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NEW YORK—The National Center for Complementary and Alternative Medicine is calling on the herbal industry to develop standardized, batch-consistent oral silymarin for use in a major national hepatitis C treatment trial.

Silymarin is a mixture of lignans thought to be the key bioactive components in Milk Thistle (Silybum marianum), one of a handful of herbs identified by NCCAM as warranting prompt investigation in Phase II or III clinical studies.

Milk Thistle has rapidly become the herb-of-choice among patients with hepatitis and other chronic liver diseases. The hepatitis trial, still in the planning stages, will be conducted under the aegis of the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK), and will assess the efficacy of silymarin as an adjunct to conventional antiviral and anti-inflammatory therapies in patients with Hepatitis C.

Silymarin, and other natural approaches to liver disease, were the topic of a lively session at the annual meeting of the American College of Gastroenterology.

Leonard Seeff, MD, senior scientist, NIDDK Hepatitis C initiative.

“Hepatitis C is a profoundly important disease in this country. Efforts to treat it have used drugs that are not very nice to take and not wholly effective. It is not surprising that people are looking elsewhere,” said Leonard Seeff, MD, a hepatologist who is senior scientist overseeing the NIDDK’s Hepatitis C initiative.

Depending on whose study you read, anywhere from 15% to 80% of liver disease clinic patients are saying, “Thistle do it.” With or without their doctors’ blessing, they are taking silymarin alone or in combination with interferon, ribavirin or other conventional pharmaceuticals.

In Europe, silymarin is more widely accepted as a treatment of liver disease; advocates claim it has anti-inflammatory and anti-fibrotic effects, and prevents progression of cirrhosis.

“It is clearly an antioxidant and free-radical scavenger,” said Dr. Seeff. The first evidence documenting Milk Thistle’s potential hepatic benefit came from studies showing silymarin is able to protect against the hepatotoxic effects of Amanita phylloides mushrooms.

The strongest case for an anti-cirrhotic effect comes from a 1989 study by Peter Ferenci, MD, of the Division of GI/Hepatology, University of Vienna. This multi-center protocol randomized 170 patients with cirrhosis of varying etiology, to either 140 mg silymarin, thrice daily, or a placebo in the form of a multivitamin.

Four-year survival was 58% in the silymarin group, versus 39% in the placebo arm. Twenty-eight percent of those on silymarin died of liver-related complications during the 4 year period, as compared to 44.6% on placebo.

Speaking at an NIH-sponsored conference on complementary and alternative medicine in liver disease last year, Dr. Ferenci said the patients most likely to benefit from silymarin are those with alcohol-associated cirrhosis, non-alcoholic steatohepatitis, cholestatic liver disease, and chronic hepatitis C unresponsive to conventional drug treatment.

Other available human studies have not shown such clear-cut benefits. There are still many unanswered questions, but Dr. Seeff said two things about silymarin seem quite clear: it does not have any demonstrable antiviral effect—meaning it won’t “cure” hepatitis—and it appears to be very safe.

“Do people feel better when they take silymarin? Maybe. I am certainly not stopping my patients from taking it,” he said at the ACG conference.

The NIDDK trial will go a long way toward determining what role—if any—silymarin should play in treatment of hepatitis C. But before that can happen, researchers want the herbal industry to develop highly purified silymarin standardized to 60% silybinum, which some believe to be the most important sub-component of silymarin. “Batch consistency is the most important thing,” Dr. Seeff said.

According to Norman Gitlin, MD, of the Division of Digestive Diseases, Emory University, “one of the problems we’ve had with herbal therapies is in the realm of safety and efficacy demonstration. If a patient says they are taking 200 mg of ‘Milk Thistle,’ you cannot always be sure they are getting the labeled level.”

Milk Thistle is one of a number of herbs suddenly catching the interest of gastroenterologists. Others include Glycerrhizin, derived from licorice root, Bupleurum, Scutellaria, and Ginseng.

Dr. Gitlin advised his colleagues to balance their new-found enthusiasm about the possible benefits of herbs with a healthy dose of safety concern. “I am not here to knock these agents. We are here to explore them. But we have to admit we have seen some hepatotoxicities (with some herbal medicines).”

Dr. Seeff said the same concerns apply to conventional pharmaceuticals as well. “We don’t really know the long term effects of many, many things. What is the cumulative effect of long term use of PEG-interferon? We don’t know. We presume it is safe, but the reality is, we don’t have any data to support that.”

THE REDUX: Silymarin, or extract of Milk Thistle, at doses of 140 mg thrice daily, appears to have anti-oxidant and anti-inflammatory effects that may slow progression of cirrhosis in hepatitis C. In light of European data and the wide popularity of the herb among liver disease patients, the NIDDK is planning a large-scale trial of silymarin with conventional antivirals in hepatitis C.