........................................................................................................43 Adverse Effects........................................................................................................................43 Beneficial Effects Regarding Liver Diseases ..........................................................................43 Specific Areas of Research ......................................................................................................43

References......................................................................................................................................45 Summary Tables ............................................................................................................................53 Evidence Tables ............................................................................................................................73 Bibliography ..................................................................................................................................99 Appendix A. Milk Thistle Search Strategies ..............................................................................113 Appendix B. Graphic Summaries ...............................................................................................115 Appendix C. Contributors...........................................................................................................143 Appendix D. Acronyms ..............................................................................................................149

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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

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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 Bradly Jacobs, MD, MPH Senior Clinical Research Fellow Osher Center for Integrative Medicine Department of Medicine University of California - San Francisco/Veterans Affairs Medical Center Cathi Dennehy, PharmD Assistant Clinical Professor University of California at San Francisco Kenneth Flora, MD, FACG 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 Department of Medicine University of Southern California School of Medicine Robert Eckel, MD Professor Division of Endocrinology, Metabolism, and Diabetes Department of Medicine University of Colorado Health Science Center

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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 Professor 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 Department of Medicine 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

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Srini Srinivasan, PhD Director Dietary Supplements Division U.S. Pharmacopoeia Kathleen Stevens, RN, EdD, FAAN Professor Department of Family Nursing The University of Texas Health Science Center at San Antonio Wendell Winters, PhD Associate Professor Department of Microbiology The University of Texas Health Science Center at San Antonio 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 Cynthia Mulrow, MD, MSc Program Director Valerie Lawrence, MD, MSc Principal Investigator

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Project Investigators Valerie Lawrence, MD, MSc Cynthia Mulrow, MD, MSc Bradly Jacobs, MD, MPH Cathi Dennehy, PharmD Jodi Sapp, RN Christine Aguilar, MD, MPH Kelly Montgomery, MPH Laura Morbidoni, MD Elaine Chiquette, PharmD Kenneth Flora, MD, FACG 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

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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

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effectiveness were limited to placebo-controlled studies. For adverse effects, all types of studies in humans were used to assess adverse clinical effects. Data Collection and Analysis

Abstractors (physicians, methodologists, pharmacists, and a nurse) independently abstracted data from trials; a nurse and physician abstracted data about adverse effects. Data were synthesized descriptively, emphasizing methodologic characteristics of the studies, such as populations enrolled, definitions of selection and outcome criteria, sample sizes, adequacy of randomization process, interventions and comparisons, cointerventions, biases in outcome assessment, and study designs. Evidence tables and graphic summaries, such as funnel plots, Galbraith plots, and forest plots, were used to examine relationships between clinical outcomes, participant characteristics, and methodologic characteristics. Trial outcomes were examined quantitatively in exploratory meta-analyses that used standardized mean differences between mean change scores as the effect size measure. Findings Mechanisms of Action

Evidence exists that milk thistle may be hepatoprotective through a number of mechanisms: antioxidant activity, toxin blockade at the membrane level, enhanced protein synthesis, antifibriotic activity, and possible anti-inflammatory or immunomodulating effects. Preparations of Milk Thistle

The largest producer of milk thistle is Madaus (Germany), which makes an extract of concentrated silymarin. However, numerous other extracts exist, and more information is needed on comparability of formulations, standardization, and bioavailability for studies of mechanisms of action and clinical trials. Benefit of Milk Thistle for Liver Disease • Sixteen prospective trials were identified. Fourteen were randomized, blinded, placebo-

controlled studies of milk thistle’s effectiveness in a variety of liver diseases. In one additional placebo-controlled trial, blinding or randomization was not clear, and one placebo-controlled study was a cohort study with a placebo comparison group.

• Seventeen additional trials used 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).

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• 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.

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• Three trials evaluated milk thistle in the setting of hepatotoxic drugs: one for therapeutic use

and two for prophylaxis with milk thistle. Results were mixed among the three trials. • Exploratory meta-analyses generally showed positive but small and nonsignificant effect

sizes and a sprinkling of significant positive effects. • No studies were identified regarding milk thistle and cholestatic liver disease or primary

hepatic malignancy. • Available evidence does not establish whether effectiveness of milk thistle varies across

preparations. One Phase II trial suggested that effectiveness may vary with dose of milk thistle.

Adverse Effects

Adverse effects associated with oral ingestion of milk thistle include gastrointestinal problems (e.g., nausea, diarrhea, dyspepsia, flatulence, abdominal bloating, abdominal fullness or pain, anorexia, and changes in bowel habits), headache, skin reactions (pruritus, rash, urticaria, and eczema), neuropsychological events (e.g., asthenia, malaise, and insomnia), arthralgia, rhinoconjunctivitis, impotence, 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.

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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.

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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. Effects of Milk Thistle 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. Effects on the following outcomes are addressed: laboratory tests, histologic findings, morbidity, and mortality. Clinical Adverse Effects of Milk Thistle

Various reported adverse effects, including dermatologic, gastrointestinal, and anaphylactoid reactions, are summarized. Background

Milk 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.

Milk 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.

Milk 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 Milk thistle is one of the most important medical members of this genus.8

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Figure 1. Evidence model: Milk thistle and liver disease

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The Plant

Milk 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 Milk Thistle

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

Milk 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

Milk 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

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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

Milk 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 Milk 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 Milk Thistle Industry

Milk 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

Milk 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 Milk Thistle

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 Milk Thistle

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

Milk thistle reportedly reduced leukotriene formation through noncompetitive inhibition of lipoxygenase, thereby suggesting possible anti-inflammatory effects.52 Current Preparations of Milk Thistle

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: Milk thistle and liver disease

Viral hepatitisIndividuals with: CholestasisAlcoholic liverdisease

Toxin- and drug-induced liver

disease

Primary hepaticmalignancy

ChronicHep AHep BHep C

AcuteHep AHep BHep C

Cirrhosis Liverfailure

Pregnancyrelated

Cholangio-carcinoma

Hepatoma

Notpregnancy

related

Acute

Liverfailure

Cirrhosis

Chronic

Silybum marianum

Clinical outcomes

Other healthpromoting actions

Mechanisms

Effects onpathology and

physiology

Silybum marianumconstituents

Powderedseeds

Otherpreparations

Seeds mash/liquid

Other activities (e.g.,antifibrotic and

antiinflammatory)

Proteinsynthesis

Toxin blockade throughmembrane stabilizationAntioxidant

Silymarin complex(silybin + silydianin +

silychristin)

Combined with othercompounds (e.g.,

phosphatidylcholine)Single agent silybin

Biochemical markersStructural changes:

Cirrhosis, fattyinfiltration

Enzyme failure:Toxemia

Overallmortality and

morbidity

Livermortality and

morbidity

Clinicaladverseeffects

Otherunexpectedbeneficial

effects

Quality of life

Acute

Liverfailure

Cirrhosis

Chronic

10

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 x xsiT C

pooled

=−

where, for a given trial i, xT and xC 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 back-calculated 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

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 random-effects 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 effect-size 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 morbidity, or improve quality of life?

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

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?

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

18

Table 2. Electronic sources searched Electronic Database Description

AMED (Alternative and Allied Medicine Database) Searched from 1985 to October 1998

This database contains 100,000 references from 400 journals on alternative and complementary medicine going back to 1985.

CINAHL (Cumulative Index to Nursing and Allied Health Literature) Searched from 1984 to July 1999

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.

CISCOM (Centralised Information Service for Complementary Medicine) Searched 1968 to July 1999

This database contains over 34,000 references and combines data from MEDLINE, AMED, and other specialist European databases.

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

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.

Dissertation Abstracts Searched from 1961 to December 1998

This library indexes doctoral dissertations and masters abstracts from more than 1,000 institutions.

EMBASE Searched from 1988 to July 1999

This database contains biomedical and pharmaceutical citations and is considered the premier biomedical database in Europe.

MEDLINE (PubMed) Searched from 1966 to July 1999 PubMed searched July 1999 to November 1999

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.

MICROMEDEX contains: DRUGDEX Product Index (drug ingredients) POISONDEX/IDENTIDEX (toxicology) DRUG-REAX (interactive drug interactions) Searched July 1999

This database provides a major source for drug, poison, and acute care information.

NAPRALERT (Natural Products Alert) Searched September 1999

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.

PHYTODOK (German Database) Searched 1995 to July 1999

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.

Science Citation Index Searched from January 1990 to March 1999

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

1,727 totalrecords

1,505 recordsexcluded

7 unobtainablerecords

215 recordsretrieved

18 studies ofadverse effects

51 records ofprimary data

included

33 trials

164 recordsexcluded

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. Milk Thistle 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

0

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f Stu

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0-14 15-30 31-60 61-90 90+ Unclear/ not given

Study Duration (days)

Figure 4. Distribution of doses for 16

0

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placebo-controlled trials

Milk Thistle Dose

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

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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). Milk Thistle and Liver Disease Milk Thistle 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. Milk Thistle 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. Milk Thistle 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). Milk 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. Milk Thistle 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

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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 Milk Thistle 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.

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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 report83 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. Milk Thistle and Cholestasis

No studies met criteria for evaluating efficacy of milk thistle in treating cholestatic liver disease, pregnancy-related or not. Milk Thistle 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 Milk Thistle

Pharmacokinetic studies indicate that one preparation of oral Silipide® (silybin-phosphatidylcholine 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.

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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 placebo-controlled studies (studies in Evidence Tables 1 and 2); (2) the 14 randomized, placebo-controlled 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.

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Adverse Effects of Milk Thistle 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 self-report 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 Effects

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 Effects

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

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apparent anaphylactoid reaction improved with prednisone and discontinuing silymarin, and there were no apparent alternative possible etiologies.95

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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 AST ALT 30, 90 daysChronic alcoholic liver disease 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’sscore

15 months

Pares68 Alb Bili AST ALT Alk phos GGTP PT Child’sscore

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

Survival 48 months

Acute viral hepatitis 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 Buzelli79 Bili AST ALT Alk phos GGTP MDA 7 days

Kiesewetter80: Reported as improvement, no change, worse

Histologicchange

90 days; 360 days combined

Note: When there was more than one study, effect sizes were pooled. aThe last time point (7 to 45 days) was selected for pooling as “≤45 day” time point. bTime 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)

OutcomeaTime of

Followup No. of

Studies Effect Size (SD units)

95% CI Effect Size,

Clinical Unitsb 95% CI p Valuec (ES ≠ 0)

Q p Valuec (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 –

AST 44.77 U/La

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 –

ALT 36.02 U/La

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 –

GGTP 153.94 U/La

2 years 1 0.38 (0.02 to 0.73) 58.5 (3.1 to 112.4) 0.04 – MDA

6.65 nmol/mla 180 days 1 -0.81 (-1.49 to -0.13) -5.4 (-9.9 to -0.9) 0.02 –

≤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 –

15 months 1 -0.05 (-0.63 to 0.53) -5.0 (-63.6 to 53.5) 0.87 –

Alkaline Phosphate 101.01 U/La

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 –

Bilirubin 0.32 g/dLa

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 – Albumin

0.74 g/dLa

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 –

15 months 1 -0.29 (-0.87 to 0.29) -5.0 (-15.1 to 5.0) 0.32 –

PT 17.39a

seconds 2 years 1 -0.18 (-0.53 to 0.17) -3.1 (-9.2 to 3.0) 0.32 –

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Table 4. Effect sizes and meta-analysis for chronic alcoholic liver disease (6 studies) (continued)

OutcomeaTime of

Follow-Up No. of


95% CI Effect Size,

Clinical Unitsb 95% CI p-Valuec (ES ≠ 0)

Q p-Valuec (Homogeneity)

15 months 1 -0.09 (-0.68 to 0.50) -0.2 (-1.7 to 1.3) 0.78 – Child’s 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.

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Table 5. Effect sizes and meta-analysis for chronic liver disease of mixed etiologies (6 studies)

OutcomeaTime of

Followup No. of


95% CI Effect Size,



≤45 days 2 -0.30 (-0.67 to 0.08) -13.4 (-30.0 to 3.6) 0.12 0.41 AST 44.77 U/La 90 days 1 -0.73 (-1.22 to -0.24) -32.7 (-54.6 to -10.7) <0.01 –

≤45 days 3 -0.13 (-0.42 to 0.17) -4.7 (-15.1 to 6.1) 0.40 0.31 ALT 36.02 U/La 90 days 1 -0.90 (-1.56 to -0.24) -32.4 (-56.2 to -8.6) 0.01 –

GGTP 153.94 U/La

≤45 days 2 -0.11 (-0.38 to 0.15) -16.9 (-58.5 to 23.1) 0.40 0.30

Alkaline phosphate

101.01 U/La

≤45 days 2 -0.14 (-0.41 to 0.12) -14.1 (-41.4 to 12.1) 0.29 0.74

≤45 days 1 -0.28 (-0.57 to 0.02) -0.1 (-0.2 to.01) 0.07 – Bilirubin 0.32 g/dLa 90 days 1 0.17 (-0.32 to 0.66) 0.05 (-0.1 to 0.2) 0.49 – Albumin 0.74 g/dL

90 days 1 0.08 (-0.41 to 0.57) 0.1 (-0.3 to 0.4) 0.75 –

≤45 days 1 0.14 (-0.16 to 0.44) 2.4 (-2.8 to 7.7) 0.35 – PT 17.39a

seconds 90 days 1 0.03 (-0.46 to 0.52) 0.5 (-8.0 to 9.0) 0.91 –

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; PT = prothrombin time; SD = standard deviation; U/L = units per liter.

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Table 6. Effect sizes and meta-analysis for viral liver disease, acute and chronic (3 studies)

OutcomeaTime of

Followup No. of

Studies Effect Size

(SD units) 95% CI Effect Size,



AST 44.77 U/La ≤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/La ≤45 days 2 0.25 (-1.46 to 1.96) 9.0 (-52.6 to 70.6) 0.77 <0.01

GGTP 153.94 U/La ≤45 days 2 -0.20 (-0.73 to 0.32) -30.8 (-112.4 to 49.3) 0.44 0.53

MDA 6.65 nmol/mla ≤45 days 1 -0.09 (-0.96 to 0.79) -0.6 (-6.4 to 5.3) 0.85 –

Alkaline phosphate

101.01 U/La≤45 days 2 -0.05 (-0.56 to 0.46) -5.1 (-56.6 to 46.5) 0.84 0.38

Bilirubin 0.32 g/dLa ≤45 days 2 -0.25 (-0.83 to 0.33) -0.1 (-0.3 to 0.1) 0.40 1.00

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; MDA = malondialdehyde; SD = standard deviation; U/L = units per liter.

37

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 Adverse Effects

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 Effects 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 cohort-comparison 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.

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References 1. Brown D. Silymarin education monograph.

Herbal Res Update 1993;Summer:23-36.

2. Foster S. Milk thistle: Silybum marianum. Austin (TX): American Botanical Council; 1990.

3. Luper S. A review of plants used in the treatment of liver disease: Part 1. Altern Med Rev 1998;3:410-21.

4. Tenney L. Milk thistle: A remarkable flavonoid antioxidant and liver protectant. Pleasant Grove (UT): Woodlands Publications; 1995.

5. Morazzoni P, Bombardelli E. Silybum marianum (Carduus marianus). Fitoterapia 1995;66:3-42.

6. Herbal remedies. Milk thistle: Protection for the liver [Web site]. Available at: http://www.healthyideas.com/healing/herb/ 980407.herb.html. [accessed June 25, 1999].

7. Hobbs C. Milk thistle: The liver herb. Loveland (CO): Interweave Press; 1994.

8. Grieve M. A modern herbal: The medicinal, culinary, cosmetic and economic properties, cultivation, and folklore of herbs, grasses, fungi, shrubs, and trees with all their modern scientific uses. Darien (CT): Hafner Publishing Company; 1931.

9. Flora K, Hahn M, Rosen H, et al. Milk thistle (Silybum marianum) for the therapy of liver disease. Am J Gastroenterol 1998;93:139-43.

10. Bergner P. Botanical medicine: Silybum marianum and liver therapy. Townsend Lett Doctors 1988;61-2:348-9.

11. Folk medicine traditions [Web site]. Available at: http://nccam.nih.gov/nccam/ what-is-cam/fields/herbals.shtml. [accessed June 28, 1999].

12. Blumenthal M, editor. Complete German Commission E monographs: Therapeutic guide to herbal medicines. Boston (MA): American Botanical Council, Integrative Medicine Communications; 1998.

13. Flora KD, Rosen HR, Benner KG. The use of naturopathic remedies for chronic liver disease. Am J Gastroenterol 1996;91:2654-5.

14. Gottlieb S. US agency to test safety of four herbs [newsletter]. BMJ 1999;319:336.

15. Miller AL. Antioxidant flavonoids: Structure, function and clinical usage. Altern Med Rev 1996;1:103-11.

16. Valenzuela A, Garrido A. Biochemical bases of the pharmacological action of the flavonoid silymarin and of its structural isomer silibinin. Biol Res 1994;27:105-12.

17. Schulz V, Hansel R, Tyler VE, editors. Rational phytotherapy: A physician’s guide to herbal medicine. 3rd, fully rev., and expanded ed. Berlin: Springer-Verlag; 1998.

18. Mascher H, Kikuta C, Weyhenmeyer R. Diastereomeric separation of free and conjugated silibinin in plasma by reversed phase HPLC after specific extraction. J Liquid Chromatogr 1993;16:2777-89.

19. Blumenthal M (National Advisory Panel Member). Personal communication from Mark Blumenthal, Dec 1999.

20. Ely H. Dermatologic therapies you’ve probably never heard of. Dermatol Clin 1989;7:19-35.

21. Blumenthal M (National Advisory Panel Member). Personal communication from Mark Blumenthal, Dec 1999 .

22. Blumenthal M (National Advisory Panel Member). Conference telephone call with the San Antonio Evidence-based Practice Center, Oct 19, 1999.

45

23. Blumenthal M (National Advisory Panel Member). Personal communication from Mark Blumenthal, Dec 1999, who cited: (A) personal communication from Madaus through E. Leng-Peschlow and A. Strenge-Hesse, Nov 1999; (B) Schulz HU, et al. Untersuchungen zum Freisetzungsverhalten und zur Bioäquivalenenz von Silymarin-Präparaten. Arzneimittelforshung 1995;45:61-4; (C) Frömming KH, et al. Silymarinhaltige Phytopharmaka: Biopharmazie als wesentliches therapeutisches Qualitätskriterium. Z Ärztl Fortbild Qual 1999;4:vi-xi.

24. Pifferi G. A new bioavailable complex of Silybin: Part I. Pharmacol Res 1993;27:123-4.

25. Barzaghi N, Crema F, Gatti G, et al. Pharmacokinetic studies on IdB 1016, a silybin-phosphatidylcholine complex, in healthy human subjects. Eur J Drug Metab Pharmacokinet 1990;15:333-8.

26. Schandalik R, Gatti G, Perucca E. Pharmacokinetics of silybin in bile following administration of silipide and silymarin in cholecystectomy patients. Arzneimittelforschung 1992;42:964-8.

27. Orlando R, Fragasso A, Lampertico M, et al. Silybin kinetics in patients with liver cirrhosis: A comparative study of silybin-phosphatidilcholine complex and silymarin. Med Sci Res 1990;18:861-3.

28. Pifferi G, Magistretti MJ. A new bioavailable complex of silybin: Part II. Pharmacol Res 1993;27:125-6.

29. Rajasekaran A, Kumar M, Krishnamoorthy G, et al. Spectrophotometric determination of silymarin. Indian J Pharm Sci 1997;59:230-1.

30. Gocan S, Cimpan G, Muresan L. Automated multiple development thin layer chromatography of some plant extracts. J Pharm Biomed Anal 1996;14:1221-7.

31. Weyhenmeyer R, Mascher H, Birkmayer J. Study on dose-linearity of the pharmacokinetics of silibinin diastereomers using a new stereospecific assay. Int J Clin Pharmacol Ther Toxicol 1992;30:134-8.

32. Hammouda F, Ismail S, Hassan N, et al. Evaluation of the silymarin content in Silybum marianum (L.) Gaertn. cultivated under different agricultural conditions. Phytother Res 1993;7:90-1.

33. Tittel G, Wagner H. High-performance liquid chromatographic separation of silymarins and their determination in a raw extract of Silybum marianum Gaertn. J Chromatogr 1977;135:499-501.

34. Quaglia MG, Bossu E, Donati E, et al. Determination of silymarine in the extract from the dried silybum marianum fruits by high performance liquid chromatography and capillary electrophoresis. J Pharm Biomed Anal 1999;19:435-42.

35. Bindoli A, Cavallini L, Siliprandi N. Inhibitory action of silymarin of lipid peroxide formation in rat liver mitochondria and microsomes. Biochem Pharmacol 1977;26:2405-9.

36. Valenzuela A, Guerra R, Videla LA. Antioxidant properties of the flavonoids silybin and (+)-cyanidanol-3: Comparison with butylated hydroxyanisole and butylated hydroxytoluene. Planta Med 1986;6:438-40.

37. Valenzuela A, Guerra R. Differential effect of silybin on the Fe2+-ADP and t-butyl hydroperoxide-induced microsomal lipid peroxidation. Experientia 1986;42:139-41.

38. Valenzuela A, Barria T, Guerra R, et al. Inhibitory effect of the flavonoid silymarin on the erythrocyte hemolysis induced by phenylhydrazine. Biochem Biophys Res Commun 1985;126:712-8.

39. Mira ML, Azevedo MS, Manso C. The neutralization of hydroxyl radical by silibin, sorbinil and bendazac. Free Radic Res Commun 1987;4:125-9.

40. Gyorgy I, Blazovics A, Feher J, et al. Reactions of inorganic free radicals with liver protecting drugs. Radiat Phys Chem 1990;36:165-7.

46

41. Muzes G, Deak G, Lang I, et al. Effect of the bioflavonoid silymarin on the in vitro activity and expression of superoxide dismutase (SOD) enzyme. Acta Physiol Hung 1991;78:3-9.

42. Campos R, Garrido A, Guerra R, et al. Silybin dihemisuccinate protects against glutathione depletion and lipid peroxidation induced by acetaminophen on rat liver. Planta Med 1989;55:417-9.

43. Halliwell B, Gutteridge JM. The antioxidants of human extracellular fluids. [Review]. [129 refs]. Arch Biochem Biophys 1990 Jul;280:1-8.

44. Feher JLI, Nekam K, Gergely P, et al. In vivo effect of free radical scavenger hepatoprotective agents on superoxide dismutase (SOD) activity in patients. Tokai J Exp Clin Med 1990;15(2-3):129-34.

45. Hikino H, Kiso Y, Wagner H, et al. Antihepatotoxic actions of flavonolignans from Silybum marianum fruits. Planta Med 1984;50:248-50.

46. Faulstich H, Jahn W, Wieland T. Silybin inhibition of amatoxin uptake in the perfused rat liver. Arzneimittelforschung 1980;30:452-4.

47. Tuchweber B, Sieck R, Trost W. Prevention of silybin of phalloidin-induced acute hepatoxicity. Toxicol Appl Pharmacol 1979;51:265-75.

48. Sonnenbichler J, Zetl I. Biochemical effects of the flavoligand silybin on RNA, protein and DNA synthesis of macromolecules in liver cells. In: Cody V, Middleton E Jr, Harborne JB, editors. Plant flavanoids in biology and medicine: Biochemical, pharmacological, and structure-activity relationships. New York: Liss; 1986. p. 319-31.

49. Magliulo E, Carosi PG, Minoli L, et al. Studies on the regenerative capacity of the liver in rats subjected to partial hepatectomy and treated with silymarin. Arzneimittelforschung 1973;23:161-7.

50. Sonnenbichler J, Goldberg M, Hane L, et al. Stimulatory effect of Silibinin on the DNA synthesis in partially hepatectomized rat livers: Non-response in hepatoma and other malign cell lines. Biochem Pharmacol 1986;35:538-41.

51. Blumenthal M (National Advisory Panel Member). Personal communication from Mark Blumenthal, Dec 1999, who cited: (A) personal communication from Madaus through E. Leng-Peschlow and A. Strenge-Hesse, Nov 1999; (B) Schuppan D, et al. Antibrotic effect of silymarin in rat secondary bilary fibrosis induced by bile duct obliteration with ethibloc [abstract]. Z Gastroenterol 1994;32:45-6; (C) Jia JD, et al. Silymarin decreases type I procollogen mRNA levels in rats with secondary biliary cirrhosis [abstract]. Gastroenterology 114;A1265; (D) Boigk G, et al. Silymarin retards collagen accumulation in early and advanced biliary fibrosis secondary to complete bile duct obliteration in rats. Hepatology 1997;26:643-9.

52. Dehmlow C, Murawski N, de Groot H. Scavenging of reactive oxygen species and inhibition of arachidonic acid metabolism by silibinin in human cells. Life Sci 1996;58:1591-600.

53. Dennehy C. Personal communication from Cathi Dennehy, Dec 1999.

54. Bode JC. Re: Flora, et al. Silymarin for the therapy of liver disease. Am J Gastroenterol 1999;94:545-6.

55. Berlin JA. Does blinding of readers affect the results of meta-analyses? University of Pennsylvania Meta-analysis Blinding Study Group. Lancet 1997;350:185-6.

56. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.

57. Hedges LV, Olkin I. Statistical methods for meta-analysis. Orlando (FL): Academic Press; 1985.

47

58. Rosenthal R. Meta-analytic procedures for social research. Rev. ed. Thousand Oaks (CA): Sage Publications; 1991.

59. Berkey CS, Hoaglin DC, Mosteller F, et al. A random-effects regression model for meta-analysis. Stat Med 1995;14:395-411.

60. Sharp S. Sbe23: Meta-regression. Stata Tech Bull 1998;42:16-22.

61. Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629-34.

62. Tobias A. Assessing heterogeneity in meta-analysis: The Galbraith plot. Stata Tech Bull 1997;41:15-7.

63. Sharp S, Sterne J. Sbe16: Meta-analysis. Stata Tech Bull 1997;38:9-14.

64. Steichen TJ. Tests for publication bias in meta-analysis. Stata Tech Bull 1997;41:9-15.

65. Flisiak R, Prokopowicz D. Effect of misoprostol on the course of viral hepatitis B. Hepatogastroenterology 1997;44:1419-25.

66. Bunout D, Hirsch S, Petermann M, et al. [Controlled study of the effect of silymarin on alcoholic liver disease]. [Spa]. Rev Med Chil 1992;120:1370-5.

67. Trinchet JC, Coste T, Levy VG, et al. [A randomized double blind trial of silymarin in 116 patients with alcoholic hepatitis]. [Fre]. Gastroenterol Clin Biol 1989;13:120-4.

68. Pares A, Planas R, Torres M, et al. Effects of silymarin in alcoholic patients with cirrhosis of the liver: Results of a controlled, double-blind, randomized and multicenter trial. J Hepatol 1998;28:615-21.

69. Salmi HA, Sarna S. Effect of silymarin on chemical, functional, and morphological alterations of the liver. A double-blind controlled study. Scand J Gastroenterol 1982;17:517-21.

70. Feher J, Deak G, Muzes G, et al. [Liver-protective action of silymarin therapy in chronic alcoholic liver diseases]. [Hun]. Orv Hetil 1989;130:2723-7.

71. Lang I, Nekam K, Deak G, et al. Immunomodulatory and hepatoprotective effects of in vivo treatment with free radical scavengers. Ital J Gastroenterol 1990;22:283-7.

72. Fintelmann V. Zur Therapie der Fettleber mit Silymarin. Therapiewoche 1970;20:23.

73. Fintelmann V, Albert A. [Double blind trial of silymarin sodium in toxic liver damage]. [Ger]. Therapiewoche 1980;30:5589-94.

74. Tanasescu C, Petrea S, Baldescu R, et al. Use of the Romanian product Silimarina(R) in the treatment of chronic liver diseases. Rev Roum Med 1988;26:311-22.

75. Ferenci P, Dragosics B, Dittrich H, et al. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol 1989;9:105-13.

76. Benda L, Dittrich H, Ferenzi P, et al. [The influence of therapy with silymarin on the survival rate of patients with liver cirrhosis (author’s transl)]. [Ger]. Wien Klin Wochenschr 1980;92:678-83.

77. Marcelli R, Bizzoni P, Conte D, et al. Randomized controlled study of the efficacy and tolerability of a short course of IdB 1016 in the treatment of chronic persistent hepatitis. Eur Bull Drug Res 1992;1:131-5.

78. Magliulo E, Gagliardi B, Fiori GP. [Results of a double blind study on the effect of silymarin in the treatment of acute viral hepatitis, carried out at two medical centres (author’s transl)]. [Ger]. Med Klin 1978;73:1060-5.

79. Buzzelli G, Moscarella S, Giusti A, et al. A pilot study on the liver protective effect of silybinphosphatidylcholine complex (IdB1016) in chronic active hepatitis. Int J Clin Pharmacol Ther Toxicol 1993;31:456-60.

48

80. Kiesewetter E, Leodolter I, Thaler H. [Results of two double-blind studies on the effect of silymarine in chronic hepatitis (author’s transl)]. [Ger]. Leber Magen Darm 1977;7:318-23.

81. Palasciano G, Portincasa P, Palmier V, et al. The effect of silymarin on plasma levels of malon-dialdehyde in patients receiving long-term treatment with psychotropic drugs. Curr Ther Res Clin Exp 1994;55:537-45.

82. Magula D, Galisova Z, Iliev N, et al. [Effect of silymarine and Fumaria alkaloids in the prophylaxis of drug-induced liver injury during antituberculotic treatment]. [Slo]. Stud Pneumol Phtiseol 1996;56:206-9.

83. Allain H, Shuck S, Lebreton S, et al. Aminotransferase levels and silymarin in de novo tacrine-treated patients with alzheimer’s disease. Dement Geriatr Cogn Disord 1999;10:181-5.

84. Blumenthal M (National Advisory Panel Member). Personal communication from Mark Blumenthal, Dec 1999, who cited: Personal communication from Madaus through E. Leng-Peschlow and A. Strenge-Hesse, Nov 1999.

85. Vailati A, Aristia L, Sozze E, et al. Randomized open study of the dose-effect relationship of a short course of IdB 1016 in patients with viral or alcoholic hepatitis. Fitoterapia 1993;64:219-28.

86. De Smet PA. An introduction to herbal pharmacoepidemiology. J Ethnopharmacol 1993;38:197-208.

87. Andrade RJ, Lucena MI, De la Cruz JP, et al. Hepatology 1998;28:629A.

88. Albrecht M, Frerick H, Kuhn U, et al. [Therapy of toxic liver disease with Legalon(R)]. [Ger]. Z Klin Med 1992;47:87-92.

89. Grungreiff K, Albrecht M, Strenge-Hesse A. [Benefit of medicinal liver therapy in general practice]. [Ger]. Med Welt 1995;46:222-7.

90. Studlar M. [Treatment of chronic liver disease with silymarin plus B-group vitamins]. [Ger]. Therapiewoche 1985;35:3375-8.

91. Frerick F, Kuhn U, Strenge-Hesse A. Silymarin—ein Phytopharmakon zur Behandlung toxischen Leberschäden: Anwendungsbeobachtung bei 2169 Patienten. Kassenarzt 1990;33:36-41.

92. Schuppan D, Strosser W, Burkard G, et al. [Influence of Legalon(TM) 140 on the metabolism of collagen in patients with chronic liver disease—Review by measurement of PIIINP-values]. [Ger]. Z Allgemeinmed 1998;74:577-84.

93. Marena C, Lampertico M. Preliminary clinical development of silipide: A new complex of silybin in toxic liver disorders [abstract]. Planta Med 1991;57:124-5.

94. Geier J, Fuchs TH, Wahl R. [Anaphylactic shock due to an extract of Silybum marianum in a patient with immediate-type allergy to Kiwi fruit]. [Ger]. Allergologie 1990;13:387-8.

95. Mironets VI, Krasovskaia EA, Polishchuk II. [A case of urticaria during carsil treatment]. [Rus]. Vrach Delo 1990;7:86-7.

96. De Smet PA, Van den Eertwegh AJ, Lesterhuis W, et al. Hepatotoxicity associated with herbal tablets. BMJ 1996;313:92.

97. Wollemann G, Seifert HU, Borelli S. Berufsbedingte Rhinokonjunktivitis auf Mariendistelsamen (Silybum marianum L.). Allergologie 1987;10:505-7.

98. Adverse Drug Reactions Advisory Committee. An adverse reaction to the herbal medication milk thistle (Silybum marianum). Med J Aust 1999;170:218-9.

99. Muzes G, Deak G, Lang I, et al. [Effect of silimarin (Legalon) therapy on the antioxidant defense mechanism and lipid peroxidation in alcoholic liver disease (double blind protocol)]. [Hun]. Orv Hetil 1990;131:863-6.

49

108. Lirussi F, Nassuato G, Orlando R, et al. Treatment of active cirrhosis with ursodeoxycholic acid and a free radical scavenger: A two year prospective study. Med Sci Res 1995;23:31-3.

100. Feher J, Lengyel G, Blazovics A. Oxidative stress in the liver and biliary tract diseases. Scand J Gastroenterol Suppl 1998;228:38-46.

101. Boari C, Montanari FM, Galletti GP, et al. [Toxic occupational liver diseases. Therapeutic effects of silymarin]. [Ita]. Minerva Med 1981;72:2679-88.

109. Roveda S, Colombo P, Pulvirenti A. [Evaluation of the efficacy and tolerance of silybin in the treatment of organic and functional diseases of the liver parenchyma]. [Ita]. Arch Med Int 1991;43:97-102. 102. Bode JC, Schmidt U, Durr HK. [Silymarin

for the treatment of acute viral hepatitis? Report of a controlled trial (author’s transl)]. [Ger]. Med Klin 1977;72:513-8.

110. Saba P, Mignani E, Pagliai, et al. [Efficacy of silymarin treatment of acute virus hepatitis]. [Ita]. Epatologia 1979;25:277-81. 103. Cavalieri S. [Controlled clinical trial of

silymarin in 40 patients]. [Ita]. Gazz Med Ital 1974;133:628-35. 111. Schopen RD, Lange OK. [Therapy of

hepatoses. Therapeutic use of Silymarin]. [Ger]. Med Welt 1970;15:691-8. 104. Del Dotto M, Neri D. [Alcoholic

hepatopathy. Aspects of drug therapy]. [Ita]. G Clin Med 1982;63:228-36. 112. Szilard S, Szentgyorgyi D, Demeter I.

Protective effect of Legalon in workers exposed to organic solvents. Acta Med Hung 1988;45:249-56.

105. De Martiis M, Barlattani A, Parenzi A, et al. [Relationship between changes of lipid metabolism and macrocytic anemia in the course of chronic liver disease. Evaluation of treatment with a membranotropic agent]. [Ita]. Clin Ter 1984;111:135-9.

113. Tkacz B, Dworniak D. [Sylimarol in the treatment of acute viral hepatitis]. [Pol]. Wiad Lek 1983;36:613-6.

114. Velussi M, Cernigoi AM, Viezzoli L, et al. Silymarin reduces hyperinsulinemia, malondialdehyde levels, and daily insulin need in cirrhotic diabetic patients. Curr Ther Res Clin Exp 1993;53:535-45.

106. De Martiis M, Fontana M, Assogna G, et al. [Milk thistle (Silybum marianum) derivatives in the therapy of chronic hepatopathies]. [Ita]. Clin Ter 1980;94:283-315.

115. Velussi M, Cernigoi AM, De Monte A, et al. Long-term (12 months) treatment with an anti-oxidant drug (silymarin) is effective on hyperinsulinemia, exogenous insulin need and malondialdehyde levels in cirrhotic diabetic patients. J Hepatol 1997;26:871-9.

107. Fintelmann V. [Postoperative behavior of serum cholinesterase and other liver enzymes]. [Ger]. Med Klin 1973;68:809-15.

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Summary Table 1. Placebo-controlled studies of milk thistle for chronic alcoholic liver disease (n = 6)

Study Design Liver DiseaseSubject

Characteristics Outcomes (favoring silymarin

unless otherwise noted) Author: Bunout66 Year: 1992 Country: Chile Language: Spanish

Study type: RCT/blind Intervention/dose/duration: Silymarin (Legalon®)/280 mg daily/446 days Control: Placebo Outcome measuresa: AST, GGTP, alk phos, bilirubin, albumin, PT Followup interval: Monthly for an average of 15 months Assessment time points with results reported: Mean of 15 months

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 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 Acuity/severity: Chronic, cirrhosis, no other information Baseline group similarity: Demos, LFTs appear similar

N: 59 Mean age: 50 Percent male: 86 Setting: Specialty clinic

Significant: Albumin Not significant: Child’s score, bilirubin, AST, GGTP, alk phos, PT, survival

Author: Feher70,99,100 Year: 1989/1990 Country: Hungary Language: Hungarian

Study type: RCT/blind Intervention/dose/duration: Silymarin (Legalon®)/420 mg daily/180 days Control: Placebo Outcome measuresa: AST, ALT, GGTP, alk phos, bilirubin, albumin Followup interval: 90 and 180 days Assessment time points with results reported: 90 and 180 days

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 Exclude: Not given Acuity/severity: Chronic, no other information Baseline group similarity: Demos, LFTs appear similar

N: 36 Mean age: 46 Percent male: 75 Setting: Unclear

Significant: AST, GGTP, MDA Not significant: (assumed for all) ALT, alk phos, albumin, PT, survival

Author: Lang71 Year: 1990 Country: Hungary Language: English

Study type: RCT/blind/three arms Interventions/dose/duration: Silymarin (Legalon®)/420 mg daily/30 days AICA-P/600 mg daily/30 days Control: Placebo Outcome measuresa: AST, ALT, GGTP, alk phos, albumin Followup interval: 28 days Assessment time points with results reported: Weekly for 1 month

Type: Alcoholic cirrhosis Include: Alcohol intake exceeding 60 g/d in men and 30 g/d women for more than 6 years; histologic diagnosis of micronodular cirrhosis Exclude: Vascular and/or parenchymal decompensation; +HBsAg Acuity/severity: Chronic, cirrhosis, no other information Baseline group similarity: LFTs appear similar


Significant: AST, ALT, GGTP Not significant: Bilirubin

Summary Table 1. Placebo-controlled studies of milk thistle for chronic alcoholic liver disease (n = 6) (continued)

Study Design Liver Disease Subject

Characteristics Outcomes (favoring silymarin

unless otherwise noted) Author: Pares68 Year: 1998 Country: Spain Language: English

Study type: RCT/blind Intervention/dose/duration: Silymarin (Legalon®)/450 mg daily/unclear Control: Placebo Outcome measuresa: AST, ALT, GGTP, alk phos, bilirubin, albumin, PT Followup interval: Every 3 months for 2 years Assessment time points with results reported: Survival at 5 years; all others at 2 years (assumed)

Type: Alcoholic cirrhosis (24 percent had superimposed alcohol hepatitis) 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 Baseline group similarity: Demos, LFTs appear similar

N: 200 Mean age: 50 Percent male: 79 Setting: Diagnosis in hospital then outpatient followup.

Significant: + Trend: Encephalopathy, UGIB, 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.

Author: Salmi69 Year: 1982 Country: Finland Language: English

Study type: RCT/blind Intervention/dose/duration: Silymarin (Legalon®)/420 mg daily/28 days Control: Placebo Outcome measuresa: AST, ALT, alk phos, bilirubin, histology Followup interval: Day 28 Assessment time points with results reported: 28 days

Type: Alcoholic liver disease Include: Increased AST and ALT for more than 1 month despite order to abstain from alcohol Exclude: Not given Acuity/severity: No other information Baseline group similarity: Aminotransferase levels reported as similar but lower in controls

N: 97 Mean age: 37 Percent male: 86 Setting: Hospital

Significant: AST, ALT, histology Not significant: Alk phos, bilirubin

Author: Trinchet67 Year: 1989 Country: France Language: French

Study type: RCT/blind Intervention/dose/duration: Silymarin (Legalon®)/420 mg daily/ 90 days Control: Placebo Outcome measuresa: AST, GGTP, bilirubin, albumin, PT, histology Followup interval: 90 days Assessment time points with results reported: 90 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 Baseline group similarity: Demos, LFTs appear similar

N: 116 Mean age: 51 Percent male: 67% Setting: Unclear

Significant: Both silymarin and placebo better with alcohol abstinence Not significant: PT, albumin, bilirubin, GGTP, AST, histology (hepatitis, fibrosis)

aResults 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)


Characteristics Outcomes (favoring silymarin unless

otherwise noted) Author: Fintelmann73 Year: 1980 Country: Germany Language: German

Study type: RCT/blind Intervention/dose/duration: Silymarin(Legalon®)/not given/not given Control: Placebo Outcome measuresa: AST, ALT, GGTP, alk phos, bilirubin Followup interval: Days 1, 3, 7, 10, 14, 21, 28 Assessment time points with results reported: Had to read off graphs, but all followups

Type: Toxic liver disease, any etiology (usually alcohol) Include: Clinical and laboratory evidence of toxic liver damage Exclude: Not given Acuity/severity: No other information Baseline group similarity: No information except age and gender “similar”

N: 66 Mean age: Not given Percent male: Not given Setting: Unclear

Significant: ALT, GGTP Not significant: AST, bilirubin, alk phos

Author: Fintelmann72 Year: 1970 Country: Germany Language: German

Study type: Cohort with comparison group/blinding unclear Intervention/dose/duration: Silymarin (Legalon®)/6 tablets daily/42 days Control: Placebo Outcome measuresa: Bilirubin, alk phos, AST, ALT Followup interval: 42 days Assessment time points with results reported: 42 days

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 Exclude: Not given Acuity/severity: All degrees of fatty liver including early cirrhosis without portal hypertension Baseline group similarity: LFTs appear similar


Significant: AST (categorical) Not significant: AST (continuous), ALT, alk phos

Summary Table 2. Placebo-controlled studies of milk thistle for chronic liver disease, mixed etiologies (n = 6) (continued)



otherwise noted) CAH CPH HCVSignificant: + Trend: ALTNot significant:

ALT, GGTP, bilirubin, alk phos, PT

GGTP, bilirubin, alk phos, PT


Author: Tanasescu74 Year: 1988 Country: Romania Language: English

Study type: RCT, randomization stratified by type of disease: CPH, CAH, HCV/blind Intervention/dose/duration: Silymarin (Silimarina®)/210 mg silybin equivalents daily/ 40 days Control: Placebo Outcome measuresa: ALT, GGTP, bilirubin, alk phos, PT Followup interval: 40 days Assessment time points with results reported: 40 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 Exclude: Not given Acuity/severity: Chronic, no other information Baseline group similarity: Age, LFTs appear similar


Note: Trend was assessed qualitatively only for this review.

Author: Ferenci75 Year: 1989 Country: Austria Language: English

Study type: RCT/blind Intervention/dose/duration: Silymarin (Legalon®)/420 mg daily/ mean 41 months, range 2 to 6 years Control: Placebo Outcome measuresa: AST, ALT, GGTP, alk phos, bilirubin, albumin, PT Followup interval: 4 years Assessment time points with results reported: 2 and 4 to 5.5 years for survival

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

N: 170 Mean age: 57 Percent male: 72 Setting: Primary care/community clinic, specialty clinic, hospital

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.

Author: Benda76 Year: 1980 Country: Germany Language: German

Study type: RCT/blind Intervention/dose/duration: Silymarin (Legalon®)/420 mg daily/ Unclear Control: Placebo MVI Outcome measuresa: Survival Followup interval: 4 years Assessment time points with results reported: 4 years

Type: Alcoholic and nonalcoholic cirrhosis Include: Biopsy-proven 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 information


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)



otherwise noted) Author: Marcelli77 Year: 1992 Country: Italy Language: English

Study type: RCT/blinding unclear Intervention/dose/duration: Silipide®/240 mg daily/90 days Control: Placebo Outcome measuresa: AST, ALT, bilirubin, albumin, PT Followup interval: 90 days Assessment time points with results reported: 90 days

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 Acuity/severity: Chronic, no other information Baseline group similarity: Demos appear similar; higher AST and ALT in Silipide® group


Significant: AST, ALT Not significant: Bilirubin, albumin, PT

aResults 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


Characteristics

Outcomes (favoring silymarin

unless otherwise noted) Author: Magliulo78 Year: 1978 Country: Italy Language: German

Study type: RCT/blind Intervention/dose/duration: Silymarin (Legalon®)/420 mg daily/25 days Control: Placebo Outcome measuresa: 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

Type: Viral HAV and HBV Include: Acute HAV and HBV patients Exclude: Not given Acuity/severity: Acute, no other information Baseline group similarity: LFTs appear similar


Significant: AST, bilirubin + Trend: ALT Not significant: Alk phos Note: Trend was assessed qualitatively only for this review.

aResults 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


Characteristics

Outcomes (favoring silymarin unless otherwise noted)

Author: Buzelli79 Year: 1993 Country: Italy Language: English

Study type: RCT/blind Intervention/dose/duration: Silipide®/240 mg silybin equivalents daily/7 days Control: Placebo Outcome measuresa: AST, ALT, GGTP, MDA, alk phos, bilirubin, albumin Followup interval: 7 days Assessment time points with results reported: 7 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 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 Baseline group similarity: Demos, LFTs appear similar


Significant: AST, ALT, GGTP Not significant: Bilirubin, alk phos, MDA, albumin

Author: Kiesewetter80 Year: 1977 Country: Austria Language: German

Study type: RCT/quasi Intervention/dose/duration: Silymarin (Legalon®)/420 mg daily/365 days Control: Placebo Outcome measuresa: Histology Followup interval: 14, 30, 60 days then every 90 days to 1 year Assessment time points with results reported: One, combined/90 to 360 days

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 Acuity/severity: Chronic, no other information Baseline group similarity: Demos, similar, no information on LFTs


Significant: + Trend: Improvement in liver biopsy Not significant: Note: Trend was assessed qualitatively only for this review.

aResults 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



otherwise noted) Author: Benda76 Year: 1980 Country: Germany Language: German


Type: Alcoholic and nonalcoholic cirrhosis Include: Biopsy-proven 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 information







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.

aResults 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)


Characteristics


Author: Pares68 Year: 1998 Country: Spain Language: English





Author: Lang71 Year: 1990 Country: Hungary Language: English

Study type: RCT/blind/three arms Interventions/dose/duration: Silymarin (Legalon®)/420 mg daily/30 days AICA-P/600 mg daily/30 days Control: Placebo Outcome measuresa: AST, ALT, GGTP, alk phos, albumin Followup interval: 28 days Assessment time points with results reported: Weekly for 1 month




aResults 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


Characteristics

Outcomes (favoring silymarin unless otherwise

noted) Author: Palasciano81 Year: 1994 Country: Italy Language: English

Study type: RCT/blind, factorial design Intervention/dose/duration: 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 discontinued Placebo and psychotropic drugs/ not given/90 days Outcome measuresa: AST, ALT, MDA Followup interval: Day 15, 30, 60, 90, 120 Assessment time points 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 Baseline group similarity: Demos similar; LFTs variable


Significant: MDA for psychotropic drugs with silymarin versus placebo Not significant: AST, ALT, MDA for psychotropic drugs discontinued, silymarin versus placebo

aResults 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


Characteristics


noted) Author: Magula82 Year: 1996 Country: Language: Slovak

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: AST, ALT, bilirubin, “liver injury,” interruption of tuberculosis medications Followup interval: Every 2 weeks for 8 weeks Assessment time points with results reported: 8 weeks (56 days)

Type: Drug-induced liver disease Include: Patients requiring tuberculosis treatment; normal LFTs at baseline Exclude: Not given Acuity/severity: No disease at baseline

N: 172 (92 tuberculosis medications alone; 29 tuberculosis medications plus silymarin) Mean age: 50 Percent male: 60 Setting: Unclear

Significant: AST, ALT Not significant:

Author: Allain83 Year: 1999 Country: France Language: English

Study type: RCT/blind/prophylaxis Intervention/dose/duration: Silymarin/420 mg daily/84 days Control: Placebo Outcome measuresa: AST, ALT Followup interval: 8 times over 15 weeks Assessment time points with results reported: 8 times over 15 weeks

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, increased bilirubin, AST, and/or ALT) Acuity/severity: No disease at baseline

N: 222 Mean age: Approximately 74 Percent male: 39 Setting: Specialty clinic

Significant: Not significant: AST, ALT

aResults not necessarily reported for all. Abbreviations used: ALT = alanine aminotransferase; AST = aspartase aminotransferase; LFT = liver function test; RCT = randomized controlled trial.

Summary Table 9. Phase II study of Silipide®


Characteristics


noted) Author: Vailati85 Year: 1993 Country: Italy Language: English

Study type: RCT/not blind/Phase II study Intervention/dose/duration: Silymarin (Silipide®)/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: AST, GGTP, bilirubin Followup interval: 7, 14 days Assessment time points 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 less Acuity/severity: Chronic, no other information

N: 60 Mean age: 50 Percent male: 62 Setting: Outpatient clinic

Significant: AST, GGTP, bilirubin for 240 or 360 mg versus 160 mg Not significant:

aResults 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)

OutcomeaTime of

Followup No. of


95% CI Effect Size, Clinical

Unitsb 95% CI p Valuec (ES ≠ 0)


≤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 90 days without outlier

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 –

AST without drug study 44.77 U/La

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 90 days 5 –0.30 (–0.73 to 0.13) –13.4 (–32.7 to 5.8) 0.17 0.03 AST with

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 7 –0.09 (–0.45 to 0.28) –3.2 (–16.2 to 10.1) 0.64 0.004 ≤45 days without outlier

6 –0.22 (–0.42 to –0.03) –7.9 (–15.1 to –1.1) 0.03 0.51

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 –

ALT without drug study 36.02 U/La

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 ≤45 days without outlier

8 –0.19 (–0.37 to –0.01) –6.8 (–13.3 to –0.4) 0.04 0.63 ALT with

drug study 36.02 U/La

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 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 0.02) –98.5 (–200.1 to 3.1) 0.06 –

15 months 1 –0.26 (–0.84 to 0.32) –40.0 (–129.3 to 49.3) 0.38 –

GGTP 153.94 U/La

2 years 1 0.38 (0.02 to 0.73) 58.5 (3.1 to 112.4) 0.04 – ≤45 days 1 –0.09 (–0.96 to 0.79) –0.6 (–6.4 to 5.3) 0.85 – MDA 6.65

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 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 –

15 months 1 –0.05 (–0.63 to 0.53) –5.0 (–63.6 to 53.5) 0.87 –

Alkaline phosphate

101.01 U/La

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)

OutcomeaTime of

Followup No. of





≤45 days 4 –0.28 (–0.52 to –0.03) –0.1 (–0.2 to –0.01) 0.03 1.00 90 days 3 0.02 (–0.33 to 0.37) 0.01(–0.1 to 0.1) 0.91 0.25 180 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 – 90 days 3 –0.08 (–0.53 to 0.38) –0.05 (–0.4 to 0.3) 0.74 0.10 180 days 1 0.19 (–0.46 to 0.84) 0.1 (–0.3 to 0.6) 0.57 –

15 months 1 0.25 (–0.35 to 0.85) 0.2 (–0.2 to 0.6) 0.42 – Albumin

0.74 g/dLa

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 – 90 days 3 –0.19 (–0.67 to 0.28) –3.3 (–11.6 to 4.9) 0.42 0.08 180 days 1 0.47 (–0.20 to 1.14) 8.2 (–3.5 to 19.8) 0.17 –

15 months 1 –0.29 (–0.87 to 0.29) –5.0 (–15.1 to 5.0) 0.32 –

PT 17.39a

seconds

2 years 1 –0.18 (–0.53 to 0.17) –3.1 (–9.2 to 3.0) 0.31 – 15 months 1 –0.09 (–0.68 to 0.50) –0.2 (–1.7 to 1.3) 0.78 – Child’s

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 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; 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)

OutcomeaTime of

Followup No. of




Q p Valuec (Homogeneity)

≤45 days 5 –0.27 (–0.52 to –0.03) –12.1 (–23.3 to –1.3) 0.03 0.76 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 –

AST without drug study 44.77 U/La

2 years 1 0.28 (–0.07 to 0.63) 12.5 (–3.1 to 28.2) 0.12 – ≤45 days 7 –0.23 (–0.46 to –0.004) –10.3 (–20.6 to –0.2) 0.046 0.85 AST with

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 6 –0.14 (–0.55 to 0.28) –5.0 (–19.8 to 10.1) 0.52 0.003 ≤45 days without outlier

5 –0.27 (–0.48 to –0.07) –9.7 (–17.3 to –2.5) 0.01 0.71

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 –

ALT without drug study 36.02 U/La

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 ≤45 days without outlier

7 –0.23 (–0.42 to –0.04) –8.3 (–15.1 to –1.4) 0.02 0.76 ALT with

drug study 36.02 U/La

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 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 0.02) –98.5 (–200.1 to 3.1) 0.06 –

15 months 1 –0.26 (–0.84 to 0.32) –40.0 (–129.3 to 49.3) 0.38 –

GGTP 153.94 U/La

2 years 1 0.38 (0.02 to 0.73) 58.5 (3.1 to 112.4) 0.04 – ≤45 days 1 –0.09 (–0.96 to 0.79) –0.6 (–6.4 to 5.3) 0.85 – MDA

6.65 nmol/mla 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 –

15 months 1 –0.05 (–0.63 to 0.53) –5.0 (–63.6 to 53.5) 0.87 –

Alkaline Phosphate 101.01 U/La

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)

OutcomeaTime of

Followup No. of

Studies Effect Size

(SD units) 95% CI Effect Size, Clinical


Q p Valuec (Homogeneity)

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 (–0.46 to 0.84) 0.1 (–0.3 to 0.6) 0.57 –

15 months 1 0.25 (–0.35 to 0.85) 0.2 (–0.2 to 0.6) 0.42 – Albumin

0.74 g/dLa

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 – 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 1.14) 8.2 (–3.5 to 19.8) 0.17 –

15 months 1 –0.29 (–0.87 to 0.29) –5.0 (–15.1 to 5.0) 0.32 –

PT 17.39a

seconds

2 years 1 –0.18 (–0.53 to 0.17) –3.1(–9.2 to 3.0) 0.31 – 15 months 1 –0.09 (–0.68 to 0.50) –0.2 (–1.7 to 1.3) 0.76 – Child’s

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 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; 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 Effects Level of Evidence Possible/probable anaphylaxis Three case reports Gastrointestinal Nausea, diarrhea, upset stomach, epigastric

discomfort, heartburn, dyspepsia, flatulence, meteorism, “uneasiness” of stomach, vomiting, anorexia, change in bowel movement, “gastric intolerance,” abdominal fullness or pain

Four RCTs: silymarin ≤ control Five cohort studies: 0.3%, ≤2%, 5%, 6%, 8% 11 occurrences/975 patients 9 occurrences/2,169 patients

Headache Three RCTs: silymarin ≤ control Two cohort studies: 0.04%, 0.04%

Skin: Itching, pruritus

Two RCTs: silymarin ≤ control Three cohort studies: 2 occurrences/2,637 patients 2 occurrences/975 patients 2 occurrences/2,169 patients

Exanthem, urticaria, skin rash, eczema Two RCTs: silymarin ≤ control Two cohort studies: 2 occurrences/975 patients 1 occurrence/2,169 patients

Other: Decreased energy, discomfort, indisposition,

decreased energy, restlessness Asthenia, malaise, irritability Insomnia Arthalgia Rhinoconjunctivitis Impotence

Cohort study: 0.3% 1 occurrence/975 patients 1 occurrence/2,169 patients One RCT: silymarin ≤ control One RCT: silymarin ≤ control One RCT: silymarin ≤ control 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. RCT = randomized controlled trial.

Evidence Table 1. Milk thistle for treatment of liver disease: Placebo-controlled, randomized, blinded trials


CharacteristicsOutcomes (favoring silymarin unless otherwise

noted) Author: Benda76 Year: 1980 Country: Germany Language: German


Type: Alcoholic and nonalcoholic cirrhosis Include: Biopsy-proven cirrhosisExclude: 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 information



Author: Bunout66 Year: 1992 Country: Chile Language: Spanish

Study type: RCT/blind Intervention/dose/duration: Silymarin (Legalon®)/280 mg daily/446 days Control: Placebo Outcome measuresa: AST, GGTP, alk phos, bilirubin, albumin, PT Followup interval: Monthly for an average of 15 months Assessment time points with results reported: Mean of 15 months

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 Acuity/severity: Chronic, cirrhosis, no other information Baseline group similarity: Demos, LFTs appear similar


Significant: Albumin Not significant: Child’s score, bilirubin, AST, GGTP, alk phos, PT

Evidence Table 1. Milk thistle for treatment of liver disease: Placebo-controlled, randomized, blinded trials (continued)



noted) Author: Buzelli79 Year: 1993 Country: Italy Language: English

Study type: RCT/blind Intervention/dose/duration: Silipide®/240 mg silybin equivalents daily/7 days Control: Placebo Outcome measuresa: AST, ALT, GGTP, MDA, alk phos, bilirubin, albumin Followup interval: 7 days Assessment time points with results reported: 7 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 Baseline group similarity: Demos, LFTs appear similar


Significant: AST, ALT, GGTP Not significant: Bilirubin, alk phos, MDA, albumin




noted) Author: Feher70,99,100 Year: 1989/1990 Country: Hungary Language: Hungarian

Study type: RCT/blind Intervention/dose/duration: Silymarin (Legalon®)/420 mg daily/180 days Control: Placebo Outcome measuresa: AST, ALT, GGTP, alk phos, bilirubin, albumin Followup interval: 90 and 180 days Assessment time points with results reported: 90 and 180 days

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 Exclude: Not given Acuity/severity: Chronic, no other information Baseline group similarity: Demos, LFTs appear similar


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 (non-alcohol 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.




noted) Author: Fintelmann73 Year: 1980 Country: Germany Language: German

Study type: RCT/blind Intervention/dose/duration: Silymarin(Legalon®)/not given/not given Control: Placebo Outcome measuresa: AST, ALT, GGTP, alk phos, bilirubin Followup interval: Days 1, 3, 7, 10, 14, 21, 28 Assessment time points with results reported: Had to read off graphs, but all followups

Type: Toxic liver disease, any etiology (usually alcohol) Include: Clinical and laboratory evidence of toxic liver damage Exclude: Not given Acuity/severity: No other information Baseline group similarity: No information except age and gender “similar”


Significant: ALT, GGTP Not significant: AST, bilirubin, alk phos

Author: Kiesewetter80 Year: 1977 Country: Austria Language: German

Study type: RCT/quasi Intervention/dose/duration: Silymarin (Legalon®)/420 mg daily/365 days Control: Placebo Outcome measuresa: Histologic findings Followup interval: 14, 30, 60 days then every 90 days to 1 year Assessment time points with results reported: One, combined/90 to 360 days

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 Acuity/severity: Chronic, no other information Baseline group similarity: Demos, similar, no information on LFTs


Significant: + Trend: Improvement in liver biopsy Not significant: Note: Trend was assessed qualitatively only for this review.




noted) Author: Lang71 Year: 1990 Country: Hungary Language: English

Study type: RCT/blind/three arms Interventions/dose/duration: Silymarin (Legalon®)/420 mg daily/30 days AICA-P/600 mg daily/30 daysControl: Placebo Outcome measuresa: AST, ALT, GGTP, alk phos, albumin Followup interval: 28 days Assessment time points with results reported: Weekly for 1 month




Author: Magliulo78 Year: 1978 Country: Italy Language: German

Study type: RCT/blind Intervention/dose/duration: Silymarin (Legalon®)/420 mg daily/25 days Control: Placebo Outcome measuresa: 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

Type: Viral HAV and HBV Include: Acute HAV and HBV patients Exclude: Not given Acuity/severity: Acute, no other information Baseline group similarity: LFTs appear similar


Significant: AST, bilirubin + Trend: ALT Not significant: Alk phos Note: Trend was assessed qualitatively only for this review.




noted) Author: Palasciano81 Year: 1994 Country: Italy Language: English

Study type: RCT/blind, factorial design Intervention/dose/duration: 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 discontinued Placebo and psychotropic drugs/ not given/90 days Outcome measuresa: AST, ALT, MDA Followup interval: Day 15, 30, 60, 90, 120 Assessment time points 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 Baseline group similarity: Demos similar; LFTs variable


Significant: MDA for psychotropic drugs with silymarin versus placebo Not significant: AST, ALT, MDA for psychotropic drugs discontinued, silymarin versus placebo




noted) Author: Pares68 Year: 1998 Country: Spain Language: English








noted) Author: Salmi69 Year: 1982 Country: Finland Language: English

Study type: RCT/blind Intervention/dose/duration: Silymarin (Legalon®)/420 mg daily/28 days Control: Placebo Outcome measuresa: AST, ALT, alk phos, bilirubin, histologic findings Followup interval: Day 28 Assessment time points with results reported: 28 days

Type: Alcoholic liver disease Include: Increased AST and ALT for more than 1 month despite order to abstain from alcohol Exclude: Not given Acuity/severity: No other information Baseline group similarity: Aminotransferase levels reported as similar but lower in controls


Significant: AST, ALT, histology Not significant: Alk phos, bilirubin

CAH CPH HCVSignificant: + Trend: ALTNot significant:


GGTP, bilirubin, alk phos, PT


Author: Tanasescu74 Year: 1988 Country: Romania Language: English

Study type: RCT, randomization stratified by type of disease: CPH, CAH, HCV/blind Intervention/dose/duration: Silymarin (Silimarina®)/210 mg silybin equivalents daily/40 days Control: Placebo Outcome measuresa: ALT, GGTP, bilirubin, alk phos, PT Followup interval: 40 days Assessment time points with results reported: 40 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 Exclude: Not given Acuity/severity: Chronic, no other information Baseline group similarity: Age, LFTs appear similar


Note: Trend was assessed qualitatively only for this review.




noted) Author: Trinchet67 Year: 1989 Country: France Language: French

Study type: RCT/blind Intervention/dose/duration: Silymarin (Legalon®)/420 mg daily/90 days Control: Placebo Outcome measuresa: AST, GGTP, bilirubin, albumin, PT, histology Followup interval: 90 days Assessment time points with results reported: 90 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 Baseline group similarity: Demos, LFTs appear similar

N: 116 Mean age: 51 Percent male: 67% Setting: Unclear

Significant: Both silymarin and placebo better with alcohol abstinence Not significant: PT, albumin, bilirubin, GGTP, AST, histologic findings (hepatitis, fibrosis)

aResults 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. Milk thistle for treatment of liver disease: Placebo-controlled, prospective trials with unclear blinding

Study Design Liver DiseasePatient

Characteristics



Study type: Cohort with comparison group/blinding unclear Intervention/dose/duration: Silymarin (Legalon®)/6 tablets daily/42 days Control: Placebo Outcome measuresa: Bilirubin, alk phos, AST, ALT Followup interval: 42 days Assessment time points with results reported: 42 days

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 Exclude: Not given Acuity/severity: All degrees of fatty liver including early cirrhosis without portal hypertension Baseline group similarity: LFTs appear similar


Significant: AST (categorical) Not significant: AST (continuous), ALT, alk phos

Author: Marcelli77 Year: 1992 Country: Italy Language: English

Study type: RCT/blinding unclear Intervention/dose/duration: Silipide®/240 mg daily/90 days Control: Placebo Outcome measuresa: AST, ALT, bilirubin, albumin, PT Followup interval: 90 days Assessment time points with results reported: 90 days

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 Acuity/severity: Chronic, no other information Baseline group similarity: Demos appear similar; higher AST and ALT in Silipide® group


Significant: AST, ALT Not significant: Bilirubin, albumin, PT

aResults not necessarily reported for all. 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.

Evidence Table 3. Milk thistle for treatment of liver disease: Studies without placebo controls

Study Design Liver DiseasePatient

Characteristics Outcomes (favoring silymarin unless otherwise

noted) Author: Boari101 Year: 1981 Country: Italy Language: Italian

Study type: RCT unclear/blinding unclear Intervention/dose/duration: Silymarin/420 mg daily/15 to 20 days Control: Vitamin B complex/not given/15 to 20 days Outcome measuresa: AST, ALT, GGTP, alk phos, bilirubin Followup interval: 20 days Assessment time points with results reported: 20 days

Type: Toxic hepatopathy caused by various substances (mostly solvents, paints, and glues); mostly suffering from chronic or subacute forms Include: Not given Exclude: Not given Acuity/severity: ? Chronic, 0 cirrhosis, 11 liver failure, 29 other, no other information


Significant: AST, ALT, GGTP, alk phos Not significant: Bilirubin

Author: Bode102 Year: 1977 Country: Germany Language: German

Study type: RCT (quasi/odd-even birthdate)/not blind Intervention/dose/duration: Silymarin (Legalon®)/420 mg daily/35 days Control: No treatment Outcome measuresa: AST, ALT, GGTP, alk phos, bilirubin, PT Followup interval: 10, 25, 35 days Assessment time points with results reported: 35 days

Type: Viral hepatitis Include: Patients with viral hepatitis Exclude: Jaundice exceeding 8 days Acuity/severity: Acute, no other information

N: 151 Mean age: Not given Percent male: 48 Setting: Unclear

Significant: Not significant: AST, bilirubin, ALT, alk phos

Evidence Table 3. Milk thistle for treatment of liver disease: Studies without placebo controls (continued)

Study Design Liver Disease Patient


noted) Author: Cavalieri103 Year: 1974 Country: Italy Language: Italian

Study type: RCT unclear/blinding unclear Intervention/dose/duration: Silymarin (Legalon®)/ 420 mg daily/variable Control: “Traditional treatment”: a 12-component cocktail including vitamin and steroids Outcome measuresa: AST, ALT, GGTP, alk phos, bilirubin, PT Followup interval: 7, 14, 28 days Assessment time points with results reported: 7, 14, 28 days

Type: Acute hepatitis (posttransfusion, contagious, presumably parenteral, and sporadic) Include: Not given Exclude: Not given Acuity/severity: Acute, no other information


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

Author: Del Dotto104 Year: 1982 Country: Italy Language: Italian

Study type: RCT unclear/blinding unclear Intervention/dose/duration: Silymarin (Legalon®)/420 mg daily/90 days Control: Vitamin B complex Outcome measuresa: AST, ALT, GGTP, PT, bilirubin, albumin, alk phos Followup interval: 30, 60, 90 days Assessment time points with results reported: 30, 60, 90 days

Type: Alcoholic liver disease Include: Patients with alcoholic liver disease Exclude: Not given Acuity/severity: Chronic, no other information


Significant: Not significant: AST, ALT, GGTP, PT, bilirubin, albumin, alk phos




noted) Author: DeMartiis105 Year: 1980 Country: Italy Language: Italian

Study type: RCT unclear/blinding unclear Intervention/dose/duration: Silymarin, traditional therapy, and diet/400 mg daily/45 to 90 days Control: Traditional therapy + diet Outcome measuresa: Bilirubin Followup interval: 90 days Assessment time points with results reported: 90 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 Acuity/severity: Chronic, no other information


Significant: Not significant: Indirect bilirubin




noted)

All Patients

CE or EC

CE EC

Significant: Alk phos Alk phos, bilirubin

Bilirubin, alk phos

Author: DeMartiis106 Year: 1980 Country: Italy Language: Italian

Study type: RCT unclear/blinding unclear Intervention/dose/duration: 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 measuresa: Alk phos, bilirubin Followup interval: Unclear Assessment time points with results reported: Unclear

Type: Chronic hepatopathies (diagnoses include chronic hepatitis, hepatic cirrhosis, and hepatic neoplasm) Include: Hepatic disease Exclude: Not given Acuity/severity: 0 acute, 21 chronic, 61 cirrhosis, no other information

N: 91 Mean age: 56 Percent male: 71 Setting: Not given

Not significant: All others All others All


Study type: RCT unclear/blinding unclear Intervention/dose/duration: Silymarin (Legalon®)/210 or 420 mg daily/preoperative and 8 days postoperative Control: No treatment Outcome measuresa: AST, ALT, alk phos, bilirubin Followup interval: 1, 2, 3 days Assessment time points with results reported: 1, 2, 3 days

Type: Cholestasis, not pregnancy related Include: Consecutive patients for cholecystectomy with cholelithiasis with or without cholecystitis Exclude: Obstructive jaundice Acuity/severity: Acute, no other information

N: 63 Mean age: Not given Percent male: 6 Setting: Hospital

Significant: + Trend: Less increase in AST, ALT on postoperative day 1 Not significant: AST, ALT, bilirubin, alk phos Note: Trend was assessed qualitatively only for this review.




noted) Author: Flisiak65 Year: 1997 Country: Poland Language: English

Study type: RCT/not blind Intervention/dose/duration: Silymarin/210 mg daily/28 days Control: Misoprostol Outcome measuresa: AST, ALT, GGTP, alk phos, bilirubin, jaundice, hepatomegaly Followup interval: 7, 14, 21, 28 days Assessment time points with results reported: 7, 14, 21, 28 days

Type: Viral HBV Include: Viral HBV by HBsAg 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 increases in bilirubin, AST, and ALT Exclude: Female patients; concomitant alcoholism, HCV or HDV infections and chronic diseases (e.g., diabetes) Acuity/severity: Acute

N: 52 Mean age: 46 Percent male: 100Setting: Hospital

Significant: Misoprostol better than silymarin for hepatomegaly bilirubin, alk phos Not significant: GGTP, AST, ALT Correspondence from Flisiak, November 2,1999: Study was not placebo controlled; subjects were blinded, but providers and outcome assessors were not blinded

Author: Flisiak65 Year: 1997 Country: Poland Language: English

Study type: Cohort with comparison group/not blind Intervention/dose/duration: Silymarin/210 mg daily/28 days Control: No treatment Outcome measuresa: AST, ALT, GGTP, alk phos, bilirubin, jaundice, hepatomegaly Followup interval: 7, 14, 21, 28 days Assessment time points with results reported: 7, 14, 21, 28 days

Type: Viral HBV Include: Viral HBV by HBsAg; male patients admitted; endoscopically confirmed stomach mucosal injury; comparable age and duration of jaundice (approximately 2 to 9 days), severe hepatocellular dysfunction with marked increases in bilirubin, AST, and ALT Exclude: Female patients, concomitant alcoholism, HCV or HDV infections and chronic disease (e.g., diabetes) Acuity/severity: Acute, no other information

N: 52 Mean age: 46 Percent male: 100Setting: Hospital

Significant: Alk phos Not significant: AST, ALT, GGTP, bilirubin, hepatomegaly Correspondence from Flisiak, November 2, 1999: Study was not placebo controlled; subjects were blinded, but providers and outcome assessors were not blinded




noted) Author: Lirussi108 Year: 1995 Country: Italy Language: English

Study type: RCT/blinding unclear Intervention/dose/duration: UDCA/600 mg daily/180 daysSilymarin (Legalon®)/420 mg/180 days Combination therapy UDCA and silymarin/600 mg UDCA and 420 mg silymarin/6 months Outcome measuresa: AST, ALT GGTP, alk phos, bilirubin Followup interval: 90, 180, 210, 300, 395 days Assessment time points with results reported: 90, 180 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 Exclude: Not given Acuity/severity: No other information

N: 23 Mean age: 58 Percent male: 36 Setting: Unclear Phase 1: Cross-over Phase 2: UDCA and silymarin versus no treatment

Significant: Not significant: AST, ALT, GGTP, bilirubin, alk phos

Author: Roveda109 Year: 1991 Country: Italy Language: Italian

Study type: RCT unclear/blinding unclear Intervention/dose/duration: Silymarin/140 or 280 mg daily or silybin/70 or 140 mg daily/90 days Outcome measuresa: AST, ALT, GGTP, alk phos, bilirubin Followup interval: 90 days Assessment time points with results reported: 90 days

Type: Organic and functional diseases of liver parenchyma Include: Not given Exclude: Not given Acuity/severity: No other information


Significant: Not significant: Hepatomegaly, gastric burning, pain on palpation




noted) Author: Saba110 Year: 1979 Country: Italy Language: Italian

Study type: RCT/blinding unclear Intervention/dose/duration: Silymarin/420 mg daily/not given Control: MVI + choline + methionin Outcome measuresa: AST, ALT, alk phos, bilirubin Followup interval: Unclear Assessment time points with results reported: Unclear

Type: Acute viral hepatitis Include: Onset in 15 days or fewer; hospitalized 4 days or fewer of onset of jaundice; no previous episodes of jaundice Exclude: More than 100 g of alcohol per day for 15 days or fewer of disease onset Acuity/severity: Acute, no other information


Significant: Time to normalization for direct bilirubin, AST, ALT, alk phos Not significant: Time to normalization for total bilirubin

Author: Schopen111 Year: 1970 Country: Germany Language: German

Study type: RCT/blinding unclear Intervention/dose/duration: 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 Outcome measuresa: AST, ALT, alk phos, bilirubin, albumin, PT Followup interval: 45 days Assessment time points 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 Exclude: Not given Acuity/severity: No other information






noted) Author: Szilard112 Year: 1988 Country: Hungary Language: English

Study type: Cohort/not blind Intervention/dose/duration: Silymarin (Legalon®) 420 mg daily/30 days Control: No treatment Outcome measuresa: AST, ALT, GGTP Followup interval: 30 days Assessment time points with results reported: 28 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 information Baseline group similarity: Demos, LFTs, appear similar except higher GGTP in treatment group

N: 49 (Legalon® = 30; no treatment = 19) Mean age: Not given Percent male: 100Setting: Workplace

Significant: AST, ALT Not significant: GGTP

Author: Tkacz113 Year: 1983 Country: Poland Language: Polish

Study type: RCT unclear/blinding unclear Intervention/dose/duration: Silimarol® (and vitamins B and C)/6 pills daily/21 days Control: Vitamins B and C and cocarboxylase Outcome measuresa: ALT, alk phos, bilirubin, PT Followup interval: 21 days Assessment time points with results reported: 21 days

Type: Viral hepatitis Include: Abnormal LFTs Exclude: Not given Acuity/severity: No other information


Significant: Not significant: ALT, PT, bilirubin, length of stay




noted) Author: Vailati85 Year: 1993 Country: Italy Language: English

Study type: RCT/not blind/phase 2 study Intervention/dose/duration: Silymarin (Silipide®)/160 mg silybin equivalents daily/14 days Silymarin (Silipide®)/240 mg silybin equivalents daily/14days Silymarin (Silipide®)/360 mg silybin equivalents daily/14 days Control: No treatment Outcome measuresa: AST, GGTP, bilirubin Followup interval: 7, 14 days Assessment time points 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 Acuity/severity: Chronic, no other information

N: 60 Mean age: 50 Percent male: 62 Setting: Outpatient clinic

Significant: AST, GGTP, bilirubin for 240 or 360 mg versus 160 mg Not significant:




noted) Author: Velussi114,115 Year: 1993, 1997 Country: Italy Language: English

Study type: RCT/not blind Intervention/dose/duration: Silymarin (Legalon®)/600 mg daily/365 days Control: No treatment Outcome measuresa: MDA, AST, ALT GGTP, alk phos, bilirubin Followup interval: 90, 180, 270, 365 days Assessment time points with results reported: 90, 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/m2; 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 Exclude: Not given Acuity/severity: Chronic, no other information

N: 60 Mean age: Not given Percent male: Not given Setting: Specialty clinic

Significant: MDA Not significant: GGTP, bilirubin, alk phos

aResults 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. Milk thistle for prophylaxis against liver disease: Ineligible (normal liver function at study entry) but provocative studies

Author Design Liver DiseasePatient

Characteristics


Author: Allain83 Year: 1999 Country: France Language: English

Study type: RCT/blind/prophylaxis Intervention/dose/duration: Silymarin/420 mg daily/84 days Control: Placebo Outcome measuresa: AST, ALT Followup interval: 8 times over 15 weeks Assessment time points with results reported: 8 times over 15 weeks

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, increased bilirubin, AST, and/or ALT) Acuity/severity: No disease at baseline

N: 222 Mean age: Approximately 74 Percent male: 39 Setting: Specialty clinic

Significant: Not significant: AST, ALT

Author: Magula82 Year: 1996 Country: Language: Slovak

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: AST, ALT, bilirubin, “liver injury,” interruption of tuberculosis medications Followup interval: Every 2 weeks for 8 weeks Assessment time points with results reported: 8 weeks (56 days)

Type: Drug-induced liver disease Include: Patients requiring tuberculosis treatment; normal LFTs at baseline Exclude: Not given Acuity/severity: No disease at baseline

N: 172 (92 tuberculosis medications alone; 29 tuberculosis medications plus silymarin) Mean age: 50 Percent male: 60 Setting: Unclear


aResults not necessarily reported for all. ALT = alanine aminotransferase; AST = aspartase aminotransferase; LFT = liver function test; RCT = randomized controlled trial.

Evidence Table 5. Milk thistle for treatment of liver disease: Adverse effects Milk Thistle Exposure Questions

Author, Year Adverse Effect Study N

Study Design Type

d af

ter

isco

n

ossi

ble?

Amount Impr

ove

dtin

ued?

Rec

halle

nged

?

Alte

rnat

ive

caus

es

p Dos

e-re

spon

se?

Bunout, 199266

Control: Pruritus Headache Treatment: Pruritus Headache

11/34 4/34

4/25 3/24

RCT

Placebo

Silymarin (Legalon®)

280 mg/d

Yes, in one patient

Not

discontinued

No

No

Not given

Not given

Not given

Not given

Ferenci, 198975

Control: Nausea, epigastric discomfort Treatment: Nausea, epigastric discomfort

2/83

2/87

RCT Placebo


420 mg/d

Yes

Yes

No

No

Not given

Not given

Not given

Not given

Total n: 11/200

Pares, 199868

Control: 4 Urticaria, pruritus, arthralgia, headache Treatment: 7 Urticaria, pruritus, arthralgia, headache

RCT Placebo


450 mg/d

Yes, 2 patients

in treatment and 1 patient

in control

No Not given Not given

Vailati, 199385

Treatment: Nausea, heartburn Dyspepsia Postprandial nausea, meteorism

3/20 1/20 2/20

RCT

Silipide®

Silipide®

160 mg/d 240 mg/d 360mg/d

Yes

Yes

No

No

Not given

Not given

Not given Not given Not given

Evidence Table 5. Milk thistle for treatment of liver disease: Adverse effects (continued)

Milk Thistle Exposure Questions


Study Design Type Amount Im

prov

ed a

fter

disc

ontin

ued?

Rec

halle

nged

?

Alte

rnat

ive

caus

es

poss

ible

?

Dos

e-re

spon

se?

Control: Not given Not givenAndrade, 199887

Treatment: Impotence

0/31

1/29

RCT

Silymarin

450 mg/d

Not given Not given

Marcelli, 199277

Control: Nausea, dyspepsia, heartburn, skin rash Treatment: Nausea, heartburn, transient headache

5/34

3/31

RCT Placebo

Silipide®

240 mg/d

Not discontinued


Allain, 199983

Control: Frequency ADE occurredb: 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 occurredb: 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%)

112

110

RCT Placebo andTacrine

Silymarin and Tacrine

420 mg/d

Not given

Not given

Not given

Not given

Not given

Not given

Not given

Not given





prov

ed a

fter

disc

ontin

ued?

Rec

halle

nged

?

Alte

rnat

ive

caus

es

poss

ible

?

Dos

e-re

spon

se?

Studlar, 198590

Temporary uneasiness of stomach

2/34 Prospectivecohort

Silibene® (a silymarin-containing

drug)

280 mg/d Not discontinued


Albrecht,a 199288

Treatment: (in 0.8% of patients): Mild diarrhea Nausea Upset stomach Itching Exanthem Headache Decreased energy and discomfort NOS

4/2,637 3/2,637 2/2,637 2/2,637 1/2,637 1/2,637 7/2,637

Prospective cohort


70 mg

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

Not given Not given Not given Not given

Marena, 199193

Gastrointestinal: Mostly upset stomach Control: Silipide®

6/117

12/232

Cohortc Placebo

Commercial extract

Silipide®

280 to 420 mg/d


Grungreiff, 199589

Frequency ADE occurredb: Changes in BM 4 Diarrhea 4

(12 patients

reported 1 adverse

effect and 4 patients reported 2 adverse effects)

Dizziness/circulatory problems 4Nausea/vomiting 2 Itching 2 Eczemas 2Indisposition 1Flatulence 1

16/975 Cohortc Silymarin 280 to 420 mg/d Not given Not given Not given Not given





prov

ed a

fter

disc

ontin

ued?

Rec

halle

nged

?

Alte

rnat

ive

caus

es

poss

ible

?

Dos

e-re

spon

se?

Frerick,a199091

Frequency ADE occurredb: Mild diarrhea 4 Nausea 3 Gastric intolerance 2 Itching 2 Eczema 1 Diffuse headaches 1 Decreased energy/ restlessness 1 No specifics 7

2,169 Cohortc Silymarin 1,210 patientsreceived 210 mg/d 583 patients received 420 mg/d 376 patients received 70 to 630 mg/d


Schuppan, 199892

12 ADEs occurred, but not specifically noted; examples were diarrhea, flatulence, abdominal fullness or pain, nausea, vomiting, and dizziness

20/998 Cohortc Silymarin 280 to 420 mg/d Not given Not given Not given Not given

Anonymous, 197298

Sweating, nausea, colicky abdominal pain, fluid diarrhea, weakness, and collapse

1 Case report MicrogenicsHerbals

M.T. Vegicaps®

1 capsule Yes Yes Yes, due to

multiherbal capsule

Not given

Geier, 199094

Anaphylactic shock: facial edema, oral mucosa swelling, marked respiratory distress, bronchospasm, and decrease blood pressure

1 Case report Silybum marianum

tea

Not given Not given Not given Not given Not given

Mironets, 199095

Urticaria, fever, laryngeal edema

1 Case report Carsil® 3 pills per day, no dosage given

Yes, and Tx Prednisone

No Not given Not given

Wollemann, 198797

Rhinoconjunctivitis 1 Case report Silybum marianum

Contact with seeds

Not given Yes Not given Not given





prov

ed a

fter

disc

ontin

ued?

Rec

halle

nged

?

Alte

rnat

ive

caus

es

poss

ible

?

Dos

e-re

spon

se?

DeSmet, 199696

Jaundice, increase LFTs 1 Case report Multiherbal tablets with unknown amount of milk thistle

6 to 15 tablets per day

Yes Yes Yes, dueto

multiherbal tablet

Not given

a The study by Albrecht is an extension of the study by Frerick and includes the same patients.19

bUnit of reporting was ADE, not patient. cUnclear 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.

Bibliography

Adverse Drug Reactions Advisory Committee. An adverse reaction to the herbal medication milk thistle (Silybum marianum). Med J Aust 1999;170:218-9. Aguilar Raminez JR, Chorne Navia R, Reyes Dorantes A, et al. [Therapeutic effect of silimarine on acute hepatic diseases of viral and alcoholic etiology]. [Spa]. Invest Med Int 1987;14:144-54. Albrecht M, Frerick H, Kuhn U, et al. [Therapy of toxic liver disease with Legalon(R)]. [Ger]. Z Klin Med 1992;47:87-92. Allain H, Shuck S, Lebreton S, et al. Aminotransferase levels and silymarin in de novo tacrine-treated patients with alzheimer's disease. Dement Geriatr Cogn Disord 1999;10:181-5. Alvisi V, Bagni B, D’Ambrosi A, et al. Modification of radionuclide liver function tests indicating therapeutic efficacy of silymarin in 41 patients with various forms of liver disease. Minerva Med 1974;65:3175-89. American Association of Poison Control Centers Toxic Exposure Surveillance System (TESS). Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System (TESS), 1984-1999. Am J Emerg Med 1984–1999 (Sept Issues). Andrade RJ, Lucena MI, De la Cruz JP, et al. Effects of silymarin on the oxidative stress in patients with alcoholic liver cirrhosis: Results from a controlled, double blind, randomized pilot clinical trial [AASLD abstract]. Hepatology 1998;28:629A. Barton P, Krejci V, Blazek M. [Possibility to influence the hepatotoxicity of some chemotherapeutic drugs by silymarine]. [Cze]. Cas Lek Cesk 1985;124:173-5. Barzaghi N, Crema F, Gatti G, et al. Pharmacokinetic studies on IdB 1016, a silybin-phosphatidylcholine complex, in healthy human subjects. Eur J Drug Metab Pharmacokinet 1990;15:333-8. Benda L, Dittrich H, Ferenzi P, et al. [The influence of therapy with silymarin on the survival rate of patients with liver cirrhosis (author’s transl)]. [Ger]. Wien Klin Wochenschr 1980;92:678-83. Benda L, Zenz W. [Silymarin in liver cirrhosis]. [Ger]. Wien Med Wochenschr 1973;123:512-6.

Bergel M. Use of hepatoprotective drugs in leprosy treatment. Nippon Rai Gakkai Zasshi 1983;52:62-3. Bergner P. Botanical medicine: Silybum marianum and liver therapy. Townsend Lett Doctors 1988;61-62:348-9. Berkey CS, Hoaglin DC, Mosteller F, et al. A random-effects regression model for meta-analysis. Stat Med 1995;14:395-411. Berlin JA. Does blinding of readers affect the results of meta-analyses? University of Pennsylvania Meta-analysis Blinding Study Group. Lancet 1997;350:185-6. Bindoli A, Cavallini L, Siliprandi N. Inhibitory action of silymarin of lipid peroxide formation in rat liver mitochondria and microsomes. Biochem Pharmacol 1977;26:2405-9. Blumenthal M, editor. Complete German Commission E monographs: Therapeutic guide to herbal medicines. Boston (MA): American Botanical Council, Integrative Medicine Communications; 1998. Blumenthal M (National Advisory Panel Member). Conference telephone call with the San Antonio Evidence-based Practice Center, Oct 19, 1999. Blumenthal M (National Advisory Panel Member). Personal communication from Mark Blumenthal, Dec 1999. Blumenthal M (National Advisory Panel Member). Personal communication from Mark Blumenthal, Dec 1999.

Blumenthal M (National Advisory Panel Member). Personal communication from Mark Blumenthal, Dec 1999 who cited: (A) personal communication from Madaus through E. Leng-Peschlow and Strenge-Hesse A, Nov 1999; (B) Schulz HU, et al. Untersuchungen zum Freisetzungsverhalten und zur Bioäquivalenenz von Silymarin-Präparaten. Arzneimittelforshung 1995;45:61-4; (C) Frömming KH, et al. Silymarinhaltige Phytopharmaka: Biopharmazie als wesentliches therapeutisches Qualitätskriterium. Zeitschrift für Ärztliche Fortbildung und Qualitätssicherung 1999;4:vi-xi.

99

Blumenthal M (National Advisory Panel Member). Personal communication from Mark Blumenthal, Dec 1999 who cited: (A) personal communication from Madaus through E. Leng-Peschlow and A. Strenge-Hesse, Nov 1999; (B) Schuppan D, et al. Antibrotic effect of silymarin in rat secondary bilary fibrosis induced by bile duct obliteration with ethibloc [abstract]. Gastroenterol 1994;32:45-6; (C) Jia JD, et al. Silymarin decreases type I procollogen mRNA levels in rats with secondary biliary cirrhosis [abstract]. Gastroenterology;114;A1265; (D) Boigk G, et al. Silymarin retards collagen accumulation in early and advanced biliary fibrosis secondary to complete bile duct obliteration in rats. Hepatology 1997;26:643-9. Blumenthal M (National Advisory Panel Member). Personal communication from Mark Blumenthal, December 1999 who cited: personal communication from Madaus through E. Leng-Peschlow and A. Strenge-Hesse, Nov 1999. Boari C, Baldi E, Dalla Pozza G, et al. [Evaluation of some parameters of liver functionality and lipids metabolism in workers exposed to organophosphate insecticides before and after administration of silymarin]. [Ita]. Epatologia 1977;23:227-36. Boari C, Montanari FM, Galletti GP, et al. [Toxic occupational liver diseases. Therapeutic effects of silymarin]. [Ita]. Minerva Med 1981;72: 2679-88. Bode JC, Schmidt U, Durr HK. [Silymarin for the treatment of acute viral hepatitis? Report of a controlled trial (author’s transl)]. [Ger]. Med Klin 1977;72:513-8. Bode JC, Vido I, Schmidt FW. [Therapy of chronic hepatitis (author’s transl)]. [Ger]. Leber Magen Darm 1977;7:310-6. Bode JC. Re: Flora et al. Silymarin for the therapy of liver disease. Am J Gastroenterol 1999;94:545-6. Bonkovsky HL. Therapy of hepatitis C: Other options. Hepatology 1997;26:143S-151S. Brailski KH, Chernev K, Eturska M, et al. [Effect of carsil and legalon in treating chronic liver diseases]. [Bul]. Vutr Boles 1986;25:43-9. Brodanová M, Filip J. Zur Behandlung der chronischen Lebererkrankungen mit Legalon®. Prakt Arzt 1976;30:354-67.

Brown D. Silymarin education monograph. Herbal Res Update 1993;Summer:23-36. Bulfoni A, Gobbato F. [Evaluation of the therapeutic activity of sylimarine in alcoholic hepatology]. [Ita]. Gazz Med Ital 1979;138:597-608. Bunout D, Hirsch S, Petermann M, et al. [Controlled study of the effect of silymarin on alcoholic liver disease]. [Spa]. Rev Med Chil 1992;120:1370-5. Buzzelli G, Moscarella S, Giusti A, et al. A pilot study on the liver protective effect of silybinphosphatidylcholine complex (IdB1016) in chronic active hepatitis. Int J Clin Pharmacol 1993;31:456-60. Caldwell SH, Feeley JW, Wieboldt TF, et al. Acute hepatitis with use of over-the-counter herbal remedies. Va Med Q 1994;121:31-3. Campos R, Garrido A, Guerra R, et al. Silybin dihemisuccinate protects against glutathione depletion and lipid peroxidation induced by acetaminophen on rat liver. Planta Med 1989;55:417-9. Canini F, Bartolucci L, Cristallini E, et al. [Use of silymarin in the treatment of alcoholic hepatic steatosis]. [Ita]. Clin Ter 1985;114:307-14. Carrescia O, Benelli L, Saraceni F, et al. Silymarin in the prevention of hepatic injury due to psychotropic agents. Experimental foundations and clinical evaluation. Clin Ter 1980;95:157-64. Carty HC. Herbal preparations under scientific scrutiny. Can Med Assoc J 1996;155:1236. Cavalieri S. [Controlled clinical trial of silymarin in 40 patients]. [Ita]. Gazz Med Ital 1974;133:628-35. Chalmers TC. Randomized controlled clinical trials in diseases of the liver. Prog Liver Dis 1976;5:450-6. Chalmers TC, Eckhardt RD, Reynolds WE, et al. The treatment of acute infectious hepatitis: Controlled studies of the effects of diet, rest, and physical reconditioning on the acute course of the disease and on the incidence of relapses and residual abnormalities. J Clin Invest 1955;34:1163-235. Chevrel B. Legalon in the treatment of alcoholic or non-alcoholic chronic liver diseases. Med Chir Dig 1994;23:475-81.

100

De Maio D, Levi Minzi A. [Clinical study of the use of silymarin in liver damage of heroin addicts]. [Ita]. Epatologia 1979;25:357-63.*** De Martiis M, Barlattani A, Parenzi A, et al. [Relationship between changes of lipid metabolism and macrocytic anemia in the course of chronic liver disease. Evaluation of treatment with a membranotropic agent]. [Ita]. Clin Ter 1984;111:135-9. De Martiis M, Fontana M, Assogna G, et al. [Milk thistle (Silybum marianum) derivatives in the therapy of chronic hepatopathies]. [Ita]. Clin Ter 1980;94:283-315. De Martiis M, Fontana M, Sebastiani F, et al. [Silymarin, a membranotropic drug: Clinical and experimental observations]. [Ita]. Clin Ter 1977;81:333-62. De Smet PA, Van den Eertwegh AJ, Lesterhuis W, et al. Hepatotoxicity associated with herbal tablets. BMJ 1996;313:92. De Smet PA. An introduction to herbal pharmacoepidemiology. J Ethnopharmacol 1993;38:197-208. Deak G, Muzes G, Lang I, et al. [Immunomodulator effect of silymarin therapy in chronic alcoholic liver diseases].[Hun]. Orv Hetil 1990;131:1291-2,1295-6. Dehmlow C, Murawski N, de Groot H. Scavenging of reactive oxygen species and inhibition of arachidonic acid metabolism by silibinin in human cells. Life Sci 1996;58:1591-600. Del Dotto M, Neri D. [Alcoholic hepatopathy. Aspects of drug therapy]. [Ita]. G Clin Med 1982;63:228-36. Dennehy C. Personal communication from Cathi Dennehy, Dec 1999. Drenska A, Tomov E, Ognyanova VNI. Carsil Pharmachim. Comparative bioavailability of different formulations in humans. Med Biol Inform 1987;4:14-6. Dubick MA. Dietary supplements and health aids: A critical evaluation. Part 3: Natural and miscellaneous products. J Nutr Educ 1983;15:123-29. Egger G. [Liver-protective substances, dietary treatment and cures in the treatment of hepatic diseases (author’s transl)]. [Ger]. Ther Umsch 1978;35:761-5.

Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629-34. Ely H. Dermatologic therapies you've probably never heard of. Dermatol Clin 1989;7:19-35. Fassati P, Fassati M. [Silymarin and various problems of current therapy of chronic liver diseases]. [Cze]. Cas Lek Cesk 1973;112:865-9. Faulstich H, Jahn W, Wieland T. Silybin inhibition of amatoxin uptake in the perfused rat liver. Arzneimittelforschung 1980;30:452-4. Feher J, Deak G, Muzes G, et al. [Liver-protective action of silymarin therapy in chronic alcoholic liver diseases]. [Hun]. Orv Hetil 1989;130:2723-7. Feher J, Lang I. Wirkmechanismen der sogenannnten Leberschutzmittel. Bayerische Internist 1988;4:35-9. Feher J, Lang I, Nekam K, et al. In vivo effect of free radical scavenger hepatoprotective agents on superoxide dismutase (SOD) activity in patients. Tokai J Exp Clin Med 1990;15-2-3:129-34. Feher J, Lengyel G, Blazovics A. Oxidative stress in the liver and biliary tract diseases. Scand J Gastroenterol Suppl 1998;228:38-46. Ferenci P, Dragosics B, Csomos G, et al. Treatment with silymarin in patients with cirrhosis of the liver: results of a controlled prospective study and of the post study surveillance [IASL abstract]. J Hepatol 1986;790. Ferenci P, Dragosics B, Dittrich H, et al. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol 1989;9:105-13. Ferenci. P, Dragosics B, Frank H, et al. Controlled prospective study on the effects of silymarin treatment on patients with cirrhosis of the liver. [EASL abstract]. J Hepatol 1985;S229. Ferenci P, Frank H, Benda L, et al. Treatment with silymarin decreases mortality in patients with cirrhosis of the liver [AASLD abstract]. J Hepatol 1984;4:1093. Fintelmann V. [Postoperative behavior of serum cholinesterase and other liver enzymes]. [Ger]. Med Klin 1973;68:809-15. Fintelmann V. [Toxic/metabolic liver damage and its treatment]. [Ger]. Z Phytother 1986;7:65-73.

101

Fintelmann V. Zur Therapie der Fettleber mit Silymarin. Therapiewoche 1970;20:23. Fintelmann V, Albert A. [Double blind trial of silymarin sodium in toxic liver damage]. [Ger]. Therapiewoche 1980;30:5589-94. Flisiak R, Prokopowicz D. Effect of misoprostol on the course of viral hepatitis B. Hepatogastroenterology 1997;44:1419-25. Floersheim GL, Weber O, Tschumi P, et al. [Clinical death-cap (Amanita phalloides) poisoning: Prognostic factors and therapeutic measures. Analysis of 205 cases]. [Ger]. Schweiz Med Wochenschr 1982;112:1164-77. Flora K, Hahn M, Rosen H, et al. Milk thistle (Silybum marianum) for the therapy of liver disease. Am J Gastroenterol 1998;93:139-43. Flora KD, Rosen HR, Benner KG. The use of naturopathic remedies for chronic liver disease. Am J Gastroenterol 1996;91:2654-5. Folk medicine traditions. [Web site]. Available at: http//:nccam.nih.gov/nccam/what-is-cam/fields/ herbals.html [accessed June 28, 1999]. Foster S. Milk thistle: Silybum marianum. Austin (TX): American Botanical Council; 1990. Frerick F, Kuhn U, Strenge-Hesse A. Silymarin—ein Phytopharmakon zur Behandlung toxischen Leberschäden: Anwendungsbeobachtung bei 2169 Patienten. Kassenarzt 1990;33:36-41. Gabetta B, Zini GF, Pifferi G. Spectroscopic studies on IdB 1016, a new flavanolignan complex [abstract]. Planta Med 1989;55:615. Galeone F, Scalabrino A, Morini S, et al. A clinical study of the effect of silymarin treatment in patients with alcoholic liver disease. Epatologia 1982;28:215-9. Gatti G, Perucca E. Plasma concentrations of free and conjugated silybin after oral intake of a silybin-phosphatidylcholine complex (silipide) in healthy volunteers. Int J Clin Pharmacol Ther 1994;32:614-7. Geier J, Fuchs TH, Wahl R. [Anaphylactic shock due to an extract of Silybum marianum in a patient with immediate-type allergy to Kiwi fruit]. [Ger]. Allergologie 1990;13:387-8.

Geller LI, Gladkikh LN, Gryaznova MV. Therapy of diabetics with fatty hepatosis. Probl Endokrinol (Mosk) 1993;39:20-2. Gluud C. “Negative trials” are positive! J Hepatol 1998;28:731-3. Gocan S, Cimpan G, Muresan L. Automated multiple development thin layer chromatography of some plant extracts. J Pharm Biomed Anal 1996;14:1221-7. Gottlieb S. US agency to test safety of four herbs [newsletter]. BMJ 1999;319:336. Griemel A, Koch H. [Peroxidase isoenzymes in silybum marianum (author’s transl)]. [Ger]. Planta Med 1977;32:323-30. Grieve M. A modern herbal: The medicinal, culinary, cosmetic and economic properties, cultivation, and folklore of herbs, grasses, fungi, shrubs, and trees with all their modern scientific uses. Darien (CT): Hafner Publishing Company; 1931. Grossi F, Viola F. [Membrane protectors and silymarin in hepatology therapy]. [Ita]. Clin Ter 1981;96:11-23. Grungreiff K, Albrecht M, Strenge-Hesse A. [Benefit of medicinal liver therapy in general practice]. [Ger]. Med Welt 1995;46:222-7. Guemes Diaz F, Perez Munoz C, Sallent Herranz J, et al. Experimental clinical study with 3 methyltaxifolin (Silimarin) in the treatment of diffuse liver diseases. Rev Clin Esp 1974;132:263-8. Gyorgy I, Blazovics A, Feher J, et al. Reactions of inorganic free radicals with liver protecting drugs. Radiat Phys Chem 1990;36:165-7. Hahn G. Wirkstoff aus der Mariendistel wirkt antihepatoxisch. Nat Med 1989; 4:482-9. Halama P. Chronic hepatopathies due to anticonvulsant agents. Therapiewoche 1984;34:2267-74. Halbach G, Trost W. [Chemistry and pharmacology of silymarin. Studies on various metabolites of silybin]. [Ger]. Arzneimittelforschung 1974;24:866-7. Halliwell B, Gutteridge JM. The antioxidants of human extracellular fluids [Review]. [129 refs]. Arch Biochem Biophys 1990;280:1-8.

102

Hamalcik M. Das Homoopathikum. Carduus marianus (Ger). Biol Medizin 1987;16:419-23. Hamburg P. [Silymarin in liver disease]. [Ger]. Therapiewoche Österreich 1991;6:9. Hamid S, Rojter S, Vierling J. Protracted cholestatic hepatitis after the use of prostata. Ann Intern Med 1997;127:169-70. Hammerl H, Pichler O, Studlar M. [Silymarin action in liver diseases]. [Ger]. Med Klin 1971;66:1204-8. Hammouda FM, Ismail SI, Hassan NM, et al. Evaluation of the silymarin content in Silybum marianum cultivated under different agricultural conditions. Planta Med 1991;57:A29. Hammouda F, Ismail S, Hassan N, et al. Evaluation of the silymarin content in Silybum marianum (L.) Gaertn. cultivated under different agricultural conditions. Phytother Res 1993;7:90-1. Hantak I, Mikulecky M, Kratochvilova H. [Changes in the biochemical picture of chronic active hepatitis in the course of interrupted treatment with Legalon (author’s transl)]. [Slo]. Bratisl Lek Listy 1980;74:555-68. Hedges LV, Olkin I. Statistical methods for meta-analysis. Orlando (FL): Academic Press; 1985. Held C. [Therapy of toxic hepatopathies: Mary’s thistle extract lowers the fibrosis activity]. [Ger]. Therapiewoche 1993;43:2002-9. Herbal remedies. Milk thistle: Protection for the liver. [Web site]. Available at: http//: www.healthyideas.com/healing/herb/ 980407.herb.html. [accessed June 25, 1999]. Hernandez R, Nazar E. [Effect of silymarin in intrahepatic cholestasis of pregnancy (preliminary communication)]. [Spa]. Rev Chil Obstet Ginecol 1982;47:22-9. Hikino H, Kiso Y, Wagner H, et al. Antihepatotoxic actions of flavonolignans from Silybum marianum fruits. Planta Med 1984;50:248-50. Hobbs C. Milk thistle: The liver herb. Loveland (CO): Interweave Press; 1994. Holzgartner H. La aplicación de legalón en la consulta de medicina interna. Therapiewoche 1970;20:1868-9.

Hruby K, Fuhrmann M, Csomos G, et al. [Pharmacotherapy of Amanita phalloides poisoning using silybin]. [Ger]. Wien Klin Wochenschr 1983;95:225-31. IdB-1016. Silybin phosphatidylcholine complex. Drugs Future 1992;17:248. IdB-1016, silybin phosphatidylcholine complex. Silipide. Drugs Future 1993;18:272. IdB-1016. Silybin phosphatidylcholine complex. Silipide. Drugs Future 1994;19:294-5. IdB-1016. Silybin phosphatidylcholine complex. Silipide. Drugs Future 1995;20:307. Immich H. [Results of two double-blind studies on the effect of silymarin in chronic hepatitis]. [Ger]. Internist Prax 1978;18:713-7. Kassler W, Blanc P, Greenblatt R. The use of medicinal herbs by human immunodeficiency virus-infected patients. Arch Intern Med 1991;151:2281-8. Kiesewetter E, Leodolter I, Thaler H. [Results of two double-blind studies on the effect of silymarine in chronic hepatitis (author’s transl)]. [Ger]. Leber Magen Darm 1977;7:318-23. Kordac V, Kalab M. [Uses of silymarin in the treatment of symptomatic hepatic porphyria (author’s transl)]. [Cze]. Cas Lek Cesk 1977;116:407-10. Koretz RL. Chronic hepatitis: More words from the literature and sponsor. Curr Hepatol 1997;17:51-96. Krustev Z, Ognianov M, Lukanov L, et al. [Comparative clinical trial of karsil and legalon in patients with chronic liver lesions. III. Comparison of the effect of karsil and legalon on a 3-point system. Bulgarian]. [Bul]. Vutr Boles 1984;23:37-9. Krylov AA. [Legalon in the complex treatment of patients with hepatic stasis in chronic circulatory insufficiency]. [Rus]. Vrach Delo 1984;22-3. Kupcova V, Turecky L, Holoman J, et al. [Therapeutic effect of silymarin in patients with liver cirrhosis]. [Slo]. Cas Lek Cesk 1987;126:1406-9. Kupcova V, Turecky L, Synek R, et al. [Serum proteins in patients with chronic liver disease and Flavobion treatment]. [Slo]. Cesk Gastroenterol Vyz 1989;43:3-12.

103

Lang I, Deak G, Nekam K, et al. Hepatoprotective and immunomodulatory effects of antioxidant therapy. Acta Med Hung 1988;45:287-95. Lang I, Nekam K, Deak G, et al. Immunomodulatory and hepatoprotective effects of in vivo treatment with free radical scavengers. Ital J Gastroenterol 1990;22:283-7. Lang I, Nekam K, Gonzalez-Cabello R, et al. Hepatoprotective and immunological effects of antioxidant drugs. Tokai J Exp Clin Med 1990;15:123-7. Langhammer L. [Anatomy and histochemistry of the fruits of Silybum]. [Ger]. Planta Med 1969;17:268-75. Larrey D. Hepatotoxicity of herbal remedies. J Hepatol 1997;26:47-51. Leng-Peschlow E, Strenge-Hesse A. [The milk thistle (Silybum marianum) and silymarin in liver therapy]. [Ger]. Z Phytother 1991;12:162-74. Lin TM, Chang HJ, Chen CJ, et al. Risk factors for nasopharyngeal carcinoma. Anticancer Res 1986;6:791-6. Lirussi F, Nassuato G, Orlando R, et al. Treatment of active cirrhosis with ursodeoxycholic acid and a free radical scavenger: A two year prospective study. Med Sci Res 1995;23:31-3. Lirussi F, Okolicsanyi L. Cytoprotection in the nineties: Experience with ursodeoxycholic acid and silymarin in chronic liver disease. Acta Physiol Hung 1992;80:363-7. Lirussi F, Orlando R, Iemmolo RM, et al. Effect of UDCA and silymarin on liver function in patients with chronic active hepatitis with cirrhosis: A prospective study [abstract]. J Hepatol 1990;12:957. Lirussi F, Temmolo R, Passera D, et al. Silymarin (SILY) vs ursodeoxycholic acid (UDCA) in active cirrhosis: A controlled cross over study [abstract]. J Hepatol 1990;11:S98. Luper S. A review of plants used in the treatment of liver disease: Part 1. Altern Med Rev 1998;3:410-21. MacGregor FB, Abernethy VE, Dahabra S, et al. Hepatotoxicity of herbal remedies. BMJ 989;299:1156-7.

Magliulo E, Carosi PG, Minoli L, et al. Studies on the regenerative capacity of the liver in rats subjected to partial hepatectomy and treated with silymarin. Arzneimittelforschung 1973;23:161-7. Magliulo E, Gagliardi B, Fiori GP. [Results of a double blind study on the effect of silymarin in the treatment of acute viral hepatitis, carried out at two medical centres (author’s transl)]. [Ger]. Med Klin 1978;73:1060-5. Magula D, Galisova Z, Iliev N, et al. Beneficial effect of silymarine and fumaria alcaloids in the prophylaxis of antituberculotics: Induced liver adverse events [abstract]. Eur Resp J 1997;10:214s. Magula D, Galisova Z, Iliev N, et al. [Effect of silymarine and Fumaria alkaloids in the prophylaxis of drug-induced liver injury during antituberculotic treatment]. [Slo]. Studia Pneumol Phtiseol 1996;56:06-9. Maneschi M, Tiberio C, Cittadini E. [Metabolic impairment of the hepatocyte in pregnancy: Prevention and therapy with a membrane-stabilizing drug]. [Ita]. Clin Ter 1981;97:625-30. Marcelli R, Bizzoni P, Conte D, et al. Randomized controlled study of the efficacy and tolerability of a short course of IdB 1016 in the treatment of chronic persistent hepatitis. Eur Bull Drug Res 1992;1:131-5. Marena C, Lampertico M. Preliminary clinical development of silipide: A new complex of silybin in toxic liver disorders [abstract]. Planta Med 1991;57:124-5. Margaroli P, Rossi M, Arcabasso G, et al. [Evaluation of the therapeutic effects of silymarin]. [Ita]. Clin Ter 1980;95:663-72. Mariendistel, Silybum marianum. Gesund Leben 1996;73:79. Martines G, Mingrino GC, Cagnetta G, et al. [Treatment of liver disorders in outpatient practice. A multicenter study]. [Ita]. Clin Ter 1980;92:33-58. Martines G, Piva M, Copponi V, et al. [Liver. Drugs. Silimarin in pregnancy and during hormonal contraceptive management. Blood chemistry and ultrastructural findings on the experimental model]. [Ita]. Arch Sci Med (Torino) 1979;136:443-54. Marwick C. Learning how phytochemicals help fight disease. JAMA 1995;274:1328-30.

104

Mascher H, Kikuta C, Weyhenmeyer R. Diastereomeric separation of free and conjugated silibinin in plasma by reversed phase HPLC after specific extraction. J Liquid Chromatogr 1993;16:2777-89. Miller AL. Antioxidant flavonoids: Structure, function and clinical usage. Altern Med Rev 1996;1:103-11. Milosavljevic Z. [Therapy of liver diseases using Silymarin (Legalon)]. [Ger]. Ther Ggw 1973;112:968 passim. Mingrino F, Tosti U, Anania S, et al. [Clinical study of the therapeutic action of silymarin in acute infectious hepatitis in childhood.]. [Ita]. Minerva Pediatr 1979;31:451-6. Mira ML, Azevedo MS, Manso C. The neutralization of hydroxyl radical by silibin, sorbinil and bendazac. Free Radic Res Commun 1987;4:125-9. Mironets VI, Krasovskaia EA, Polishchuk II. [A case of urticaria during carsil treatment]. [Rus]. Vrach Delo 1990;7:86-7. Morazzoni P, Bombardelli E. Silybum marianum (Carduus marianus). Fitoterapia 1995;66:3-42. Morris VC, Levander OA. Selenium content of foods. J Nutr 1970;100:1383-8. Muscher CH. [Silymarin in chronic liver diseases]. [Ger]. Ther Ggw 1972;111:1768-70. Musso A, Giacchino M, Vietti M, et al. [The use of silymarin and SAMe in the treatment of acute infective hepatitis in childhood]. [Ita]. Minerva Pediatr 1980; 32:1057-67. Muting D, Hammes PH, Ecknauer R. Das Verhalten von Serumenzymen und Metaboliten bei 140 chronisch Leberkranken unter einer standardisierten Gehbelastung. Munch Med Wochenschr 1974;116:1873-80. Muzes G, Deak G, Lang I, et al. Effect of the bioflavonoid silymarin on the in vitro activity and expression of superoxide dismutase (SOD) enzyme. Acta Physiol Hung 1991;78:3-9.

Muzes G, Deak G, Lang I, et al. [Effect of silimarin (Legalon) therapy on the antioxidant defense mechanism and lipid peroxidation in alcoholic liver disease (double blind protocol)]. [Hun]. Orv Hetil 1990;131:863-6. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45. Nassuato G, Iemmolo R, Strazzabosco M, et al. Effect of Silibinin on biliary lipid composition. Experimental and clinical study. J Hepatol 1991;12:290-5. Nefzger M, Chalmers TC. The treatment of acute infectious hepatitis: Ten-year follow-up study of the effects of diet and rest. Am J Med 1963;35:299-309. Orlando R, Fragasso A, Lampertico M, et al. Silybin kinetics in patients with liver cirrhosis: A comparative study of silybin-phosphatidilcholine complex and silymarin. Med Sci Res 1990;18:861-3. Palasciano G, Portincasa P, Palmier V, et al. The effect of silymarin on plasma levels of malon-dialdehyde in patients receiving long-term treatment with psychotropic drugs. Curr Ther Res Clin Exp 1994;55:537-45. Pares A, Planas R, Torres M, et al. Effects of silymarin in alcoholic patients with cirrhosis of the liver: Results of a controlled, double-blind, randomized and multicenter trial. J Hepatol 1998;28:615-21. Parmar VS, Gupta AK, Jha HN, et al. Metal content of the medicinal plants Agave americana, Sambucus nigra and Silybum marianum. Int J Pharmacognosy 1993;31:324-6. Patera L. [Silymarin in the treatment of acute viral hepatitis]. [Cze]. Cesk Gastroenterol Vyz 1978;32:533-4. Pepping J. Milk thistle: Silybum marianum. Am J Health Syst Pharm 1999;56:1195-7. Perhaps not everyone knows that... Ann Oncol 1997;8:721-2. Petronelli A, Roda E, Briganti M, et al. Effect of the administration of silymarin on serum lipid levels. Clin Ter 1981;99:471-82. Pifferi G. A new bioavailable complex of Silybin: Part I. Pharmacol Res 1993;27:123-4.

105

Pifferi G. Silipide: A new bioavailable complex of Silybin. Planta Med 1991;57:A12. Pifferi G, Magistretti MJ. A new bioavailable complex of silybin: Part II. Pharmacol Res 1993;27:125-6. Piqueras Carrasco J. [Poisoning by mushrooms of the Amanita phalloides type]. [Spa]. Med Clin (Barc) 1985;85:330-40. Plomteux G, Albert A. Action hépato-protectrice de la silymarine dans le traitement de l’hépatite virale chez l’Homme [abstract]. Therapie 1977;32:652-59. Plomteux G, Defrance P, Delforge M, et al. Clinical study of a new hepatoprotective agent, silymarin (coniferylpolyhydroxy 2 phenylchromanone). Ann Gastroenterol Hepatol (Paris) 1974;10:533-41. Poser G. [Experience in the treatment of chronic hepatopathies with silymarin]. [Ger]. Arzneimittelforschung 1971;21:1209-12. Quaglia MG, Bossu E, Donati E, et al. Determination of silymarine in the extract from the dried silybum marianum fruits by high performance liquid chromatography and capillary electrophoresis. J Pharm Biomed Anal 1999;19:435-42. Rajasekaran A, Kumar M, Krishnamoorthy G, et al. Spectrophotometric determination of silymarin. Indian J Pharm Sci 1997;59:230-1. Ravetta A. [Ambulatory treatment of hepatic damage: comparison of 2 therapeutic modalities]. [Ita]. Clin Ter 1981;99:149-53. Realini S, Gonvers JJ, Hofstetter JR. [Clinical investigation of silymarin in chronic liver diseases (author’s transl)]. [Fre]. Schweiz Rundsch Med Prax 1975;64:595-8. Realini S, Gonvers J, Hofstetter J. [Clinical trial of silymarin in chronic liver diseases]. [Fre]. Praxis 1975;64:595-8. Reutter FW, Haase W. [Clinical experience with silymarin in the treatment of chronic liver disease (author’s transl)]. [Ger]. Schweiz Rundsch Med Prax 1975;64:1145-51. Reyes H, Simon FR. Intrahepatic cholestasis of pregnancy: An estrogen-related disease. Semin Liver Dis 1993;13:289-301.

Rosenthal R. Meta-analytic procedures for social research. Rev. ed. Thousand Oaks (CA): Sage Publications; 1991. Roveda S, Colombo P, Pulvirenti A. [Evaluation of the efficacy and tolerance of silybin in the treatment of organic and functional diseases of the liver parenchyma]. [Ita]. Arch Med Int 1991;43:97-102. Saba P, Galeone F, Salvadorini F, et al. Therapeutic effects of Silymarin in chronic liver diseases due to psychodrugs. Gazz Med Ital 1976;135:236-51. Saba P, Mignani E, Pagliai, et al. [Efficacy of silymarin treatment of acute virus hepatitis:]. [Ita]. Epatologia 1979;25:277-81. Saba P, Mignani E, Pagliai E, et al. Efficacy of treatment with silymarin in viral hepatitis. IRCS J Med Sci 1980;8:46. Saller R, Kristof O, Reichling J. Zubereitungen und Inhaltsstoffe aus Mariendistel (Silybum marianum L.) als Phytotherapeutika. Internist Prax 1998;38:387-93. Saller R, Reichling J. Mariendistel—eine Arzneipflanze mit Leberschutzfunktion. Erfahrungsheilkunde 1996;6:384-91. Salmi HA, Sarna S. Effect of silymarin on chemical, functional, and morphological alterations of the liver. A double-blind controlled study. Scand J Gastroenterol 1982;17:517-21. Salvagnini M, Martines D, Piccoli A, et al. Silymarin treatment in alcoholic liver disease: A double blind randomized clinical trial [EASL abstract.]. J Hepatol 1985;S124. Sanders D, Kennedy N, McKendrick MW. Monitoring the safety of herbal remedies. Herbal remedies have a heterogeneous nature. BMJ 1995;311:1569. Sawaryn T, Szymonski K, Machalska M. [Sylimarine in the treatment of chronic hepatitis]. [Pol]. Przegl Epidemiol 1977;31:445-50. Schandalik R, Gatti G, Perucca E. Pharmacokinetics of silybin in bile following administration of silipide and silymarin in cholecystectomy patients. Arzneimittelforschung 1992;42:964-8.

106

Scheiber V, Wohlzogen FX. Analysis of a certain type of 2 x 3 tables, exemplified by biopsy findings in a controlled clinical trial. Int J Clin Pharmacol 1978;16:533-5. Schmidt U, Duerr HK, Bode JC. [Treatment of acute viral hepatitis by silymarin. Report of a controlled study]. [Ger]. Verh Dtsch Ges Inn Med 1977;83:563-5. Schopen RD, Lange OK. [Therapy of hepatoses. Therapeutic use of Silymarin]. [Ger]. Med Welt 1970;15:691-8. Schopen RD, Lange OK, Panne C, et al. [Searching for a new therapeutic principle. Experience with hepatic therapeutic agent Legalon]. [Ger]. Med Welt 1969;20:888-93. Schulz V, Hansel R, Tyler VE, editors. Rational phytotherapy: A physician's guide to herbal medicine. 3rd, fully rev. and expanded ed. Berlin: Springer-Verlag; 1998. Schuppan D. [Attempts of antifibrotic therapy in chronic hepatitis]. [Ger]. Z Allgemeinmed 1995;71:1153-7. Schuppan D, Strosser W, Burkard G, et al. [Influence of Legalon(TM) 140 on the metabolism of collagen in patients with chronic liver disease—Review by measurement of PIIINP-values]. [Ger]. Z Allgemeinmed 1998;74:577-84. Seitz HK. Alcoholic hepatitis. Praxis Magazin Med 1993;9:10-3. Sharp S. Sbe23: Meta-regression. Stata Tech Bull 1998;42:16-22. Sharp S, Sterne J. Sbe16: Meta-analysis. Stata Tech Bull 1997;38:9-14. Shaw D, Leon C, Kolev S, et al. Traditional remedies and food supplements. A 5-year toxicological study (1991-1995). Drug Saf 1997;17:342-56. [Silymarin treatment of alcoholic liver disease]. [Hun]. Orv Hetil 1990;131:1607-9. Skakun N, Moseichuk I. [Clinical pharmacology of legalon]. [Rus]. Vrach Delo 1988;5:5-10.

Sonnenbichler J, Goldberg M, Hane L, et al. Stimulatory effect of Silibinin on the DNA synthesis in partially hepatectomized rat livers: Non-response in hepatoma and other malign cell lines. Biochem Pharmacol 1986;35:538-41. Sonnenbichler J, Zetl I. Biochemical effects of the flavoligand silybin on RNA, protein and DNA synthesis of macromolecules in liver cells. In: Cody V, Middleton E Jr, Harborne JB, editors. Plant flavanoids in biology and medicine: Biochemical, pharmacological, and structure-activity relationships. New York: Liss; 1986. p. 319-31. Spitzova I. Cultivation of Silybum marianum (L.) Gaertn. Cesk Farm 1990;39:327-9. Steichen TJ. Tests for publication bias in meta-analysis. Stata Tech Bull 1997;41:9-15. Studlar M. [Treatment of chronic liver disease with silymarin plus B-group vitamins]. [Ger]. Therapiewoche 1985;35:3375-8. Szilard S, Szentgyorgyi D, Demeter I. Protective effect of Legalon in workers exposed to organic solvents. Acta Med Hung 1988;45:249-56. Takemoto T, Ikegawa S, Nomoto K. [Studies on constituents of Silybum marianum (L.) Gaertn. I. New flavonolignans named 2,3-dehydrosilymarin and 2,3-dehydrosilychristin]. [Jap]. Yakugaku Zasshi 1975;95:1017-21. Tanaka H, Hiroo M, Ichino K, et al. Total synthesis of silychristin, an antihepatotoxic flavonolignan. Chem Pharm Bull (Tokyo) 1989;37:1441-5. Tanasescu C, Miron C, Pappo A. Present-day possibilities of diagnosis and treatment of chronic liver diseases. Contributions of the research work in the “N. Gh. Lupu” Institute of Internal Medicine. Rev Roum Med Intern 1990;28:3-12. Tanasescu C, Petrea S, Baldescu R, et al. Use of the Romanian product Silimarina(R) in the treatment of chronic liver diseases. Rev Roum Med Intern 1988;26:311-22. Tenney L. Milk thistle: A remarkable flavonoid antioxidant and liver protectant. Pleasant Grove (UT): Woodlands Publications; 1995. Thabrew MI, Hughes RD. Phytogenic agents in the therapy of the liver disease. Phytother Res 1996;10:461-7.

107

Tittel G, Wagner H. High-performance liquid chromatographic separation of silymarins and their determination in a raw extract of Silybum marianum Gaertn. J Chromatogr 1977;135:499-501. Tkacz B, Dworniak D. [Sylimarol in the treatment of acute viral hepatitis]. [Pol]. Wiad Lek 1983;36:613-6. Tobias A. Assessing heterogeneity in meta-analysis: The Galbraith plot. Stata Tech Bull 1997;41:15-7. Trinchet JC, Coste T, Levy VG, et al. [A randomized double blind trial of silymarin in 116 patients with alcoholic hepatitis]. [Fre]. Gastroenterol Clin Biol 1989;13:120-4. Tuchweber B, Sieck R, Trost W. Prevention of silybin of phalloidin-induced acute hepatoxicity. Toxicol Appl Pharmacol 1979;51:265-75. Turecky L, Kupcova V, Synak R, et al. [Serum proteins in patients with chronic liver disease and flavobion treatment. I. Proteins of the acute stage]. [Slo]. Cesk Gastroenterol Vyz 1988;42:424-9. Ulicna O, Brixova E. [The effect of silymarin on lipids in the blood and liver in steatosis]. [Slo]. Vnitr Lek 1985;31:15-9. Vailati A, Aristia L, Sozze E, et al. Randomized open study of the dose-effect relationship of a short course of IdB 1016 in patients with viral or alcoholic hepatitis. Fitoterapia 1993;64:219-28. Valenzuela A, Barria T, Guerra R, et al. Inhibitory effect of the flavonoid silymarin on the erythrocyte hemolysis induced by phenylhydrazine. Biochem Biophys Res Commun 1985;126:712-8. Valenzuela A, Garrido A. Biochemical bases of the pharmacological action of the flavonoid silymarin and of its structural isomer silibinin. Biol Res 1994;27:105-12. Valenzuela A, Guerra R. Differential effect of silybin on the Fe2+-ADP and t-butyl hydroperoxide-induced microsomal lipid peroxidation. Experientia 1986;42:139-41. Valenzuela A, Guerra R, Videla LA. Antioxidant properties of the flavonoids silybin and (+)-cyanidanol-3: Comparison with butylated hydroxyanisole and butylated hydroxytoluene. Planta Med 1986;6:438-40.

Varis K, Salmi HA, Siurala M. Die Therapie der Lebererkrankung mit Legalon@; eine kontrolllerte Doppelblindstudie [abstract]. Aktuelle Hepatologie, Third International Symposium; 1978 Nov 15-17; Cologne, Germany. Lubeck: Hanseatisches Verlagskontor; 1978. p. 42-3. Velussi M, Cernigoi AM, De Monte A, et al. Long-term (12 months) treatment with an anti-oxidant drug (silymarin) is effective on hyperinsulinemia, exogenous insulin need and malondialdehyde levels in cirrhotic diabetic patients. J Hepatol 1997;26:871-9. Velussi M, Cernigoi AM, Viezzoli L, et al. Silymarin reduces hyperinsulinemia, malondialdehyde levels, and daily insulin need in cirrhotic diabetic patients. Curr Ther Res Clin Exp 1993;53:535-45. Ventura P. Treatment of hepatic parenchyma organic and functional pain with silybin. Acta Toxicol Ther 1991;12:81-96. Vonnahme FJ. Der antifibrotische Effekt des Silymarins in der Therapie chronischer Lebererkrankungen. In: Loew D, Rietbrock N, Hrsg. Phytopharmaka II: Forschung und klinischer Anwendung. Darmstadt: Steinkopf; 1996. p.139-43. Walti M, Neftel A, Jost R, et al. IgE and IgG antibodies against flavonoids after treatment with flavonoid drugs. Schweiz Med Wochenschr 1986;116:98-103. Weyhenmeyer R, Mascher H, Birkmayer J. Study on dose-linearity of the pharmacokinetics of silibinin diastereomers using a new stereospecific assay. Int J Clin Pharmacol 1992;30:134-8. Wilhelm H. [The effect of silymarin treatment on the course of acute and chronic liver diseases]. [Ger]. Z Therap 1972;10:482-94. Wilhelm H, Haase W. Comparative study on the results of therapy in patients with acute hepatitis. Therapiewoche 1973;23:3276-85. Wolf J. [Micro-thin layer chromatography: Silybum marianum]. [Ger]. Pharm Zeitung 1998;143:50. Wolf J. [Micro thin layer chromatography: Silymarin]. [Ger]. Pharm Zeitung 1995;140:50. Wollemann G, Seifert HU, Borelli S. Berufsbedingte Rhinokonjunktivitis auf Mariendistelsamen (Silybum marianum L.). Allergologie 1987;10:505-7.

108

Wong SM, Wong MM, Seligmann O, et al. New antihepatotoxic naphtho-pyrone glycosides from the of Cassia tora. Planta Med 1989;55-276-80.

Zirm KL. [Treatment of subacute and chronic forms of hepatitis as well as of chronic degenerative liver diseases using Silymarin]. [Ger]. Wien Med Wochenschr 1973;123:302-5. Zvenigorodskaia LA, Speranskaia IE. [Hepatoprotective preparations in the treatment of circulatory failure]. [Rus]. Sov Med 1988;3:67-71.

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Appendix A. Milk Thistle Search Strategies

All papers MEDLINE

Date: 18-Jun-1999

Name: sily1, sily2, sily3, sily3a, sily4 (SAVED AS SILYMEDL)

Database: Medline <1966 to present>

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 26 587 028 27 and 1 2 029 liver.tw. 285638 030 29 and 27 19 031 2 and 29 31 032 31 or 26 555 033 amanita phalloides.tw. 323 034 33 and 2 0 035 32 555

113

All papers EMBASE

Date: 18-Jun-1999

Name: silyem1

Database: EMBASE <1988 to present>

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 028 26 and 27 182 029 28 and 15 35 030 or/16-25 431 031 30 or 29 464 032 31 464

114

Figure 1-1. Aspartate aminotransferase, less drug study, <45 days Begg's funnel plot with pseudo 95% confidence limits

Effe

ct S

ize

Standard Error 0 0.2 0.4 0.6

-1

0

1

Figure 1-2. Aspartate aminotransferase, less drug study, <45 days

Z S

tatis

tic

Inverse of Standard Error 0 2 4 6

-3.2

-2

0

2

117

Figure 1-3. Aspartate aminotransferase, less drug study, <45 days

Effect Size -1.5 -1 -0.5 0 0.5 1

Combined

Salmi 1982

Magliulo 1978

Lang 1990

telmann 1980

telmann 1970

Buzelli 1993

Figure 1-4. Aspartate aminotransferase, less drug study, 90 days Begg's funnel plot with pseudo 95% confidence limits

Effe

ct S

ize

Standard Error 0 0.1 0.2 0.3 0.4

-1

-0.5

0

0.5

Trinchet 1989

Marcelli 1992

118

Figure 1-5. Aspartate aminotransferase, less drug study, 90 days

Z S

tatis

tic

Inverse of Standard Error 0 2 4

-2.9

-2

0

2

Trinchet 1989

Marcelli 1992

Figure 1-6a. Aspartate aminotransferase, less drug study, 90 days

Effect Size -1.5 -1 -0.5 0 0.5 1

Combined

Trinchet 1989

Marcelli 1992

Feher 1990

119

Figure 1-6b. Aspartate aminotransferase, less drug study, less outlier, 90 days

Effect Size -1.5 -1 -0.5 0 0.5 1

Combined

Marcelli 1992

Feher 1990

Figure 1-7. Aspartate aminotransferase, < 45 days

Begg's funnel plot with pseudo 95% confidence limits

Effe

ct S

ize


-1

0

1

120

Figure 1-8. Aspartate aminotransferase, < 45 days

Z St

atis

tic


-3.0

-2

0

2

Figure 1-9. Aspartate aminotransferase, <45 days

Effect Size -1.5 -1 -0.5 0 0.5 1

Combined

Salmi 1982

Palasciano 1994

Palasciano 1994

Magliulo 1978

Lang 1990

Fintelmann 1980

Fintelmann 1970

Buzelli 1993

121

Figure 1-10. Aspartate aminotransferase, 90 days Begg's funnel plot with pseudo 95% confidence limits

Effe

ct S

ize


-1

-0.5

0

0.5

Marcelli 1992

Trinchet 1989

Figure 1-11. Aspartate aminotransferase, 90 days

Z St

atis

tic


-3.1

-2

0

2

Trinchet 1989

Marcelli 1992

122

Figure 1-12a. Aspartate aminotransferase, 90 days

Effect Size -1.5 -1 -0.5 0 0.5 0

Combined

Trinchet 1989

Palasciano 1994

Marcelli 1992

Feher 1990

Palasciano 1994

Figure 1-12b. Aspartate aminotransferase, less outlier, 90 days

Effect Size -1.5 -1 -0.5 0 0.5 1

Combined

Palasciano 1994

Marcelli 1992

Feher 1990

Palasciano 1994

123

Figure 1-13. Alanine aminotransferase, less drug study, <45 days Begg's funnel plot with pseudo 95% confidence limits

Effe

ct S

ize

Standard Error 0 0.2 0.4

-1

-0.5

0

0.5

1 Magliulo 1978

Figure 1-14. Alanine aminotransferase, less drug study, <45 days

Z St

atis

tic


-2.7

-2

0

2

Magliulo 1978

124

Figure 1-15a. Alanine aminotransferase, less drug study, <45 days

Effect Size -1.5 -1 -0.5 0 0.5 1 1.5

Combined

Tanasescu 1988

Salmi 1982

Magliulo 1978

Lang 1990

Fintelmann 1970

Buzelli 1993

Fintelmann 1980

Figure 1-15b. Alanine aminotransferase, less drug study, less outlier, <45 days

Effect Size -1.5 -1 -0.5 0 0.5 1 1.5

Combined

Tanasescu 1988

Salmi 1982

Lang 1990

Fintelmann 1980

Fintelmann 1970

Buzelli 1993

125

Figure 1-16. Alanine aminotransferase, less drug study, 90 days Begg's funnel plot with pseudo 95% confidence limits

Effe

ct S

ize


-1.5

-1

-0.5

0

Figure 1-17. Alanine aminotransferase, less drug study, 90 days

Z St

atis

tic


-3.9

-2

0

2 2

126

Figure 1-18. Alanine aminotransferase, less drug study, 90 days

Effect Size -1.5 -1 -0.5 0 0.5 1 1.5

Combined

Marcelli 1992

Feher 1990

Figure 1-19. Alanine aminotransferase, <45 days


Effe

ct S

ize

Standard Error 0 0.2 0.4

-1

-0.5

0

0.5

1 Magliulo 1978

127

Figure 1-20. Alanine aminotransferase, <45 days

Z St

atis

tic


-2.6

-2

0

2 2

Magliulo 1978

Figure 1-21a. Alanine aminotransferase, <45 days

Effect Size -1.5 -1 -0.5 0 0.5 1 1.5

Combined

Tanasescu 1988

Salmi 1982

Palasciano 1994

Palasciano 1994

Magliulo 1978

Lang 1990

Fintelmann 1980

Fintelmann 1970

Buzelli 1993

128

Figure 1-21b. Alanine aminotransferase, less outlier, <45 days

Effect Size -1.5 -1 -0.5 0 0.5 1 1.5

Combined

Tanasescu 1988

Salmi 1982

Palasciano 1994

Palasciano 1994

Lang 1990

Fintelmann 1980

Fintelmann 1970

Buzelli 1993

Figure 1-22. Alanine aminotransferase, 90 days Begg's funnel plot with pseudo 95% confidence limits

Effe

ct S

ize


-1.5

-1

-0.5

0

0.5

129

Figure 1-23. Alanine aminotransferase, 90 days

Z St

atis

tic

Inverse of Standard Error0 1 2 3

-3.4

-2

0

2 2

Figure 1-24. Alanine aminotransferase, 90 days

Effect Size -1.5 -1 -0.5 0 0.5 1 1.5

Combined

Palasciano 1994

Palasciano 1994

Marcelli 1992

Feher 1990

130

Figure 1-25. Gammaglutamyl transpeptidase, <45 daysBegg's funnel plot with pseudo 95% confidence limits

Effe

ct S

ize


-1

0

1

Figure 1-26. Gammaglutamyl transpeptidase, <45 days

Z St

atis

tic


-3.3

-2

0

2 2

131

Figure 1-27. Gammaglutamyl transpeptidase, <45 days

Effect Size -1.5 -1 -0.5 0 0.5 1

Combined

Tanasescu 1988

Magliulo 1978

Lang 1990

Fintelmann 1980

Buzelli 1993

Figure 1-28. Gammaglutamyl transpeptidase, 90 days Begg's funnel plot with pseudo 95% confidence limits

Effe

ct S

ize


-1

-0.5

0

0.5

132

Figure 1-29. Gammaglutamyl transpeptidase, 90 days

Z St

atis

tic


-2.2 -2

0

2 2

Figure 1-30. Gammaglutamyl transpeptidase, 90 days

Effect Size -1.5 -1 -0.5 0 0.5 1

Combined

Trinchet 1989

Feher 1990

133

Figure 1-31. Alkaline phosphatase, <45 days Begg's funnel plot with pseudo 95% confidence limits

Effe

ct S

ize


-1

-0.5

0

0.5

1

Figure 1-32. Alkaline phosphatase, <45 days

Z St

atis

tic


-2.3 -2

0

2 2

134

Figure 1-33. Alkaline phosphatase, <45 days

Effect Size -1 -0.5 0 0.5 1 1.5

Combined

Tanasescu 1988

Salmi 1982

Magliulo 1978

Fintelmann 1970

Buzelli 1993

Figure 1-34. Bilirubin, <45 days


Effe

ct S

ize


-1

0

1

135


Z St

atis

tic


-3.8

-2

0

2 2


Effect Size -1.5 -1 -0.5 0 0.5 1

Combined

Tanasescu 1988

Magliulo 1978

Lang 1990

Buzelli 1993

136

Figure 1-37. Bilirubin, 90 daysBegg's funnel plot with pseudo 95% confidence limits

Effe

ct S

ize


-0.5

0

0.5

1

Figure 1-38. Bilirubin, 90 days

Z St

atis

tic


-2 -2

0

2 2.2

137

Figure 1-39. Bilirubin, 90 days

Effect Size -1.5 -1 -0.5 0 0.5 1

Combined

Trinchet 1989

Marcelli 1992

Feher 1990

Figure 1-40. Albumin, 90 daysBegg's funnel plot with pseudo 95% confidence limits

Effe

ct S

ize


-1

-0.5

0

0.5

138

Figure 1-41. Albumin, 90 days

Z St

atis

tic


-2.6

-2

0

2 2

Figure 1-42. Albumin, 90 days

Effect Size -1 -0.5 0 0.5 1

Combined

Trinchet 1989

Marcelli 1992

Feher 1990

139

Figure 1-43. Prothrombin time, 90 days Begg's funnel plot with pseudo 95% confidence limits

Effe

ct S

ize


-1

-0.5

0

0.5

Figure 1-44. Prothrombin time, 90 days

Z St

atis

tic


-3.1

-2

0

2 2

140

Figure 1-45. Prothrombin time, 90 days

Effect Size -1 -0.5 0 0.5 1

Combined

Trinchet 1989

Marcelli 1992

Feher 1990

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 …mulrow c, lawrence v, jacobs b, et al. milk...

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