5Future Research

Adverse Effects

The type, frequency, and severity of adverse effects related to milk thistle preparations should be quantified. Whether adverse effects are specific to dose, particular preparations, or additional herbal ingredients needs elucidation, especially in light of equivalent frequencies of adverse effects in available randomized trials. When adverse effects are reported, concomitant use of other medications and product content analysis should also be reported so that other drugs, excipients, or contaminants may be scrutinized as potential causal factors. The most serious potential adverse effects of milk thistle reported thus far are anaphylactoid reactions and anaphylaxis, and available data are extremely limited regarding causality.

Beneficial Effects Regarding Liver Diseases

Studies in humans with physiologic outcomes are limited by unclear study populations, randomization procedures, small sample sizes, variable and sometimes short duration of treatment, unclear blinding for outcome assessment, and unclear or inadequate information about potential confounders. Characteristics of future studies should include longer and larger randomized trials; clinical, as well as physiologic, outcome measures; histologic outcomes; adequate blinding; detailed data about compliance and dropouts; systematic standardized surveillance for adverse effects; and sophisticated considerations regarding study populations and potential confounders. There also should be detailed attention to preparation, standardization, and bioavailability of different formulations of milk thistle (e.g., standardized silymarin extract and silybin-phosphatidylcholine complex).

There are several important considerations for study populations and confounders. After correction for baseline risk differences, our meta-analyses found generally adequate statistical homogeneity, despite poorly defined and heterogeneous study populations. Yet, clinical heterogeneity in study populations regarding etiology, chronicity, and severity of liver disease might have masked subgroup differences in outcomes. There are numerous important potential confounders and combinations of confounders that might affect outcomes in individual subjects. These include the following: comorbidities, baseline and ongoing use of alcohol, various combinations of alcoholic and viral liver disease in individual patients, various etiologies of concomitant fatty liver disease, coinfection with HIV and HBV and/or HCV, treatment with antiviral medications for HIV, and use of interferon for HCV. Thus, future research should assess baseline status regarding alcohol, HBV, HCV, and HIV, as well as systematic surveillance for these factors through the duration of studies.

Specific Areas of Research

Precise mechanisms of action specific to different etiologies and stages of liver disease need explication. Further mechanistic investigations are needed and should be considered before, or in concert with, studies of clinical effectiveness. Several specific research directions appear especially relevant at this time. The high prevalence of alcoholic liver disease and the increasing prevalence of HCV liver disease in the United States and high prevalence of HBV infection in intravenous drug users and in developing countries warrant research focusing on these populations. Effectiveness of milk thistle in cholesetatic disease and nonalcohol steatohepatitis has not been studied. Because of provocative data from two small trials, further research is needed regarding prophylactic use of milk thistle in the setting of potentially hepatotoxic medications or as treatment for iatrogenic liver dysfunction.

More information is needed about effectiveness of milk thistle for severe acute ingestion of hepatotoxins, such as occupational exposures, acetaminophen overdose, and amanita poisoning. The available data are limited to case reports and small case series in Europe for amanita poisoning and occupational exposures to hepatotoxins. We identified no trials of milk thistle for acetaminophen hepatoxicity. Because of the low incidence and ethical issues, it is premature to consider randomized clinical trials. However, a systematic review of the evidence at hand and then careful consideration of the feasibility and utility of well-designed case-control or cohort-comparison studies would be useful. Such data could inform the decision regarding trials of n-acetylcysteine with and without milk thistle or treatment for other acute toxic exposures.