Tuesday, May 14, 2013

Is There a Future for Milk Thistle In HCV?

This summary highlights current information on the use of oral silymarin (the active ingredient in milk thistle found in the seeds of the plant) for hepatitis C.

As once a HCV patient myself who successfully treated the virus with conventional therapy in 2000, I never used the supplement, nor do I endorse it, but I had a few close friends who did. They found it to be well tolerated when used according to the recommended dose, as for the benefits? I can only comment that it seemed to help my friends endure the virus, especially when standard therapy failed them.

Today I point you to the research, a few studies which offer a better understanding of the popular supplement, including the possible benefits. Personally I have no opinions of my own to share, except a grave concern for anyone using milk thistle under the pretense it will eradicate the virus. Still, a part of me can't help to wonder if HCV patients will continue to use milk thistle after interferon free therapies become available? Yes, no, maybe. 

When It All Began

In 1990 when blood screening for hepatitis C began there was little hope for people infected with the virus. Back then milk thistle was commonly used by HCV patients, although the use of milk thistle is not as common as it once was, in regards to liver disease it is still used today by people living with the virus.

Why Was Milk Thistle Considered An Alternative To HCV Treatment?

In 1990 HCV was still in its early infancy, we didn't have many treatment options, from 1991-1997 interferon was the only therapy available. Not until 1998 was ribavirin added to interferon with the approval of  Rebetron - Schering’s combo of Intron A and ribavirin. Later in 2001 the first pegylated interferon went to market, it was Schering’s Peg-Intron followed in 2002 by Genentech’s Pegasys.

A decade later standard therapy for genotype 1 HCV patients still involves peginterferon and ribavirin, used along with (Incivek) Telaprevir or (Vicrelis) Boceprevir both protease inhibitors were approved in 2011. However, not everyone will respond to triple therapy or a regimen of peginterferon and ribavirin alone, plus some people are unable to tolerate interferon. With few options left milk thistle is generally explored by HCV patients.

Use of Herbal Supplements for Hepatitis C

Research on silymarin suggests that it may protect the liver from inflammation. But it does not have a direct effect on viruses that cause hepatitis, such as the hepatitis C. The National Institutes of Health, National Center for Complementary and Alternative Medicine this month updated - Hepatitis C and Dietary Supplements:What the Science Says

Another great resource on the use of herbs and supplements including their interactions is available at HCV Advocate, download the PDF here, updated April 2013.

A few words about the supplements listed in this glossary:

The goal was to choose supplements that may be particularly pertinent to those with liver disease, especially viral hepatitis

The information applies to supplements, NOT food. For instance, under artichoke, it says,

“Avoid with bile duct obstruction or gallstones. Use cautiously in liver patients with clotting problems as artichoke may increase risk of bleeding.” This means to use caution when taking extracts and formulations that have high doses of the active ingredients

Heads Up

This information is not intended as medical advice or endorsement of the use of dietary supplements. Always talk to your medical provider before taking any herbs or supplements. All herbs, drugs, and other substances have potential side effects. Allergic reactions have been reported for nearly every herb, sometimes with life-threatening consequences. If you suspect you are having an allergic reaction or other serious side effect, stop taking the substance and seek immediate medical advice. If you have trouble breathing or feel faint, call 911.

If you are scheduled for a medical or surgical procedure, particularly if anesthesia will be used, or plan to undergo chemotherapy, report supplement use to your medical provider. You may need to stop supplement use for a week or more before the procedure since many supplements interfere with anesthesia and/or blood clotting.
Download PDF 

Commercial Milk Thistle

The U.S. Food and Drug Administration (FDA) does not regulate supplements in the same way it regulates medicines. A dietary supplement can be sold with limited or no research on how well it works. The form you buy in health food or grocery stores may not be the same as the form used in research. For instance in one article "Antioxidant and Anti-Hepatitis C Viral Activities of Commercial Milk Thistle Food Supplements" researchers analyzed 45 products from local stores for their silymarin content, antioxidant activities, and antiviral activity against HCV. Some of these samples were found to vary widely in their silymarin content.

The 2013 research paper Antioxidant and Anti-Hepatitis C Viral Activities of Commercial Milk Thistle Food Supplements - Anthony, K.; Subramanya, G.; Uprichard, S.; Hammouda, F.; Saleh, M. is available online @ MDPI AG - Antioxidants
*About the journal.

Excerpt from a 2010 article found in the HCV Advocate Newsletter, written by Lucinda K. Porter, RN

All milk thistle is not alike and what is in the bottle may not match what is promised on the label. In a startling report published by ConsumerLab.com (CL), only one of 10 products passed the necessary tests in order to carry the CL seal of approval.

CL is an independent organization that provides information and testing of nutritional products. They have been around for about ten years. Some information is free, but product reports are available only to subscribers. A one year subscription is $30 and worth every penny. www.consumerlab.com

The Research

In 2013 patients with hepatitis C still use alternative therapies in hopes of some added benefit. The most common as mentioned above is silymarin, an antioxidant that exhibits anti-inflammatory properties.  According to research close to a third of HCV and cirrhosis patients report using the milk thistle extract, even when studies have shown inconsistent results regarding its benefit.

The most rigorous trial to date to test the herbal extract milk thistle (silymarin), was published in the 2012 issue of  the Journal of the American Medical Association (JAMA),  researchers reported oral silymarin was not superior to placebo (A substance containing no medication) in decreasing disease activity or its symptoms.

The Study

Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: A randomized controlled trial. JAMA 2012 Jul 18; 308:274. 

How many patients were in the study?

154 patients (median age, 54; 71% men) with chronic HCV infection who previously failed interferon-based therapy.

What dose of silymarin did the patients receive?

The researchers randomly assigned the patients to one of three groups, two of which took high doses of a standardized form of silymarin at 420mg or 700mg three times daily for 24 weeks. The third group took a placebo.

The two oral doses of pure silymarin were determined by earlier dose finding studies and were three to five times higher than concentrations used in previous studies.

Unlike previous trials, this study used a pure, quantifiable formulation of silymarin and well-defined outcomes, its cohort was large and representative of the patient population, the treatment period was sufficiently long, and both medication and visit adherence rates were high.

What was the baseline ALT of patients who participated in the study?

The patients in the study had serum alanine aminotransferase (ALT) enzyme levels greater than 65 IU/L, with a median of 106 IU/L at baseline. A normal level is 45 IU/L.

Did patients respond, was ALT lowered?

Of the 138 patients who completed the 24-week study, 90% were able to adhere to at least 80% of the pill regimen. In spite of the compliance, however, the mean drop in serum ALT was not significantly different between the three groups.

After six months, one person in the placebo group had a serum ALT less then 45 IU, as did two patients in each of the silymarin arms. Additionally, two patients in the placebo and high-dose silymarin groups had at least a 50% decline in baseline ALT to less then 65 IU, as did one patient in the 420-mg silymarin arm.

Side effects

The most common types of adverse events were gastrointestinal, musculoskeletal, dermatologic, infection, and physical injury. Six patients in the 420-mg silymarin arm and five in the 700-mg arm had serious adverse events, compared with one in the placebo group.

This trial found that oral silymarin used at higher than customary doses (three to five times the typical dose) did  not significantly alter biochemical or virological markers of disease activity.

MedPage Today
 2012 issue of JAMA

Video summary of trial published in the Journal of the American Medical Association

Is There a Future for Milk Thistle In HCV?

In the June 2012 issue of Gastroenterology & Endoscopy News, Christina Frangou reported on the AASLD 2011 meeting and the above study, the author noted commentary from Joseph K. Lim, MD on the future role of milk thistle for patients with liver disease and hepatitis C. The director of the Yale Viral Hepatitis Program cited three studies of interest where the extract was given in higher doses or different formulations

With the latest study results, it is unlikely that oral silymarin will have a future role in the care of patients with hepatitis C infection, although it still will be considered for other liver conditions for which no therapeutic options exist, said Joseph K. Lim, MD, associate professor of medicine and director of the Yale Viral Hepatitis Program at the Yale University School of Medicine, New Haven, Conn.

“Although the study cannot entirely exclude the possibility of a benefit from much higher doses of oral silymarin or intravenous silymarin, in this era of rapid advances in high-potency direct-acting antiviral agents, which may soon eliminate interferon, clinical interest in adjunctive therapies with significant pill burden or intravenous formulations with unproven benefit will be very limited.”

Dr. Lim added, “Once simplified nontoxic, oral–oral regimens with high sustained viral response rates materialize in the next several years, supplements such as silymarin may lose relevance.”
Attendees at the meeting said that they hope patients pay attention to the results of the study.
“Thank you for saving our patients from financial stress and false hope, possibly leading to delays in definitive therapy,” one attendee tweeted during the session.

However, to others, the results were disappointing. In poorer areas of the world where the newer hepatitis drugs are simply too expensive, the silymarin compound could be extremely useful, said one hepatologist.

It may be that there is a future role for silymarin or silibinin in hepatitis treatment when the extract is given in higher doses or different formulations than used in the current randomized study. In one study published in January in the Journal of Hepatology, investigators studied changes in HCV RNA levels in 25 patients receiving 10, 15 or 20 mg/kg per day of Legalon SIL, a chemically hydrophilized version of silibinin (Guedj J et al. 2012;56:1019-1024). Patients showed a significant drop in viral load, particularly between days 2 and 7. The investigators concluded that Legalon SIL may affect hepatitis virus by blocking both viral infection and production/release. In another study, investigators found that IV-administered silibinin had a “substantial antiviral effect” against HCV in 20 IFN nonresponders (Ferenci P et al. Gastroenterology 2008;135:1561-1567). And, still another study showed that oral Silybum marianum significantly affected serum HCV RNA levels, ALT levels, quality of life and psychological well-being (Gordon A et al. J Gastroenterol Hepatol 2006;21:275-280).

Mushroom Poisoning and intravenous silibinin

In 2011 Georgetown University researchers reported that intravenous silibinin, another milk thistle extract, helped patients with liver toxicity resulting from mushroom poisoning.

Treating HCV without Interferon

HCV drugs currently in clinical trials without interferon have shown great promise, Gilead Sciences Inc and Abbvie Inc are two pharmaceutical companies that seem to be leading the race, with treatments that are predicted to reach the market some time next year. Pegylated interferons will hopefully one day be obsolete, however most likely, treatment may still include ribavirin, a drug with difficult side effects. The future is looking promising for the millions of people currently afflicted with HCV. But these therapies may come to late for HCV patients in need of a liver transplant or battling liver cancer. Dr. Scott Biggins with the University of Colorado School of Medicine recently reported there were 126,862 new candidates for first liver transplant registered with Organ Procurement and Transplantation Network (OPTN), with 41% of these having HCV, the article is available here.

This brings us full circle to a paper published in the March 2013 issue of Journal of Hepatology - Silibinin: An old drug in the high tech era of liver transplantation. 

The study concluded:
Intravenous silibinin (Iv-SIL) is safe but by the currently used applications cannot prevent graft reinfection or eradicate HCV from the transplanted liver in most patients. At present there is no alternative of an interferon-free approach in the peritransplant setting and silibinin may be the ideal drug until safe and effective HCV RNA polymerase inhibitors with a high genetic barrier become available. Nevertheless, there is a need for improvements in treatment schedules before such a treatment can be recommended. Flushing the liver graft with a solution containing silibinin as it has been done to prevent oxidative damage to the liver [15] should be tested in order to determine if it helps prevent recurrence.

In the future hepatitis C patients will be spared the debilitating side effects of interferon. The dream begins. Fast forward to today with online analysts predicating interferon-free regimens reaching patients by 2014. However, some people infected with HCV will still be left behind, for these people silymarin will most likely be used and yes - even relevant.

Additional Links

More on silibinin

Expert's Picks: Silymarin for NAFLD

From National Institutes of Health • National Center for Complementary and Alternative Medicine
Updated May 2013
Hepatitis C and Dietary Supplements

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