Milk Thistle for Treatment of Acute Hepatitis, Chronic Hepatitis, and Cirrhosis
Milk Thistle for Treatment of Acute Hepatitis, Chronic Hepatitis, and Cirrhosis
October 1998; Volume 1: 113-116
By E.P. Barrette, MD
Since the introduction of tests for hepatitis c, public awareness of chronic hepatitis has become acute. In the United States, 1.4% of adults have hepatitis C, which is the number one reason for liver transplantation. Up to 85% of acute hepatitis C infections develop into chronic hepatitis which may then progress to cirrhosis. Other important causes of chronic hepatitis are hepatitis B virus, alcoholism, toxic drug side effects, and autoimmune disease.
Milk thistle has been promoted for treatment of acute and chronic liver conditions, resulting in U.S. sales of more than $3 million in 1997. In Germany, milk thistle ranks among the top 10 herbal supplements, with sales of $18 million annually.1
Botany and Nomenclature
Milk thistle (Silybum marianum and, in older texts, Carduus marianus) is found widely in Europe, Eastern Africa, and North America. It is a member of the aster family (Compositae/Asteraceae) and grows up to 10 feet tall. It bears a bright purple brushlike flower, and, in summer, it produces black seeds from which the drug is derived.
Other common names have been used including holy thistle, St. Mary thistle, marian thistle, lady's thistle, and royal thistle. Its spiritual names stem from the belief that the white veins on the plant's leaves carried the milk of the Virgin Mary; its chivalrous names come as it is found near Dumbarton Castle.2
History
The milk thistle has been used for 2000 years as a medicinal herb. The Latin name, Silybum, was derived by Dioscorides, an herbalist in ancient Greece who used the term silybon to describe thistle-like plants. Pliny the Elder, a Roman writer (AD 23-79), recorded that the plant's juice was excellent for "carrying off bile." Culpepper (1787), an English herbalist, described its use in removing obstructions to the liver and spleen and as a remedy for jaundice. The Eclectics, a late 19th century school of medical herbalists, used milk thistle for congestion in the liver, spleen, kidney, varicose veins, and in menstrual disorders. Milk thistle is widely used in Europe, where it has been commercially available for almost 30 years.
Pharmacology and Pharmacokinetics
In 1968, a mixture of flavonolignans, called silymarin, was first isolated from milk thistle. The fruit contains 4-6% of silymarin. The isomeric components of silymarin are silybin, silychristin, and silydianin. Silybin is reportedly the most biologically active component. Schulz reports that there are four active isomers, and silybinin is the most active. He breaks down silybin to silybinin and isosilbinin, and says that silymarin is most concentrated in the protein layer of the seed husk.3
Silymarin has poor water solubility. Oral bioavailability ranges from 23% to 47%. Absorption is rapid, with peak plasma concentrations measured in 1-2 hours. Less than 10% is excreted in the urine, and 20-40% is recovered in the bile as glucoronide and sulfate conjugates. Ninety percent of the total silybin in plasma is conjugated. The elimination half-life is estimated to be six hours. A phosphatidylcholine silybin complex was developed to improve bioavailability.4
Mechanism of Action
Multiple actions have been proposed, including antioxidation, liver cell regeneration through protein synthesis, and membrane stabilization. In vitro studies demonstrate antioxidant activity against the hydroxyl free radical (a reactive oxygen molecule) and increased protein synthesis in hepatocytes. A mechanism involving stabilization of lipid membranes is based on studies showing silymarin inhibition of lipid peroxidation of hepatocytes, Kupffer cells, and microsomal membranes in rats. Also, inhibition of leukotriene formation, which has a role in liver damage, by silymarin in phagocytes from human livers has been seen.5
Clinical Studies
Several studies of acute viral hepatitis treated with silymarin suggest improved outcomes. In a randomized, double-blind controlled trial (RDCT) of 57 patients with acute hepatitis A or B treated with silymarin 140 mg tid or placebo for 3-4 weeks, AST, ALT, and bilirubin levels were lower by day five in the treatment group.6 At three weeks, more patients had normalized their bilirubin and AST in the silymarin group. Treatment did not improve the clearance of hepatitis B surface antigen (HBsAg).
However, a more recent study of misoprostol for acute hepatitis B included a silymarin arm that did not confirm these results.7 Fifty-two nonalcoholic males were randomly assigned to silymarin 210 mg/d (20 subjects), misoprostol 800 mcg/d (20 subjects), or no drug treatment (12 control subjects). Treatment was started less than four days after the onset of jaundice and continued for four weeks. No improvement in bilirubin, AST, ALT, duration of hospitalization, or clearance of HBsAg was seen with silymarin, compared with controls.
The studies of silymarin and chronic liver disease are likewise mixed. A double-blind trial of 30 alcoholic patients with biopsy-confirmed cirrhosis excluding those with hepatic decompensation showed normalization of AST, ALT, bilirubin, and suppressed lymphocytotoxicity at one month with silymarin 140 mg tid compared to placebo.8 No attempts to monitor continued alcohol use were made.
However, a larger RDCT of 116 patients with histologically confirmed alcoholic hepatitis compared silymarin 420 mg/d with placebo for three months.9 Fifty-eight patients had cirrhosis on biopsy. Both silymarin and placebo gave similar improvements in laboratory and histological parameters after three months.
Two frequently quoted studies support the use of milk thistle. The first is a RDCT in which 106 young soldiers were enrolled after admission to a military hospital for an elevated ALT or AST persisting longer than one month.10 Subjects were randomized to silymarin 420 mg/d or placebo for one month. Although alcohol was the presumed cause in all subjects, 20% denied daily alcohol use at entry. At four weeks, statistically significant improvements in the mean percentage change of the AST (silymarin decreased 30% vs placebo increased 5%) and ALT (silymarin decreased 41% vs placebo increased 3%) were seen. Liver biopsies were performed on 90 patients at entry but only 29 at four weeks. Silymarin treatment improved histology, but the reasons for the low rate of repeat biopsy were not detailed and no measure of alcohol abstinence was included in the study.
In the second trial, 170 patients with cirrhosis were randomized to treatment with silymarin 140 mg tid or placebo for 2-6 years (mean follow-up, 41 months).11 In each arm, 54% were alcoholic. Patients with known malignancies, end-stage liver disease, primary biliary cirrhosis, or who were receiving immunosuppressive therapy were excluded. No improvement in transaminases or bilirubin was seen in the 105 patients completing the planned two-year study. Overall survival at two years was better with silymarin (77% vs 67%; P = 0.07). Subgroup analysis showed the survival benefit to be limited to alcoholics (P = 0.01) and to those rated Child A at entry (P = 0.03). More patients receiving placebo continued to drink than those receiving silymarin.
One other recently published study was unable to confirm a mortality benefit with silymarin for cirrhosis but suggested one for hepatitis C. Two hundred alcoholic patients with histologically confirmed cirrhosis were entered in a RDCT comparing silymarin 150 mg tid with placebo.12 Patients with life expectancy of less than six months, hepatitis B, autoimmune disease, primary biliary cirrhosis, or who were receiving colchicine or corticosteroids were excluded. Forty-two patients dropped out, while 125 patients completed the two-year study. Clinical and laboratory parameters improved equally with silymarin or placebo.
Provocatively, stored sera for 75 patients were analyzed for hepatitis C, and 39% were positive. Silymarin may have influenced survival for hepatitis C positive patients (0 deaths in 13 patients receiving silymarin vs 4 deaths in 16 receiving placebo). Although this difference was not statistically significant (P = 0.059), it was still impressive.
Adverse Effects
No serious adverse have been seen with milk thistle. Animals subjected to very high doses of milk thistle showed no toxic effects. Some patients report looser stools. In the largest clinical trial, arthralgias, headaches, and urticaria were rarely reported. There are no reported drug interactions.
Table
Sample Milk Thistle Prices
| Brand | Formulation | Price/Count |
| Nature's Resource | 140 mg (70% silymarin) | $11.99/50 |
| 200 mg (80% silymarin) | $26.99/100 | |
| NaturaLife | 175 mg (80% silymarin) | $12.99/40 |
| Nature Fingerprint | 200 mg (80% silymarin) | $21.99/100 |
| Jarrow | 150 mg (80% silymarin) | $11.49/100 |
| Pure Encapsulations | 250 mg (80% silymarin) | $11.80/120 |
Sample Allopathic Medication Prices
Interfero $225/month
Rebetron (Ribavirin/ 84 capsules of $720/two weeks Interferon Alpha-2b) 200 mg ribavirin (starting (AWP) 1200 pack dose for > 75 kg) and supply of interferon in multi-dose vial
Rebetron (Ribavirin/ 70 capsules of $651.59/two weeks Interferon Alpha-2b) 200 mg ribavirin (AWP) 1000 pack (starting dose for < 75 kg) and supply of interferon
Formulation and Dosage
Milk thistle products are standardized by the amount of silymarin extract, which is generally 70-80%. Because of the drug's poor water solubility, teas and water-based infusions provide less than 10% of the initial silymarin content. The German Commission E, an expert committee responsible for evaluating the safety and efficacy of herbal medicines, has recommended milk thistle as supportive treatment for chronic inflammatory liver conditions. Unless otherwise prescribed, the Commission E recommends a daily dose of 12-15 g, or a formulation equivalent to 200-400 mg of at least 70% silymarin. No one makes recommendations for duration of therapy.
Summary
Milk thistle has become a popular herbal supplement for hepatitis and cirrhosis. There is extensive in vitro and animal data suggesting a hepatoprotective benefit with silymarin. However, the clinical studies are mixed. The positive studies in alcoholic hepatitis and cirrhosis showing improved transaminase levels and mortality must be viewed alongside studies that are equally well done and that show milk thistle to be no better than placebo. There are no published controlled trials with milk thistle and hepatitis C, although investigators at Cedars-Sinai in Los Angeles have recently initiated one. The FDA recently approved the use of ribaviran with interferon alpha-2b for chronic hepatitis C infection in adults whose disease has relapsed following alpha interferon monotherapy. This combination increases the sustained response to 40-50%, compared to less than 20% for interferon alone. However, these treatments have frequent adverse effects and are expensive.
Recommendations
For patients with hepatitis or cirrhosis, milk thistle appears to be safe and inexpensive. For patients with alcoholic liver disease, abstinence remains the cornerstone of therapy, and, for patients at risk for hepatitis A and B, vaccines are available. For patients with chronic hepatitis C, milk thistle remains unproven. For patients with acute viral hepatitis, alcoholic hepatitis, and cirrhosis, a modest benefit may exist, but the evidence remains inconclusive. Physicians may wish to try milk thistle for chronic hepatitis but should know the evidence only suggests a benefit in early cirrhosis and chronic hepatitis.
References
1. Herbalgram 1997;39:68.
2. Milk Thistle monograph. The Review of Natural Products. St. Louis, MO: Facts and Comparisons, a Wolters Kluwer Company; January 1997.
3. Schulz V, et al. Rational Phytotherapy. New York: Springer-Verlag; 1998:214-216.
4. Flora K, et al. Milk thistle (Silybum marianum) for the therapy of liver disease. Am J Gastroenterol 1998; 93:139-143.
5. Dehmlow C, et al. Inhibition of Kupffer cell functions as an explanation for the hepatoprotective properties of silibinin. Hepatology 1996;23:749-754.
6. Magliulo E, et al. Zur Wirkung von Silymarin bei der Behandlung der akuten Virushepatitis. Med Klin 1978;73:1060-1065.
7. Flisiak R, Prokopowicz D. Effect of misoprostol on the course of viral hepatitis B. Hepato-Gastro 1997; 44:1419-1425.
8. Lang I, et al. Hepatoprotective and immunological effects of antioxidant drugs. Tokai J Exp Clin Med 1990;15:123-127.
9. Trinchet JC, et al. Traitement de l'hepatite alcoolique par la silymarine. Une etude comparative en double insu chez 116 malades. Gastroenterol Clin Biol 1989;13:120-124.
10. Salmi HA, Sarna S. Effect of silymarin on chemical, functional, and morphological alterations of the liver. Scand J Gastroenterol 1982;17:517-521.
11. Ferenci P, et al. Randomized control trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol 1989;9:105-113.
12. Pares A, et al. Effects of silymarin in alcoholic patients with cirrhosis of the liver: Results of a controlled, double-blind, randomized and multicenter trial. J Hepatol 1998;28:615-621.
October 1998; Volume 1: 113-116Subscribe Now for Access
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