Milk Thistle: Effects on Liver Disease and Cirrhosis - Parents of Kids ...

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effectiveness were limited to placebo-controlled studies. For adverse effects, all types of studies in humans were used to assess adverse clinical effects. Data Collection and Analysis Abstractors (physicians, methodologists, pharmacists, and a nurse) independently abstracted data from trials; a nurse and physician abstracted data about adverse effects. Data were synthesized descriptively, emphasizing methodologic characteristics of the studies, such as populations enrolled, definitions of selection and outcome criteria, sample sizes, adequacy of randomization process, interventions and comparisons, cointerventions, biases in outcome assessment, and study designs. Evidence tables and graphic summaries, such as funnel plots, Galbraith plots, and forest plots, were used to examine relationships between clinical outcomes, participant characteristics, and methodologic characteristics. Trial outcomes were examined quantitatively in exploratory meta-analyses that used standardized mean differences between mean change scores as the effect size measure. Findings Mechanisms of Action Evidence exists that milk thistle may be hepatoprotective through a number of mechanisms: antioxidant activity, toxin blockade at the membrane level, enhanced protein synthesis, antifibriotic activity, and possible anti-inflammatory or immunomodulating effects. Preparations of <strong>Milk</strong> <strong>Thistle</strong> The largest producer of milk thistle is Madaus (Germany), which makes an extract of concentrated silymarin. However, numerous other extracts exist, and more information is needed on comparability of formulations, standardization, and bioavailability for studies of mechanisms of action and clinical trials. Benefit of <strong>Milk</strong> <strong>Thistle</strong> for Liver Disease • Sixteen prospective trials were identified. Fourteen were randomized, blinded, placebocontrolled studies of milk thistle’s effectiveness in a variety of liver diseases. In one additional placebo-controlled trial, blinding or randomization was not clear, and one placebocontrolled study was a cohort study with a placebo comparison group. • Seventeen additional trials used nonplacebo controls; two other trials studied milk thistle as prophylaxis in patients with no known liver disease who were starting potentially hepatotoxic drugs. The identified studies addressed alcohol-related liver disease, toxin-induced liver disease, and viral liver disease. No studies were found that evaluated milk thistle for cholestatic liver disease or primary hepatic malignancy (hepatocellular carcinoma, cholangiocarcinoma). 2
• There were problems in assessing the evidence because of incomplete information about multiple methodologic issues, including etiology and severity of liver disease, study design, subject characteristics, and potential confounders. It is difficult to say if the lack of information reflects poor scientific quality of study methods or poor reporting quality or both. • Detailed data evaluation and syntheses were limited to the 16 placebo-controlled studies. Distribution of durations of therapy across trials was wide (7 days to 2 years), inconsistent, and sometimes not given. Eleven studies used Legalon ® , and eight of those used the same dose. Outcome measures varied among studies, as did duration of therapy and the followup for which outcome measures were reported. • Among six studies of milk thistle and chronic alcoholic liver disease, four reported significant improvement in at least one measurement of liver function (i.e., aminotransferases, albumin, and/or malondialdehyde) or histologic findings with milk thistle compared with placebo, but also reported no difference between groups for other outcome measures. • Available data were insufficient to sort six studies into specific etiologic categories; these were grouped as chronic liver disease of mixed etiologies. In three of the six studies that reported multiple outcome measures, at least one outcome measure improved significantly with milk thistle compared with placebo, but there were no differences between milk thistle and placebo for one or more of the other outcome measures in each study. Two studies indicated a possible survival benefit. • Three placebo-controlled studies evaluated milk thistle for viral hepatitis. The one acute viral hepatitis study reported latest outcome measures at 28 days and showed significant improvement in aspartate aminotransferase and bilirubin. The two studies of chronic viral hepatitis differed markedly in duration of therapy (7 days and 1 year). The shorter study showed improvement in aminotransferases for milk thistle compared with placebo but not other laboratory measures. In the longer study, milk thistle was associated with a nonsignificant trend toward histologic improvement, the only outcome measure reported. • Two trials included patients with alcoholic or nonalcoholic cirrhosis. The milk thistle arms showed a trend toward improved survival in one trial and significantly improved survival for subgroups with alcoholic cirrhosis or Child’s Group A severity. The second study reported no significant improvement in laboratory measures and survival for other clinical subgroups, but no data were given. • Two trials specifically studied patients with alcoholic cirrhosis. Duration of therapy was unclear in the first, which reported no improvement in laboratory measures of liver function, hepatomegaly, jaundice, ascites, or survival. However, there were nonsignificant trends favoring milk thistle in incidence of encephalopathy and gastrointestinal bleeding and in survival for subjects with concomitant hepatitis C. The second study, after treatment for 30 days, reported significant improvements in aminotransferases but not bilirubin for milk thistle compared with placebo. 3
Page 1 and 2: Evidence Report/Technology Assessme
Page 3: Evidence Report/Technology Assessme
Page 7 and 8: Structured Abstract Objectives. Thi
Page 9 and 10: Contents Summary...................
Page 11 and 12: Appendix C. Contributors We owe a m
Page 13 and 14: Wolfgang Fleig, MD Professor and Ch
Page 15: Project Investigators Valerie Lawre
Page 20 and 21: • Three trials evaluated milk thi
Page 23 and 24: Chapter 1. Introduction Scope and O
Page 25 and 26: The Plant Milk thi
Page 27 and 28: using over-the-counter “alternati
Page 29 and 30: controls. 41,42 Another study demon
Page 31 and 32: Figure 1. Evidence model: M
Page 33 and 34: Table 1. Key questions and selectio
Page 35 and 36: Table 2. Electronic sources searche
Page 37 and 38: Initially, we planned to limit effi
Page 39 and 40: Heterogeneity among trials was test
Page 41 and 42: Table 2. Electronic sources searche
Page 43 and 44: Chapter 3. Results Overview of the
Page 45 and 46: Among the 17 nonplacebo-controlled
Page 47 and 48: presented for cirrhotic patients in
Page 49 and 50: In the Phase II study, 60 subjects
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Page 57: apparent anaphylactoid reaction imp
Page 60 and 61: Table 3. Outcome measures and follo
Page 62 and 63: Table 4. Effect sizes and meta-anal
Page 64 and 65: Table 6. Effect sizes and meta-anal
Page 67 and 68: Chapter 5. Future Research Adverse
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References 1. Brown D. Silymarin ed
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41. Muzes G, Deak G, Lang I, et al.
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80. Kiesewetter E, Leodolter I, Tha
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Summary Table 1. Placebo-controlled
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Summary Table 8. Prophylactic milk
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Summary Table 10. Effect sizes and
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Summary Table 11. Effect sizes and
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Summary Table 12. Adverse effects o
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Evidence Table 1. Milk</str
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Blumenthal M (National Advisory Pan
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Fintelmann V. Zur Therapie der Fett
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Lang I, Deak G, Nekam K, et al. Hep
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Pifferi G. Silipide: A new bioavail
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Tittel G, Wagner H. High-performanc
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Appendix A. Milk <
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Z Statistic Effect Size -3.2 -1 2 0
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Feher 1990 Marcelli 1992 Trinchet 1
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Z Statistic -3.0 Buzelli 1993 2 0 -
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Feher 1990 Marcelli 1992 Palasciano
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Buzelli 1993 Fintelmann 1970 Fintel
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Feher 1990 Marcelli 1992 Combined E
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Buzelli 1993 Fintelmann 1970 Fintel
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Z Statistic Effect Size -1 2 0 -2 -
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Z Statistic -2 -2.2 Feher 1990 Trin
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Buzelli 1993 Fintelmann 1970 Magliu
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Z Statistic Effect Size 2.2 2 1 0.5
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Z Statistic -2.6 Feher 1990 Marcell
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Feher 1990 Marcelli 1992 Trinchet 1
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