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Milk thistle for the treatment of liver disease
REVIEW
Milk Thistle for the Treatment of Liver Disease: A Systematic Review and Meta-Analysis Bradly P. Jacobs, MD, MPH, Cathi Dennehy, PharmD, Gilbert Ramirez, DrPH, Jodi Sapp, RN, Valerie A. Lawrence, MD, MSc PURPOSE: Milk thistle, an herbal compound, is the dietary supplement taken most frequently by patients with chronic liver disease. We performed a systematic review of the literature to determine the efficacy and safety of this herb for the treatment of liver disease. METHODS: We searched English and non-English reports through July 1999 using thirteen databases and reference lists, and contacting manufacturers and technical experts. Reviewers independently screened all reports to identify randomized placebo-controlled trials that evaluated milk thistle for the treatment of liver disease. Outcomes of primary interest included mortality, histological findings on liver biopsy specimens, serum aminotransferase and albumin levels, and prothrombin times. RESULTS: Fourteen trials met inclusion criteria. Four trials reported outcomes for mortality among 433 participants. The overall summary odds ratio for mortality in the milk thistle group compared with placebo was 0.8 (95% confidence interval [CI]: 0.5 to 1.5; P ⫽ 0.6). Three trials assessed histology on liver biopsy; study quality was inversely associated with the likelihood of histological benefit for milk thistle compared with pla-
cebo. There were no differences in serum alanine aminotransferase, aspartate aminotransferase, or albumin levels, or prothrombin times, among participants assigned to milk thistle compared with those assigned to placebo. The only statistically significant difference was a greater reduction in alanine aminotransferase levels among patients with chronic liver disease assigned to milk thistle (⫺9 IU/L, 95% CI: ⫺18 to ⫺1 IU/L; P ⫽ 0.05), but this reduction was of negligible clinical importance and no longer statistically significant after limiting analyses to studies of longer duration or of higher quality. The frequency of adverse effects was low and, in clinical trials, indistinguishable from placebo. CONCLUSION: Treatment with milk thistle appears to be safe and well tolerated. We found no reduction in mortality, in improvements in histology at liver biopsy, or in biochemical markers of liver function among patients with chronic liver disease. Data are too limited to exclude a substantial benefit or harm of milk thistle on mortality, and also to support recommending this herbal compound for the treatment of liver disease. Am J Med. 2002;113:506 –515. ©2002 by Excerpta Medica, Inc.
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Chronic liver disease causes more than 25,000 deaths annually in the United States, and liver failure ranks 10th as a cause of death (4). The most common causes of chronic liver disease are alcohol use and viral hepatitis, in particular hepatitis B and C (5,6). Abstinence is the only treatment proven to affect long-term mortality in alcohol-related liver disease (7). Combination lamivudine and interferon alfa-2b for hepatitis B has been associated with a mortality benefit and sustained virologic response rates of 40% to 50% (8,9). Optimal treatment with pegylated interferon alpha-2b and ribavirin for hepatitis C infection has not demonstrated mortality benefit, although it is associated with a sustained virologic response in more than half of patients (10). The cost of a 48-week course of combination therapy is approximately $18,000, and adverse effects are common and often disabling (11–16). In search of better treatment options, many patients have turned to alternative medicines in the hopes of identifying “natural” substances with less toxicity but equal effectiveness. The use of milk thistle for medicinal purposes was described in the first century AD by Dioscorides, who claimed the plant was used “for those that be bitten
ilk thistle is one of the most popular herbal remedies used by patients with liver disease. A survey of patients at a hepatology clinic found that 31% reported using herbal supplements to treat their liver disease, of which milk thistle was the most common (1). Sales of milk thistle in the United States increased 51% from 1998 to 1999 (2). In 2000, milk thistle ranked 10th in U.S. sales among all supplements sold (3). From the Department of Medicine (BPJ), the Osher Center Department of Clinical Pharmacy (CD), University of California, San Francisco, San Francisco, California; the San Antonio Evidence-Based Practice Center (GR,VAL), University of Texas Health Science Center at San Antonio, San Antonio, Texas; and Veterans Evidence-Based Research (JS,VAL), Dissemination, and Implementation Center, Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, Texas. This study was prepared by the San Antonio Evidence-Based Practice Center under contract 290-97-0012, task order 3, to the Agency for Healthcare Research and Quality (formerly the Agency for Health Care Policy and Research), Rockville, Maryland. Requests for reprints should be addressed to Bradly P. Jacobs, MD, MPH, Osher Center for Integrative Medicine, University of California, San Francisco, Box 1726, San Francisco, California 94143, or [email protected]. Manuscript submitted July 5, 2001, and accepted in revised form May 22, 2002. 506
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of serpents,” and by Pliny the Elder, who stated the plant was used for “carrying off the bile” (17,18). The active complex in milk thistle, silymarin, is a lipophilic extract from the seeds of the plant and is composed of three isomer flavonolignans: silybin, silychristin, and silydianin (19,20). Silybin makes up 50% of silymarin and is regarded as the most biologically active constituent (21). Most standardized milk thistle extracts contain 70% to 80% of silymarin and are odorless (22; Norman Farnsworth, PharmD, University of Illinois at Chicago College of Pharmacy, oral communication, March 2002). Currently, milk thistle is advocated for the treatment of cirrhosis, chronic hepatitis, and liver disease associated with alcohol consumption, and environmental toxin exposure (2). Similar to pharmaceutical drug studies, clinical trials of herbal products attempt to match placebos for color, taste, odor, size, and texture. According to experts and manufacturers in the field (Norman Farnsworth, PharmD, written communication, March 2002; Mark Blumenthal, Executive Director, American Botanical Council, written communication, March 2002), creating matched placebos of the standardized silymarin extract preparation can be accomplished with relative ease. As an antioxidant, milk thistle may reduce free radical production and lipid peroxidation in the setting of hepatotoxicity (23,24). As an antifibrotic agent, it reduces markers for collagen accumulation in the liver measured by serum procollagen type III formation (25). As a toxin blockade agent, it may bind to the hepatocyte cell membrane receptor site, inhibiting binding of toxins to these sites (18,26,27). Evidence for protein synthesis is derived from one study that reported more rapid hepatocyte regeneration after partial hepatectomy in rats (28). In animals, milk thistle reduces liver injury caused by acetaminophen (24,29), carbon tetrachloride (30), radiation (31), iron overload (32), phenylhydrazine (20), alcohol (33), cold ischemia (34), and Amanita phalloides (35). In human clinical trials, milk thistle has been used to treat alcoholic liver disease, acute and chronic viral hepatitis, and toxin-induced liver injuries (17,18). Despite inconsistencies in study outcomes, the use of milk thistle remains prevalent in the United States and throughout Europe. Our goal was to review randomized placebo-controlled trials involving milk thistle in the treatment of acute and chronic liver disease. Principal outcomes of interest included mortality, histological findings on liver biopsy specimens, and changes in serum aminotransferase and albumin levels, and prothrombin times. To evaluate the safety of this herb in humans, we reviewed all published reports of adverse drug events.
METHODS Literature Search and Data Sources We searched for all English- and non–English-language publications on milk thistle in the treatment of liver dis-
ease, using the Latin names for milk thistle and names of milk thistle products or constituents. The following data sources were used: MEDLINE (1966 through July 1999), using the full text terms sily$, legalon$, milk thistle$, mariendistel, and carduus; EMBASE (1974 through July 1999), using the Chemsearch database registration number, a list of synonyms, and the EMBASE descriptor silymarin; Cochrane Collaboration Controlled Trial Registry, using the July 1999 CD-ROM update; BIOSIS (1985 through 1999); Current Contents database; CINAHL (1984 through July 1999); Dissertation Abstracts (1961 through December 1998); Micromedex (through July 1999); and Science Citation Index (1990 through March 1999). We also searched several alternative and complementary medicine registries, including AMED (1985 through October 1998), NAPRALERT (1650 through July 1999), CISCOM (1968 through July 1999), and Phytodok (July 1999); contacts with manufacturers and technical experts; and references from retrieved review and clinical trial articles. Two independent reviewers examined the retrieved references to make an initial judgment of eligibility. For adverse effects, we also conducted an updated search to November 1, 1999, using MEDLINE and EMBASE.
Study Selection Inclusion and exclusion criteria for efficacy were defined a priori (36). Initial eligibility criteria for reports on efficacy and adverse events required screened studies to have met the following criteria: included human subjects; used a preparation or constituent of silymarin; and reported details on the treatment of liver disease. Full articles were retrieved for all citations meeting these criteria and for those citations where eligibility was not clear. Reports on efficacy had to meet the following secondary eligibility criteria: an explicit statement of random assignment; a parallel control group receiving placebo; outcomes calculated for both groups; and milk thistle used as a treatment for liver disease and not as a prophylactic agent against potentially hepatotoxic drugs. We contacted authors when it was unclear if a report met final eligibility criteria or if outcomes reported were unclear.
Quality Assessment Trials were scored using a standard quality scale (37). This three-item, five-point scale evaluates the adequacy of random assignment, double-blinding, and reporting of subjects who withdraw or drop out.
Data Abstraction Two reviewers with clinical and methodological expertise independently abstracted data from each eligible study. They were not blinded either to the study title or to author’s name. Disagreement was resolved through consensus. Outcomes of primary interest included mortality; serum alanine aminotransferase, aspartate aminotransferase, and albumin levels; and prothrombin times. Study
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508
Table. Summary of Randomized Placebo-Controlled Trials Meeting Inclusion Criteria*
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Jadad Score
Acuity of Disease
Trinchet (63)
116
5
Chronic
Alcohol
Mixed
Pare´ s (68)
200
5
Chronic
Alcohol
Ferenci (70)
170
5
Chronic
Bunout (64)
71
3
Salmi (65)
97
Fintelmann (69)
Etiology of Liver Disease†
Severity of Liver Disease‡
Daily Dose (mg)
Therapy (days)
Legalon
420
90
French
Cirrhosis
Legalon
450
730
French
Mixed
Cirrhosis
Legalon
420
730
English
Chronic
Alcohol
Mixed
Legalon
280
446
Spanish
3
Chronic
Alcohol
Unknown
Legalon
420
28
English
66
3
Chronic
Alcohol
Unknown
Legalon
Not given
28
German
Tanasescu (71)
177
3
Chronic
Mixed
Mixed
Silimarina
210
40
English
Magliulo (60)
59
3
Acute
Viral
Hepatitis
Legalon
420
25
German
Buzelli (62)
20
3
Chronic
Viral
Hepatitis
Silipide
240
7
English
Palasciano (72)储
60
3
Chronic
Drug-induced
Unknown
Nonstandard
800
90
English
Lang (66)
60
2
Chronic
Alcohol
Cirrhosis
Legalon
420
30
English
Feher (67)
36
2
Chronic
Alcohol
Mixed
Legalon
420
180
Hungarian
Kiesewetter (61) Marcelli (59)
24 65
1 1
Chronic Chronic
Viral Mixed
Hepatitis Hepatitis
Legalon Silipide
420 240
365 90
German English
* All trials except Marcelli (59) reported double-blind study design. † Mixed ⫽ alcohol and other forms of liver disease. ‡ Mixed ⫽ cirrhosis and other degrees of disease. § Data not reported. 储 One publication with two parallel clinical trials.
Milk Thistle Formulation
Language Published
Outcomes Mortality, histology, aspartate aminotransferase, albumin, prothrombin time Mortality, aspartate aminotransferase, alanine aminotransferase, albumin, prothrombin time Mortality, (aspartate aminotransferase, alanine aminotransferase)§ Mortality, aspartate aminotransferase, albumin, prothrombin time Histology, aspartate aminotransferase, alanine aminotransferase Aspartate aminotransferase, alanine aminotransferase Alanine aminotransferase, prothrombin time Aspartate aminotransferase, alanine aminotransferase Aspartate aminotransferase, alanine aminotransferase Aspartate aminotransferase, alanine aminotransferase Aspartate aminotransferase, alanine aminotransferase Aspartate aminotransferase, alanine aminotransferase albumin, prothrombin time Histology Aspartate aminotransferase, alanine aminotransferase, albumin, prothrombin time
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Sample Size
Author (Reference)
Milk Thistle for the Treatment of Liver Disease/Jacobs et al
Figure 1. Forest plots for randomized placebo-controlled trials reporting mortality results among patients with liver disease. The solid vertical line at 1.0 along the horizontal axis designates the point at which no effect is seen. Negative effect size (to the left of 1.0) suggests the study result favored milk thistle, and positive effect sizes (to the right of 1.0) suggest the study result favored placebo. Odds ratios (OR) compare mortality among participants assigned to milk thistle compared with those assigned to placebo. Summary odds ratio is based on a random-effects model. The area of the shaded box correlates with the contribution toward the weighted average of the summary estimate. The horizontal line for each study denotes the 95% confidence intervals. The 95% confidence interval for the combined estimate is denoted within the parentheses.
quality was defined as “high” if it received a Jadad score of 3 or greater and “low” if the score was less than 3. Liver disease was categorized by etiology (hepatitis A, B, or C; alcohol; mixed; or unknown), acuity (acute vs. chronic), and the presence of cirrhosis diagnosed by liver biopsy or laparoscopic examination.
Quantitative Data Synthesis The decision to proceed with quantitative analyses of mortality rates and biochemical markers of liver function was based on identification of trials with adequate study quality, small-to-moderate sample size, and similar study samples. Trials with outcomes on histology at liver biopsy did not have similar study samples and therefore did not meet the criteria for quantitative analysis. All estimates were adjusted for baseline differences between treatment and control groups. We calculated odds ratios and 95% confidence intervals (CI), comparing mortality between patients assigned to milk thistle and those assigned to placebo. Investigators who were contacted to obtain mortality data from the study period on patients who dropped out were unable to provide this data; therefore, these patients were excluded. In a sensitivity analysis, we performed an intention-to-treat analysis for mortality that assumed all patients who dropped out died. Continuous outcome measures were analyzed
using the Hedges-Olkin method for standardized mean differences to generate an effect size, which divides the difference between the treatment and placebo group outcome scores by the pooled standard deviation of the two groups. Effect sizes were then adjusted for between-group baseline differences and for small sample size bias using the Hedges-Olkin adjustment factor (38). To aid in interpreting the standardized mean difference effect sizes, these results were converted to equivalent laboratory values by multiplying the average of the standard deviations from the studies of each outcome by the effect size. Meta-analyses were conducted using the randomeffects model. Heterogeneity of results among studies was assessed using chi-squared tests for heterogeneity (␣ ⫽ 0.10). We performed preplanned sensitivity analyses by etiology, severity, and acuity of disease; duration of treatment; standardization of milk thistle therapy; and study quality. All analyses were performed using STATA 8.1 software (SAS Institute, Cary, North Carolina).
RESULTS We identified 1726 reports, of which 1505 were in vitro studies, animal studies, studies unrelated to liver disease, duplicate reports, or contained no primary data about
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Figure 2. Forest plots for trials of patients with chronic liver disease reporting serum alanine aminotransferase levels. The lower horizontal axis is the equivalent clinical laboratory value. The upper horizontal line represents the standardized effect sizes. The solid vertical line at 0 along the horizontal axis designates the point at which no effect is seen. Negative effect size (to the left of 0) suggests the study result favored milk thistle, and positive effect sizes (to the right of 0) suggest the study result favored placebo. The area of the shaded box correlates with the contribution toward the weighted average of the summary estimate. The horizontal line for each study denotes the 95% confidence intervals. The 95% confidence interval for the overall result is contained within the parentheses.
effectiveness. These studies did not meet inclusion criteria. Seven reports were unobtainable, one of which was a clinical trial from the abstract. We were unable to retrieve this citation because it was indexed incorrectly in the source registry (39). Full manuscripts were reviewed for the remaining 214 reports. Of these, 180 did not meet inclusion criteria. Two studies were excluded because milk thistle was used for prophylaxis among patients using hepatotoxic agents (40,41). Thirty-two controlled clinical trials remained eligible; of these, one was a duplicate study (42) and 17 were not randomized placebocontrolled trials (32,43–58). Thus, 14 trials involving 1209 participants satisfied eligibility criteria for the systematic review of efficacy (Table) (59 –72). Adverse drug effect reports were identified in 18 records.
Quality Assessment and Data Extraction Only one of these trials did not report a double-blind study design (59). Patients with acute liver disease were studied in one trial (60); the other trials studied patients with chronic liver disease. The etiology of liver disease was attributed to viral disease in three studies (60 – 62), alcoholic liver disease in seven (63– 69), mixed or unknown etiologies in three (59,70,71), and drugs in one (72). The severity of liver disease among participants in the trials varied, with three of 14 trials requiring a diagnosis of cirrhosis for study entry, including two for alcohol-related cirrhosis (66,68) and one for cirrhosis of mixed etiologies (70). 510
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All but two trials used standardized formulations of milk thistle (71,72). Specifically, 10 used Legalon (Madaus Corporation, Cologne, Germany) and two used Silipide (Inverni Della Beffa Research and Development Laboratories, Milan, Italy), which was formulated to enhance bioavailability using a 1:1 ratio of silybin and phosphatidylcholine. Eight trials were published in English, three in German, and one each in Spanish, French, and Hungarian. Sample size varied from 20 to 200 subjects, with five trials enrolling 90 or more patients. Six trials were considered short term (⬍90 days of treatment). Duration of therapy ranged from 7 days to 2 years. Baseline screening was conducted for hepatitis B antigen in seven trials and for hepatitis C infection in one trial (62). No trial screened for human immunodeficiency virus infection or subsequent exposure to hepatitis B or C at study end. Few studies employed systematic laboratory monitoring for alcohol use during the study. Quality scores were fair, with 10 (71%) of 14 trials receiving a score of 3 or higher on the Jadad scale. The mean (⫾SD) quality score for all trials was 3.0 ⫾ 1.3.
Mortality Four trials (63,64,68,70), involving 433 participants who completed the trials (557 participants were enrolled), reported mortality data. All trials were high-quality studies (Jadad score ⱖ3; Table). All trials included patients with alcohol-related liver disease; three trials limited inclusion
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Figure 3. Forest plots for trials of patients with liver disease reporting serum aspartate aminotransferase levels. The lower horizontal axis is the equivalent clinical laboratory value. The upper horizontal line represents the standardized effect sizes. The solid vertical line at 0 along the horizontal axis designates the point at which no effect is seen. Negative effect size (to the left of 0) suggests the study result favored milk thistle, and positive effect sizes (to the right of 0) suggest the study result favored placebo. The area of the shaded box correlates with the contribution toward the weighted average of the summary estimate. The horizontal line for each study denotes the 95% confidence intervals. The 95% confidence interval for the overall result is contained within the parentheses.
to patients with alcohol-related liver disease (63,64,68), two trials limited inclusion to patients with cirrhosis (68,70), and three trials provided treatment for more than 12 months (25,68,70). The overall summary odds ratio for mortality in the milk thistle group compared with placebo was 0.8 (95% CI: 0.5 to 1.5; P ⫽ 0.6; test for heterogeneity, P ⫽ 0.3; Figure 1). In subgroup analyses of participants with alcohol-related liver disease, the summary odds ratio for the milk thistle group compared with placebo was 0.8 (95% CI: 0.4 to 1.7; P ⫽ 0.6; test for heterogeneity, P ⫽ 0.2). Limiting analyses to trials with at least 12 months of therapy and sensitivity analysis to account for subjects who dropped out yielded similar results.
Histology Three trials involving 237 participants assessed histology of liver biopsy specimens (Table) (61,63,64). We limited the review to a qualitative assessment because of variable study samples and limited data. Study quality was inversely associated with the likelihood of reporting a clinical benefit for milk thistle compared with placebo. The trial with the highest quality score (Jadad score of 5) found that treatment had no effect on histology (63). A second trial (Jadad score of 3) found treatment to be associated with statistically significant improvements in
liver histology (64), and a third trial (Jadad score of 1) identified a substantive clinical effect on improved liver histology results (61); however, the sample size was small and the findings did not reach statistical significance (P ⫽ 0.05 to 0.10).
Biochemical Markers We identified 11 randomized, placebo-controlled trials (n ⫽ 840 patients) that reported serum alanine aminotransferase levels. Overall, there was a 5-IU/L reduction in alanine aminotransferase levels among patients assigned to milk thistle compared with placebo (95% CI: ⫺17 to 6 IU/L; P ⫽ 0.3; test for heterogeneity, P ⫽ 0.001). Among the 10 studies enrolling patients with chronic liver disease, there was a 9-IU/L reduction in levels among those assigned to milk thistle compared with placebo (95% CI: ⫺18 to ⫺1 IU/L; P ⫽ 0.05; test for heterogeneity, P ⫽ 0.06; Figure 2). This statistically significant improvement was no longer present after limiting analyses to studies of longer duration (P ⫽ 0.15) or higher quality (P ⫽ 0.5). In 12 trials (n ⫽ 838) that assessed serum aspartate aminotransferase levels, the milk thistle group had a 5-IU/L greater reduction in levels than did the placebo group (95% CI: ⫺15 to 5 IU/L; P ⫽ 0.3; test for heterogeneity, P ⫽ 0.03; Figure 3). Limiting the analysis to stud-
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Figure 4. Forest plots for trials of patients with chronic liver disease reporting serum albumin levels. The lower horizontal axis is the equivalent clinical laboratory value. The upper horizontal line represents the standardized effect sizes. The solid vertical line at 0 along the horizontal axis designates the point at which no effect is seen. Negative effect size (to the left of 0) suggests the study result favored milk thistle, and positive effect sizes (to the right of 0) suggest the study result favored placebo. The area of the shaded box correlates with the contribution toward the weighted average of the summary estimate. The horizontal line for each study denotes the 95% confidence intervals. The 95% confidence interval for the overall result is contained within the parentheses.
ies of patients with chronic liver disease removed heterogeneity but revealed similar results. Five trials that assessed serum albumin levels in 476 participants found a 0.06-g/dL greater reduction in albumin levels among those assigned to milk thistle compared with placebo (95% CI: ⫺0.3 to 0.1 g/dL; P ⫽ 0.6; test for heterogeneity, P ⫽ 0.17; Figure 4). Six randomized, placebo-controlled trials involving 496 participants reported changes in prothrombin times: a 2-second greater reduction among patients assigned to milk thistle compared with placebo (95% CI: ⫺6 to 2 seconds; P ⫽ 0.3; test for heterogeneity, P ⫽ 0.1; Figure 5). Subgroup and sensitivity analyses for each outcome revealed similar results.
Adverse Drug Effects Adverse drug effects were identified in 18 reports, which included seven randomized controlled clinical trials (41,48,59,64,68,70,73), six cohort studies (74 –79) (including one abstract [76]), and five case reports (80 – 84) involving more than 7000 participants. These reports did not indicate whether events were ascertained through standardized monitoring or voluntary self-report. There were three reports of serious adverse effects. In one, the patient developed gastroenteritis symptoms associated with “collapse” from a combination herbal formula containing milk thistle, with recurrent symptoms after the patient was rechallenged (80). The other two described anaphylactic reactions from ingestion of silybum marianum tea (81) and Carsil (82). Gastrointestinal symp512
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toms were the most common adverse effects reported. Overall, the frequency was low, ranging from 2% to 10% in controlled trials, which was indistinguishable from that of placebo. Other adverse effects included dermatological symptoms and headaches, which were similar in frequency between placebo and treatment groups.
DISCUSSION This systematic review of the efficacy and adverse effects of milk thistle for the treatment of liver disease found no mortality benefit during a 3-month to 4-year follow-up and no improvement in biochemical liver function tests. There were, however, limited data to address the effect of milk thistle on mortality. We found a statistically significant greater reduction in serum alanine aminotransferase levels among studies enrolling patients with chronic liver disease, although this reduction was of negligible clinical importance and no longer statistically significant after limiting analyses to studies of longer duration or of higher quality. The adverse effects of milk thistle were indistinguishable from those of placebo. Heterogeneity of study samples precluded calculating a summary estimate of the effect of milk thistle on liver histology. Although the difference in mortality between groups did not achieve statistical significance, two studies reported a mortality benefit for selected participants. Ferenci et al. (70) reported a mortality benefit in a subgroup
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Figure 5. Forest plots for trials of patients with chronic liver disease reporting serum prothrombin time. The lower horizontal axis is the equivalent clinical laboratory value. The upper horizontal line represents the standardized effect sizes. The solid vertical line at 0 along the horizontal axis designates the point at which no effect is seen. Negative effect size (to the left of 0) suggests the study result favored milk thistle, and positive effect sizes (to the right of 0) suggest the study result favored placebo. The area of the shaded box correlates with the contribution toward the weighted average of the summary estimate. The horizontal line for each study denotes the 95% confidence intervals. The 95% confidence interval for the overall result is contained within the parentheses.
analysis of patients with alcohol-related cirrhosis or Child’s class A cirrhosis. Pare´ s and colleagues studied patients with alcohol-related cirrhosis and performed a post hoc analysis using stored serum from 75 of the 200 patients in the study (68). They reported a trend for statistical significance in decreased mortality among patients with alcohol-related cirrhosis who had hepatitis C infection. These subgroup findings should be viewed with caution. Among the 18 reports reporting drug-related adverse effects, milk thistle appeared safe for patients and well tolerated. We recognize it is difficult to interpret the risk of adverse events from the literature for several reasons. Events may be missed because search terms related to adverse events are often not indexed, and causality is difficult to discern when events are published in a case report or case series. This systematic review has several limitations. The main finding of no difference in mortality among persons treated with milk thistle versus placebo is based on the results of only four trials that included 433 subjects. The small sample limits the power of the meta-analysis to assess any mortality benefit (or harm) attributed to milk thistle; thus, the confidence interval for the pooled estimate is sufficiently wide that a substantial benefit or harm cannot be excluded. Furthermore, we defined liver disease broadly, and our approach may have included types of liver disease that are un-
responsive to milk thistle, resulting in a more conservative summary estimate of effect. However, the proposed mechanisms of action of milk thistle are not directed at a specific toxin or virus, and therefore the etiology of liver disease should not affect outcome. Most studies included in the review used imprecise definitions of liver disease, such as cirrhosis “regardless of etiology.” Determination of cirrhosis status was made by histological criteria in only a few studies. Etiology of liver disease was either not reported or divided into alcohol and non–alcohol related only. Screening for hepatitis B was performed inconsistently, and hepatitis C screening predated all but one study. Given the high prevalence of hepatitis C infection among patients formerly diagnosed with non-A–non-B hepatitis, we hypothesize that a large proportion of subjects were infected with hepatitis C. Finally, few investigators screened for ongoing alcohol consumption, which, if prevalent, might have reduced the efficacy of treatment. In summary, treatment with milk thistle appears to be safe and well tolerated, but has no effect on mortality or improvements in liver histology or biochemical markers of liver function among patients with chronic liver disease. Future trials on milk thistle must have adequate sample size, enroll patients with well-defined liver disease, and devote adequate resources to monitor outcomes for subjects who dropped out. At this time, there is insufficient evidence to
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support recommending this herbal compound to patients for the treatment of liver disease.
ACKNOWLEDGMENT We are indebted to the following for their contributions to this project: Kenneth Flora, MD, for expert advice regarding liver disease; Christine Aguilar, MD, MPH, Laura Morbidoni, MD, and Kelly Montgomery, MPH, for assistance in data abstraction; Andrew Vickers, MD, and Molly Harris, MLS, MA, for performing the literature search; Jennifer Arterburn, MTSC, for assistance with technical writing and coordinating peer review; and Diane Garvin for coordinating study materials between the University of California, San Francisco, and the University of Texas Health Science Center at San Antonio.
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19. Wagner H, Siligman O, Seilz M, et al. Silydianin und Silychristin, zwei isomere Silymarine aus Silybum marianum L. Gaertn (Mariendistel). Z Naturforsch. 1976;31b:876 –884 20. Valenzuela A, Guerra R. Protective effect of the flavonoid silybin dihemisuccinate on the toxicity of phenylhydrazine on rat liver. FEBS Lett. 1985;181:291–294. 21. Schulz V, Ha¨ nsel R, Tyler VE. Rational Phytotherapy: A Physician’s Guide to Herbal Medicine. 3rd ed. Berlin, Heidelberg, Germany: Springer-Verlag; 1998:306. 22. Luper S. A review of plants used in the treatment of liver disease: part 1. Alt Med Rev. 1998;3:410 –421. 23. Fehe´ r J, La´ ng I, Ne´ ka´ m Kj, et al. In vivo effect of free radical scavenger hepatoprotective agents on superoxide dismutase (SOD) activity in patients. Tokai J Exp Clin Med. 1990;15:129 –134. 24. Campos R, Garrido A, Guerra R, Valenzuela A. Silybin dihemisuccinate protects against glutathione depletion and lipid peroxidation induced by acetaminophen on rat liver. Planta Med. 1989;55:417–419. 25. Boigk G, Stroedter L, Herbst H, et al. Silymarin retards collagen accumulation in early and advanced biliary fibrosis secondary to complete bile duct obliteration in rats. Hepatology. 1997;26:643–649. 26. Tuchweber B, Sieck R, Trost W. Prevention of silybin of phalloidininduced acute hepatoxicity. Toxicol Appl Pharmacol. 1979;51:265–275. 27. Faulstich H, Jahn W, Wieland T. Silybin inhibition of amatoxin uptake in the perfused rat liver. Arzneimittelforschung. 1980;30: 452–454. 28. Magliulo E, Carosi PG, Minoli L, Gorini S. Studies on the regenerative capacity of the liver in rats subjected to partial hepatectomy and treated with silymarin. Arzneimittelforschung. 1973;23:161–167. 29. Muriel P, Garciapin˜ a T, Perez-Alvarez V, Mourelle M. Silymarin protects against paracetamol-induced lipid peroxidation and liver damage. J Appl Toxicol. 1992;12:439 –442. 30. Halim AB, el-Ahmady O, Hassab-Allah S, et al. Biochemical effect of antioxidants on lipids and liver function in experimentally-induced liver damage. Ann Clin Biochem. 1997;34(pt 6):656 –663. 31. Hakova H, Misu´ rova´ E. The effect of silymarin and gamma radiation on nucleic acids in rat organs. J Pharm Pharmacol. 1993;45: 910 –912. 32. Szila´ rd S, Szentgyo¨ rgyi D, Demeter I. Protective effect of Legalon威 in workers exposed to organic solvents. Acta Medica Hung. 1988; 45:249 –256. 33. Comoglio A, Tomasi A, Malandrino S, et al. Scavenging effect of silipide, a new silybin-phospholipid complex, on ethanol-derived free radicals. Biochem Pharmacol. 1995;50:1313–1316. 34. De Groot H, Dehmlow C, Rauen U. Tissue injury by free radicals and the protective effects of flavonoids. Methods Find Exp Clin Pharmacol. 1996;18(suppl B):23–25. 35. Vogel G, Tuchweber B, Trost W, Mengs U. Protection by silibinin against Amanita phalloides intoxication in beagles. Toxicol Appl Pharmacol. 1984;73:355–362. 36. Lawrence VA, Jacobs BP, Dennehy C, et al. Evidence Report/Technology Assessment on Milk Thistle: Effects on Liver Disease and Cirrhosis and Clinical Adverse Effects. Rockville, Maryland: Agency for Healthcare Research and Quality; 2000. 37. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1–12. 38. Hedges L, Olkin I. Statistical Methods for Meta-Analysis. Orlando, Florida: Academic Press; 1985. 39. Berenguer J, Carrasco D. Double blind trial of silymarin versus placebo in the treatment of chronic hepatitis [in German]. Munch Med Wochenschr. 1977;119:240 –260. 40. 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 [in Slovakian]. Stud Pneumol Phtiseol. 1996;56:206 –209.
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Milk Thistle for the Treatment of Liver Disease/Jacobs et al 41. 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;10:181–185. 42. Benda L, Dittrich H, Ferenci P, et al. The influence of therapy with silymarin on the survival rate of patients with liver cirrhosis [in German]. Wien Klin Wochenschr. 1980;92:678 –683. 43. Fintelmann V. Zur therapie der fettleber mit silymarin. Therapiewoche. 1970;20:23. 44. Schopen RD, Lange OK. Therapy of hepatoses. Therapeutic use of silymarin [in German]. Med Welt. 1970;15:691–698. 45. Flisiak R, Prokopowicz D. Effect of misoprostol on the course of viral hepatitis B. Hepato-Gastroenterology. 1997;44:1419 –1425. 46. 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;26:871–879. 47. 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;23:31–33. 48. 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 –228. 49. Fintelmann V. Postoperative behavior of serum cholinesterase and other liver enzymes [in German]. Med Klin. 1973;68:809 –815. 50. 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 [in Italian]. Arch Med Interna. 1991; 43:97–102. 51. De Martiis M, Barlattani A, Parenzi A, Sebastiani F. Relationship between changes of lipid metabolism and macrocytic anemia in the course of chronic liver disease. Evaluation of treatment with a membranotropic agent [in Italian]. Clin Ter. 1984;111:135–139. 52. Boari C, Montanari FM, Galletti GP, et al. Toxic occupational liver diseases. Therapeutic effects of silymarin [in Italian]. Minerva Med. 1981;72:2679 –2688. 53. Saba P, Mignani E, Pagliai G, et al. Efficacy of silymarin treatment of acute virus hepatitis [in Italian]. Epatologia. 1979;25:277–281. 54. De Martiis M, Fontana M, Assogna G, et al. Milk thistle (Silybum marianum) derivatives in the therapy of chronic hepatopathies [in Italian]. Clin Ter. 1980;94:283–315. 55. Cavieri S. Controlled clinical trial of silymarin in 40 patients [in Italian]. Gazz Med Ital. 1974;133:628 –635. 56. Tkacz B, Dworniak D. Sylimarol in the treatment of acute viral hepatitis [in Polish]. Wiad Lek. 1983;36:613–616. 57. Del Dotto M, Neri D. Alcoholic hepatopathy. Aspects of drug therapy [in Italian]. G Clin Med. 1982;63:228 –236. 58. Bode JC, Schmidt U, Durr HK. Silymarin for the treatment of acute viral hepatitis? Report of a controlled trial [in German]. Med Klin. 1977;72:513–518. 59. 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; 1:131–135. 60. Magliulo E, Gagliardi B, Fiori G. Results of a double blind study on the effect of silymarin in the treatment of acute viral hepatitis, carried out at two medical centres [in German]. Med Klin. 1978;73: 1060 –1065. 61. Kiesewetter E, Leodolter I, Thaler H. Results of two double-blind studies on the effect of silymarine in chronic hepatitis [in German]. Leber Magen Darm. 1977;7:318 –323. 62. Buzzelli G, Moscarella S, Giusti A, et al. A pilot study on the liver protective effect of silybin-phosphatidylcholine complex (IdB1016) in chronic active hepatitis. Int J Clin Pharmacol Ther Toxicol. 1993;31:456 –460.
63. Trinchet JC, Coste T, Levy VG, et al. A randomized double blind trial of silymarin in 116 patients with alcoholic hepatitis [in French]. Gastroenterol Clin Biol. 1989;13:120 –124. 64. Bunout D, Hirsch S, Petermann M, et al. Controlled study of the effect of silymarin on alcoholic liver disease [in Spanish]. Rev Med Chil. 1992;120:1370 –1375. 65. 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;17:517–521. 66. Lang I, Nekam K, Deak G, et al. Immunomodulatory and hepatoprotective effects of in vivo treatment with free radical scavengers. Ital J Gastroenterol. 1990;22:283–287. 67. Feher J, Dea´ k G, Muzes G, et al. Liver-protective action of silymarin therapy in chronic alcoholic liver diseases [in Hungarian]. Orv Hetil. 1989;130:2723–2727. 68. Pare´ s 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;28:615–621. 69. Fintelmann V, Albert A. Double blind trial of silymarin sodium in toxic liver damage [in German]. Therapiewoche. 1980;30:5589–5594. 70. Ferenci P, Dragosics B, Dittrich H, et al. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol. 1989;9:105–113. 71. Tanasescu C, Petrea S, Baldescu R, et al. Use of the Romanian product silimarina in the treatment of chronic liver diseases. Rev Roum Med. 1988;26:311–322. 72. Palasciano G, Portincasa P, Palmieri V, et al. The effect of silymarin on plasma levels of malon-dialdehyde in patients receiving longterm treatment with psychotropic drugs. Curr Ther Res-Clin Exp. 1994;55:537–545. 73. 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. Hepatology. 1998;28:629A. 74. Studlar M. Treatment of chronic liver disease with silymarin plus Bgroup vitamins [in German]. Therapiewoche. 1985;35:3375–3378. 75. Albrecht M, Frerick H, Kuhn U, Strenge-Hesse A. Therapy of toxic liver disease with Legalon [in German]. Z Klin Med. 1992;47:87–92. 76. Marena C, Lampertico M. Preliminary clinical development of silipide: a new complex of silybin in toxic liver disorders. Planta Med. 1991;57:124 –125. 77. Grungrieff K, Albrecht M, Strenge-Hesse A. Benefit of medicinal liver therapy in general practice [in German]. Med Welt. 1995;46: 222–227. 78. Frerick F, Kuhn U, Strenge-Hesse A. Silymarin-ein phytopharmakon zur behandlung toxischen leberschaden: anwendungsbeobachtung bei 2169 patienten. Kassenarzt. 1990;33:36 –41. 79. Schuppan D, Strosser W, Burkard G, Walosek G. Influence of Legalon 140 on the metabolism of collagen in patients with chronic liver disease—review by measurement of PIIINP-values [in German]. Z Allgemeinmed. 1998;74:577–584. 80. Adverse Drug Reactions Advisory Committee. An adverse reaction to the herbal medication milk thistle (Silybum marianum). Med J Aust. 1999;170:218 –219. 81. 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 [in German]. Allergologie. 1990;13:387–388. 82. Mironets VI, Krasovskaia EA. A case of urticaria during carsil treatment [in Russian]. Vrach Delo. 1990;7:86 –87. 83. Wollemann G, Seifert HU, Borelli S. Berufsbedingte rhinokonjunktivitis auf mariendistelsamen (Silybum marianum L.). Allergologie. 1987;10:505–507. 84. De Smet PA, Van den Eertwegh AJ, Lesterhuis W, Stricker BH. Hepatotoxicity associated with herbal tablets. BMJ. 1996;313:92.
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Milk Thistle for the Treatment of Liver Disease: A Systematic Review and Meta-Analysis Bradly P. Jacobs, MD, MPH, Cathi Dennehy, PharmD, Gilbert Ramirez, DrPH, Jodi Sapp, RN, Valerie A. Lawrence, MD, MSc PURPOSE: Milk thistle, an herbal compound, is the dietary supplement taken most frequently by patients with chronic liver disease. We performed a systematic review of the literature to determine the efficacy and safety of this herb for the treatment of liver disease. METHODS: We searched English and non-English reports through July 1999 using thirteen databases and reference lists, and contacting manufacturers and technical experts. Reviewers independently screened all reports to identify randomized placebo-controlled trials that evaluated milk thistle for the treatment of liver disease. Outcomes of primary interest included mortality, histological findings on liver biopsy specimens, serum aminotransferase and albumin levels, and prothrombin times. RESULTS: Fourteen trials met inclusion criteria. Four trials reported outcomes for mortality among 433 participants. The overall summary odds ratio for mortality in the milk thistle group compared with placebo was 0.8 (95% confidence interval [CI]: 0.5 to 1.5; P ⫽ 0.6). Three trials assessed histology on liver biopsy; study quality was inversely associated with the likelihood of histological benefit for milk thistle compared with pla-
cebo. There were no differences in serum alanine aminotransferase, aspartate aminotransferase, or albumin levels, or prothrombin times, among participants assigned to milk thistle compared with those assigned to placebo. The only statistically significant difference was a greater reduction in alanine aminotransferase levels among patients with chronic liver disease assigned to milk thistle (⫺9 IU/L, 95% CI: ⫺18 to ⫺1 IU/L; P ⫽ 0.05), but this reduction was of negligible clinical importance and no longer statistically significant after limiting analyses to studies of longer duration or of higher quality. The frequency of adverse effects was low and, in clinical trials, indistinguishable from placebo. CONCLUSION: Treatment with milk thistle appears to be safe and well tolerated. We found no reduction in mortality, in improvements in histology at liver biopsy, or in biochemical markers of liver function among patients with chronic liver disease. Data are too limited to exclude a substantial benefit or harm of milk thistle on mortality, and also to support recommending this herbal compound for the treatment of liver disease. Am J Med. 2002;113:506 –515. ©2002 by Excerpta Medica, Inc.
M
Chronic liver disease causes more than 25,000 deaths annually in the United States, and liver failure ranks 10th as a cause of death (4). The most common causes of chronic liver disease are alcohol use and viral hepatitis, in particular hepatitis B and C (5,6). Abstinence is the only treatment proven to affect long-term mortality in alcohol-related liver disease (7). Combination lamivudine and interferon alfa-2b for hepatitis B has been associated with a mortality benefit and sustained virologic response rates of 40% to 50% (8,9). Optimal treatment with pegylated interferon alpha-2b and ribavirin for hepatitis C infection has not demonstrated mortality benefit, although it is associated with a sustained virologic response in more than half of patients (10). The cost of a 48-week course of combination therapy is approximately $18,000, and adverse effects are common and often disabling (11–16). In search of better treatment options, many patients have turned to alternative medicines in the hopes of identifying “natural” substances with less toxicity but equal effectiveness. The use of milk thistle for medicinal purposes was described in the first century AD by Dioscorides, who claimed the plant was used “for those that be bitten
ilk thistle is one of the most popular herbal remedies used by patients with liver disease. A survey of patients at a hepatology clinic found that 31% reported using herbal supplements to treat their liver disease, of which milk thistle was the most common (1). Sales of milk thistle in the United States increased 51% from 1998 to 1999 (2). In 2000, milk thistle ranked 10th in U.S. sales among all supplements sold (3). From the Department of Medicine (BPJ), the Osher Center Department of Clinical Pharmacy (CD), University of California, San Francisco, San Francisco, California; the San Antonio Evidence-Based Practice Center (GR,VAL), University of Texas Health Science Center at San Antonio, San Antonio, Texas; and Veterans Evidence-Based Research (JS,VAL), Dissemination, and Implementation Center, Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, Texas. This study was prepared by the San Antonio Evidence-Based Practice Center under contract 290-97-0012, task order 3, to the Agency for Healthcare Research and Quality (formerly the Agency for Health Care Policy and Research), Rockville, Maryland. Requests for reprints should be addressed to Bradly P. Jacobs, MD, MPH, Osher Center for Integrative Medicine, University of California, San Francisco, Box 1726, San Francisco, California 94143, or [email protected]. Manuscript submitted July 5, 2001, and accepted in revised form May 22, 2002. 506
©2002 by Excerpta Medica, Inc. All rights reserved.
0002-9343/02/$–see front matter PII S0002-9343(02)01244-5
Milk Thistle for the Treatment of Liver Disease/Jacobs et al
of serpents,” and by Pliny the Elder, who stated the plant was used for “carrying off the bile” (17,18). The active complex in milk thistle, silymarin, is a lipophilic extract from the seeds of the plant and is composed of three isomer flavonolignans: silybin, silychristin, and silydianin (19,20). Silybin makes up 50% of silymarin and is regarded as the most biologically active constituent (21). Most standardized milk thistle extracts contain 70% to 80% of silymarin and are odorless (22; Norman Farnsworth, PharmD, University of Illinois at Chicago College of Pharmacy, oral communication, March 2002). Currently, milk thistle is advocated for the treatment of cirrhosis, chronic hepatitis, and liver disease associated with alcohol consumption, and environmental toxin exposure (2). Similar to pharmaceutical drug studies, clinical trials of herbal products attempt to match placebos for color, taste, odor, size, and texture. According to experts and manufacturers in the field (Norman Farnsworth, PharmD, written communication, March 2002; Mark Blumenthal, Executive Director, American Botanical Council, written communication, March 2002), creating matched placebos of the standardized silymarin extract preparation can be accomplished with relative ease. As an antioxidant, milk thistle may reduce free radical production and lipid peroxidation in the setting of hepatotoxicity (23,24). As an antifibrotic agent, it reduces markers for collagen accumulation in the liver measured by serum procollagen type III formation (25). As a toxin blockade agent, it may bind to the hepatocyte cell membrane receptor site, inhibiting binding of toxins to these sites (18,26,27). Evidence for protein synthesis is derived from one study that reported more rapid hepatocyte regeneration after partial hepatectomy in rats (28). In animals, milk thistle reduces liver injury caused by acetaminophen (24,29), carbon tetrachloride (30), radiation (31), iron overload (32), phenylhydrazine (20), alcohol (33), cold ischemia (34), and Amanita phalloides (35). In human clinical trials, milk thistle has been used to treat alcoholic liver disease, acute and chronic viral hepatitis, and toxin-induced liver injuries (17,18). Despite inconsistencies in study outcomes, the use of milk thistle remains prevalent in the United States and throughout Europe. Our goal was to review randomized placebo-controlled trials involving milk thistle in the treatment of acute and chronic liver disease. Principal outcomes of interest included mortality, histological findings on liver biopsy specimens, and changes in serum aminotransferase and albumin levels, and prothrombin times. To evaluate the safety of this herb in humans, we reviewed all published reports of adverse drug events.
METHODS Literature Search and Data Sources We searched for all English- and non–English-language publications on milk thistle in the treatment of liver dis-
ease, using the Latin names for milk thistle and names of milk thistle products or constituents. The following data sources were used: MEDLINE (1966 through July 1999), using the full text terms sily$, legalon$, milk thistle$, mariendistel, and carduus; EMBASE (1974 through July 1999), using the Chemsearch database registration number, a list of synonyms, and the EMBASE descriptor silymarin; Cochrane Collaboration Controlled Trial Registry, using the July 1999 CD-ROM update; BIOSIS (1985 through 1999); Current Contents database; CINAHL (1984 through July 1999); Dissertation Abstracts (1961 through December 1998); Micromedex (through July 1999); and Science Citation Index (1990 through March 1999). We also searched several alternative and complementary medicine registries, including AMED (1985 through October 1998), NAPRALERT (1650 through July 1999), CISCOM (1968 through July 1999), and Phytodok (July 1999); contacts with manufacturers and technical experts; and references from retrieved review and clinical trial articles. Two independent reviewers examined the retrieved references to make an initial judgment of eligibility. For adverse effects, we also conducted an updated search to November 1, 1999, using MEDLINE and EMBASE.
Study Selection Inclusion and exclusion criteria for efficacy were defined a priori (36). Initial eligibility criteria for reports on efficacy and adverse events required screened studies to have met the following criteria: included human subjects; used a preparation or constituent of silymarin; and reported details on the treatment of liver disease. Full articles were retrieved for all citations meeting these criteria and for those citations where eligibility was not clear. Reports on efficacy had to meet the following secondary eligibility criteria: an explicit statement of random assignment; a parallel control group receiving placebo; outcomes calculated for both groups; and milk thistle used as a treatment for liver disease and not as a prophylactic agent against potentially hepatotoxic drugs. We contacted authors when it was unclear if a report met final eligibility criteria or if outcomes reported were unclear.
Quality Assessment Trials were scored using a standard quality scale (37). This three-item, five-point scale evaluates the adequacy of random assignment, double-blinding, and reporting of subjects who withdraw or drop out.
Data Abstraction Two reviewers with clinical and methodological expertise independently abstracted data from each eligible study. They were not blinded either to the study title or to author’s name. Disagreement was resolved through consensus. Outcomes of primary interest included mortality; serum alanine aminotransferase, aspartate aminotransferase, and albumin levels; and prothrombin times. Study
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508
Table. Summary of Randomized Placebo-Controlled Trials Meeting Inclusion Criteria*
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Jadad Score
Acuity of Disease
Trinchet (63)
116
5
Chronic
Alcohol
Mixed
Pare´ s (68)
200
5
Chronic
Alcohol
Ferenci (70)
170
5
Chronic
Bunout (64)
71
3
Salmi (65)
97
Fintelmann (69)
Etiology of Liver Disease†
Severity of Liver Disease‡
Daily Dose (mg)
Therapy (days)
Legalon
420
90
French
Cirrhosis
Legalon
450
730
French
Mixed
Cirrhosis
Legalon
420
730
English
Chronic
Alcohol
Mixed
Legalon
280
446
Spanish
3
Chronic
Alcohol
Unknown
Legalon
420
28
English
66
3
Chronic
Alcohol
Unknown
Legalon
Not given
28
German
Tanasescu (71)
177
3
Chronic
Mixed
Mixed
Silimarina
210
40
English
Magliulo (60)
59
3
Acute
Viral
Hepatitis
Legalon
420
25
German
Buzelli (62)
20
3
Chronic
Viral
Hepatitis
Silipide
240
7
English
Palasciano (72)储
60
3
Chronic
Drug-induced
Unknown
Nonstandard
800
90
English
Lang (66)
60
2
Chronic
Alcohol
Cirrhosis
Legalon
420
30
English
Feher (67)
36
2
Chronic
Alcohol
Mixed
Legalon
420
180
Hungarian
Kiesewetter (61) Marcelli (59)
24 65
1 1
Chronic Chronic
Viral Mixed
Hepatitis Hepatitis
Legalon Silipide
420 240
365 90
German English
* All trials except Marcelli (59) reported double-blind study design. † Mixed ⫽ alcohol and other forms of liver disease. ‡ Mixed ⫽ cirrhosis and other degrees of disease. § Data not reported. 储 One publication with two parallel clinical trials.
Milk Thistle Formulation
Language Published
Outcomes Mortality, histology, aspartate aminotransferase, albumin, prothrombin time Mortality, aspartate aminotransferase, alanine aminotransferase, albumin, prothrombin time Mortality, (aspartate aminotransferase, alanine aminotransferase)§ Mortality, aspartate aminotransferase, albumin, prothrombin time Histology, aspartate aminotransferase, alanine aminotransferase Aspartate aminotransferase, alanine aminotransferase Alanine aminotransferase, prothrombin time Aspartate aminotransferase, alanine aminotransferase Aspartate aminotransferase, alanine aminotransferase Aspartate aminotransferase, alanine aminotransferase Aspartate aminotransferase, alanine aminotransferase Aspartate aminotransferase, alanine aminotransferase albumin, prothrombin time Histology Aspartate aminotransferase, alanine aminotransferase, albumin, prothrombin time
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Sample Size
Author (Reference)
Milk Thistle for the Treatment of Liver Disease/Jacobs et al
Figure 1. Forest plots for randomized placebo-controlled trials reporting mortality results among patients with liver disease. The solid vertical line at 1.0 along the horizontal axis designates the point at which no effect is seen. Negative effect size (to the left of 1.0) suggests the study result favored milk thistle, and positive effect sizes (to the right of 1.0) suggest the study result favored placebo. Odds ratios (OR) compare mortality among participants assigned to milk thistle compared with those assigned to placebo. Summary odds ratio is based on a random-effects model. The area of the shaded box correlates with the contribution toward the weighted average of the summary estimate. The horizontal line for each study denotes the 95% confidence intervals. The 95% confidence interval for the combined estimate is denoted within the parentheses.
quality was defined as “high” if it received a Jadad score of 3 or greater and “low” if the score was less than 3. Liver disease was categorized by etiology (hepatitis A, B, or C; alcohol; mixed; or unknown), acuity (acute vs. chronic), and the presence of cirrhosis diagnosed by liver biopsy or laparoscopic examination.
Quantitative Data Synthesis The decision to proceed with quantitative analyses of mortality rates and biochemical markers of liver function was based on identification of trials with adequate study quality, small-to-moderate sample size, and similar study samples. Trials with outcomes on histology at liver biopsy did not have similar study samples and therefore did not meet the criteria for quantitative analysis. All estimates were adjusted for baseline differences between treatment and control groups. We calculated odds ratios and 95% confidence intervals (CI), comparing mortality between patients assigned to milk thistle and those assigned to placebo. Investigators who were contacted to obtain mortality data from the study period on patients who dropped out were unable to provide this data; therefore, these patients were excluded. In a sensitivity analysis, we performed an intention-to-treat analysis for mortality that assumed all patients who dropped out died. Continuous outcome measures were analyzed
using the Hedges-Olkin method for standardized mean differences to generate an effect size, which divides the difference between the treatment and placebo group outcome scores by the pooled standard deviation of the two groups. Effect sizes were then adjusted for between-group baseline differences and for small sample size bias using the Hedges-Olkin adjustment factor (38). To aid in interpreting the standardized mean difference effect sizes, these results were converted to equivalent laboratory values by multiplying the average of the standard deviations from the studies of each outcome by the effect size. Meta-analyses were conducted using the randomeffects model. Heterogeneity of results among studies was assessed using chi-squared tests for heterogeneity (␣ ⫽ 0.10). We performed preplanned sensitivity analyses by etiology, severity, and acuity of disease; duration of treatment; standardization of milk thistle therapy; and study quality. All analyses were performed using STATA 8.1 software (SAS Institute, Cary, North Carolina).
RESULTS We identified 1726 reports, of which 1505 were in vitro studies, animal studies, studies unrelated to liver disease, duplicate reports, or contained no primary data about
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Figure 2. Forest plots for trials of patients with chronic liver disease reporting serum alanine aminotransferase levels. The lower horizontal axis is the equivalent clinical laboratory value. The upper horizontal line represents the standardized effect sizes. The solid vertical line at 0 along the horizontal axis designates the point at which no effect is seen. Negative effect size (to the left of 0) suggests the study result favored milk thistle, and positive effect sizes (to the right of 0) suggest the study result favored placebo. The area of the shaded box correlates with the contribution toward the weighted average of the summary estimate. The horizontal line for each study denotes the 95% confidence intervals. The 95% confidence interval for the overall result is contained within the parentheses.
effectiveness. These studies did not meet inclusion criteria. Seven reports were unobtainable, one of which was a clinical trial from the abstract. We were unable to retrieve this citation because it was indexed incorrectly in the source registry (39). Full manuscripts were reviewed for the remaining 214 reports. Of these, 180 did not meet inclusion criteria. Two studies were excluded because milk thistle was used for prophylaxis among patients using hepatotoxic agents (40,41). Thirty-two controlled clinical trials remained eligible; of these, one was a duplicate study (42) and 17 were not randomized placebocontrolled trials (32,43–58). Thus, 14 trials involving 1209 participants satisfied eligibility criteria for the systematic review of efficacy (Table) (59 –72). Adverse drug effect reports were identified in 18 records.
Quality Assessment and Data Extraction Only one of these trials did not report a double-blind study design (59). Patients with acute liver disease were studied in one trial (60); the other trials studied patients with chronic liver disease. The etiology of liver disease was attributed to viral disease in three studies (60 – 62), alcoholic liver disease in seven (63– 69), mixed or unknown etiologies in three (59,70,71), and drugs in one (72). The severity of liver disease among participants in the trials varied, with three of 14 trials requiring a diagnosis of cirrhosis for study entry, including two for alcohol-related cirrhosis (66,68) and one for cirrhosis of mixed etiologies (70). 510
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All but two trials used standardized formulations of milk thistle (71,72). Specifically, 10 used Legalon (Madaus Corporation, Cologne, Germany) and two used Silipide (Inverni Della Beffa Research and Development Laboratories, Milan, Italy), which was formulated to enhance bioavailability using a 1:1 ratio of silybin and phosphatidylcholine. Eight trials were published in English, three in German, and one each in Spanish, French, and Hungarian. Sample size varied from 20 to 200 subjects, with five trials enrolling 90 or more patients. Six trials were considered short term (⬍90 days of treatment). Duration of therapy ranged from 7 days to 2 years. Baseline screening was conducted for hepatitis B antigen in seven trials and for hepatitis C infection in one trial (62). No trial screened for human immunodeficiency virus infection or subsequent exposure to hepatitis B or C at study end. Few studies employed systematic laboratory monitoring for alcohol use during the study. Quality scores were fair, with 10 (71%) of 14 trials receiving a score of 3 or higher on the Jadad scale. The mean (⫾SD) quality score for all trials was 3.0 ⫾ 1.3.
Mortality Four trials (63,64,68,70), involving 433 participants who completed the trials (557 participants were enrolled), reported mortality data. All trials were high-quality studies (Jadad score ⱖ3; Table). All trials included patients with alcohol-related liver disease; three trials limited inclusion
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Figure 3. Forest plots for trials of patients with liver disease reporting serum aspartate aminotransferase levels. The lower horizontal axis is the equivalent clinical laboratory value. The upper horizontal line represents the standardized effect sizes. The solid vertical line at 0 along the horizontal axis designates the point at which no effect is seen. Negative effect size (to the left of 0) suggests the study result favored milk thistle, and positive effect sizes (to the right of 0) suggest the study result favored placebo. The area of the shaded box correlates with the contribution toward the weighted average of the summary estimate. The horizontal line for each study denotes the 95% confidence intervals. The 95% confidence interval for the overall result is contained within the parentheses.
to patients with alcohol-related liver disease (63,64,68), two trials limited inclusion to patients with cirrhosis (68,70), and three trials provided treatment for more than 12 months (25,68,70). The overall summary odds ratio for mortality in the milk thistle group compared with placebo was 0.8 (95% CI: 0.5 to 1.5; P ⫽ 0.6; test for heterogeneity, P ⫽ 0.3; Figure 1). In subgroup analyses of participants with alcohol-related liver disease, the summary odds ratio for the milk thistle group compared with placebo was 0.8 (95% CI: 0.4 to 1.7; P ⫽ 0.6; test for heterogeneity, P ⫽ 0.2). Limiting analyses to trials with at least 12 months of therapy and sensitivity analysis to account for subjects who dropped out yielded similar results.
Histology Three trials involving 237 participants assessed histology of liver biopsy specimens (Table) (61,63,64). We limited the review to a qualitative assessment because of variable study samples and limited data. Study quality was inversely associated with the likelihood of reporting a clinical benefit for milk thistle compared with placebo. The trial with the highest quality score (Jadad score of 5) found that treatment had no effect on histology (63). A second trial (Jadad score of 3) found treatment to be associated with statistically significant improvements in
liver histology (64), and a third trial (Jadad score of 1) identified a substantive clinical effect on improved liver histology results (61); however, the sample size was small and the findings did not reach statistical significance (P ⫽ 0.05 to 0.10).
Biochemical Markers We identified 11 randomized, placebo-controlled trials (n ⫽ 840 patients) that reported serum alanine aminotransferase levels. Overall, there was a 5-IU/L reduction in alanine aminotransferase levels among patients assigned to milk thistle compared with placebo (95% CI: ⫺17 to 6 IU/L; P ⫽ 0.3; test for heterogeneity, P ⫽ 0.001). Among the 10 studies enrolling patients with chronic liver disease, there was a 9-IU/L reduction in levels among those assigned to milk thistle compared with placebo (95% CI: ⫺18 to ⫺1 IU/L; P ⫽ 0.05; test for heterogeneity, P ⫽ 0.06; Figure 2). This statistically significant improvement was no longer present after limiting analyses to studies of longer duration (P ⫽ 0.15) or higher quality (P ⫽ 0.5). In 12 trials (n ⫽ 838) that assessed serum aspartate aminotransferase levels, the milk thistle group had a 5-IU/L greater reduction in levels than did the placebo group (95% CI: ⫺15 to 5 IU/L; P ⫽ 0.3; test for heterogeneity, P ⫽ 0.03; Figure 3). Limiting the analysis to stud-
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Figure 4. Forest plots for trials of patients with chronic liver disease reporting serum albumin levels. The lower horizontal axis is the equivalent clinical laboratory value. The upper horizontal line represents the standardized effect sizes. The solid vertical line at 0 along the horizontal axis designates the point at which no effect is seen. Negative effect size (to the left of 0) suggests the study result favored milk thistle, and positive effect sizes (to the right of 0) suggest the study result favored placebo. The area of the shaded box correlates with the contribution toward the weighted average of the summary estimate. The horizontal line for each study denotes the 95% confidence intervals. The 95% confidence interval for the overall result is contained within the parentheses.
ies of patients with chronic liver disease removed heterogeneity but revealed similar results. Five trials that assessed serum albumin levels in 476 participants found a 0.06-g/dL greater reduction in albumin levels among those assigned to milk thistle compared with placebo (95% CI: ⫺0.3 to 0.1 g/dL; P ⫽ 0.6; test for heterogeneity, P ⫽ 0.17; Figure 4). Six randomized, placebo-controlled trials involving 496 participants reported changes in prothrombin times: a 2-second greater reduction among patients assigned to milk thistle compared with placebo (95% CI: ⫺6 to 2 seconds; P ⫽ 0.3; test for heterogeneity, P ⫽ 0.1; Figure 5). Subgroup and sensitivity analyses for each outcome revealed similar results.
Adverse Drug Effects Adverse drug effects were identified in 18 reports, which included seven randomized controlled clinical trials (41,48,59,64,68,70,73), six cohort studies (74 –79) (including one abstract [76]), and five case reports (80 – 84) involving more than 7000 participants. These reports did not indicate whether events were ascertained through standardized monitoring or voluntary self-report. There were three reports of serious adverse effects. In one, the patient developed gastroenteritis symptoms associated with “collapse” from a combination herbal formula containing milk thistle, with recurrent symptoms after the patient was rechallenged (80). The other two described anaphylactic reactions from ingestion of silybum marianum tea (81) and Carsil (82). Gastrointestinal symp512
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toms were the most common adverse effects reported. Overall, the frequency was low, ranging from 2% to 10% in controlled trials, which was indistinguishable from that of placebo. Other adverse effects included dermatological symptoms and headaches, which were similar in frequency between placebo and treatment groups.
DISCUSSION This systematic review of the efficacy and adverse effects of milk thistle for the treatment of liver disease found no mortality benefit during a 3-month to 4-year follow-up and no improvement in biochemical liver function tests. There were, however, limited data to address the effect of milk thistle on mortality. We found a statistically significant greater reduction in serum alanine aminotransferase levels among studies enrolling patients with chronic liver disease, although this reduction was of negligible clinical importance and no longer statistically significant after limiting analyses to studies of longer duration or of higher quality. The adverse effects of milk thistle were indistinguishable from those of placebo. Heterogeneity of study samples precluded calculating a summary estimate of the effect of milk thistle on liver histology. Although the difference in mortality between groups did not achieve statistical significance, two studies reported a mortality benefit for selected participants. Ferenci et al. (70) reported a mortality benefit in a subgroup
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Figure 5. Forest plots for trials of patients with chronic liver disease reporting serum prothrombin time. The lower horizontal axis is the equivalent clinical laboratory value. The upper horizontal line represents the standardized effect sizes. The solid vertical line at 0 along the horizontal axis designates the point at which no effect is seen. Negative effect size (to the left of 0) suggests the study result favored milk thistle, and positive effect sizes (to the right of 0) suggest the study result favored placebo. The area of the shaded box correlates with the contribution toward the weighted average of the summary estimate. The horizontal line for each study denotes the 95% confidence intervals. The 95% confidence interval for the overall result is contained within the parentheses.
analysis of patients with alcohol-related cirrhosis or Child’s class A cirrhosis. Pare´ s and colleagues studied patients with alcohol-related cirrhosis and performed a post hoc analysis using stored serum from 75 of the 200 patients in the study (68). They reported a trend for statistical significance in decreased mortality among patients with alcohol-related cirrhosis who had hepatitis C infection. These subgroup findings should be viewed with caution. Among the 18 reports reporting drug-related adverse effects, milk thistle appeared safe for patients and well tolerated. We recognize it is difficult to interpret the risk of adverse events from the literature for several reasons. Events may be missed because search terms related to adverse events are often not indexed, and causality is difficult to discern when events are published in a case report or case series. This systematic review has several limitations. The main finding of no difference in mortality among persons treated with milk thistle versus placebo is based on the results of only four trials that included 433 subjects. The small sample limits the power of the meta-analysis to assess any mortality benefit (or harm) attributed to milk thistle; thus, the confidence interval for the pooled estimate is sufficiently wide that a substantial benefit or harm cannot be excluded. Furthermore, we defined liver disease broadly, and our approach may have included types of liver disease that are un-
responsive to milk thistle, resulting in a more conservative summary estimate of effect. However, the proposed mechanisms of action of milk thistle are not directed at a specific toxin or virus, and therefore the etiology of liver disease should not affect outcome. Most studies included in the review used imprecise definitions of liver disease, such as cirrhosis “regardless of etiology.” Determination of cirrhosis status was made by histological criteria in only a few studies. Etiology of liver disease was either not reported or divided into alcohol and non–alcohol related only. Screening for hepatitis B was performed inconsistently, and hepatitis C screening predated all but one study. Given the high prevalence of hepatitis C infection among patients formerly diagnosed with non-A–non-B hepatitis, we hypothesize that a large proportion of subjects were infected with hepatitis C. Finally, few investigators screened for ongoing alcohol consumption, which, if prevalent, might have reduced the efficacy of treatment. In summary, treatment with milk thistle appears to be safe and well tolerated, but has no effect on mortality or improvements in liver histology or biochemical markers of liver function among patients with chronic liver disease. Future trials on milk thistle must have adequate sample size, enroll patients with well-defined liver disease, and devote adequate resources to monitor outcomes for subjects who dropped out. At this time, there is insufficient evidence to
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support recommending this herbal compound to patients for the treatment of liver disease.
ACKNOWLEDGMENT We are indebted to the following for their contributions to this project: Kenneth Flora, MD, for expert advice regarding liver disease; Christine Aguilar, MD, MPH, Laura Morbidoni, MD, and Kelly Montgomery, MPH, for assistance in data abstraction; Andrew Vickers, MD, and Molly Harris, MLS, MA, for performing the literature search; Jennifer Arterburn, MTSC, for assistance with technical writing and coordinating peer review; and Diane Garvin for coordinating study materials between the University of California, San Francisco, and the University of Texas Health Science Center at San Antonio.
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