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AHRQ Evidence reports and summaries AHRQ Evidence Reports, Numbers 1-60 21. Milk Thistle: Effects on Liver Disease and Cirrhosis and Clinical Adverse Effects Evidence Report/Technology Assessment Number 21 Prepared for: U.S. Department of Health and Human Services Contract No. 290-97-0012 Prepared by: AHRQ Publication No. 01-E025 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.
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.
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: 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 EvidenceSpecifically, 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. MethodologySearch 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 CriteriaPreliminary 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 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 AnalysisAbstractors (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. FindingsMechanisms 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 ThistleThe 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
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. ConclusionsClinical efficacy of milk thistle is not clearly established. Interpretation of the evidence is hampered by poor study methods and/or poor quality of reporting in publications. Problems in study design include heterogeneity in etiology and extent of liver disease, small sample sizes, and variation in formulation, dosing, and duration of milk thistle therapy. Possible benefit has been shown most frequently, but not consistently, for improvement in aminotransferases and liver function tests are overwhelmingly the most common outcome measure studied. Survival and other clinical outcome measures have been studied least often, with both positive and negative findings. Available evidence is not sufficient to suggest whether milk thistle may be more effective for some liver diseases than others or if effectiveness might be related to duration of therapy or chronicity and severity of liver disease. Regarding adverse effects, little evidence is available regarding causality, but available evidence does suggest that milk thistle is associated with few, and generally minor, adverse effects. Despite substantial in vitro and animal research, the mechanism of action of milk thistle is not fully defined and may be multifactorial. A systematic review of this evidence to clarify what is known and identify gaps in knowledge would be important to guide design of future studies of the mechanisms of milk thistle and clinical trials. Future ResearchThe 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. |