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Clinical studies with silymarin: Fibrosis progression is the end point

With interest the report by Angulo et al.on 27 patients with primary biliary cirrhosis (PBC) who did not respond biochemically to ursodeoxycholic acid (UDCA). In a noncontrolled one-armed study the authors investigated the effect of adding oral silymarin for 1 year to the standard regimen with UDCA. Since silymarin did not alter alkaline phosphatase, bilirubin, aspartate transaminase, albumin, or the Mayo risk score, they concluded that silymarin is not effective in patients with PBC who do not respond to UDCA and that further controlled trials of silymarin in PBC are not warranted.

The patients were at an early clinical stage of the disease, in which the Mayo score has limited prognostic value. In addition, a treatment time interval of 1 year is generally too short to assess disease progression, with or without medication. If one chooses to argue that 1 year is sufficient, then the finding of no progression of disease could be interpreted as evidence for a beneficial effect of silymarin.

The outcome parameters for the efficacy of silymarin (alkaline phosphatase, aspartate transaminase, albumin, bilirubin, and the Mayo risk score) are, at best, indirect measures of disease progression and unreliable as predictors of fibrosis, particularly in patients receiving UDCA.Since progression of fibrosis ultimately determines the prognosis of PBC, fibrosis-related parameters should be monitored, including sequential histology, aminoterminal procollagen type III peptide, collagen IV, hyaluronic acid, and others.

The authors failed to note a large experimental study of secondary biliary fibrosis in rats, which showed a highly significant antifibrotic effect of silymarin in early as well as advanced disease.Although not using an exact model of human PBC, the study may be informative in that the antifibrotic action of silymarin was unaccompanied by decreases in either bilirubin or liver enzymes. This finding may be attributable to the fact that silymarin appears to act on activated hepatic stellate cells and myofibroblasts,with only indirect effects on hepatocytes.

The dose of 420 mg/d used by Angulo et al. may be too low. The effect of silymarin in the experimental model9 was clearly dose-dependent. The contradictory results on survival in the 2 long-term studies of patients with (alcohol-induced) cirrhosis performed by Ferenci et al.and Pares et al. also may be due to differences in dose. We are currently conducting a multicenter study of patients with chronic hepatitis C resistant to interferon-ribavirin combination therapy, using a daily dose of 840 mg for 2 years. The primary end point is fibrosis progression, as assessed by sequential histology with connective tissue morphometry and a battery of surrogate markers of liver fibrosis.

Silymarin should not be classified as an alternative medicine, because its composition is now defined, including 60 % of silibinin-1 with which many of the cited in vitro studies of efficacy have been performed.16

The study of Angulo et al. contributes importantly to the effort to find more effective treatments to halt progression of PBC and other chronic liver diseases. We would point out, however, that in trials of potential antifibrotic agents it is important to include end points relevant to fibrosis.

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