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

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  • avansi7465
    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
    Message 1 of 12 , Dec 28, 2005
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      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 Thistle.
      Happy New Year!
      Anne

      -----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 Benefit
      >
      >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 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-N2-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:
      >
      >o chronic alcoholic liver disease included 657 patients, of which the
      >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 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:
      >
      >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= 0%)
      >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 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 (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 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 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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    • claudine intexas
      I didn t think this study (or more accurately, a review of other studies) really answered any questions. I will also keep taking milk thistle. About 8 months
      Message 2 of 12 , Dec 28, 2005
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        I didn't think this study (or more accurately, a review of other studies) really answered any questions.

        I will also keep taking milk thistle. About 8 months ago I realized I was accumulating a large stock-pile of it since I get an automatic shipment of a three month supply every three months and I had gotten very sloppy about taking it. My AST and ALT had been running about double the upper limits of normal for several years. I decided to double the recommended dose of milk thistle from 3 per day to 6 per day and see if it made a difference. After 6 months my AST was normal and my ALT was only 4 pts over normal. I thought that was pretty good. I can't say for sure if the milk thistle made the difference, but I do think it works much better when I actually take it instead of leaving it to sit on a shelf in my cabinet! :)

        Claudine

        avansi7465 <avansi7465@...> wrote:
        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 Thistle.
        Happy New Year!
        Anne



        [Non-text portions of this message have been removed]
      • alleypat
        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. Alley If the
        Message 3 of 12 , Dec 28, 2005
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          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.
          Alley


          "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
          Benefit


          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
          Thistle.
          Happy New Year!
          Anne

          -----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
          Benefit
          >
          >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
          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-N2-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:
          >
          >o chronic alcoholic liver disease included 657 patients, of which
          the
          >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
          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:
          >
          >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=
          0%)
          >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
          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 (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
          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 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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        • avansi7465
          Hi Claudine, Thanks for sharing that. I, too, have been known to let the vits and mt slide a bit. I really have NO excuse, mine sit right there on my kitchen
          Message 4 of 12 , Dec 29, 2005
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            Hi Claudine,

            Thanks for sharing that. I, too, have been known to let the vits and mt slide a bit. I really have NO excuse, mine sit right there on my kitchen cabinet next to the sink.........close to water and a glass, even.

            I have been taking one a day, but after reading your e-mail, I think I'll up that to two and see how the liver enzymes respond to that. Thanks for the advise..........which you always freely give, if we would but pay attention.

            Happy New Year!

            Anne

            -----Original Message-----
            >From: claudine intexas <claudineintexas@...>
            >Sent: Dec 28, 2005 9:26 PM
            >To: GIWorld-Hepatitis@yahoogroups.com
            >Subject: Re: [GIWorld-Hepatitis] FW: NATAP: Milk Thistle Study Found No Benefit
            >
            >I didn't think this study (or more accurately, a review of other studies) really answered any questions.
            >
            > I will also keep taking milk thistle. About 8 months ago I realized I was accumulating a large stock-pile of it since I get an automatic shipment of a three month supply every three months and I had gotten very sloppy about taking it. My AST and ALT had been running about double the upper limits of normal for several years. I decided to double the recommended dose of milk thistle from 3 per day to 6 per day and see if it made a difference. After 6 months my AST was normal and my ALT was only 4 pts over normal. I thought that was pretty good. I can't say for sure if the milk thistle made the difference, but I do think it works much better when I actually take it instead of leaving it to sit on a shelf in my cabinet! :)
            >
            > Claudine
            >
            >avansi7465 <avansi7465@...> wrote:
            > 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 Thistle.
            >Happy New Year!
            >Anne
            >
            >
            >
            >[Non-text portions of this message have been removed]
            >
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            >
            >
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          • avansi7465
            Dear Alley, Maybe it depends on your metabolism or diet. Who knows? The docs obviously don t. Everything I ve heard or read about it is purely
            Message 5 of 12 , Dec 29, 2005
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              Dear Alley,

              Maybe it depends on your metabolism or diet. Who knows? The docs obviously don't. Everything I've heard or read about it is purely anecdotal......as we've shared, here. Since my training is in research biology, I tend to want proof. However, I'm an "ole Carolina" girl and won't knock what works. The only other change I made in those months was to go back to drinking 2 or 3 cups of coffee/day. Go figure?

              How are you feeling?

              Happy 2006!
              Anne

              -----Original Message-----
              >From: alleypat <alleypat@...>
              >Sent: Dec 29, 2005 2:39 AM
              >To: GIWorld-Hepatitis@yahoogroups.com
              >Subject: RE: [GIWorld-Hepatitis] FW: NATAP: Milk Thistle Study Found No Benefit
              >
              >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.
              >Alley
              >
              >
              >"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
              >Benefit
              >
              >
              > 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
              >Thistle.
              > Happy New Year!
              > Anne
              >
              > -----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
              >Benefit
              > >
              > >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
              >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-N2-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:
              > >
              > >o chronic alcoholic liver disease included 657 patients, of which
              >the
              > >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
              >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:
              > >
              > >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=
              >0%)
              > >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
              >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 (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
              >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 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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            • alleypat
              Anne I agree. so much is individual. I m good. Still on short term disability from work for this sciatica. I ve lost strength and some motion in my right leg
              Message 6 of 12 , Dec 30, 2005
              • 0 Attachment
                Anne I agree. so much is individual.

                I'm good. Still on short term disability from work for this sciatica. I've
                lost strength and some motion in my right leg and I'm thinking it's from a
                combination of the recent surgery (removal of right groin lymph nodes) and
                my lower back fusing/problems I've had since forever. It's mostly a big
                inconvenience cause if it wasn't for this darn thing acting up when it did,
                I'd already be on my cancer trial. So that part sucks but I've got the tests
                coming up next week (so the trial nurse said I need to call him today,
                thanks for reminding me :) and an MRI next week for the sciatica. My main
                hope is that there are no tumors spreading to my hip area which is unlikely
                but at this point, I'll take any good news :)

                I can't believe the new year is here so fast! what a great year t his will
                be for us all :)

                Alley
                www.alleypat.com
                www.geocites.com/dfwhcv


                [Non-text portions of this message have been removed]
              • w.landstra
                Hi Alley.You are indeed a very very taft girl.I admire your courage and positiveness.May you have more luck in 2006.Willem. ... From: alleypat To:
                Message 7 of 12 , Dec 30, 2005
                • 0 Attachment
                  Hi Alley.You are indeed a very very taft girl.I admire your courage and positiveness.May you have more luck in 2006.Willem.
                  ----- Original Message -----
                  From: alleypat
                  To: GIWorld-Hepatitis@yahoogroups.com
                  Sent: Friday, December 30, 2005 4:25 PM
                  Subject: RE: [GIWorld-Hepatitis] FW: NATAP: Milk Thistle Study Found No Benefit


                  Anne I agree. so much is individual.

                  I'm good. Still on short term disability from work for this sciatica. I've
                  lost strength and some motion in my right leg and I'm thinking it's from a
                  combination of the recent surgery (removal of right groin lymph nodes) and
                  my lower back fusing/problems I've had since forever. It's mostly a big
                  inconvenience cause if it wasn't for this darn thing acting up when it did,
                  I'd already be on my cancer trial. So that part sucks but I've got the tests
                  coming up next week (so the trial nurse said I need to call him today,
                  thanks for reminding me :) and an MRI next week for the sciatica. My main
                  hope is that there are no tumors spreading to my hip area which is unlikely
                  but at this point, I'll take any good news :)

                  I can't believe the new year is here so fast! what a great year t his will
                  be for us all :)

                  Alley
                  www.alleypat.com
                  www.geocites.com/dfwhcv


                  [Non-text portions of this message have been removed]



                  Welcome to GIHepWorld

                  Post message: GIWorld-Hepatitis@yahoogroups.com
                  Subscribe: GIWorld-Hepatitis-subscribe@yahoogroups.com
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                • alleypat
                  taft?? what the heck is taft? Now if you d said daft I d agree with ya! HAPPY NEW YEAR YALL!!!!!!!!!!!!!!!! Alley If the doctor told me I had six minutes
                  Message 8 of 12 , Dec 31, 2005
                  • 0 Attachment
                    taft?? what the heck is taft? Now if you'd said "daft" I'd agree with ya!

                    HAPPY NEW YEAR YALL!!!!!!!!!!!!!!!!

                    Alley

                    "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 w.landstra
                    Sent: Friday, December 30, 2005 12:05 PM
                    To: GIWorld-Hepatitis@yahoogroups.com
                    Subject: Re: [GIWorld-Hepatitis] FW: NATAP: Milk Thistle Study Found No
                    Benefit


                    Hi Alley.You are indeed a very very taft girl.I admire your courage and
                    positiveness.May you have more luck in 2006.Willem.
                    ----- Original Message -----
                    From: alleypat
                    To: GIWorld-Hepatitis@yahoogroups.com
                    Sent: Friday, December 30, 2005 4:25 PM
                    Subject: RE: [GIWorld-Hepatitis] FW: NATAP: Milk Thistle Study Found No
                    Benefit


                    Anne I agree. so much is individual.

                    I'm good. Still on short term disability from work for this sciatica.
                    I've
                    lost strength and some motion in my right leg and I'm thinking it's from
                    a
                    combination of the recent surgery (removal of right groin lymph nodes)
                    and
                    my lower back fusing/problems I've had since forever. It's mostly a big
                    inconvenience cause if it wasn't for this darn thing acting up when it
                    did,
                    I'd already be on my cancer trial. So that part sucks but I've got the
                    tests
                    coming up next week (so the trial nurse said I need to call him today,
                    thanks for reminding me :) and an MRI next week for the sciatica. My
                    main
                    hope is that there are no tumors spreading to my hip area which is
                    unlikely
                    but at this point, I'll take any good news :)

                    I can't believe the new year is here so fast! what a great year t his
                    will
                    be for us all :)

                    Alley
                    www.alleypat.com
                    www.geocites.com/dfwhcv


                    [Non-text portions of this message have been removed]



                    Welcome to GIHepWorld

                    Post message: GIWorld-Hepatitis@yahoogroups.com
                    Subscribe: GIWorld-Hepatitis-subscribe@yahoogroups.com
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                  • avansi7465
                    Hi Alley, Sciatica is a B****! I, too, have had it for years. Lately it s been being nice to me, but ya never know when it s going to rear it s ugly head
                    Message 9 of 12 , Jan 1, 2006
                    • 0 Attachment
                      Hi Alley,
                      Sciatica is a B****! I, too, have had it for years. Lately it's been being nice to me, but ya never know when it's going to rear it's ugly "head" and put me back on the cane. Hydro therapy has turned out to be the best thing that I can do to prevent it from crippling me.

                      Good luck on the trial. Sometimes timing happens for a reason. Remember to take care of yourself.

                      This, for me, has been a really good year. My next project is to lose all the flab I gained to go back on treatment. So I'm going to sit back, eat my milk thistle, celebrate my 50th birthday and pray that we all have a wonderful 2006.

                      -----Original Message-----
                      >From: alleypat <alleypat@...>
                      >Sent: Dec 30, 2005 10:25 AM
                      >To: GIWorld-Hepatitis@yahoogroups.com
                      >Subject: RE: [GIWorld-Hepatitis] FW: NATAP: Milk Thistle Study Found No Benefit
                      >
                      >Anne I agree. so much is individual.
                      >
                      >I'm good. Still on short term disability from work for this sciatica. I've
                      >lost strength and some motion in my right leg and I'm thinking it's from a
                      >combination of the recent surgery (removal of right groin lymph nodes) and
                      >my lower back fusing/problems I've had since forever. It's mostly a big
                      >inconvenience cause if it wasn't for this darn thing acting up when it did,
                      >I'd already be on my cancer trial. So that part sucks but I've got the tests
                      >coming up next week (so the trial nurse said I need to call him today,
                      >thanks for reminding me :) and an MRI next week for the sciatica. My main
                      >hope is that there are no tumors spreading to my hip area which is unlikely
                      >but at this point, I'll take any good news :)
                      >
                      >I can't believe the new year is here so fast! what a great year t his will
                      >be for us all :)
                      >
                      >Alley
                      >www.alleypat.com
                      >www.geocites.com/dfwhcv
                      >
                      >
                      >[Non-text portions of this message have been removed]
                      >
                      >
                      >
                      >
                      >Welcome to GIHepWorld
                      >
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                    • alleypat
                      Happy 50th! If the doctor told me I had six minutes to live, I d type a little faster. --Isaac Asimov ... From: GIWorld-Hepatitis@yahoogroups.com
                      Message 10 of 12 , Jan 1, 2006
                      • 0 Attachment
                        Happy 50th!

                        "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: Sunday, January 01, 2006 9:40 AM
                        To: GIWorld-Hepatitis@yahoogroups.com
                        Subject: RE: [GIWorld-Hepatitis] FW: NATAP: Milk Thistle Study Found No
                        Benefit


                        Hi Alley,
                        Sciatica is a B****! I, too, have had it for years. Lately it's been
                        being nice to me, but ya never know when it's going to rear it's ugly "head"
                        and put me back on the cane. Hydro therapy has turned out to be the best
                        thing that I can do to prevent it from crippling me.

                        Good luck on the trial. Sometimes timing happens for a reason. Remember
                        to take care of yourself.

                        This, for me, has been a really good year. My next project is to lose all
                        the flab I gained to go back on treatment. So I'm going to sit back, eat my
                        milk thistle, celebrate my 50th birthday and pray that we all have a
                        wonderful 2006.

                        -----Original Message-----
                        >From: alleypat <alleypat@...>
                        >Sent: Dec 30, 2005 10:25 AM
                        >To: GIWorld-Hepatitis@yahoogroups.com
                        >Subject: RE: [GIWorld-Hepatitis] FW: NATAP: Milk Thistle Study Found No
                        Benefit
                        >
                        >Anne I agree. so much is individual.
                        >
                        >I'm good. Still on short term disability from work for this sciatica.
                        I've
                        >lost strength and some motion in my right leg and I'm thinking it's from
                        a
                        >combination of the recent surgery (removal of right groin lymph nodes)
                        and
                        >my lower back fusing/problems I've had since forever. It's mostly a big
                        >inconvenience cause if it wasn't for this darn thing acting up when it
                        did,
                        >I'd already be on my cancer trial. So that part sucks but I've got the
                        tests
                        >coming up next week (so the trial nurse said I need to call him today,
                        >thanks for reminding me :) and an MRI next week for the sciatica. My main
                        >hope is that there are no tumors spreading to my hip area which is
                        unlikely
                        >but at this point, I'll take any good news :)
                        >
                        >I can't believe the new year is here so fast! what a great year t his
                        will
                        >be for us all :)
                        >
                        >Alley
                        >www.alleypat.com
                        >www.geocites.com/dfwhcv
                        >
                        >
                        >[Non-text portions of this message have been removed]
                        >
                        >
                        >
                        >
                        >Welcome to GIHepWorld
                        >
                        >Post message: GIWorld-Hepatitis@yahoogroups.com
                        >Subscribe: GIWorld-Hepatitis-subscribe@yahoogroups.com
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                      • avansi7465
                        Thank you....I ll try not to bore you guys with my age crisis.......assuming I have one. Glad to see another Asimov fan out there.
                        Message 11 of 12 , Jan 1, 2006
                        • 0 Attachment
                          Thank you....I'll try not to bore you guys with my age crisis.......assuming I have one. Glad to see another Asimov fan out there.

                          -----Original Message-----
                          >From: alleypat <alleypat@...>
                          >Sent: Jan 1, 2006 10:54 AM
                          >To: GIWorld-Hepatitis@yahoogroups.com
                          >Subject: RE: [GIWorld-Hepatitis] FW: NATAP: Milk Thistle Study Found No Benefit
                          >
                          >Happy 50th!
                          >
                          >"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: Sunday, January 01, 2006 9:40 AM
                          > To: GIWorld-Hepatitis@yahoogroups.com
                          > Subject: RE: [GIWorld-Hepatitis] FW: NATAP: Milk Thistle Study Found No
                          >Benefit
                          >
                          >
                          > Hi Alley,
                          > Sciatica is a B****! I, too, have had it for years. Lately it's been
                          >being nice to me, but ya never know when it's going to rear it's ugly "head"
                          >and put me back on the cane. Hydro therapy has turned out to be the best
                          >thing that I can do to prevent it from crippling me.
                          >
                          > Good luck on the trial. Sometimes timing happens for a reason. Remember
                          >to take care of yourself.
                          >
                          > This, for me, has been a really good year. My next project is to lose all
                          >the flab I gained to go back on treatment. So I'm going to sit back, eat my
                          >milk thistle, celebrate my 50th birthday and pray that we all have a
                          >wonderful 2006.
                          >
                          > -----Original Message-----
                          > >From: alleypat <alleypat@...>
                          > >Sent: Dec 30, 2005 10:25 AM
                          > >To: GIWorld-Hepatitis@yahoogroups.com
                          > >Subject: RE: [GIWorld-Hepatitis] FW: NATAP: Milk Thistle Study Found No
                          >Benefit
                          > >
                          > >Anne I agree. so much is individual.
                          > >
                          > >I'm good. Still on short term disability from work for this sciatica.
                          >I've
                          > >lost strength and some motion in my right leg and I'm thinking it's from
                          >a
                          > >combination of the recent surgery (removal of right groin lymph nodes)
                          >and
                          > >my lower back fusing/problems I've had since forever. It's mostly a big
                          > >inconvenience cause if it wasn't for this darn thing acting up when it
                          >did,
                          > >I'd already be on my cancer trial. So that part sucks but I've got the
                          >tests
                          > >coming up next week (so the trial nurse said I need to call him today,
                          > >thanks for reminding me :) and an MRI next week for the sciatica. My main
                          > >hope is that there are no tumors spreading to my hip area which is
                          >unlikely
                          > >but at this point, I'll take any good news :)
                          > >
                          > >I can't believe the new year is here so fast! what a great year t his
                          >will
                          > >be for us all :)
                          > >
                          > >Alley
                          > >www.alleypat.com
                          > >www.geocites.com/dfwhcv
                          > >
                          > >
                          > >[Non-text portions of this message have been removed]
                          > >
                          > >
                          > >
                          > >
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