Wide net cast by paper clouds issue of liver injury risk posed by supplements, critics say
The recent paper, published in the journal Hepatology, is titled “Liver Injury from Herbal and Dietary Supplements” and was written by Victor Navarro, PhD, who is with the Einstein Health Care network in Philadelphia, PA and who is also the director of the national Drug Induced Liver Injury Network (DILIN). One of Navarro’s coauthors is Ikhlas Khan, PhD, of the National Center for Natural Products Research (NCNPR) at the University of Mississippi in Oxford, MS. The paper’s main conclusion is that the incidence of major hepatotoxic events attributable to dietary supplements is rising, and now accounts for 20% of all events tracked by the network.
Navarro first put forward the methodology for his approach to evaluating the liver injury risk posed by dietary supplements at a meeting sponsored by NCNPR in Oxford in late 2014. In his practice Navarro sees a number of patients suffering from partial liver failure, some of whom fit into the bodybuilding category. A common strategy for product formulators in this product category has been to pose certain suspect ingredients as extracts of rarely heard of herbs. Navarro, rather than trying to parse out which of these products were ‘legitimate’ dietary supplements and which were in fact illegal drugs, chose to lump all of them together with more common herbals products featuring green tea extact or other botanicals under the umbrella of “Herbal and Dietary Supplements” or HDS. For Navarro, it it looks like a supplement, it is a supplement, and it if mentions an herb on the label, it’s an herbal product, even though the paper itself acknowledges that this grouping casts a very wide net.
“The major implicated agents include anabolic steroids, green tea extract, and multi-ingredient nutritional supplements (MINS). Anabolic steroids marketed as bodybuilding supplements typically induce a prolonged cholestatic, but ultimately self-limiting liver injury that has a distinctive serum biochemical as well as histological phenotype. Green tea extract and many other products, in contrast, tend to cause an acute-hepatitis like injury. Currently, however, the majority of cases of HDS- associated liver injury are due to MINS, and the component responsible for the toxicity is usually unknown or can only be suspected,” the paper says.
Experts contacted by NutraIngredients-USA said that the issue of potential liver injury is a grave one, but that the approach taken by Navarro and his collaborators tends to confuse the issue of whether properly made dietary supplements could pose a significant risk in this regard.
Lot of noise but little clarity
Rick Kingston, PharmD, is president of regulatory and scientific affairs at SafetyCall International, a consulting firm that helps dietary supplement companies manage risk and conduct product recalls. Kingston is also a clinical professor of pharmacy at the University of Minnesota, and so has insight into both sides of this toxicological coin.
“I’m disappointed. I don’t know how else to put it,” Kingston told NutraIngredients-USA. “They keep coming up with the same dogmatic approach without adding clarity to the issue. It’s unfortunate that the terminology they use to describe these products has the effect of implicating all herbal supplements.”
“If you look only at the data that Navarro collected I don’t think there’s any doubt the percentage of liver injury assigned to dietary supplements has risen over the past 10 years. But I think the paper also shows that the overall occurrence of liver injury attributable to dietary supplements is fairly low,” said Stefan Gafner, PhD, chief scientific officer for the American Botanical Council.
“What exactly is behind that is a little more difficult for me to say. Is it better reporting? I do believe that there are herbal ingredients that can be an issue with people who might have sensitivities and demonstrate idiosyncratic effects. But the paper also included products that seemed to contain anabolic steroids that are clearly not dietary supplements,” he said.
One issue that Navarro has expressed frustration with in the past is the difficulty in determining what is in some multi-ingredient products that might be causing a patient’s liver issues. He said it makes life hard for a clinician who is trying to treat a patient without knowing where to look for what might have caused the liver injury.
“A major obstacle to better understanding and improving the safety of HDS is the difficulty in determining what is actually in a supplement. Although there are Current Good Manufacturing Practice regulations for supplements, which include some controls over the quality of products, the enigmatic term “proprietary blend” is commonly used,” the paper reads.
In the past, the dietary supplement industry has resisted the notion of a notification procedure for new products. Though various voluntary and ad hoc label database schemes have been developed, the notion of a mandated procedure was seen as being the first step on a slippery slope of premarket approval. Gafner said that that attitude might be shifting, and that industry executives are starting to warm to the idea that it should be easier for someone in Navarro’s position to quickly be able to determine from a central, authoritative source what’s in a given product.
“I do believe that industry is looking at that point with different eyes and has changed its view in the past year. There is more agreement for the need for a database of what’s on the market and what the ingredients are in those products,” Gafner said.
“Liver Injury from Herbal and Dietary Supplements”
2016 Sep 27. doi: 10.1002/hep.28813. [Epub ahead of print]
Authors: Navarro V, Khan, I, Björnsson E, et al.