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16028RE: [GIWorld-Hepatitis] FW: NATAP: Milk Thistle Study Found No Benefit

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  • alleypat
    Dec 28, 2005
      didn't seem to help me either way and just seemed like something else for my
      liver to filter out, make it work more. Hope it works for someone.

      "If the doctor told me I had six minutes to live, I'd type a little
      faster." --Isaac Asimov

      -----Original Message-----
      From: GIWorld-Hepatitis@yahoogroups.com
      [mailto:GIWorld-Hepatitis@yahoogroups.com]On Behalf Of avansi7465
      Sent: Wednesday, December 28, 2005 4:29 PM
      To: GIWorld-Hepatitis@yahoogroups.com
      Subject: Re: [GIWorld-Hepatitis] FW: NATAP: Milk Thistle Study Found No

      Well, at least it doesn't do any damage...........so.......considering
      that my liver.........for the first time.......is showing signs of
      regeneration, I think I'll stick with the program, which does include Milk
      Happy New Year!

      -----Original Message-----
      >From: alleypat <alleypat@...>
      >Sent: Dec 28, 2005 10:47 AM
      >To: GIWorld-Hepatitis@yahoogroups.com, happyheppers@yahoogroups.com
      >Subject: [GIWorld-Hepatitis] FW: NATAP: Milk Thistle Study Found No
      >Milk Thistle for Alcoholic and/or Hepatitis B or C Liver Diseases: study
      >showed no benefit-A 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
      >M.D.3, and Christian Gluud, M.D., Dr. Med. Sci.1
      >OBJECTIVES: Our objectives were to assess the beneficial and harmful
      >of milk thistle (MT) or MT constituents versus placebo or no intervention
      >patients with alcoholic liver disease and/or hepatitis B and/or C liver
      >METHODS: Randomized clinical trials studying patients with alcoholic
      >hepatitis B or C liver diseases were included (December 2003). The
      >randomized clinical trials were evaluated by components of methodological
      >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
      >no intervention for a median duration of 6 months had no significant
      >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
      >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.
      >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
      >against various hepatotoxins including acetaminophen (4, 5), radiation
      >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).
      >lipid peroxidation is frequent in all stages of liver damage from
      >and non-alcoholic liver disease (17). MT may also reduce liver
      >(18, 19).
      >This systematic review summarizes the data from randomized clinical
      >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
      >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
      >etiologies of chronic liver diseases in the Western World (20).
      >We found no significant effect of MT on all-cause mortality. We observed
      >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
      >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
      >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
      >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.
      >systematic review included five more randomized clinical trials (41, 44,
      >54, 55), excluded data from quasi-randomized clinical trials (59), which
      >significantly bias estimates of interventions effects (26, 60), and
      >more patients with alcoholic liver disease (3).
      >The statistically significant effect of MT on all-cause mortality
      >in subgroup analysis of patients with alcohol-related liver disease were
      >confirmed in a further subgroup analysis including patients with
      >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
      >We found that MT significantly improved two liver biochemical variables,
      >s-bilirubin and GGT. For the remainder of our analyses on liver
      >markers, MT had either effects that were dependent on the statistical
      >we used or had no significant effects. Further, when focusing on
      >high-quality trials we could not demonstrate significant effects (24-26).
      >all circumstances the effects of MT on liver biochemistry were not
      >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
      >harm cannot be excluded. Our review does not preclude the possibility of
      >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
      >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
      >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
      >in patients with suspected alcoholic liver disease. Further, hepatitis B
      >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
      >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
      >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
      >the risk of adverse events from the literature for several reasons (62).
      >Events may be missed since search terms related to adverse events are
      >not indexed, and causality is difficult to discern when events are
      >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
      >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
      >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
      >Search Results
      >We identified 1,833 references through electronic searches of The
      >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
      >other patient types. Therefore, these references did not meet our
      >criteria and were excluded. The remaining 67 publications were on
      >with alcoholic and/or hepatitis B or C liver diseases treated with MT. Of
      >these, 41 publications were excluded because they were observational
      >or randomized trials that did not fulfil our inclusion criteria.
      >Accordingly, 26 references referring to 13 randomized clinical trials
      >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,
      >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
      >phosphatidylcholine in a molar ratio of 1:1) (31, 54); and
      >silybin-N2-cyclodextrin, a new oral formulation containing silybin, in
      >randomized clinical trial (41).
      >The randomized clinical trials could be divided into four groups
      >to etiology:
      >o chronic alcoholic liver disease included 657 patients, of which
      >majority had cirrhosis (30, 34, 39, 41, 44, 48, 51, 52, 55);
      >o hepatitis B included 8 patients with acute hepatitis B (49);
      >o hepatitis C included 10 patients with chronic hepatitis C (54);
      >o alcoholic and/or hepatitis B or C liver diseases (31, 50), of
      >one trial included 20 patients with hepatitis B and hepatitis C (31) and
      >other included 200 patients with alcoholic liver disease with or without
      >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
      >(available on request), were excluded mainly because they were
      >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
      >(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
      >presentation in the control arm (31, 39, 41, 44, 50, 51). None of the
      >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
      >All the trials but three (30, 41, 44) presumably used intention-to-treat
      >All-Cause Mortality
      >Combining the results of the 13 randomized clinical trials demonstrated
      >significant effect of MT given for a median duration of 6 months (range 1
      >to 41 months) on all-cause mortality (RR 0.78, 95% CI 0.53-1.15). There
      >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.
      >Subgroup analyses stratifying the randomized clinical trials according to
      >the single methodological quality components (generation of the
      >sequence, allocation concealment, blinding, and follow-up) did not
      >demonstrate significant differences regarding the effect of MT on
      >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
      >MT on all-cause mortality.
      >MT did not significantly influence all-cause mortality in the trials with
      >treatment duration less than 6 months (RR 0.35; 95% CI 0.04-3.22) or in
      >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
      >(data not shown); the RR in the trials including patients with acute
      >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%
      >0.75-1.58). None of the trials reported mortality data distributed on
      >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,
      >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
      >This finding could not be confirmed nor refuted in two high-quality
      >(RR 0.34, 95% CI 0.06-2.11) (44, 51).
      >In patients with alcoholic liver disease or alcoholic liver disease with
      >antibody positivity (50), MT demonstrated no significant effect on
      >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
      >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
      >the MT and 10 in the control group.
      >Liver-Related Mortality
      >Among the 13 trials only four reported liver-related mortality (Fig. 4)
      >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
      >significant heterogeneity (I2= 0%). In the MT group, 16/422 (3.8%)
      >died versus 31/422 (7.3%) patients in the control group.
      >Subgroup analysis demonstrated no significant effect of MT on
      >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
      >than 100 patients randomized (39). There was no significant difference
      >between the two estimates (test of interaction z = 0.57). The effect of
      >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
      >no significant effect of MT on liver-related mortality (RR 0.81, 95% CI
      >Liver-Related Complications
      >In the only trial reporting individual liver-related complications, MT
      >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:
      >o s-bilirubin: WMD -4.68 N<mol/L (95% CI -7.72 to -1.64 N<mol/L; p<
      >0.05) (fixed effect model). There was no significant heterogeneity (I2=
      >o 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
      >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
      >of non-serious adverse events (RR 0.83, 95% CI 0.46-1.50). In the MT
      >16/456 (3.5%) patients had non-serious adverse events versus 20/459
      >patients in the control group. The adverse events observed in the MT
      >encompassed impotence (one patient), pruritus (four patients), cephalea
      >(three patients), and nausea (one patient). The authors did not report
      >type of adverse event in seven patients. The adverse events observed in
      >control group were pruritus (11 patients), cephalea (four patients), and
      >nausea (one patient). The authors did not report the type of adverse
      >in four patients.
      >Inclusion Criteria
      >We applied The Cochrane Collaboration methodology (21) and followed our
      >predefined, peer-reviewed, published Cochrane Hepato-Biliary Group
      >(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
      >constituent at any dose or duration versus placebo or no intervention
      >Types of Outcome Measures
      >The primary outcome measure was the number of patients dying (22).
      >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
      >Controlled Trials on The Cochrane Library (Issue 4, 2003), MEDLINE (1966
      >December 2003), and EMBASE (1974 to December 2003) using the search terms
      >"milk thistle" or "silymarin" or "silybin" or "silibinin" or "silydianin"
      >"silychristin" or commercial names (LegalonB., SilipideB., RealsilB.,
      >CarsilB., SiliphosB.) 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
      >Group (23).
      >The principal authors of the identified trials were approached and
      >about additional randomized clinical trials. Pharmaceutical companies
      >involved in the production of MT products were contacted in order to
      >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
      >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
      >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
      >from The Cochrane Collaboration (http://www.cochrane.org). We examined
      >outcomes with both the random effects model and the fixed effect model
      >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 O2 test (p<
      >0.1) and a useful statistic for quantifying inconsistency (I2=[(Q -
      >df )/Q]C 100%, where Q is the O2 statistic and df is its degrees of
      >freedom) (29). Potential causes for heterogeneity were explored by
      >performing subgroup analyses.
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