This RCT compared the safety and effect of a standard dose of silymarin three times daily to a placebo in patients with acute hepatitis. No adverse events or side-effects were detected thereby supporting silymarin’s safety and tolerability. The study was not designed to evaluate the effect of silymarin on individual viral causes of acute hepatitis, thus making our findings generalizable to other clinically diagnosed cases of acute clinical hepatitis.
Although reports from Europe in the late-1970s suggested that silymarin was beneficial to patients with acute clinical hepatitis, they were not subsequently replicated.(Bode et al., 1977
, Magliulo et al., 1978
, Patera, 1978
) Since then, studies focused on chronic viral infections or alcoholic hepatitis showed inconsistent results.(Deak et al., 1990
, Strickland et al., 2005
, Tanamly et al., 2004
) Although silymarin is known to have non-specific hepatoprotective effects, yet most studies on chronic hepatitis focused on specific outcomes that are known to be unaffected by silymarin, e.g., viral clearance, liver cirrhosis, and liver-related mortality. This culminated in the conclusion of recent meta-analyses of the literature (almost exclusively studies on chronic hepatitis) that there is insufficient evidence to support or refute the use of silymarin in treatment of chronic viral hepatitis.(Jacobs et al., 2002
, Mayer et al., 2005
, Rambaldi et al., 2005
However, a recent publication by Ferenci et al. demonstrated that high doses of intravenous silibinin had a potent antiviral effect in chronically infected HCV patients (Ferenci et al. 2008
). Furthermore, patients treated with high doses of silymarin (or its most active component, silybin) shortly after ingesting the deadly toadstool, Amanita phalloides,
survive; and multiple studies of silymarin in experimental animal models show it has a broad spectrum of hepatoprotective and antioxidant effects, protecting them against injury from several toxins, including Amanita phalloides
, carbon tetrachloride, ethanol, and galactosamine, even when given after exposure.(Vogel et al., 1984
Our definition for acute clinical hepatitis was the presence of an ALT level > 2.5 times normal and compatible clinical symptoms and signs of less than one month duration in the absence of a history of toxic exposures. Sixty (57.1%) of our patients were diagnosed with AVH. Another 19 (18.1%) were diagnosed as “flare-ups” of chronic viral infections, with all but one of these having chronic HCV. We previously reported that “flare-ups” of chronic HCV are a very common cause of a milder form of acute hepatitis in Egypt.(Meky et al., 2006
) Also, since testing for anti-HCV IgM is an inadequate indicator of acute HCV infection, some of our patients having both anti-HCV and HCV-RNA could have been acute incident cases that presented to the hospital after developing detectable anti-HCV.
The trend for greater improvement in symptoms and signs related to biliary retention in subjects receiving silymarin is biologically plausible given that silymarin is known to act by membrane stabilization, and neutralization and scavenging of free radicals, thereby possibly protecting neighboring healthy hepatocytes from lysozymes and free radicals released by damaged cells. This would reduce inflammation thereby relieving mechanical compression of bile canaliculi and allowing better excretion of bile and bile salts. Our modest sample size and multiple etiologies for acute hepatitis may have attenuated a true finding.
Other than indirect bilirubin (p=0.012), many of the significant improvements in this clinical trial were either clinical (dark urine, jaundice and scleral icterus) or subjectively reported (fatigue, malaise and anorexia). These “soft” findings are not unique to our study. A recent report by Seeff et al examining reported self-use and potential effects of silymarin was conducted in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial on its 1,145 study participants. Silymarin use was self-motivated and uncontrolled and constituted 72% of 60 herbals used at enrollment. There was no significant improvement in ALT. After adjusting for covariates of age, race, education, alcohol consumption, exercise, body mass index, and smoking, silymarin users were found to have significantly fewer liver-related symptoms such as fatigue (p=0.01), nausea (p=0.02), liver pain (p=0.02), anorexia (p=0.01), muscle and joint pain (p=0.003), and they had higher quality of life scores (all p<0.03).(Seeff et al., 2008
Many patients in Egypt and elsewhere are empirically given silymarin for symptomatic management of acute hepatitis, particularly AVH.(Strickland, 2006
) Although our study showed that the standard 420 mg daily dose of silymarin is safe and well-tolerated by patients with acute clinical hepatitis, it showed a trend towards improvement that was mostly subjective and clinical without a corresponding decline in biomarkers of inflammation. The dose of silymarin currently recommended is a fraction of that given in successful experimental animal studies,(Vogel et al., 1984
) and this report and others show the standard 420 mg dose per day of silymarin to be safe and well tolerated. The fact that effects of silymarin were noted mainly on subjective symptoms suggests that there may be a potential beneficial effect of silymarin that is not being captured by traditional laboratory biomarkers, and future studies should incorporate novel biomarkers that can correlate with reported symptoms improvement. Alternatively, larger studies and higher doses of silymarin in both acute and chronic hepatitis may be warranted to detect measurable differences in traditional biomarkers of viral hepatitis such as liver enzymes and viral loads.