On December 21, 2013, The New York Times published an article by reporter Anahad O’Connor titled “Spike in Harm to Liver Is Tied to Dietary Aids,”1 based on a presentation by Victor Navarro, MD, chair of hepatology at the Einstein Healthcare Network in Philadelphia, Pennsylvania, given at the American Association for the Study of Liver Diseases’ “Liver Meeting” conference in early November 2013. In his lecture, Dr. Navarro pointed out that “the percentage of liver injuries related to herbal dietary supplements (HDS) products in a research cohort of patients referred to the Drug-Induced Liver Injury (DILI) Network* increased from 7% of cases between 2004 and 2005 to 20% between 2010 and 2012 (P<0.001). This trend was significant both for cases attributable to bodybuilding products (P=0.01) and for all other HDS products (P=0.05).”2 Based on the reported statistics, the data from Dr. Navarro would amount to an average of four cases of liver injury that are connected to HDS per year between 2004 and 2005, and 20 cases per year between 2010 and 2012. These data and their percentages are based on 130 hepatotoxicity cases linked to dietary supplements from a total of 839 people for which reports were entered into the final analysis for the 10-year period between 2004 and 2013. Besides addressing bodybuilding and weight-loss supplements, the piece by O’Connor1 mentioned green tea (Camellia sinensis, Theaceae) extract as frequently implicated in dietary supplement-associated liver toxicity, and the author provided details from a case report published earlier by Patel et al.3
More details about HDS-related liver injuries reported to the DILI Network subsequently have been published in the scientific journal Hepatology.4 The publication received considerable attention from the media, and led — in some instances — to the dissemination of inaccurate information to the public with headlines such as “Liver injuries from dietary supplements rose in one population over the last decade. They caused more deaths than traditional [i.e., conventional] medications, too,” and “Supplements now more likely than medications to cause death.”5,6
Incidence of Herbal Dietary Supplement-Induced Liver Injury
There are no reliable population-based statistics for the incidence of liver toxicity attributable to HDS in the United States. In order to put the numbers for HDS-induced liver injury in perspective, it is important to consider the widespread use of HDS. Herb usage by the adult population in the United States has remained fairly popular for the past 15 years or more, with retail sales climbing almost every year,7 but actual statistics on the use of dietary supplements in the US vary depending on the source. For example, a 2003 survey showed that about 34% of the US adult population used herbal dietary supplements, while a 2010 survey suggested that perhaps up to 47% of American consumers had used an HDS in the previous year (although the difference may simply reflect the growth in use in the seven-year period).8,9 The LiverTox®† database estimates 40% of the US population uses alternative therapies, most often HDS.10 On the other hand, according to the 2013 CRN Consumer Survey on Dietary Supplements from the Council for Responsible Nutrition, an industry trade organization, only 19% of Americans take herbal and botanical dietary supplements on a regular basis.11 Based on an estimated US population of 318 million in June 2014, with approximately 77% of people over the age of 18, this would indicate that between 47 and 115 million adults use HDS. So even if the number of cases reported to the DILI Network comprises only a small fraction of all dietary supplement-related incidences of hepatotoxicity, the risk of hepatotoxicity due to botanicals would still be relatively low and, most probably, not as significant as some of the media reports have suggested.
In the Drug-Induced Liver Injury Network, HDS generally were implicated in approximately 10% of reported cases (the remaining 90% were due to pharmaceutical drugs), but this rate appears to be increasing and most recently accounted for more than 20% of cases.4 The newly released American College of Gastroenterology (ACG) clinical guideline on the diagnosis and management of idiosyncratic DILI even suggests that “herbal and dietary supplements are among the most common therapeutic classes to cause DILI in the Western world.”12
On the other hand, according to the LiverTox database, the incidence of liver toxicity caused by HDS is likely to be very low.10 A retrospective cohort study from 2009 reported that the main substances involved in acute liver failure were acetaminophen (which accounts for 40% of the cases), followed by anti-tuberculosis drugs (8%), antiepileptic drugs (7%), and antibacterial drugs (6%), while herbal products (primarily as dietary supplements) made up less than 1%.13 Similarly, a review article on acute liver failure reported that acetaminophen-related acute liver failure accounts for 75% of drug-induced cases, while the remaining 25% involved other hepatotoxic conventional pharmaceutical medications.14 Since that 25% includes anti-tuberculosis, antiepileptic, and antibacterial drugs, one can conclude that the supplement-related acute liver failures in this review make up a lower percentage than the most recent statistics from the DILI Network.
Data from the Spanish DILI registry published over a 10-year period between 1994 and 2004 implicated herbal ingredients in approximately 2% of livery injury cases, while an earlier prospective study from Spain found that up to 11% of DILI cases were related to botanicals.15,16 Data from a population-based cohort study in Iceland found an annual incidence rate of 19.1 cases per 100,000 habitants. Liver injury due to acetaminophen was excluded in the study. Dietary supplements were implicated in 16% of the annual incidence rate, or about three cases per 100,000 habitants.17 Independent from the actual numbers, the increase in DILI in which HDS are implicated is disconcerting. And while bodybuilding products have been singled out as a major contributor for the rise in HDS-induced liver injury, the numbers from other supplement categories have risen as well.
According to Rick Kingston, PharmD, president of regulatory and scientific affairs at SafetyCall International and clinical professor of pharmacy at the University of Minnesota, one major problem with trying to accurately interpret the recent increase in liver injuries involving products marketed as dietary supplements relates to the question of whether the implicated products are what they are claimed to be: Some of them may be adulterated and/or contaminated. In addition, the researchers do not seem to realize the importance of distinguishing between appropriately designed and manufactured HDS products and adulterated products or illegal drugs (e.g., the erectile dysfunction drug sildenafil and analogues) sold as dietary supplements before they implicate a product that purports to be an HDS in a case of liver toxicity.
The Safety of Green Tea Extract
Liver toxicity is a serious health concern, and the data potentially associating GTE‡ with hepatotoxicity have to be carefully evaluated. In the toxicological evaluation of a hydroalcoholic GTE by the National Toxicology Program (NTP), rats and mice were administered between 0 (vehicle control) and 1,000 mg GTE/kg body weight in deionized water by gavage five days per week for three months.18 In the three-month study in mice, six males and four females administered 1,000 mg/kg died before the end of the study; early deaths were due to liver necrosis.
In the two-year NTP study, rats received between 0 and 1,000 mg green tea extract/kg body weight in deionized water by gavage, while mice were fed between 0 and 300 mg GTE/kg. The study showed a statistically significant increase in liver necrosis in rats receiving the highest dosage of GTE (1000 mg/kg), but not at 300 mg/kg or below. On the other hand, the study indicated a lower incidence of primary liver neoplasms in female and male mice at higher GTE dosages. For example, in the two-year study in male mice, hepatocellular adenomas, hepatocellular carcinomas, and hepatoblastomas occurred in 40 out of 50 mice (80%) receiving the vehicle control, and in 39 (78%), 35 (70%), and 22 (44%) out of 50 mice receiving 30 mg/kg, 100 mg/kg, and 300 mg/kg GTE, respectively. When the numbers were adjusted for survival, the incidence rates were 83%, 80%, 71%, and 47%, respectively. This reduction in occurrence of liver neoplasms would suggest a chemopreventive effect of GTE.
The safety of green tea extract in humans has been evaluated extensively by the United States Pharmacopeia (USP) Dietary Supplements Information Expert Committee (DSI EC).19 Based on a review of all 34 case studies available through 2007, the committee ranked GTE as a class 2 supplement. Class 2 indicates “articles for which the DSI EC is unaware of significant safety issues … when that article is used and formulated appropriately provided there is a warning statement in the labeling section.” The DSI EC later changed its position and re-classified GTE as a class A supplement (supplements for which the available evidence does not indicate a serious risk to health or other public health concern that precludes inclusion of a quality monograph into the compendia), for which a warning label is not required.20
Most of the cases involving GTE-containing products present other possible confounding factors (e.g., concomitant use of over-the-counter or prescription drugs, use of polyherbal formulations, or incomplete patient data).19,21 A majority of the green tea case reports listed by Navarro et al indicate that the putatively hepatotoxic products reported to the DILI Network contained GTE with other ingredients, or were cases in which GTE was used in combination with other HDS.4 The USP DSI EC emphasized that the individual case reports were not strong, and that the most frequently implicated product contained a hydroalcoholic GTE, which, on the surface, should not pose any unusual hepatotoxic risk. (That GTE-containing product was Exolise®, a weight-loss formulation made by Arkopharma [Carros, France], which was later recalled). However, the DSI EC also noted that plasma concentrations of the purported hepatotoxin epigallocatechin gallate (EGCG), one of the key catechins in green tea and GTE, are considerably higher when concentrated GTEs are consumed when fasting, as may often be the case with a weight-loss product like Exolise. The purported hepatotoxic GTE products listed in the USP report were analyzed in only one of the reported adverse events, so it remains unclear if the actual composition of the products corresponded to the label claims or if potentially toxic contaminants (e.g., certain residual solvents that may have been used in the extraction process) also were present.19 (According to records at the American Botanical Council, the manufacturer of Exolise claimed that no other solvents other than ethanol and water were used in the preparation of the GTE used in Exolise.)
More recently, Navarro et al analyzed 97 HDS products implicated in hepatotoxicity cases for catechins but found no statistically significant correlation between the amount of catechins consumed and the severity or pattern of liver injury.22 Additionally, there are very few reports of liver injury after drinking green tea, so the traditional use of green tea as a beverage should not be considered a safety concern. The second edition of the American Herbal Products Association’s Botanical Safety Handbook (BSH2) lists green tea as class 1 safety ingredient, meaning that history of widespread safe use and other evidence strongly support the proposition that green tea can be consumed safely when used appropriately. As a precautionary statement, the BSH2 indicates that “ethanol extracts of green tea should be taken with a meal.”23
Other Herbal Ingredients
In the LiverTox database, a number of single herbs have been implicated in liver toxicity.10 Examples of herbs and herbal products that have a well-established potential to cause liver injury include those containing certain types of pyrrolizidine alkaloids — i.e., pyrrolizidines with a chemical structure characterized by an unsaturated necine ring (saturated pyrrolizidines are not considered hepatotoxic)24 — found in comfrey (Symphytum x uplandicum, Boraginaceae) leaf and root, coltsfoot (Tussilago farfara, Asteraceae) herb, butterbur (Petasites hybridus, Asteraceae) leaf and root, and others. In addition, other plants with reports of hepatotoxicity include herbs such as chaparral (Larrea tridentata, Zygophyllaceae) leaf, germander (Teucrium spp., Lamiaceae) herb, celandine (Chelidonium majus, Papaveraceae) herb, pennyroyal (Mentha pulegium, Lamiaceae) essential oil, mistletoe (Viscum album, Viscaceae), kava (Piper methysticum, Piperaceae), and weight-loss preparations containing usnic acid (a compound that can be obtained from several lichen species). In the ACG clinical guideline, the authors specifically mention the following items under the header “herbals and dietary supplements”: GTE, anabolic steroids§, pyrrolizidine alkaloids, and flavocoxidTM — a proprietary mixture of flavonoids extracted from Chinese skullcap (Scutellaria baicalensis, Lamiaceae), catechins from betelnut palm (Areca catechu, Arecaceae), and zinc bisglycinate sold under the brand name Limbrel® (Primus Pharmaceuticals; Phoenix, Arizona), a medical foodǁ that is available by prescription only.12 With regard to Limbrel, Robert Levy, MD, the director of clinical development at Primus, explained that “liver toxicity is seen with many drugs, herbal supplements, chemicals and other environmental agents either due to direct cellular toxic effects or, more commonly, due to hypersensitivity reactions. In clinical trials against [the NSAID] naproxen, Limbrel and naproxen had similar levels of liver toxicity although Limbrel had a better overall safety profile.” Dr Levy added, “The Limbrel package insert outlines this toxicity and, in fact, uses language almost identical to that which appears in the package insert of every non-steroidal anti-inflammatory drug. Overall, we have seen a small number of liver function test abnormalities, about 5% in clinical trials, with occasional reports to us in our detailed post-marketing surveillance” [R. Levy email to M. Blumenthal, September 5, 2014].
A recent publication by Teschke et al highlights the hepatotoxic potential of herbal ingredients used in Traditional Chinese Medicine (TCM).25 The compilation lists 39 potentially hepatotoxic individual herbs. In hepatotoxity case reports of single herbs used in TCM published since 2011 where the Council for International Organizations of Medical Sciences (CIOMS) scale was applied, probable and highly probable causality gradings were found for du huo (Angelica archangelica, Apiaceae) root, he shou wu or fo-ti (Polygonum multiflorum, Polygonaceae, syn. Reynoutria multiflora) root, and the liver-toxic unsaturated pyrrolizidine alkaloid-containing herb shan chi (Gynura japonica, Asteraceae, syn. G. segetum, G. pinnatifida). Chinese and other Asian herbal medicines also are listed as potentially hepatotoxic in the LiverTox database.10 The most frequently implicated single herbs or mixtures are ba jiao lian (Dysosma pleianthus, Berberidaceae), chi ryun (Breynia vitis-idaea, Phyllanthaceae, syn. B. officinalis), jin bu huan — an herbal mixture of variable composition¶ that can include Aristolochia yunnanensis, Aristolochiaceae; Huperzia serrata, Lycopodiaceae; Panax pseudoginseng, Araliaceae; Polygala chinensis, Polygalaceae; Rumex madaio, Polygonaceae; R. patientia, Polygonaceae; Selaginella tamariscina, Selaginellaceae, syn. S. involvens; and/or Stephania spp., Menispermaceae — ma huang (Ephedra sinica, Ephedraceae and other Ephedra spp.), and shou wu pian (containing he shou wu).
The Assessment of Herbal Dietary Supplement-Induced Liver Injury
In general, the establishment of HDS-associated liver injury needs to be based on the principles of causality assessment, including a chronology establishing that the HDS was taken before the onset of the liver injury, the exclusion of other causes of liver disease, and symptom improvement after product use is ceased. Appearance of the symptoms after re-administration of the HDS (positive re-challenge) is another strong indicator that may link a product to liver injury, but is not advised due to ethical reasons. Some case reports involving a particular HDS turn out to be with patients who had other risk factors like pre-existing liver conditions, co-medication with pharmaceutical drugs with potential liver liabilities, and/or alcohol consumption.26-28 One analysis of 573 cases with assumed herbal-induced liver injury found alternative causes unrelated to the initially alleged herb in 48.5% of these cases, and an additional 29% of cases were barely assessable.26 The authors of a review in 2011 of all published case reports of hepatotoxicity related to consumption of black cohosh (Actaea racemosa, Ranunculaceae, syn. Cimicifuga racemosa) products concluded that black cohosh did not pose an apparent risk for liver injury.29 However, even if there are other factors that may have led to the liver injury, the association between HDS consumption and liver injury still may be possible since the HDS may impact or enhance the toxicity of co-medication with a pharmaceutical drug or co-consumption of alcohol.
The question of which objective methods should be used to assess the causality of drug-induced hepatotoxicity is still a matter of debate, since the different methods tend to suffer from low concordance. According to Neil Kaplowitz, MD, professor of medicine and chief of the division of gastrointestinal and liver disease at the University of Southern California Liver Transplant Program and Center for Liver Disease, attribution of causality is a major challenge, and “in the absence of a convenient gold standard, the diagnosis is subjective and is made with a varying level of confidence.”30
A review of case reports of herbal hepatotoxicity linked to Traditional Chinese Medicine listed 18 defined TCM mixtures, a group of unclassifiable TCM mixtures, and 39 individual herbs as posing a risk of liver injury; however, the authors noted that “firmly determining individual causality with exclusion of possible alternative causes was rarely done in these reports.”25 Teschke et al have examined the many scoring systems used to determine DILI and are particularly critical of the use of the Naranjo scale31 employed by the USP, since it is not validated specifically for hepatotoxicity. They recommend the CIOMS scale32 since it has been validated for liver toxicity, is considered to be quantitative, and is more widely used for the determination of DILI.33 On the other hand, the authors of the systematic review of green tea liver toxicity specifically used the Naranjo scale because it allowed a scoring of the probability of case reports’ association with GTEs despite the lack of important information in many of those case reports.19 Finally, the authors of the new ACG clinical guideline argue that an approach based on expert opinions is the current “gold standard” in attributing causality of herbal-induced liver injury.12 From a practical point of view, it seems doubtful that clinicians will use any of the proposed scoring systems, which will most likely lead to a continuation of the already ongoing discussions and debate regarding the safety of botanical extracts.
In many cases of putative HDS-induced liver injury, it is not known if the consumer followed the dosage regimen indicated on the product label. For a number of HDS ingredients, the potential for liver injury after prolonged use is not well known. Ingesting excessive amounts of HDS to achieve faster results (e.g., in the weight-loss category) possibly will increase the risk of adverse events, including the potential for liver injury. More data on compliance with the dosage recommendations are needed to have a better idea of the hepatotoxic potential of certain herbal ingredients. However, most cases of presumed or ostensible HDS-induced liver injury are idiosyncratic: that is, the toxicity is not directly related to the chemistry of the product and/or its dosage, but stems from complex interactions among non-genetic (e.g., age, sex, drug interactions, and conditions such as human immunodeficiency virus [HIV] infection) and genetic factors.34 The low frequency and unpredictability of DILI suggest that genetic mutations in drug-metabolizing enzymes or drug receptors can make a consumer overly sensitive to certain ingredients. For example, polymorphisms in the liver enzyme (i.e., different forms of the enzyme depending on the individual’s genetic composition) cytochrome P450 2D6 — which is involved in the metabolism of many xenobiotics (e.g., pharmaceutical drugs, artificial preservatives, or plasticizers to which the body is not exposed as part of the normal metabolism) — have been implicated in the hepatotoxicity of senna (Senna alexandrina, Fabaceae).35
In addition, according to Dr. Kingston, little is known about the relative risk of liver injury occurring from the use of an herbal ingredient. Contrary to pharmaceutical drugs, data on the number of liver injury cases in relation to the frequency of use of HDS are not available in many cases, and, combined with the variability of the composition (e.g., due to different manufacturing processes) and dosage regimens, a risk assessment is very difficult. Some herbal ingredients inevitably will lead to liver injury at a certain dosage (e.g., herbs containing certain pyrrolizidine alkaloids), while others may cause liver toxicity only in a few sensitive individuals. In the latter case, reports on liver injury from very widely used botanicals like GTE or licorice (Glycyrrhiza glabra, Fabaceae) root will more likely be found than from those that have only a marginal use. This could lead to a situation in which a widely used and comparatively safe herb may be considered hepatotoxic, or that a potentially hepatotoxic herb is considered safe.
A good example of this problem is the recent ruling by a German administrative court in Cologne to overturn the ban of kava sales, which was implemented by the BfArM (Bundesamt für Arzneimittel und Medizinprodukte; German Federal Institute for Drugs and Medical Devices) after the appearance of case reports of liver toxicity due to kava product consumption.36 The court stated that the authorities must demonstrate risk in a reproducible manner. If the risk cannot be clearly corroborated, the government’s withdrawal of marketing authorizations for kava medicinal products is unlawful, and, in view of the exposure data, the risk does not seem unusually high. Based on the relatively widespread use of kava, the incidence of liver toxicity has to be rated as “rare” or “very rare.” Furthermore, the court concluded that BfArM used duplicate case reports in support of the ban, and, therefore, the quantity of case reports alone is of little significance.
Need for Appropriate Authentication of Herbal Materials Implicated in Liver Injury Cases
Although the FDA mandates that dietary supplement labels accurately reflect the products’ contents, there is evidence for cases of contamination and presence of adulterants in various HDS products. Adulterants can be either undeclared botanical materials or sometimes even prescription drugs.** Contaminants also can include herbicides and pesticides, heavy metals, microbes, and/or residual solvents used in the preparation of extracts. A number of prescription drugs, solvents, and pesticides are known liver-toxicants.37 The individual levels of any of these contaminants would likely be too low to cause liver effects alone. However, the aggregate exposure of multiple contaminants with liver liabilities may exacerbate hepatotoxicity.
Authentication of the implicated product by appropriate means (e.g., chemical analysis) is crucial in assigning causality to a listed ingredient and/or product, but such analyses were not performed in a majority of the published reports. Analytical phytochemistry of HDS products associated with liver injury often reveals adulteration or contamination of one or more of the ingredients in the product, and it sometimes exposes mislabeling or absence of the botanical listed on the label and/or presence of a related or unrelated herb that may be the hepatotoxic agent. Examples of adulterants found in herbal preparations include germander in products labeled as skullcap38 and various Asian Actaea species in products labeled as black cohosh.39,40 Furthermore, some of the liver toxicity cases associated with Chinese medicinal herbs were later found to be the result of the presence of adulterants, such as the purported liver toxicity of jing tian san qi (Sedum aizoon, Crassulaceae) that was due to substitution with the pyrrolizidine alkaloid-containing plant shan chi, or cases of jin bu huan (anodyne¶, manufactured by Kwangsi Pai Se Pharmaceutical/Bose Drug Manufactory; Kwangsi, China) tablets supposedly containing Polygala chinensis (Polygalaceae) that were found to be a mixture of synthetic l-tetrahydropalmatine and starch.41,42
Owing to the popularity and increased use of HDS and the FDA mandate for manufacturers to report serious adverse events involving HDS, the amount of available data on hepatotoxicity and HDS has continued to grow. Future adverse event reports may identify indicators requiring investigation of other herbs for a possible link to liver injury when used by themselves or in combination with other herbs, similar to the case of coltsfoot in the 1990s. Accumulating more data on the safety of HDS products can be beneficial for everyone interested in herbal products. However, the sensational nature of recent media coverage may lead to increasing concerns about the safety of HDS by the consumer and by health professionals, even if the appropriate use of most ingredients found in herbal dietary supplements should be considered relatively safe with little risk of causing harm to the liver.
* The Drug-Induced Liver Injury Network was established in 2003 by the National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to collect and analyze cases of severe liver injury caused by prescription drugs, over-the-counter drugs, and alternative medicines such as herbal products and supplements.
† The LiverTox database is a website with information on liver injuries caused by prescription drugs, nonprescription drugs, and dietary supplements, produced by the NIDDK and the National Library of Medicine (NLM).
‡ In general this paper refers to green tea extract with the acronym GTE. However, there is no singular standard for what constitutes GTE; there are numerous extracts available with various chemical profiles standardized to varying levels of catechins (e.g., 60%, 90%, etc.).
§ Anabolic steroids are listed as controlled substances in the United States and are available by prescription only. By law, anabolic steroids legally cannot be sold as dietary supplements.
ǁ A medical food is defined in the United States Code, Title 21, section 360ee (b)(3) as “a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific management of a disease or condition for which distinctive nutritional requirements based on scientific principles are established by medical evaluation.”
¶ Products called “jin bu huan” appear to be sold with a variety of different ingredients depending on the manufacturer. In the case of the commercial jin bu huan preparation anodyne, the product was supposed to contain Polygala chinensis without some of the other ingredients that may be otherwise found in jin bu huan.
** The FDA and dietary supplement industry trade associations have clarified that consumer products sold as dietary supplements found to contain undeclared levels of prescription drugs should be more accurately characterized as illegal unapproved new drugs marketed or masquerading as dietary supplements.43
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- Patel SS, Beer S, Kearney DL, Phillips G, Carter BA. Green tea extract: a potential cause of acute liver failure. World J Gastroenterol. 2013;19(31):5175-5177.
- Navarro V, Barnhart H, Bonkovsky H, et al. Liver injury from herbals and dietary supplements in the US drug induced liver injury network [published online July 12, 2014]. Hepatology. 2014. doi: 10.1002/hep.27317.
- Engel M. Supplements cause more liver damage, decade-long study finds. Consumer Affairs. September 4, 2014. Available at: www.nydailynews.com/life-style/health/supplements-liver-damage-study-article-1.1927820. Accessed September 8, 2014.
- Levis T. Supplements now more likely than medications to cause death. New York Daily News. September 4, 2014. Available at: www.consumeraffairs.com/news/supplements-now-more-likely-than-medications-to-cause-death-090414.html. Accessed September 8, 2014.
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- Smith T. Nutrition industry and market research organizations fill data gaps on supplement use. HerbalGram 2012;93:64-66. Available at: http://cms.herbalgram.org/heg/volume8/12December/DSsurveysDataGap.html?t=1323040269. Accessed October 6, 2014.
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