NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Lawrence V, Jacobs B, Dennehy C, et al. Milk Thistle: Effects on Liver Disease and Cirrhosis and Clinical Adverse Effects. Rockville (MD): Agency for Healthcare Research and Quality (US); 2000 Oct. (Evidence Reports/Technology Assessments, No. 21.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Cover of Milk Thistle: Effects on Liver Disease and Cirrhosis and Clinical Adverse Effects

Milk Thistle: Effects on Liver Disease and Cirrhosis and Clinical Adverse Effects.

Show details

1Introduction

Scope and Objectives

This evidence report about milk thistle was requested by the National Center for Complementary and Alternative Medicine, a component of the National Institutes of Health, and was contracted by the Agency for Healthcare Research and Quality. This chapter highlights the history of milk thistle, its chemistry, recent research, the variety in available commercial preparations, and challenges in conducting research and interpreting the evidence in humans. The evidence report is a systematic review that summarizes studies in humans that address the effects of milk thistle in treating liver disease of alcohol, viral, toxin, cholestatic, and primary malignancy etiologies. Figure 1 shows the evidence model, which was formulated by the national advisory and technical expert panels that guided the review.

Figure 1. Evidence model: Milk thistle and liver disease.

Figure

Figure 1. Evidence model: Milk thistle and liver disease.

Effects of Milk Thistle on Hepatic Disease

Results of trials comparing milk thistle preparations with placebo or other agents are presented. A formal summary of the evidence uses only available placebo controlled trials. Effects on the following outcomes are addressed: laboratory tests, histologic findings, morbidity, and mortality.

Clinical Adverse Effects of Milk Thistle

Various reported adverse effects, including dermatologic, gastrointestinal, and anaphylactoid reactions, are summarized.

Background

Milk thistle has been used since the time of ancient physicians and herbalists to treat a range of liver and gallbladder disorders, including hepatitis, cirrhosis, and jaundice, and to protect the liver against poisoning from chemical and environmental toxins, including snake bites, insect stings, mushroom poisoning, and alcohol.

Milk thistle's history begins with its name. The scientific name for milk thistle is Silybum marianum: "Silybum" is the name Dioscorides gave to edible thistles,1 and "marianum" comes from the legend that the white veins running through the plant's leaves were caused by a drop of the Virgin Mary's milk. 1 2 3 4 While looking for a place to nurse the infant Jesus when leaving Egypt, Mary could only find shelter in a bower formed by the thorny leaves of the milk thistle. 5 From this story was born the folk belief that the plant was good for nursing mothers. 6 Other names that have been attributed to milk thistle include Marian thistle, Mary thistle, St. Mary's thistle, Lady's thistle, Holy thistle, sow thistle, thistle of the blessed virgin, Christ's crown, Venus thistle, heal thistle, variegated thistle, and wild artichoke.

Milk thistle is a member of the aster or daisy family (Asteracae), which includes, in addition to asters and daisies, a host of other thistles and the artichoke. 7 Milk thistle is one of the most important medical members of this genus. 8

The Plant

Milk thistle is a tall plant that can grow up to 10 feet with thorny stems, dark glossy green leaves, and milky-white veins running throughout. Its most distinguishing feature is the large, bright purple flower sprouting at the top.3 7 8

Historical Uses of Milk Thistle

For centuries, nearly every part of the plant-from root to hull-has been used in some way. 4 6 In her famous book, Maud Grieve explained several ways the milk thistle can be eaten, including the heads like an artichoke, raw stalks (which are considered palatable and nutritious), and the leaves as a salad.8 She also quoted Bryant, who wrote in his Flora Dietetica, "The young shoots in the Spring, cut close to the root with part of the stalk on, is one of the best boiling salads that is eaten, and surpasses the finest cabbage. They were sometimes baked in pies. The roots may be eaten like those of Salsify." 8

Milk thistle has also historically been used for animal feed. Grieve wrote that in parts of England, the leaves are called "pig leaves" because pigs liked them; also, the seeds are a favorite food of goldfinches. 8 In Scotland, the leaves were used extensively as food for cattle and horses (the leaves were beaten and crushed to rid them of prickles) before the introduction of special green crops. 8 The milk thistle prickles have also been used historically as a substitute for barbed wire. 9 Despite this wide spectrum of perceived value, farmers considered it and other thistles a sign of untidiness and neglect. 8

Most sources on milk thistle, which is native to southern Europe (specifically Mediterranean areas) and Asia, 5 put its beginning at 2,000 years ago. 1 2 6 9 One of the earliest mentions of thistles in general is in the Bible (Genesis 3:18). In this verse, God told Adam and Eve when they were banished from the Garden of Eden that "thorns also and thistles shall it bring forth to thee."

Some of the earliest people to use and write about milk thistle were ancient Greek and Roman physicians and herbalists, each of whom seemed to have their own name for the herb. Dioscorides called it "sillybon," Pliny the Elder called it "sillybum," and Theophrastus called it "pternix."5 Dioscorides' use of milk thistle is one of the oldest known references to the medicinal use of this plant. He suggested preparing it in a tea "for those that be bitten of serpents." 10 Another famous ancient herbalist, Pliny the Elder, wrote that mixing the juice of the plant with honey was good for "carrying off bile." 1 9

Milk thistle is mentioned in several works from the Middle Ages, one of the first being in a record of old Saxon remedies, which claimed that "this wort if hung upon a man's neck it setteth snakes to flight." 8 One of the best known herbalists from this time, John Gerard (1545-1612), recommended milk thistle for expelling melancholy and its related diseases (melancholy diseases were described in medicine in the Middle Ages as related to the liver and also called "black bile"). 8 9 10 Another well known English herbalist, Nicholas Culpeper (1616-54), recommended milk thistle for several maladies: breaking and expelling stones, removing obstructions of the liver and spleen, treating jaundice and infections of the plague, and cleansing the blood. 8 9

Maud Grieve, who compiled her book of herbal information in 1931, quoted several early English herbalists on their love for and use of milk thistle. She reports that in 1694 Westmacott wrote of milk thistle, "It is a friend to the liver and blood: the prickles cut off, they were formerly used to be boiled in the spring and eaten with other herbs; but as the World decays, so does the use of good old things and other more delicate and less virtuous brought in." 8 She also reports that John Evelyn wrote, "Disarmed of its prickles and boiled it is worthy of esteem, and thought to be a great breeder of milk and proper diet for women who are nursing."8

Although milk thistle's use during the 17th century is most often associated with English herbalists, many monasteries cultivated and used the plant for medicinal purposes as well. St. Hildegard von Bingen (1098-1179) recommended the roots, herbs, and leaves for swelling and erysipelas.5

Milk thistle was popular with German herbalists and scientists, also. Otto Brunfels (1488-1534), Hieronimous Bock (1498-1554), Jacob Theodorus (1520-90), Adam Lonicerus (1528-86), and Pietro Andrea Mattioli (1501-77) all recommended milk thistle for treating liver diseases. 5 9 Another German physician from the 19th century, Johannes Gottfried Rademacher, developed a tincture made from milk thistle seeds for his liver patients. 1 4 Rademacher's Tincture is an ethanol extract from the seeds used for hepatosplenic disorders. 9

In the United States, milk thistle enjoyed popularity in the 19th century with the Eclectics movement, an officially recognized branch of North American medicine that predominantly used Native American herbs. The Eclectics used milk thistle for varicose veins, menstrual difficulty, and congestion of the liver, spleen, and kidneys. 1 7 Milk thistle was also used as part of the naturopathic medical tradition and Native American medical practices. 10 So popular was milk thistle that a tincture of the whole plant was listed in the first United States Homeopathic Pharmacopoeia. 1 2

Available history does not seem to tell us how (i.e., by what anecdotal or empirical evidence) milk thistle came to be advised for liver and gallbladder problems. Although milk thistle is most often associated with treating liver disorders, physicians have tried to apply its curative properties to other ailments, including stimulating breast-milk production and bile secretion, treating depression, and protecting against the poisonous mushroom Amanita phalliodesand other environmental toxins.4

The Milk Thistle Industry

Milk thistle enjoys significant popularity in the current herbal industry. The World Health Organization estimates that 4 billion people (nearly two-thirds of persons in developing countries) use herbal medicine for some aspect of health care. Herbal medicine is a major component in all indigenous peoples' traditional medicine and a common element in Ayurvedic, homeopathic, naturopathic, traditional oriental, Chinese, and Native American Indian medicine. 11

Milk thistle has been available in Europe since 1969, and more than $180 million worth of products were sold in one recent year. 10 In Germany alone, milk thistle was the 11th most frequently prescribed monopreparation herbal, with $16 million (U.S. dollars) in sales in 1996.12

In the United States, the herbal market was estimated at about $1.6 billion in 1994 with some projections reaching about $3.5 billion in 1997. Of the 14 top-selling herbal supplements in the United States in 1997 in food, drug, and mass-market retail outlets, milk thistle ranked 13th (more than $3 million). 12 However, it is difficult to determine the actual size of the herbal market because herbal products were formerly sold mostly through channels of distribution normally not subject to econometric tracking services (e.g., health food stores, mail order, multilevel marketing organizations). 12

Attesting to milk thistle's popularity in this country, a recent poll of patients attending a hepatology clinic at Oregon Health Sciences University found that 31 percent of patients were using over-the-counter "alternative agents" for the therapy of their liver disease. The most commonly used nontraditional therapy was milk thistle, and over 50 percent of those patients felt they had experienced subjective improvement in their symptoms. 13 In the United States, milk thistle is now being tested for safety by the U.S. National Toxicology Program, along with aloe vera, ginseng, and kava. 14

Chemistry and Pharmacokinetics of Milk Thistle

Flavonoids, of bioflavonoids, are a ubiquitous group of polyphenolic substances that are present in most plants and concentrated in seeds, fruit skin or peel, bark, and flowers. A great number of plant medicines contain flavonoids, which have been reported as having antibacterial, anti-inflammatory, antiallergic, antimutagenic, antiviral, antineoplastic, antithrombotic, and vasodilatory actions. The structural components common to these molecules include two benzene rings on either side of a three-carbon ring. Multiple combinations of hydroxyl groups, sugars, oxygens, and methyl groups attached to these structures create the various classes of flavonoids: flavanols, flavanones, flavones, flavan-3-ols (catechins), anthocyanins, and isoflavones. Flavonoids have been shown in a number of studies to be potent antioxidants, capable of scavenging hydroxyl radicals, superoxide anions, and lipid oxygen radicals due to lipid peroxidation. 15

As reviewed by Bindole, et al., in 1968 Wagner isolated and called the flavonoid complex in milk thistle "silymarin." Silymarin, the active component of milk thistle responsible for its putative hepatoprotective actions, is a mixture of silybin (also known as silybinin or silibinin), silychristin (or silicristin), and silydianin (also silidianin). 16 Silybin is the most prevalent of the three (about 50 percent of silymarin) and the most biologically active. 9 17 Silydianin is very heavily metabolized, whereas silycristin is only absorbed to a very slight extent in the gastrointestinal tract. 18 Silymarin is found throughout the entire plant, but concentrations of silymarin are highest in the seeds and leaves. 3 It is typically extracted with 95 percent ethyl alcohol, yielding a bright yellow fluid ("lavonoids"is derived from "lavus," meaning yellow) or acetone. 9 However, the leading manufacturer of milk thistle, (Madaus, a German company) prepares its product Legalon® with ethylacetate as the primary solvent. 19 Subsequent research in Germany has revealed other constituents in milk thistle, including dehydrosilybin, desoxysilydianin (silymonin), silandrin, and silybinomer. 20

German research initially led to a standardized milk thistle extract of 70 percent silymarin. 1 Standardized silymarin extract now contains 70 to 80 percent silymarin. Madaus' Legalon® is sold in tablets containing 70 or 140 milligrams (mg) silymarin and is given in a dose of one to two tablets up to three times daily, with a maximum dosage of 420 mg. Madaus now outsources production of crude silymarin to the Italian firm Indena in Milan. This crude extract is made exclusively for Madaus according to their standards, cannot be sold to other companies, and is further processed back in Madaus' facilities to produce the extract sold as Legalon® 21 22 Silymarin preparations, although standardized on silymarin content, differ regarding the in vitro release of silymarin or silybin; as a result, the availability of silybin for absorption differs also. In two studies of nine and six silymarin preparations, respectively, release of silybin from Legalon® was more rapid and higher compared with other preparations.23

From standardized silymarin, silybin can be isolated and complexed with phosphatidylcholine. 24 This formulation, called IdB 1016, is now sold as Silipide® (Inverni, Italy) and is expressed as silybin equivalents. Silipide® has been shown to be more bioavailable than standardized silymarin after oral ingestion in normal volunteers, cirrhotics, and patients after cholecystectomy. 9 25 26 27 28 The bioavailability of silybin in Silipide® is approximately tenfold greater than the silybin content of standard milk thistle preparations. 5

Various methods have been developed to identify the constituents of silymarin, including thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), colorimetry, and electrophoresis. 18 29 30 31 32 33 34 There are two species of the silymarin plant: S. marianum (L.) Gaertn. and S. eburneum Coss. Dur Of the S. marianum species, there are two varieties: the common purple flower and the much less common white flower. HPLC can distinguish between the two species. 28 There are also two chemotypes for the purple variety, which can be distinguished by TLC and HPLC. One has a relatively high silybin content and a high silybin:silydianin ratio. The other has a relatively high silydianin content and low silybin:silydianin ratio. They appear to be stable chemotypes with characteristic silybin and silydianin contents and proportions for several generations under the same field conditions. 28 In summary, chromatography can thus far distinguish four biochemical profiles: three for S. marianum and one for S. eburneum. Differences are smaller between S. marianum and S. eburneum than between the white and purple varieties of S. marianum.

Mechanisms of Milk Thistle

Currently, milk thistle (silymarin, silybin, and Silipide®) is primarily advocated as a therapeutic and hepatoprotective agent, especially in the settings of cirrhosis, chronic hepatitis, alcohol consumption, and environmental toxin exposure. Silymarin, silybin, and Silipide® have multiple mechanisms of action that may be hepatoprotective, including antioxidant activity, toxin blockade, enhanced protein synthesis, and antifibrotic activity.

Antioxidant Activity

Silymarin is thought to have antioxidant activity in the liver, as well as the small intestine and stomach. As an antioxidant, this compound may reduce free radical production and lipid peroxidation in the setting of hepatotoxicity. Lipid peroxidation is the end result of unstable free radicals' damage to membrane lipids. These membranes contain fatty acids that are transformed to lipoperoxidases, peroxides, and lipidic hydroperoxides. Malondialdehyde is a biproduct of phospholipid turnover and linoleic acid and is frequently used in clinical and in vitro studies as a surrogate marker for oxidation activity. Multiple in vitro studies have demonstrated lipid peroxidation inhibition using malondialdehyde as a marker in rat hepatic microsomes and mitochondria. 35 36 37 38 Furthermore, the phenolic conformation of silymarin is thought to permit the formation of stable compounds from hydroxylic and oxygen radicals. 39 40 Primary defenses against oxidation or free radical production include glutathione, catalase, and superoxide dismutase. In the setting of an acute toxic event, if stores of these compounds are depleted in intracellular or extracellular (sinusoidal) compartments, oxidative injury is unimpeded. 41 42 43

The phenol structure of silymarin led investigators to postulate that silymarin might have potential activity as an antioxidant. In vivo studies in rats indicate that silymarin can reduce the free radical load. One study exposed rats to acetaminophen at toxic doses, and then measured levels of reduced glutathione and superoxide dismutase in experimental and control rats. In another study, mice exposed to acetaminophen at toxic doses had increased levels of reduced glutathione and superoxide dismutase when treated with silymarin compared with the levels in controls. 41 42 Another study demonstrated preserved hepatic glutathione stores and improved reduced:oxidized glutathione ratios in rats exposed to acetaminophen and ethyl alcohol at high doses when compared with those in controls. 42 Similarly, in humans, investigators have demonstrated increases in serum glutathione peroxidase and erythrocyte and lymphocyte superoxide dismutase. 44

Silymarin may also protect hepatocyte-lipid membranes. Studies demonstrated that silymarin can inhibit cell lysis as measured by changes in alanine aminotransferase levels when exposing isolated hepatocytes to carbon tetrachloride and galactosamine. 45

Toxin Blockade

Studies demonstrated improvements in cytosol liver and histologic markers in animals receiving silymarin compared with those in controls for an array of hepatotoxins including carbon tetrachloride, galactosamine, thioacetamide, ethanol, and acetaminophen. 5 The mechanism of action is thought to be mediated by competitive inhibition, membrane stabilization, and antioxidant activity. However, in many studies the mechanism was not clearly identified. Silymarin can bind to liver cell membrane receptors to protect cells from toxins. One study demonstrated this effect using the death cap mushroom, Amanita phalloides. The toxins in this fungus are amanititin and phalloidin. Several studies showed that silymarin competes with the toxin for cell membrane receptor sites, thus reducing the effect of the toxin. 46 47

Enhanced Protein Synthesis

Regeneration of hepatocytes is necessary for hepatic recovery from acute or chronic insults. In chronic injury, fibrosis occurs simultaneously with regeneration; the ultimate outcome is determined by which process dominates. Several studies identified mechanisms through which silybin may facilitate hepatocyte regeneration. In several rat studies, silybin appeared to stimulate ribonucleic acid (RNA) polymerase I and ribosomal RNA. 48 49 This effect leads to more rapid formation of ribosomes, which in turn increases protein synthesis. The exact mechanism of how RNA polymerase I is stimulated is unclear. One study demonstrated that silymarin binds to a steroid receptor, 48 and it is hypothesized that structural similarity with steroids permits binding. Silymarin then, like steroids, may be able to modulate RNA synthesis. Additionally, one study in rats suggested that silymarin can also enhance deoxyribonucleic acid synthesis and, therefore, possibly enhance hepatocyte regeneration. 50 Thus far, one study demonstrated hepatocyte regeneration in rats with silymarin. 49

Antifibrotic Activity

To date, the evidence for antifibrotic activity comes largely from animal studies. Reportedly, human trials are in progress with Legalon® that are examining antifibrotic activity. According to Madaus, Legalon® administered orally in a rat biliary fibrosis model reduced hepatic collagen accumulation and levels of a serum marker for fibrosis. Another study reportedly slowed down regeneration of procollagen RNA by silymarin in rat livers. 51

Other Postulated Mechanisms

Milk thistle reportedly reduced leukotriene formation through noncompetitive inhibition of lipoxygenase, thereby suggesting possible anti-inflammatory effects. 52

Current Preparations of Milk Thistle

Because silymarin is poorly soluble in water, teas are considered to have a less than 10 percent bioavailability. Since absorption of silymarin from the gastrointestinal tract is only 20 to 50 percent, oral tinctures, or alcohol-extracted preparations, are considered suboptimal, and effective oral therapy is assumed to require concentrated products. A water-soluble derivative of silybinin (silybinin dihemisccinate disodium) is available from Madaus, Germany, and is used parenterally in Europe for deathcap mushroom (Amanita phalloides) poisoning. 53

The most common oral formulation is capsules containing powdered seeds or a seed extract. Formulation includes extraction with alcohol, filtration, and evaporation and may also include pressing, heat drying, and blending with other compounds. Some brands may add choline, inositol, tumeric extract, artichoke extract, whole herb powders, dandelion, licorice, curcuma, boldo, iron, or Vitamins A and C. One formulation is combined with kutkin, the roots and rhizome of Picrorhize kurroa, a perennial herb found only in the higher mountains of the northwestern Himalayas. Other concentrated oral formulations include tablets and softgel capsules. Silipide® is the complex of one part silybin and two parts phosphatidycholine from soybean phopholipids (lecithin), for which standardization is expressed as silybin equivalents.

Challenges in Interpreting the Evidence

The primary difficulty in interpreting the available evidence is the quality of study designs and the quality of published reports. 9 54 Quality of trials is hampered by heterogeneity in etiologies, chronicity, and severity of liver disease both within and between trials; adequacy of randomization; amount and duration silymarin dosing; assessment of alcohol use during trials; types of controls; and recruitment and sampling strategies. Only placebo-controlled trials permit assessment of the liver's intrinsic regenerative capacity when the source of injury is removed (e.g., alcohol and resolution of hepatitis). In addition, even if investigators attended to these important issues of study design and methods, there is a very problematic lack of information in many published reports. Much information is lacking on type and homogeneity of liver disease, recruitment settings and methods for study subjects, chronicity and severity of liver disease, dose and duration of treatment with silymarin, whether statistical comparisons are within or between intervention and control groups, exactly what statistical comparisons were done, and the actual results. Few studies report screening subjects for human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV), and screening and systematic monitoring for alcohol intake. Few trials adjust for these and other potential confounders; most trials are small, and randomization sometimes did not adequately balance known potential cofounders. Little information is available regarding compliance with milk thistle and placebo and adequacy of blinding. Many of the trials are small, and Type II errors cannot be excluded. Much of the trial data are in languages other than English, raising problems with retrieving the evidence, identifying peer-reviewed journals, and the potential risks of error in translating the information and interpreting the data. 9 54

PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...