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FW: NATAP: Milk Thistle Study Found No Benefit

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  • alleypat
    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
    Message 1 of 12 , Dec 28, 2005
    • 0 Attachment
      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
      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 2 of 12 , Dec 28, 2005
      • 0 Attachment
        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 3 of 12 , Dec 28, 2005
        • 0 Attachment
          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 4 of 12 , Dec 28, 2005
          • 0 Attachment
            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 5 of 12 , Dec 29, 2005
            • 0 Attachment
              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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              >
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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 6 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 7 of 12 , Dec 30, 2005
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                  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 8 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]



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                    [Non-text portions of this message have been removed]
                  • 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 9 of 12 , Dec 31, 2005
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                      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

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                      [Non-text portions of this message have been removed]
                    • 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 10 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
                        >
                        >Post message: GIWorld-Hepatitis@yahoogroups.com
                        >Subscribe: GIWorld-Hepatitis-subscribe@yahoogroups.com
                        >Unsubscribe: GIWorld-Hepatitis-unsubscribe@yahoogroups.com
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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 11 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
                          >Unsubscribe: GIWorld-Hepatitis-unsubscribe@yahoogroups.com
                          >List owner: GIWorld-Hepatitis-owner@yahoogroups.com
                          >URL to this page: http://groups.yahoo.com/group/GIWorld-Hepatitis
                          >
                          >Yahoo! Groups Links
                          >
                          >
                          >
                          >
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                          >



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                          [Non-text portions of this message have been removed]
                        • 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 12 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]
                            > >
                            > >
                            > >
                            > >
                            > >Welcome to GIHepWorld
                            > >
                            > >Post message: GIWorld-Hepatitis@yahoogroups.com
                            > >Subscribe: GIWorld-Hepatitis-subscribe@yahoogroups.com
                            > >Unsubscribe: GIWorld-Hepatitis-unsubscribe@yahoogroups.com
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                            > >URL to this page: http://groups.yahoo.com/group/GIWorld-Hepatitis
                            > >
                            > >Yahoo! Groups Links
                            > >
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                            > >
                            > >
                            > >
                            > >
                            >
                            >
                            >
                            > Welcome to GIHepWorld
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