Silybum marianum

(Milk thistle)

Milk thistle (Silybum marianum) is a member of the daisy or aster family. No food use of milk thistle is given in Kiple and Ornelas (2000) although it has been used as a medicinal herb for thousands of years. The main use of milk thistle today is in the treatment of liver diseases or to protect the liver from damage by chemical (including alcohol) or viral damage. It is the ripe seeds or fruits of the plant that are usually used to make dietary supplements and herbal medicines.

The active constituents of milk thistle are referred to collectively as silymarin, a group of polymeric flavonoids referred to as flavonolignans. Three of the constituents of silymarin are silybin (which is assumed to be the most active ingredient), silydianin and silychristin. Extracts of milk thistle should be standardised to contain 70-80% silymarin. Silymarin is not readily soluble in water so making tea from dried milk thistle is not an effective way of taking it.

In many experimental studies using isolated liver cells and a variety of animal species, milk thistle has been shown to protect the liver from several chemical insults, for example from hepatotoxic drugs such as acetaminophen, from carbon tetrachloride and phenylhydrazine and from alcohol. In experimental studies with animals silymarin has been shown to be effective in preventing the frequently fatal liver damage caused by poisoning with Amanita mushrooms (death caps). For example, Vogel et al. (1984) showed that silymarin administered up to 24 hours after a toxic dose of death cap fungus in dogs had the following effects.

• It suppressed the serum changes and changes in prothrombin that were indicative of liver damage in the control dogs.

• It reduced the amount of haemorrhagic liver necrosis.

• It reduced the death rate from 2/6 to 0/6.

There are several case reports (many not in English) which suggest that silymarin has been successful in reducing the expected consequences of accidental ingestion of these toxic mushrooms when administered up to 48 hours after poisoning. Silymarin is used and regarded as an effective emergency treatment for accidental Amanita poisoning in several European countries.

One of the more recent of the many in vitro and animal experimental studies of the hepato-protective effects of silymarin was conducted in baboons. Lieber et al. (2003) fed 12 baboons alcohol with or without silymarin for a period of three years. Several biochemical markers and morphological indicators of liver damage were reduced in the silymarin group. These results suggest that silymarin slows the development of alcohol-induced liver fibrosis in baboons. Lieber et al. (2003) suggest that their results support the findings of several positive clinical trials in humans. They further suggest that some of the negative results from clinical trials may have been caused by poor compliance with the therapy resulting in low or irregular silymarin intake. It is important to note that whilst silymarin appeared to slow the development of alcoholic cirrhosis in this primate study, it did not prevent it. Silymarin should not be regarded as a way of compensating for chronic alcohol abuse.

Valenzuela and Garrido (1994) suggest that silymarin may exert its hepato-protective effects at three levels:

• By reducing oxidative liver damage by scavenging free radicals and raising the concentration of glutathione

• By an effect on the hepatocyte cell membrane which reduces uptake of harmful chemicals and reduces cell breakdown

• By increasing protein synthesis via an effect on DNA transcription.

It may also have an anti-inflammatory effect, which would reduce swelling of liver cells in response to injury.

The many experimental studies with isolated hepatocytes and with animal models of liver injury together with the case reports on human Amanita poisoning suggest that milk thistle (silymarin) may be beneficial in some liver diseases especially in the early stages of the disease. The results from many controlled clinical trials are generally mixed and inconclusive. The Agency for Healthcare Research and Quality in the USA commissioned a major review of the efficacy of milk thistle in liver conditions. This group identified fourteen prospective, randomised, placebo-controlled trials of milk thistle for a variety of liver diseases up to the end of 1999. They also identified many other non-placebo-controlled trials. Their overall conclusion was that the efficacy of milk thistle was not established for any liver condition by the data then available. The most common outcomes measured were laboratory tests of liver function and whilst there were several studies which did suggest benefit the results were not consistent. Four of six studies of milk thistle in chronic liver disease showed a significant improvement in at least one measure of liver function or histology in the milk thistle group compared with the placebo group. There were some inconclusive suggestions of benefit in measures of liver function in chronic hepatitis. Trials in patients with cirrhosis were mixed as were those where milk thistle was given in conjunction with hepatotoxic drugs. A meta-analysis of the fourteen controlled trials was published in 2002. The only statistically significant effect from this meta-analysis was a greater reduction in alanine aminotransferase in patients with chronic liver disease receiving milk thistle, which, they say, was of negligible clinical importance. Like many other reviewers of clinical trials of dietary supplements, they concluded that the poor quality and inadequate reporting of the data made proper analysis and interpretation difficult. The general conclusion was that milk thistle was safe and well tolerated.

A recent large (177 patients), one-year study of Egyptian patients with chronic hepatitis C, found that silymarin had no more effect than multivitamin supplements on any objective outcome measure.

In general, clinical trials of milk thistle provide unconvincing support for the many in vitro and animal studies which have indicated a likely hepato-protective effect of silymarin. There still seems to be a case for large multi-centred trials of controlled doses of milk thistle in well-matched patients with specific liver conditions. The evidence is insufficient to recommend milk thistle as a useful dietary supplement; indeed, taking it in the expectation that it may protect the liver from alcohol or drug damage may be counterproductive by giving users a false sense of security.

A 100 mg tablet of standardised milk thistle extract should provide about 80 mg of silymarin and this is equivalent to 3 g of seeds. Recommended doses of dietary supplements are 100 mg of extract per day but doses used in clinical trials have been up to 10 times this daily amount. People who are allergic to members of the daisy or aster family should not take milk thistle. Barnes (2002b) reports that about 1% of 3500 people taking 560 mg of silymarin daily for eight weeks reported usually mild and transient adverse effects, mainly gastrointestinal effects.