The investigation—carried out by researchers in the Department of Internal Medicine, Division of Gastroenterology and Hepatology, at the University of Michigan—looked back at nationally representative data from the National Health and Nutrition Examination Survey (NHANES) to determine reasons for and frequency of botanical use in the United States and extrapolated population estimates from the 2020 U.S. Census.
Among the 9,685 adults enrolled in the NHANES cohort, the researchers reported that the prevalence of use within the last 30 days was 7.5% for herbal dietary supplements (HDS) overall and 4.7% for the six botanicals classified as potentially hepatotoxic. These included turmeric or curcumin, green tea extract, Garcinia cambogia, black cohosh, red yeast rice and ashwagandha.
“In this survey study, an estimated 15.6 million U.S. adults consumed at least one botanical product with liver liability within the past 30 days, comparable with the number of people who consumed nonsteroidal anti-inflammatory drugs and a commonly prescribed hypolipidemic drug,” the paper concluded. “Given a lack of regulatory oversight on the manufacturing and testing of botanical products, clinicians should be aware of possible adverse events from consumption of these largely unregulated products.”
Considering the data
The JAMA paper noted that dietary supplementation in the U.S. has increased dramatically over time, growing from 32.9% in the NHANES 1971-1974 cohort to 52% in the NHANES 2011-2012 cohort and 57.6% in the NHANES 2017-2018 cohort.
In addition, the researchers cited findings from the Drug Induced Liver Injury Network (DILIN)—which collects and analyzes cases of severe liver injury caused by prescription and over-the-counter drugs and alternative medicines—indicating that the proportion of hepatotoxicity cases from herbal dietary supplements has grown concurrently with the expansion of supplement use, “nearly tripling from 7% in 2004 to 2005 to 20% in 2013 to 2014.” Also referenced was evidence of increasing incidence of acute liver failure cases related to complementary and alternative medicines through 2015.
While Stefan Gafner, PhD, chief science officer at the American Botanical Council, said that estimating the use of botanical dietary supplements based on the NHANES data is acceptable, he took issue with the implication that some 15 million U.S. adults are exposed to potentially hepatotoxic botanicals when the actual risk of liver injury from these six botanicals is low.
“The authors provide several references to support the liver injury potential of botanicals, but these data are provided without proper context and hence suggest that the risk of liver injury is much greater than it actually is,” he told Nutraingredients-USA.
Rick Kingston of SafetyCall International and clinical professor of pharmacy at the University of Minnesota, provided context with a breakdown of actual numbers. He shared that it is important to consider that of the 130 patients who experienced liver damage from HDS over the 10 year period, 85 consumed traditional HDS, and 45 consumed bodybuilding HDS.
"Bodybuilding HDS have been known to be the target of adulteration with steroids for their bodybuilding properties," he said. "If you exclude the 45 bodybuilding products, that would leave about eight patients per year with potential liver damage secondary to mainstream HDS."
Dr. Gafner also noted that the primary data used in the study may be flawed, since the researchers appeared to base estimates on the total U.S. population (including minors) rather than the U.S. adult population. According to 2020 U.S. Census numbers, the resident population over the age of 18 was 256,662,010 and not the 329,484,123 cited in the JAMA paper.
Issues with the approach
Although the paper breaks down the number of products identified per botanical in the survey, it does not examine the potential hepatotoxicity of their ingredients or compounds, review adverse events reported or identify toxicity risks when used at studied therapeutic doses.
Commenting on the survey study’s approach, Dr. Gafner said that there are several issues, particularly the lack of an assessment of the relative risk of liver injury in the comparison to pharmaceutical drugs.
“Regrettably, when case reports are published, the botanical ingredients in the products allegedly causing harm are rarely authenticated by appropriate analytical techniques, and several cases of liver injury reportedly due to a botanical extract have been later assigned to the presence of conventional drugs or to other types of adulteration,” he explained, emphasizing that correct identification of the ingredients is a crucial aspect of a causality assessment.
He added that other important factors to consider when assessing adverse events in future case reports include underlying health conditions, concomitant medication, age, sex, dosage, manufacturing process, duration of use and time of use, in addition to a person’s genetic predispositions that may play a crucial role in susceptibility to liver injury, e.g., from green tea extracts or turmeric extracts.
Dr. Kingston highlighted that the authors do not have a denominator for how much HDS consumption is associated with the six botanicals referenced.
"For context and considering the widespread use of HDS, the number of servings is very likely in the billions," he said. "This hardly represents an epidemic."
As survey study limitations, the authors on the paper listed a low survey response rate for the pre-pandemic NHANES cohort, lack of opportunity to determine associations with clinical outcomes, the self-reported nature of supplement and medication use and possible discrepancies between ingredients in product and on label.
“In addition, this survey sample size was not adequate to detect hepatotoxic effects from botanicals or other adverse events since these arise in less than 1% of exposed individuals,” they wrote. “Thus, our study was not designed to identify any causal relationship between consumption of the six botanicals of interest and the development of liver injury over time.”
Enforcement rather than regulation needed
In conclusion, the University of Michigan researchers harnessed their investigation to call for “increasing regulatory oversight on how botanicals are produced, marketed, tested and monitored in the general population.”
While Dr. Gafner dispelled the misconception that the industry lacks regulation, he said that the DILIN paper—which reported 140 (51%) of the products analyzed as mislabeled and 91 of these as containing a known hepatotoxic compound, i.e., aflatoxins, anabolic steroids, anthraquinones, pyrrolizidine alkaloids and pharmaceuticals—suggests that there are existing quality problems with some products.
“A number of these adulterants included steroids or prescription drugs; hence these products are not dietary supplements but pharmaceutical drugs masquerading as dietary supplements,” he said. “As such, I agree that the DILIN data point to the issue of adulteration in some of the products on the market and a lack of sufficient enforcement of the current regulations by authorities.”
Reacting to the publication, the Council for Responsible Nutrition, said that contrary to misleading headlines about potential hepatotoxicity of these products, there is nothing in the findings that exposes any new risk of liver injury or that should alarm consumers of these supplements.
“What consumers and healthcare practitioners should take away from this study is that there is great—and growing—interest in using herbal supplements to promote health and wellness,” Steve Mister, president and CEO at CRN, shared in a statement. “Practitioners should encourage candid and open-minded conversations with their patients about supplement usage.”
In a response issued by the Consumer Healthcare Products Association (CHPA), the organization communicated that the six ingredients included in the survey have been studied extensively and have a long history of safe use.
“CHPA will continue to reiterate the importance of ensuring accurate, responsible and rigorous approaches to such research,” said Duffy McKay, senior vice president of dietary supplements at CHPA. “This is especially critical considering the impact and far-reaching consequences misleading studies can have, both in terms of threatening consumer trust and also discounting the decades of research reinforcing the beneficial role supplementation plays in optimizing health.”
Source: JAMA Network Open
doi: 10.1001/jamanetworkopen.2024.25822
“Estimated Exposure to 6 Potentially Hepatotoxic Botanicals in US Adults”
Authors: Alisa Likhitsup et al.
