Herbal Products and Liver Injury

Stakeholders Meet to Share Ideas, Info on Liver Injury and Dietary Supplements

Experts from academia, government and medical institutions gathered at NIH headquarters for an inaugural conference on liver injury and dietary supplements, especially botanicals.

Experts in liver injury, toxicology, regulatory affairs, botanicals, laboratory testing and dietary supplements gathered earlier this week on the main campus of the National Institutes of Health (NIH) for a workshop on liver injury and dietary supplements, with a particular focus on herbal products. The goal was to share information on herbal and dietary supplements (HBDs) and liver injuries in an effort to get a better idea of the extent of HBD use and associated hepatoxicity. This sharing of info and data was intended to get stakeholders to work together on developing a plan and system for monitoring and reacting to liver injuries from HBDs going forward.

At last year’s International Conference on the Science of Botanicals (ICSB), held each year at Ole Miss in Oxford, MS, the challenges of tracking liver injuries associated with HBD use were presented by Victor Navarro, M.D., chairman of the Division of Hepatology and medical director of liver transplantation at Einstein Medical Center, Philadelphia. He outlined the work and scope of the Drug Induced Liver Injury Network (DILIN) which was created in 2003 by NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to gather and analyze severe liver injury cases linked to drugs, over-the-counter (OTC) medicines, alternative medicines and dietary supplements, including botanicals.

Navarro said liver damage is hard to detect, and usage habits of HBD consumers make the job even more difficult. Among the challenges mentioned were gaps in methods applied by doctors, confounding factors and medical history, timeliness in diagnosis of liver patients, and some nuances to dietary supplements including the growing trend toward multi-ingredient formulas. He said bodybuilding supplements were involved in the highest number of cases of non-drug liver injury and led to high hospitalization rates (about71 percent).

At this year’s ICSB, Navarro shared stats showing HBD was second only to antimicrobials on the list of top therapeutic classes linked to liver injury in the United States in 2013. Of 262 HBDs consumed by 136 patients listed in DILIN, most (about 82 percent total) of the supplements involved were bodybuilding, weight-loss and depression products.

This all set the stage for the recent NIH workshop on liver injury and HBDs. Over the course of two-days, there were short presentations from NIDDK, the National Center for Complementary and Integrative Health, Office of Dietary Supplements (ODS), American Botanical Council (ABC), FDA, National Toxicology Program (NTP), Centers for Disease Control and Prevention (CDC), U.S. Pharmacopeia (USP), USDA, National Institute of Environmental Health Sciences, and numerous hospitals, universities and medical centers.

Topics included the scope of HBD use and liver injury in the United States, and HBD-associated liver injury around the world—Iceland, Europe, Latin America, India and China were specifically discussed.  Experts in testing and hepatology shared info on particular cases of known hepatotoxicity, including botanicals such as green tea (EGCG) and black cohosh, and CDC reviewed the most recent HBD-linked liver injury epidemic involving the OxyElite Pro sports supplement. CDC’s Ethyl Taylor said attributing liver injury to a specific herb is challenging due to multiple ingredient formulas, product variability and lack of testing to confirm exposure to a product. She suggested clinicians should report possible liver injury cases to both FDA MedWatch and state and local health officials—the Health Department of Hawaii was first to act on the cluster of cases being reported in the island state in 2013.

Two big challenges with HBDs are authentication of ingredients, especially botanicals, and rooting out adulteration. Ikhlas Kahn, Ph.D., from the National Center for Natural Products Research (NCNPR) at Ole Miss, explained chemical standardization is limited when starting materials are not well characterized botanically. USDA’s James Harnly, Ph.D., outlined the various testing methods used to test botanicals, noting most herbal products are processed by extraction or other methods, which breaks up or destroys DNA and make DNA testing inappropriate for authentication. He suggested chemical fingerprinting, such as various types of chromatography and spectrometry are better methods. Jamie Dunn, Ph.D., a chemist in FDA’s Center for Drug Evaluation and research (CDER), reported on the agency’s efforts to use portable and benchtop screening devices (ion mobility spectrometry) to find adulterated and illegal supplements/ingredients at U.S. facilities that process international mail.

Dunn reported the pass/fail technology flagged 91 percent of 168 weight-loss products screened since 2011 for possibly containing the drug sibutramine. In one sample of supplements screened, the IMS method found a total 65 percent adulteration rate with 55 percent sibutramine adulteration in 88 weight-loss products tested and 79 percent sildenafil adulteration in 67 male sex/erectile dysfunction products tested. She noted flagged products can be sent to a full lab for further analysis and confirmation of adulteration using various versions of mass spectrometry (MS). If labs scientists find a new analogue, they isolate it. Dunn said bodybuilding products are often misbranded, as they often claim to contain an anabolic compound r steroid, but they contain either no such compounds or a different compound than is labeled.

Overall, Dunn said FDA/CDER has a library of 7,500 compounds and has programmed 12 additional adulterants into the portable and benchtop machines, but these are not yet in the field. She pointed out the FDA Safety and Innovation Act (FDASIA) provided the agency increased authority and stiffer penalties to deal with adulterated, counterfeit and misbranded drug-related products.

NTP provided two separate presentations, one outlining the agency’s two research programs designed to characterize the variability in biological responses from consumption of HBDs with complex mixtures of constituents, and the other providing details on the agency’s Tox21 program of screening thousands of chemicals, including HBDs, for potential effects on specific cellular pathways such as nuclear receptors and cellular stress. Building off its prior controversial research finding Ginkgo biloba extract (GBE) was linked to cancer in rats, NTPs new research on GBE aims to identify and analyze marker compounds in 20 lots of GBE and test a handful of these extracts in rats to determine gene expression changes in the liver. The other study subjects several herbal ingredients to Tox21 high throughput screening to compare biological responses to different lots. The Tox21 program has three phases. Now in phase III, Tox21 will address the limitations of earlier phases that featured engineered cell lines by looking at in silico (computer-based) and in vitro liver models to better reflect human physiological response to tested compounds, including HBDs.

Larry Walker, Ph.D., Director of NCNPR at Ole Miss, said his team has done a lot of the work analyzing what is in plants versus what is in products. In fact, he noted DMAA was pulled from the market based largely on the work of NCNPR. He advised the audience the sports market replacement for DMAA is called AMP citrate. He stated the problem with many sports market compounds is the combination of abuses from both manufacturers and this unique group of consumers. He brought up an interesting scenario whereby scientists, regulators and health experts have seen toxicity from compounds not normally considered toxic. The key, he suggested, may be in immune-mediated response, as research has shown the presence of LPS (lipolysaccharide) can trigger an acute inflammatory cascade.

“We are all behind the eight ball if we don’t know all the chemicals patients are ingesting," said Neil Kaplowitz, M.D., University of Southern California (USC) Research Center for Liver Diseases.  He said any hepatotoxitcy from plants comes from the evolutionary battle between plants and animals—both try to survive the other’s dangers. Over time plants have created ways to deal with physical and chemical attacks, which is why plants can have compounds that can be both positive and negative for human health. One of the other issues with most plant compounds found in HBDs is the latency or delay in the body’s accumulating phytotoxic compounds and displaying injury. For better monitoring liver injuries from botanical ingestion, he stressed the importance of fully characterizing HBDs chemically and carefully adjudicating liver injury cases and adverse event reports (AERs).

Pieter Cohen, M.D., an internist at Cambridge Health Alliance, Harvard Medical School, offered his well-publicized recommendations for regulatory changes to dietary supplement oversight, noting DSHEA (Dietary Supplement Health and Education Act) is fine for vitamins and minerals but is “flawed for botanicals." He advocated for “uncoupling vitamins and minerals from botanicals." Despite this position, he said he is a big fan of supplements and recommends them every day to his patients. However, he challenged some widely held assumptions tied to DHSEA, including that all supplements are inherently safe and FDA can remove any dangerous products. He said it is difficult to determine what is in dietary supplements, as more and more such products involve complex mixtures of ingredients, including botanicals. He took issue with the current regulatory method of leaving the quality control and testing protocols for the manufacturers to decide and noted despite the low bar dietary supplement GMPs 9(good manufacturing practices) established, non-compliance rates are high—he referenced statistics provided in an earlier presentation from FDA’s acting director of its dietary supplement division, Cara Welch. Cohen also suggested individual supplements (and their contents) should be required to register with FDA before being marketed, as the current requirement is for only the supplement manufacturer to be registered, not the products. Among his other suggestions were to require contraindication and possible adverse effects information on supplement labels and closing the loophole that allows proprietary blends to list only the ingredient names, but not the amount of each ingredient in the blend.

Jay Hoofnagle, M.D. deputy director of the Liver Disease Branch at NIDDK, closed the workshop by talking about how traditional medicinal use of botanicals is being twisted by modern western methods, taking what were likely modest doses over short periods and extracting active compounds and ramping up the dosage and frequency of use. “One of the biggest catastrophes with herbals was with tobacco, which Native Americans used safely—smoked a pipe of it once every three months or so—but westerners came along and decided to roll it up and use it often, leading to the largest epidemic of lung cancer and emphysema," he said. In a similar manner, he added, OxyElite Pro was a westernized version of aegeline. Further, the westernization of traditional botanicals has caused many such herbs to fall onto the endangered species list, as demand far outpaced supply. Black cohosh in America and Hoodia in South Africa were two examples put forth. He reiterated the challenges mixtures of botanicals and compounds pose to liver injury monitoring.

Dan Fabricant, CEO and executive director of the Natural Products Association (NPA), wrote to members that the biggest takeaway for him was the apparent lack of knowledge related to estimates of incidence of liver injury from supplements. He noted Navarro said liver injury from HBD use is rare and the scope of liver problems from HBDs is unknown. He also noted the workshop revealed there is no data showing a link between increased HBD use and liver injury risk or incidence.

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