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Milk Thistle for Alcoholic and/or Hepatitis B or C Liver Diseases: study showed no benefit-A
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Systematic Cochrane Hepato-Biliary Group Review with Meta-Analyses of Randomized Clinical Trials
The American Journal of Gastroenterology
Volume 100 Page 2583 - November 2005
Andrea Rambaldi, M.D.1, Bradly P. Jacobs, M.D., M.P.H.2, Gaetano Iaquinto, M.D.3, and Christian Gluud, M.D., Dr. Med. Sci.1
ABSTRACT
OBJECTIVES: Our objectives were to assess the beneficial and harmful effects of milk thistle (MT)or MT constituents versus placebo or no intervention in patients with alcoholic liver disease and/or hepatitis B and/or C liver diseases.
METHODS: Randomized clinical trials studying patients with alcoholic and/or hepatitis B or C liver diseases were included (December 2003). The randomized clinical trials were evaluated by components of methodological quality.
RESULTS: Thirteen randomized clinical trials assessed MT in 915 patients with alcoholic and/or hepatitis B or C liver diseases. The methodological quality was low: only 23% of the trials reported adequate allocation concealment and only 46% were considered double blind. MT versus placebo or no intervention for a median duration of 6 months had no significant effects on all-cause mortality (relative risk (RR)0.78, 95% confidence interval (CI)0.53-1.15), complications of liver disease, or liver histology. Liver-related mortality was significantly reduced by MT in all trials (RR 0.50, 95% CI 0.29-0.88), but not in high-quality trials (RR 0.57, 95% CI 0.28-1.19). MT was not associated with a significantly increased risk of adverse events.
CONCLUSIONS: Based on high-quality trials, MT does not seem to significantly influence the course of patients with alcoholic and/or hepatitis B or C liver diseases. MT could potentially affect liver injury. Adequately conducted randomized clinical trials on MT versus placebo may be needed.
INTRODUCTION
Extracts of milk thistle (MT), Silybum marianum (L)Gaertneri, have been used as medical remedies since the time of ancient Greece and are widely used as an alternative medication (1-3). Silymarin is the collective name for the flavonolignans (silybin or silibinin, silydianin, silychristin)extracted from the MT (2). These extracts have been shown to protect animals against various hepatotoxins including acetaminophen (4, 5), radiation (6), iron overload (7), phaloidin (8, 9), carbon tetrachloride (10-12), and thioacetamide (13). The "hepatoprotective" actions of MT may include inhibition of lipid peroxide formation, scavenging of free radicals, and changing of the physical properties of cell membranes (1, 14-16). Increased lipid peroxidation is frequent in all stages of liver damage from alcoholic and non-alcoholic liver disease (17). MT may also reduce liver fibrogenesis (18, 19).
This systematic review summarizes the data from randomized clinical trials to examine the beneficial and harmful effects of MT for alcoholic and/or hepatitis B or C liver diseases. The reasons for focusing on these disorders, having different etiologies, are the following. First, many trials conducted before the 1980s did not exclude the etiology of hepatitis B virus and many trials conducted before the 1990s did not exclude the etiology of hepatitis C virus. Second, alcoholic and viral liver diseases often coexist. Third, alcohol and hepatitis B and/or C constitute the major etiologies of chronic liver diseases in the Western World (20).
DISCUSSION
We found no significant effect of MT on all-cause mortality. We observed a potential beneficial effect of MT on mortality in patients with alcoholic liver disease, but this effect could not be confirmed in two high-quality trials. We also observed a potential beneficial effect of MT on liver-related mortality, but again this effect could not be demonstrated in three high-quality trials. As the methodological quality of some of the trials was low, we are not able to exclude bias as the cause of our positive findings (24-26). The methods and definitions used to establish liver-related mortality varied or were unclear. Therefore, this outcome measure should be cautiously evaluated. Further, publication bias and selective reporting bias must be considered (56, 57). The estimate on all-cause mortality in high-quality trials was a RR of 0.95 (95% CI 0.55-1.65). This estimate is compatible with a 45% reduction in all-cause mortality as well as with a 65% increase in all-cause mortality. In general, one should only introduce interventions based on findings in high-quality trials (24-26).
Our observations confirm two recent meta-analyses on MT for patients with liver disease of any cause (3, 58, 59), in spite of the following facts. Our systematic review included five more randomized clinical trials (41, 44, 52, 54, 55), excluded data from quasi-randomized clinical trials (59), which may significantly bias estimates of interventions effects (26, 60), and included more patients with alcoholic liver disease (3).
The statistically significant effect of MT on all-cause mortality identified in subgroup analysis of patients with alcohol-related liver disease were not confirmed in a further subgroup analysis including patients with alcoholic liver disease co-infected by HCV. Further, this effect could not be demonstrated in three high-quality trials (24-26). Therefore our findings are not robust enough to form a fundament for therapeutic recommendations.
We found that MT significantly improved two liver biochemical variables, s-bilirubin and GGT. For the remainder of our analyses on liver biochemistry markers, MT had either effects that were dependent on the statistical model we used or had no significant effects. Further, when focusing on high-quality trials we could not demonstrate significant effects (24-26). In all circumstances the effects of MT on liver biochemistry were not dramatic.
This systematic review has a number of potential limitations. First, the small sample size limits the power of our meta-analyses. The CI for the pooled estimate is sufficiently wide, meaning that a substantial benefit or harm cannot be excluded. Our review does not preclude the possibility of a beneficial or harmful effect of MT in alcoholic liver disease or in other forms of liver disease for that matter. Evidence show how much effects of medical intervention may change over time. Ioannidis and Lau (61)applied "recursive cumulative meta-analyses" of randomized clinical trials to evaluate the relative change in the pooled treatment effect over time for 60 medical interventions within pregnancy/perinatal medicine and cardiology. When 2,000 patients have been randomized, the pooled RR may change by a factor 0.7 to 1.3. At present, only about 1,000 patients with alcoholic liver disease and/or hepatitis B and C have been randomized to MT versus placebo or no intervention. Second, we chose to include only alcoholic liver disease and viral liver disease in the review. The major reason is that viral and alcohol-related liver diseases frequently coexist in the same patient. Several trials were old and did not check for viral liver disease in patients with suspected alcoholic liver disease. Further, hepatitis B or C marker positivity was not an exclusion criterion for the entry of the patient in one of the trials on patients with alcoholic liver disease (50). Other liver diseases like non-alcoholic liver disease and toxic liver diseases should be considered in other reviews. Finally, the duration of treatment as well as the dosing and the preparation of MT varied. This may have caused variable intervention effects. However, none of our subgroup analyses revealed that these factors were responsible for our finding of lack of intervention effects.
Among the randomized clinical trials reporting adverse drug events, MT appeared safe and well tolerated. We recognize it is difficult to interpret the risk of adverse events from the literature for several reasons (62). Events may be missed since 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. Among the studies that we excluded were some randomized clinical trials considering 180 patients with unspecified form of liver diseases (63). MT seemed to be well tolerated in this trial, although adverse events have been reported in the literature (64).
In conclusion, although MT constituents have been used as a medical intervention for more than 2,500 yr, there remains insufficient evidence to support or to refute its use for liver patients. We need to conduct high-quality, placebo-controlled randomized trials before MT or MT constituents can be advocated for patients with alcoholic and/or viral liver disease.
RESULTS
Search Results
We identified 1,833 references through electronic searches of The Cochrane Hepato-Biliary Group Controlled Trials Register (n = 40), The Cochrane Library (n = 75), and MEDLINE and EMBASE (n = 1,716)and through reading bibliographies (n = 2)(Fig. 1). Of these, 1,766 were in vitro studies, animal studies, studies unrelated to liver disease, duplicate reports, or on other patient types. Therefore, these references did not meet our inclusion criteria and were excluded. The remaining 67 publications were on patients with alcoholic and/or hepatitis B or C liver diseases treated with MT. Of these, 41 publications were excluded because they were observational studies or randomized trials that did not fulfil our inclusion criteria. Accordingly, 26 references referring to 13 randomized clinical trials could be included (30-55).
Included Trials
Eleven of the 13 randomized clinical trials were described in full paper articles (30, 31, 34, 39, 41, 44, 48-52)and two in abstract only (54, 55).
The experimental treatment consisted of silymarin orally in 10 randomized clinical trials (30, 34, 39, 44, 48-52, 55); IdB1016 orally in two randomized clinical trials (IdB1016 is a lipophilic complex with silybin and phosphatidylcholine in a molar ratio of 1:1)(31, 54); and silybin-B-cyclodextrin, a new oral formulation containing silybin, in one randomized clinical trial (41).
The randomized clinical trials could be divided into four groups according to etiology:
- chronic alcoholic liver disease included 657 patients, of which the majority had cirrhosis (30, 34, 39, 41, 44, 48, 51, 52, 55);
- hepatitis B included 8 patients with acute hepatitis B (49);
- hepatitis C included 10 patients with chronic hepatitis C (54);
- alcoholic and/or hepatitis B or C liver diseases (31, 50), of which one trial included 20 patients with hepatitis B and hepatitis C (31)and the other
included 200 patients with alcoholic liver disease with or without HCV antibody positivity (50). Anti-HCV antibodies were positive in 29 (13 receiving MT and 16 receiving placebo)of the 75 patients for whom stored sera were available after completion of the trial (50).
Excluded Studies
A total of 33 studies on MT for liver diseases, described in 43 publications (available on request), were excluded mainly because they were observational studies or case series.
Methodological Quality of Included Trials
Only one (51)of the 13 randomized clinical trials provided a sample size estimation that was based on liver histology.
The method to generate the allocation sequence was considered adequate in six (46.2%)of the trials (30, 39, 41, 44, 50, 51).
Only three (23.1%)of the trials described adequate allocation concealment (44, 50, 51).
All but one of the trials (52)were described as double blinded (92.3%). However, only six (46.2%)trials described the use of placebo with identical presentation in the control arm (31, 39, 41, 44, 50, 51). None of the trials checked the success of blinding.
There was a fair description of follow-up and withdrawals/drop-outs in 12 (92.3%)trials (30, 31, 34, 39, 41, 44, 48-52, 54). None of the trials stated that they used an intention-to-treat method to evaluate their data. All the trials but three (30, 41, 44)presumably used intention-to-treat analysis.
All-Cause Mortality
Combining the results of the 13 randomized clinical trials demonstrated no significant effect of MT given for a median duration of 6 months (range 1 wk to 41 months)on all-cause mortality (RR 0.78, 95% CI 0.53-1.15). There was no significant heterogeneity (I2= 5.9%). In the MT group, 36/456 (7.9%)patients died versus 45/459 (9.8%)patients in the control group (Fig. 2).
Subgroup analyses stratifying the randomized clinical trials according to the single methodological quality components (generation of the allocation sequence, allocation concealment, blinding, and follow-up)did not demonstrate significant differences regarding the effect of MT on all-cause mortality between trials with and without adequate methodology.
Subgroup analysis stratifying the randomized clinical trials into trials with all components adequate, trials having some components adequate, and trials without any of components adequate (not estimable since no events occurred in this group)(Fig. 3), did not demonstrate significant effects of MT on all-cause mortality.
MT did not significantly influence all-cause mortality in the trials with a treatment duration less than 6 months (RR 0.35; 95% CI 0.04-3.22)or in the trials with a duration of treatment of at least 6 months (RR 0.81, 95% CI 0.54-1.20); or in the trials including patients with chronic liver disease (data not shown); the RR in the trials including patients with acute liver disease was not estimable since no events occurred in this group. A worst-case scenario analysis considering all patients who dropped out or were withdrawn dead did not find a significant effect of MT (RR 1.09; 95% CI 0.75-1.58). None of the trials reported mortality data distributed on Child class or other prognostic classification.
MT significantly decreased all-cause mortality in patients with alcoholic liver disease (RR 0.58, 95% CI 0.34-0.98; p= 0.04)(30, 34, 39, 41, 44, 48, 51, 52, 55). There was no significant heterogeneity (I2= 0%). In the MT group 16/325 (4.9%)patients died versus 28/332 (8.4%)in the control group. This finding could not be confirmed nor refuted in two high-quality trials (RR 0.34, 95% CI 0.06-2.11)(44, 51).
In patients with alcoholic liver disease or alcoholic liver disease with HCV antibody positivity (50), MT demonstrated no significant effect on all-cause mortality (RR 1.11, 95% CI 0.62-1.99). In the MT group 20/103 (19.4%)patients died versus 17/97 (17.5%)in the control group. In patients with hepatitis B (49)none of the patients died out of the 13 in the MT and 15 in the control group. In patients with hepatitis C (54)none of the patients died out of the 5 in the MT and 5 in the control group. In patients with hepatitis B and hepatitis C (31)none of the patients died out of the 10 in the MT and 10 in the control group.
Liver-Related Mortality
Among the 13 trials only four reported liver-related mortality (Fig. 4)(39, 44, 50, 51). Three of the trials included patients with alcoholic liver disease (39, 44, 51)and the Pares et al. trial included patients with alcoholic liver disease or alcoholic liver disease with HCV antibody positivity (50). These trials found a significant effect of MT on liver-related mortality (RR 0.50, 95% CI 0.29-0.88; p= 0.02). There was no significant heterogeneity (I2= 0%). In the MT group, 16/422 (3.8%)patients died versus 31/422 (7.3%)patients in the control group.
Subgroup analysis demonstrated no significant effect of MT on liver-related mortality in the three trials having all four methodological components adequate (RR 0.57, 95% CI 0.28-1.19)whereas MT significantly decreased mortality in the trials having only one or more components adequate (RR 0.41, 95% CI 0.17-0.97). This effect was based on only one trial with less than 100 patients randomized (39). There was no significant difference between the two estimates (test of interaction z = 0.57). The effect of MT on liver-related deaths in the trials with no adequate methodological component was not estimable due to any deaths. A worst-case scenario analysis of patients with alcoholic liver disease (all patients who dropped-out or were withdrawn were considered dead)changed the estimate to no significant effect of MT on liver-related mortality (RR 0.81, 95% CI 0.58-1.13).
Liver-Related Complications
In the only trial reporting individual liver-related complications, MT did not significantly affect the incidence of patients with ascites, hepatic encephalopathy, or gastro-intestinal bleeding (50). MT demonstrated no significant effect on combined liver-related complications (44, 50).
Liver Biochemistry and Liver Histology
MT significantly decreased s-bilirubin concentration and GGT activity in both fixed effect and random effects model analyses:
- s-bilirubin: WMD -4.68 Mmol/L (95% CI -7.72 to -1.64 Mmol/L; p< 0.05)(fixed effect model). There was no significant heterogeneity (I2= 0%)
- GGT: WMD -26.80 U/L (95% CI -32.86 to -20.73 U/L; p< 0.05)(fixed effect model). There was significant heterogeneity (I2= 68%).
MT showed a significant beneficial effect on AST and ALT when analyzed by the fixed effect model, but not in the random effects model. MT did not significantly influence prothrombin or s-albumin. There were no significant effects of MT on liver biopsy findings in the only trial reporting this outcome (51).
Adverse Events
In the MT group 0/456 patients had serious adverse events versus 0/459 patient in the control group. MT did not significantly affect the occurrence of non-serious adverse events (RR 0.83, 95% CI 0.46-1.50). In the MT group, 16/456 (3.5%)patients had non-serious adverse events versus 20/459 (4.4%)patients in the control group. The adverse events observed in the MT group encompassed impotence (one patient), pruritus (four patients), cephalea (three patients), and nausea (one patient). The authors did not report the type of adverse event in seven patients. The adverse events observed in the control group were pruritus (11 patients), cephalea (four patients), and nausea (one patient). The authors did not report the type of adverse events in four patients.
PATIENTS AND METHODS
Inclusion Criteria
We applied The Cochrane Collaboration methodology (21)and followed our predefined, peer-reviewed, published Cochrane Hepato-Biliary Group protocol (22). Only randomized clinical trials were included (22). Patients with alcoholic liver cirrhosis, liver fibrosis, hepatitis, and/or steatosis as well as patients with viral induced liver disease (hepatitis B and/or hepatitis C)according to the diagnostic work-up used in the individual trial were included (22). The trials should have administered MT or any MT constituent at any dose or duration versus placebo or no intervention (22).
Types of Outcome Measures
The primary outcome measure was the number of patients dying (22). Secondary outcomes measures were the development of clinical symptoms and complications analyzed separately and combined, liver biochemistry, liver biopsy findings, as well as number and type of adverse events (22).
Search Strategy for Trials
The following databases were searched: The Cochrane Hepato-Biliary Group Controlled Trials Register (December 2003), The Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 4, 2003), MEDLINE (1966 to December 2003), and EMBASE (1974 to December 2003)using the search terms "milk thistle" or "silymarin" or "silybin" or "silibinin" or "silydianin" or "silychristin" or commercial names (Legalon , Silipide , Realsil , Carsil , Siliphos )and "liver disease" or "alcoholic liver disease" or "viral liver disease" or "hepatitis B" or "hepatitis C" (22). The MEDLINE search was combined with the search strategy of The Cochrane Hepato-Biliary Group (23).
The principal authors of the identified trials were approached and inquired about additional randomized clinical trials. Pharmaceutical companies involved in the production of MT products were contacted in order to obtain unidentified published or unpublished randomized clinical trials.
Patient Characteristics, Diagnosis, and Interventions
The following items were recorded from the individual randomized clinical trials: mean (or median)age, sex ratio, liver disease according to the etiology, duration of liver disease, severity of liver disease at entry, alcohol consumption at entry, type and dose of MT-intervention, and type of control intervention. Development of clinical symptoms and complications, liver biochemistry (serum (s)-bilirubin, prothrombin time, s-albumin, s-aspartate aminotransferase (AST), s-alanine aminotransferase (ALT), s-alkaline phosphatases (AP), s-gamma-glutamyl transferase (GGT)), liver biopsy findings, alcohol consumption, quality of life, and adverse events during follow-up were registered.
Assessment of Methodological Quality
The methodological quality of the randomized clinical trials was assessed using individual components of methodological quality (22, 24-26). We registered whether the randomized clinical trial reported the use of intention-to-treat analysis, i.e., all patients randomized must be retained in the trial (22). Data on the number of patients with each outcome by allocated treatment group, irrespective of compliance of follow-up, were sought to allow an intention-to-treat analysis.
Statistical Analyses
The meta-analyses were performed in Review Manager Software (version 4.2.7)from The Cochrane Collaboration (http://www.cochrane.org). We examined all outcomes with both the random effects model and the fixed effect model (27, 28). Dichotomous data were analyzed by calculating the relative risk (RR)and continuous outcomes as weighed mean difference (WMD), both with 95% confidence intervals (CI). Heterogeneity was examined by the X2 test (p< 0.1)and a useful statistic for quantifying inconsistency (I2=[(Q - df )/Q]X 100%, where Q is the X2 statistic and df is its degrees of freedom)(29). Potential causes for heterogeneity were explored by performing subgroup analyses.
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