To some hepatitis C patients, the cure seems worse than the disease. The long duration and possible side effects of interferon/ribavirin treatment send many people looking for other treatment options. Rather than trying to eliminate the virus with the standard therapy, these patients are looking for a natural treatment that will promote liver health. These patients face difficult choices because most of the herbal products advertised to support the liver are unproven -– and a few are known to be dangerous. So, have any complementary or alternative remedies been scientifically proven to help?

“Research into alternative/herbal remedies for liver disease is largely scattershot,” says Christopher Maloney, N.D., who practices holistic medicine in Augusta, Maine. Dr. Maloney, a frequent contributor to Liver Health Today, says it is easy to find information about prescription drugs because of the research done by the pharmaceutical companies, but information on natural remedies is more difficult to obtain. “It’s a very frustrating field,” he says. “Nobody’s actually spent the time, energy or money to really become an authority on a single herb.”

Research involving herbal or alternative medicines for liver disease has indeed been limited to relatively few, small-scale trials. Studies of licorice root (glycyrrhizin) have shown it to be promising. A 1997 retrospective (survey-based) study found that hepatitis C patients treated with licorice root had lower rates of liver cancer than patients who had not been treated with either glycyrrhizin or interferon. Studies done in 1999 and 2001 found that glycyrrhizin reduced liver enzyme levels in hepatitis C patients, although it was not found to affect HCV viral load. Animal studies indicate that ginseng extract can lower liver enzyme levels and inhibit liver cell death. Thymus extract was studied in several small trials involving hepatitis B and C patients during the 1980s and 1990s, but these trials found few if any benefits. Case reports and reviews of colloidal silver, often advertised as a treatment for hepatitis, note that the supplement has not been found to be effective against any disease and that it is potentially harmful.

Milk thistle
“Most of these alternative medicines, when you really evaluate them, turn out not to be better than placebo,” says George Strickland, M.D., Ph.D., of the University of Maryland School of Medicine. He has been involved in several studies involving milk thistle extract (silymarin) in hepatitis patients. “I think there’s a chance (milk thistle) might turn out to be useful,” he says.

Dr. Strickland didn’t set out to study viral hepatitis or milk thistle, but this is where his research has led him. During the 1990s he was in Egypt studying schistosomiasis, a parasitic infection that has been known to exist in that country since the days of the Pharaohs. He found that schistosomiasis is no longer a major health threat in Egypt, but that liver disease is.

According to Dr. Strickland, Egypt has approximately 8 million people with hepatitis C – compared to 4 million in the United States, which has a much larger population. He says that the cost and difficulty of interferon/ribavirin treatment make it impractical for most Egyptians. “I was checking the (medical) literature for something else we could do and came across milk thistle that’s been used for 2,000 years to treat liver disease,” he says. “It goes back to Roman times, when they described using milk thistle for the treatment of bile.”

The University of Maryland researchers conducted trials of silymarin in Egyptian patients with chronic hepatitis C and in patients with acute viral hepatitis. The advantage of studying the extract in patients with an acute infection, Dr. Strickland says, is that it is easier to see the results during the acute phase of an infection. “If it’s a disease that takes 20 to 30 years to manifest, how do you expect to find something in one or two years?” he asks. “You might see some changes in the way the patient feels, you might see some changes in some blood tests – if you do liver biopsies you might see a little improvement in a liver biopsy. In acute viral hepatitis we might be able to see manifestations sooner.”

In the acute infection trial, silymarin was shown to be worthy of further study. “Certainly it’s safe,” Dr. Strickland says. “All the patients tolerated it as well as they did placebo. There wasn’t a great deal of difference, but it looked like ... the people that got the silymarin cleared their bile and the symptoms associated with biliary retention (jaundice) sooner. These were statistically significant.”

Dr. Strickland says the data from both trials indicated that silymarin needs to be studied at a higher dose, so the university is in the process of organizing another trial of silymarin in people with acute hepatitis. “If we show that it works in acute viral hepatitis, it should also be useful in chronic hepatitis,” he says. “It won’t cure the virus – we have no data that suggest it will do that – but it might protect their liver from the effects of the virus.”

The University of Maryland studies differ from most alternative medicine research because the patients received a scheduled, specific dose of a silymarin extract that was prepared by a company that uses pharmaceutical industry standards to ensure the consistency of its product. These criteria are important so that the data reflects multiple patients receiving the same regimen. “I’m discussing giving it like a drug, a pharmaceutical product that’s given on a regular basis,” Dr. Strickland says of the upcoming trial.

Dr. Victor Navarro, medical director of hepatology and liver transplants at Thomas Jefferson University Hospital in Philadelphia, agrees. “Milk thistle has never been studied as a pharmaceutical, so our goal is to take it and treat it as a pharmaceutical,” he says. Dr. Navarro is one of four principal investigators in a multicenter study known as SyNCH (silymarin for NASH and C hepatitis).

The SyNCH study is funded by the National Institutes of Health through its National Center for Complementary and Alternative Medicine (NCCAM), and it involves two separate trials. The phase I trial, which recently concluded, studied the safety, tolerability and pharmacokinetics of escalating doses of silymarin in patients with hepatitis C and in patients with NASH (nonalcoholic steatohepatitis, also known as fatty liver).

The phase II study, which began enrolling patients in November, has a hepatitis C arm and a NASH arm. About 200 hepatitis C patients, for whom treatment previously failed, will receive silymarin for six months, and their liver enzymes will be monitored. A similar number of NASH patients will receive silymarin for one year, and researchers will compare biopsies taken before and after the year of treatment.

The SyNCH trial is using the same brand of silymarin extract used in the University of Maryland studies, Legalon, which is manufactured by the German company Madaus. In addition to Thomas Jefferson University, the trial is being conducted at Harvard University, the University of Pennsylvania and the University of North Carolina.

“There has not been any well-designed, scientific trial (of milk thistle for NASH) to date. Ours is the first,” says Dr. Navarro. He notes, however, that milk thistle has been used safely to treat liver problems for thousands of years. “Now it’s time to step back and study it scientifically.”

Although researchers are still reviewing the pharmacokinetic data from the phase I trial, the safety data is encouraging. Dr. Navarro says, “We have found that even at doses of 500 or more milligrams a day, which is about three times the label dose, it appears to be quite safe and well tolerated.”

What remains to be seen is whether silymarin will help the condition of patients with NASH or hepatitis C. “What we’re looking to do is see if this can really quiet inflammation, and we’re going to use the liver (enzyme) test as a marker for that,” Dr. Navarro says. “We don’t expect it to have any antiviral effect. Although we’ll be looking at the hepatitis C levels, we don’t expect it to have any effect on them.”

Laboratory tests
Dr. Navarro and his colleagues just might be in for a surprise, according to research being done at the University of Washington’s department of laboratory medicine by research associate professor Stephen Polyak and his colleagues. Dr. Polyak, who holds a Ph.D. in cellular and molecular virology, says their research contradicts the conventional wisdom about milk thistle’s ability to fight the virus. “My group just published a paper in Gastroenterology this year showing that a highly standardized preparation of milk thistle would actually inhibit hepatitis C virus infection in cell culture,” he says. “The caveat is that we’ve shown it has antiviral activity in the lab, but we have to be careful about interpreting that to the in vivo (in live subjects) situation.”

Dr. Polyak’s team of researchers has been testing the individual components of milk thistle in the laboratory. “We’ve found that some compounds within the milk thistle seem to be more potent than the extract itself,” he says, adding that this research possibly could lead to the development of milk thistle-derived therapies.

Because the SyNCH trial will monitor viral loads in hepatitis C patients, Dr. Polyak believes the trial will determine whether milk thistle has an antiviral effect in patients. “They’ll be able to say whether milk thistle really does have hepatoprotection,” he says.

Hepatoprotection -– protecting or strengthening the liver – is the goal of most herbal hepatitis treatments. “A lot of these herbs, either in traditional Chinese medicine or in Japanese Kampo medicine or herbal supplements, are touted to have hepatoprotective effects,” Dr. Polyak says. “But hepatoprotection entails many activities. If we’re talking about hep C, it could be antiviral. There’s a lot of inflammation in the hepatitis C virus-infected liver, so hepatoprotection could involve anti-inflammatory effects. There’s a lot of oxidative stress in the hep C liver, so it could also act as an antioxidant. Also, it could protect the liver by modulating the immune system.”

Of these areas in which a supplement might protect the liver, Dr. Polyak says his research indicates that milk thistle could work as an anti-inflammatory or an antiviral agent. “But that sort of contrasts with in vivo studies on milk thistle, which haven’t shown the compound to do anything to viral loads,” he says. “We’re really the first study to show that it blocks virus infection and replication.”

SST
Dr. Polyak’s team also is conducting laboratory research on sho-saiko-to (SST), an herbal formula used in traditional Chinese medicine and Japanese Kampo. Dr. Polyak says his research team has applied for funds from the NCCAM for a clinical trial of SST in hepatitis patients, but he says that due to budget constraints and the fact that the NCCAM is the only major source of funds for this type of research, most requests for research grants go unfunded. “There are a lot of people doing research and not enough money to go around right now.”

SST has attracted the attention of other researchers, including those at Memorial Sloan-Kettering Cancer Center in New York, who are currently investigating the effects of SST on hepatitis C patients. “We want to see if this herbal formulation can delay the progression of fibrosis,” says the trial’s principal investigator, Dr. Gary Deng, who holds an M.D. from Beijing Medical University and a Ph.D. from the University of Miami. He has done research on numerous alternative and complementary treatments for cancer and is interested in SST as an inhibitor of cirrhosis, which can lead to liver cancer.

Dr. Deng describes the trial as a single-arm study in which 25 hepatitis C patients who did not respond to previous interferon/ribavirin therapy are given SST three times daily for 12 months. Most of the patients have already enrolled, so it should be about a year before the last of the patients completes the regimen. The research team will check biopsies before and after treatment and will monitor patients’ viral load and liver enzyme levels during the trial.

The endpoint, or measure of success, is improved biopsy scores. “We don’t think it’s an antiviral agent,” Dr. Deng says. “It’s more like a possible anti-inflammatory or immunomodulatory agent.”

As is the case with the SyNCH trial, it is important for researchers to know that the patients are receiving a product of consistent potency. “It’s difficult to obtain a quality study agent,” Dr. Deng says. “That’s a common challenge in doing botanical research.” He says that Honso, the company that manufactures the brand of SST used in the study, supplied the FDA with quality control data prior to the agency’s approval of the trial.

Even if the trial finds that SST improves biopsy scores, Dr. Deng says researchers will not know whether one individual ingredient of the SST is causing the improvement or whether it is the combination of herbs that does the trick. “It’s challenging to have standardized and reliable studies (due to) the nature of botanical agents,” he says. “There are so many compounds in (botanical mixtures) – in many cases you don’t really have a clear idea which one is the active ingredient.”

Despite these difficulties, Dr. Deng and other researchers will continue to explore nature’s medicines in their efforts to improve the lives of people living with liver disease.

http://www.liverhealthtoday.org/viewarticle.cfm?aid=295