Milk Thistle ‘Hepato-neutral’ for People with Hepatitis C
Abstract & Commentary
By David Kiefer, MD
Synopsis: In patients with hepatitis C, having already been treated (unsuccessfully) with interferon, three times daily silymarin in two doses (both supratherapeutic) did not change serum ALT after 24 weeks.
Source: Fried MW, et al. Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: A randomized controlled trial. JAMA 2012;308:274-282.
For chronic conditions with minimal treatment options, there is always the hope for a new approach that can reverse, or stall, the disease process. Such is the case for people suffering from interferon-resistant hepatitis C (HCV). The researchers of this randomized, controlled trial explored the effect of two high doses of silymarin, the active compound in milk thistle (Silybum marianum, Family Asteraceae), as a hepatoprotectant, staving off the damaging effects of chronic hepatitis C infection on hepatocytes and their function.
Inclusion criteria were previous interferon treatment without sustained viral response, measurable serum HCV viral RNA levels, and a serum alanine aminotransferase (ALT) level ≥ 65 U/L. Exclusion criteria included concomitant HIV or hepatitis B infection, pathophysiological changes on liver biopsy, or milk thistle use within the last month.
The researchers randomized 154 study participants into one of three groups, all dosed three times daily for 24 weeks: placebo, 420 mg silymarin, and 700 mg silymarin. The silymarin doses were considered “supratherapeutic,” three and five times higher, respectively, than “customary” doses as based on preliminary dose range testing. The milk thistle product used was Legalon 140, a dry extract of milk thistle fruits, commonly used and prescribed in Europe. Each capsule of Legalon 140 is standardized to contain 140 mg silymarin. Therefore, the protocol consisted of five capsules three times daily, either all placebo capsules, three Legalon 140 capsules plus two placebo capsules (420 mg of silymarin per dose), or five Legalon 140 capsules (700 mg per dose).
The primary outcome measurement of interest was a serum ALT < 45 U/L, considered a standard level of interferon efficacy in HCV. The researchers also followed the change in ALT with treatment, serum HCV RNA, adverse events, and quality of life (via the Chronic Liver Disease Questionnaire).
Seventy-one percent of the study participants were men, and 91% had HCV genotype 1 infection. Baseline ALT values for each group were statistically similar (range 105-110 U/L). At the end of 24 weeks, five study participants (one in the placebo group, two in each of the treatment groups) achieved a reduction in ALT to a value below 45 U/L, the primary outcome measure. This improvement was statistically similar across each of the groups. In addition, when the serum ALT was analyzed as a continuous variable over time, again, no difference was noted between any of the groups. Furthermore, no statistically significant difference was noted between groups in quantitative serum HCV RNA or in quality-of-life survey scores over the study period. The trends described above did not change with intention-to-treat analyses, nor when only those 125 patients with > 80% adherence to the study protocol were analyzed separately.
With respect to adverse effects, the study was likely too small and adverse effects too infrequent to allow accurate detection and conclusions. That said, there was no statistically significant difference in adverse events between placebo and treatment groups (34, 31, and 29, respectively, P = 0.84) even though 12% of both silymarin groups reported mild-to-moderate gastrointestinal distress, the most commonly reported adverse event, vs 5% of the placebo group (P = 0.56).
The authors of this study aptly point out the relevance of their work; citations are provided for the fact that 3% of people suffer from chronic hepatitis C infection, and 33% of those with that infection in the United States take or have taken milk thistle for their condition. It would be nice if those patients were on the right track about the usefulness of this plant for HCV, which is exactly what these researchers strived to corroborate.
Silymarin, a series of four isomeric flavanolignan compounds, should function in this capacity, given what is known about its physiological effects.1 One proven effect is as an “antitoxic” agent, protecting hepatocytes from insults, possibly by stabilizing the cell membrane; a classic example is the use of silymarin in Amanita phalloides mushroom poisoning.1,2 Silymarin also has antioxidant effects (particularly relevant to one proposed mechanism of HCV-induced liver damage) and prevents glutathione depletion in hepatocytes. Therefore, the in vitro results and proposed clinical effects are in line and relevant.
Addressing inconsistent clinical results in past research, this study used an improved methodology. The authors’ aim was to improve on this research backdrop, and it seems as if they did. Prior work had flaws with lack of specific endpoints, a varied study patient population, and non-standardized milk thistle preparations;3 these issues were addressed specifically in this research protocol. In addition, pharmacokinetic concerns were tackled by their dosing regimen. At first glance, the use of “supratherapeutic” dosing seems to put the researchers out of touch with practical, common clinical use of this botanical medicine. Indeed, most randomized controlled trials of milk thistle in chronic liver disease have used doses of silymarin, or its isomers, from 200-480 mg daily, not the 1260-2100 mg daily used in this study. However, as the researchers point out, milk thistle is rapidly metabolized after an oral dose, its short half-life leading to the need for frequent dosing, or, as in this case, higher individual doses, in order to achieve the best chance of a clinical therapeutic effect. Furthermore, somehow, miraculously, the researchers achieved a high adherence with so many capsules prescribed daily; 95% of the participants met or exceeded a 80% threshold for adherence. It could be argued that this figure is a testament to the researchers’ competence in research design and implementation.
Limitations? ALT is an indirect measure of liver health, albeit a much safer intervention than the definitive determination of hepatocyte pathology, a liver biopsy. Changes in hepatocytes may have been occurring with milk thistle treatment, but not appearing in serum ALT. In addition, compounds with a low half-life ideally should be dosed more frequently, not just at a higher dose; it is unclear how the researchers’ approach may have improved the chances of milk thistle clinical efficacy. These two minor complaints may or may not have affected the overall outcome.
Should this, or will this, change clinical practice? The demographic studied here is a limited one, so the researchers’ results cannot necessarily be applied to patients with other genotypes of HCV, HCV of different severity (interferon-sensitive HCV, for instance), or other types of hepatitis. It appears to be a safe treatment, even in such high doses, so that might sway some clinicians or patients to continue using milk thistle in these cases given the lack of other treatment options. Alternatively, our favorite hepato-protectant may actually just be hepato-neutral for people with interferon-resistant HCV and they may opt to spend their dietary supplement dollars elsewhere.
1. Schulz V, et al. Rational Phytotherapy. Berlin: Springer-Verlag; 2004.
2. Mayer KE, et al. Silymarin treatment of viral hepatitis: A systematic review. J Viral Hepat 2005;12:559-567.
3. Rambaldi A, et al. Milk thistle for alcoholic and/or hepatitis B or C virus liver diseases. Cochrane Database Syst Rev 2007;(4):CD003620.