Challenges in herbal‐induced liver injury identification and prevention

Abstract

Herbal and dietary supplements (HDS) are being used worldwide at an increasing rate. Mirroring this trend, HDS‐induced liver injury, also known as HDS‐induced liver injury (HILI), has increased significantly over the past three decades in the Drug‐Induced Liver Injury Network (DILIN), now accounting for 20% of cases of drug‐induced liver injury (DILI). There are significant challenges in the identification and prevention of HILI due to varying presentations, ability to make clear diagnosis, identification of the responsible ingredient, lack of treatment, and lack of regulatory oversight of HDS products to confirm their ingredients and ensure safety. The major implicated agents include anabolic steroids, green tea extract, garcinia cambogia, kratom, ashwagandha, turmeric and multi‐ingredient nutritional supplements. Fortunately, with the formation of major DILI consortiums across the world, the last decade has seen advances in the identification of at‐risk genetic phenotypes, the use of chemical analysis on multi‐ingredient nutritional supplements, and the publication of data/injury patterns of potentially risky HDS.

Abbreviations

COVID

coronavirus disease 2019

DILI

drug‐induced liver injury

DILIN

Drug‐Induced Liver Injury Network

DSHEA

Dietary Supplement Health and Education Act of 1994

EU

European Union

FDA

United States by the Food and Drug Administration

HDS

herbal and dietary supplements

HILI

herbal and dietary supplement‐induced liver injury

RECAM

Revised Electronic Causality Assessment Method

RUCAM

Roussel‐Uclaf Causality Assessment Method

Key points.

• Herbal and dietary supplement‐induced liver injury is an increasing cause of liver injury.

• Advances in the identification of at‐risk genetic phenotypes and greater oversight from regulatory organizations are underway but more is needed to protect consumers.

1. INTRODUCTION

Herbal and dietary supplement (HDS)‐induced liver injury (HILI) is a liver injury caused by an HDS and is now a well‐recognized potential cause of both acute and chronic liver injury; and even carries the potential for fulminant liver failure, resulting in liver transplantation or death. ¹ , ² However, the risk of HILI is complicated by the fact that there are over 1000 HDS available in the United States and even more worldwide. ¹ Unlike conventional medicines, HDS products generally contain multiple ingredients making their pharmacological characteristics and safety unclear. ³ Most patients use them for general well‐being, immune support and weight loss. ⁴ Available data on the true frequency of HILI cases are overall lacking, due to under‐recognition/diagnosis and under‐reporting. ⁵ Despite this, increased reporting of HILI has been noted, in example, cases reported to the United States DILI Network (DILIN) have increased from 7% of all drug‐induced liver injury (DILI) cases in 2005 to 20% in 2014, with HDS representing the second leading class of compounds causing liver injury after antibiotics. ⁶

The diagnosis of HILI remains a challenge due to a lack of assessment tools, multi‐ingredient supplements, unclear injury patterns and lack of clarity on which ingredients have the potential to cause hepatotoxicity. Important advancements in the field of HILI have been seen over the last 20 years with the development of multiple drug‐induced liver injury registries across the world, identification of specific ingredients through chemical analysis at risk of causing HILI, and potential genetic and immunologic susceptibility for the development of potential liver injury. ¹ , ⁴ , ⁶ , ⁷ In this review, we will further analyse reasons for increased HILI cases, identify HDS with the potential to cause HILI, and discuss tools for potential early identification including genetic subtypes and chemical analysis. Finally, we will review ongoing and future efforts for HILI prevention. ⁸

2. HISTORIC REVIEW OF HERBAL AND DIETARY SUPPLEMENT USE AND REGULATION

Over the last three decades, the use of herbal supplements, natural products and alternative medicines has risen. In 2012, a report from the American Botanical Council revealed that herbal product sales in the United States surpassed $5.3 billion in 2011, marking a 4% increase compared to 2010. ⁹ Further increases have been seen since the Coronavirus disease 2019 (COVID) pandemic, raised the general population's interest in seeking HDS leading to record‐breaking HDS sales in the United States exceeding $10 billion for the first time in 2020, reaching approximately $11.261 billion, signifying a 17.3% upsurge from 2019. ¹⁰ HDS usage is most common among those with the following features: middle‐aged, female gender, holding college degree or higher, and using prescription or OTC medications. ⁸ People often gravitate toward HDS as a ‘natural cures’ to a variety of ailments are under the impression that ‘natural means safe’. Most report using supplements for wellness but 40% do so to treat an underlying medical condition. ⁸ , ⁹ Additionally, over 25% HDS users do not disclose the use of HDS to the clinicians due to fear of disapproval and recommendation to discontinue use. ¹¹ , ¹²

HDS regulation is overseen in the United States by the Food and Drug Administration (FDA) as guided by the Dietary Supplement Health and Education Act of 1994 (DSHEA). ¹³ Under DSHEA, HDS products are exempt from investigational clinical trials for efficacy documentation. Additionally, manufacturers bear the responsibility for attesting to safety without confirmation, and listing dietary composition, and appropriate serving sizes on the product label. ¹³ HDS manufacturers are required to provide a comprehensive list of dietary ingredients. ¹³ , ¹⁴ Despite this requirement, many HDS products have been recalled from the market due to discrepancies between the listed dietary ingredients and the actual product formulation. ¹⁵ Research from our group has indicated a high rate of mislabelling of dietary ingredients, reaching as high as 51%. ¹⁵ Mislabelled HDS products occasionally include undisclosed ingredients, while some of the listed substances are actually absent from the actual composition despite being on the label. ¹⁶ The relative lack of regulatory control over HDS in the United States compared to prescription medications, means there are fewer protections available to the consumer, such as quality control. In contrast to the United States, HDS products undergo a more stringent regulatory process in the European Union (EU) where, according to Directive 2004/24/EC, herbal medicinal products are required to not only be registered in the EU but also manufacturers must comply with specific quality standards. ¹⁶ , ¹⁷ , ¹⁸ This may explain why there appears to be a lower burden of HILI in Europe compared to the United States. ¹⁵ , ¹⁷ , ¹⁸

3. THE RISE OF HILI

Despite the rise of reported HILI cases in the literature, the true frequency of HILI is unclear, in part due to underdiagnosis and under‐reporting. ⁸ The incidence of HILI in mainland China is estimated to be 6.38 per 100 000 based on the large retrospective study. ¹⁹ In the United States, the estimated incidence of HILI was 1.16 per 100 000 based on a small prospective study conducted by our group in the state of Delaware. ²⁰ In terms of the risk of HILI in the EU, the best data come from a prospective population‐based study from Iceland that found, 16% of cases of DILI were attributed to HDS at an incidence of 3 per 100 000. ²¹ Registry‐based frequency data demonstrate HDS responsible for 8% and 4% of DILI cases reported by the Latin DILI and Spanish DILI Networks, respectively. ¹⁷ , ¹⁸ However, despite the overall low incidence of HILI, the consequences of this liver injury can be deadly and is preventable.

The risk of severe liver injury from HDS is best seen by data from the US Acute Liver Failure Study Group, who reported 253 (9.6%) patients with idiosyncratic DILI with 16.3% of those related to HDS between 1998 and 2015. Mirroring the DILIN's findings, the fraction of HDS among drug‐induced acute liver failure increased over time from 12.4% from 1998 to 2007 up to 21.1% 2007–2015. Alarmingly, HDS‐induced acute liver failure resulted in transplant or death more often than cases due to prescription medication (83% vs. 66%). ¹² , ²² In a 2015 population study, over 18% of acute liver failure cases were attributed to HDS with 50% resulting in death or liver transplant. ¹² , ²³

4. ASSESSMENT FOR SUSPECTED HILI

The majority of HILI cases are idiosyncratic, rather than a predictable occurrence. The clinical presentation of hepatotoxicity can vary, ranging from asymptomatic elevated liver tests to symptoms such as fatigue, nausea, and abdominal pain to jaundice and encephalopathy. Once liver injury is recognized and other causes of liver injury are excluded, there must be a high index of suspicion that it may be due to supplement use. ¹² While the timing of symptoms with the beginning of HDS is suggestive, products consumed previously must also be considered as the contents of products may vary over time.

Structured causality assessment tools, such as the Roussel‐Uclaf Causality Assessment Method (RUCAM), are confounded by several factors unique to HDS. First, it is well known that HDS is often multi‐ingredient and is vulnerable to intentional or inadvertent inclusion of ingredients. Non‐botanical ingredients include chemicals, pesticides and heavy metals. Additionally, the lack of knowledge and awareness of potential liver injury from these widely used, over‐the‐counter supplements may cause the injury to go unrecognized by patients and providers. ¹ Efforts to improve the RUCAM are underway as seen with the now available revised electronic causality assessment method (RECAM) with the goal of increasing objectivity top improve precision and reliability of DILI diagnosis. ²⁴ In comparison to RUCAM, RECAM developed a free text field to incorporate such additional information such as liver biopsy or imaging, response to rechallenge (if performed) and if any drug‐induced skin reactions occurred (e.g. drug rash with eosinophilia) in support of a DILI diagnosis. ²⁴ Unfortunately, RECAM has not yet been validated specifically in HILI.

5. HDS COMMONLY ASSOCIATED WITH HILI

HILI encompasses a spectrum of presentations due to the variable mechanisms in which specific HDS products cause hepatotoxicity. As with DILI, patients with HILI can be classified into hepatocellular, mixed or cholestatic liver injury. This pattern is defined by the R value ([ALT/ULN] ÷ [Alk P/ULN]), in which a value >5 is interpreted as hepatocellular, <2 as cholestatic and 2–5 as mixed hepatic injury. Across the world, HILI appears to be more commonly associated with a hepatocellular pattern of injury. However, other specific HILI patterns have been noted. One such pattern is anabolic steroid‐related jaundice, resulting from the use of illicit synthetic derivatives of androgens that present as a highly characteristic cholestatic phenotype. ²⁵ , ²⁶ The second is acute liver injury that follows the use of an identifiable specific, single botanical product or traditional herbal medicine, with the most common ingredient in this category being green tea extract. The third is the occurrence of acute liver injury associated with a multi‐ingredient supplement that usually challenges and makes it difficult to implicate a single ingredient. ²⁵ , ²⁶ A complicating factor is that the implicated product may also be contaminated with a synthetic chemical or with an unknown and toxic botanical. ²⁶

See Table 1 with a list of commonly implicated ingredients in HILI and hepatotoxicity phenotype.

TABLE 1.

Common HDS ingredients implicated in HILI.

Ingredient	Chemical structure	Reasons for use	Hepatotoxicity pattern	Injury course
Ashwagandha 41 , 42	Steroidal lactone	Neuroprotection, anti‐inflammatory	Cholestatic or mixed	Recovery typical
Green tea extract 43	Catechin‐polyphenol	Weight loss	Hepatocellular	Most recover; fatalities reported
Garcinia cambogia 31	(−)‐hydroxycitric acid	Weight loss	Hepatocellular	Most recover; fatalities reported
Polygonum multiflorum 30	Stilbenes and anthraquinones	Anti‐ageing, intestinal function	Hepatocellular or mixed	Most recover; fatalities reported
Chinese skullcap 44	Flavonoid	Anxiety, insomnia, neurological disorders	Hepatocellular	Recovery typical
Kratom 45	Tetracyclic indole and pentacyclic oxindole alkaloids	Anxiety, opiate effect or withdrawal	Mixed	Recovery typical
Anabolic steroids 46	Steroid backbone	Bodybuilding, performance enhancement	Cholestasis	Prolonged jaundice, full recovery
Turmeric 32	Polyphenol	Anti‐inflammatory, well‐being	Hepatocellular	Most recover; fatalities reported

6. UPDATES IN GENETICS AND CHEMICAL ANALYSIS

Increasing evidence has pointed to genetic and immunologic susceptibility being a key factor in the development of HILI in addition to DILI. ²⁷ , ²⁸ , ²⁹ A study by Hoofnagle et al. described remarkably strong link between liver injury related to green tea extract (GTE) consumption and the HLA allele B*35:01. ²⁹ The HLA allele B*35:01 is prevalent in 5% to 15% of US populations. ¹⁰ This allele was identified in 72% of patients with liver injury linked to green tea and in over 90% of those in whom the injury was categorized as highly probable or certain. ²⁹ Alleles carriers were younger at presentation, had shorter latency periods, higher median ALT values, and more severe presentation. ²⁹ Notably, HLA‐B*35:01 has also been linked to liver injury induced by Polygonum multiflorum, Garcinia cambogia and turmeric. ³⁰ , ³¹ , ³² With detailed analyses of hepatotoxicity due to specific ingredients, recognition of characteristic toxicity patterns arises. The polyphenolic backbone of the GTE is exploited for its antioxidant potential but is likely also responsible for liver injury.

As stated previously, our group has previously shown that HDS labels are often inaccurate, as confirmed by chemical analysis using high‐performance liquid chromatography with mass spectroscopy. ¹⁵ Chemical analysis techniques have long been available and been applied to non‐prescribed products. ¹⁵ Common applications have included detection of adulterants in performance‐enhancing products and pharmaceuticals that might promote a marketed purpose for use of the HDS. ¹⁵ , ³³ , ³⁴ Chemical analysis alone is insufficient to confidently attribute an adverse event to a detected analyte. The confidence to connect a suspected analyte as the cause for injury is strengthened by other factors such as the timing of exposure, exclusion of other causes that could explain injury, and when available, a reported pattern of similar injuries that were associated with the identified agent.

7. PREVENTION OF HILI

As noted earlier, a major obstacle to better understanding and improving the safety of HDS is the difficulty in determining what is contained in a marketed supplement. Although we are making advances in identifying genetic phenotypes at risk of DILI/HILI and chemical analysis of HDS, these methods are not yet mainstream. The most important tactic we have currently to prevent HILI is to raise awareness of this issue among clinicians, consumers and regulatory organizations.

One of the most important attempts at raising awareness of DILI was the creation of Livertox which officially went online in 2012. ³⁵ Livertox is a database founded and maintained by the National Institute of Health available for free to anyone via its website. ³⁵ As of May 2024, it lists 1419 drugs, including 151 HDS, and their potential for hepatotoxicity. Likelihood scores are attributed to each herbal or supplement, ranging A‐E, as designed by the United States DILIN to determine causality. Easily searchable, the Livertox database allows clinicians to review information about HDS that their patients may be taking or to better understand its pattern of hepatotoxicity. ³⁵

In 2019, the US FDA released a statement announcing plans for major policy changes towards the oversight of the HDS industry. This included improvements in the adverse reporting system and a proposal to require the listing of the ingredients of dietary supplements with the FDA. ⁸ , ³⁶ Since then, the proposal to register ingredients of various supplements has been a primary objective of the FDA with both the 2020 and 2021 budget proposals to Congress including a provision for this. In addition, the FDA has asked for a mandate to allow them to act against products and manufacturers providing misleading information. ⁸ , ³⁷ However, both proposals have been met with significant resistance from the herbal industry and have yet to become enacted into law. A major step in terms of regulation was the passage of the Designer Anabolic Steroid Control Act of 2014, which prohibited distributing or dispensing any anabolic steroid, or any product containing an anabolic steroid, unless the label clearly identifies the presence of an anabolic steroid. ³⁸ , ³⁹ Early data have shown a decrease in DILI secondary to anabolic steroids since this new regulation. ⁴⁰

8. CONCLUSION

HILI continues to be a growing concern worldwide. Variability in regulation across the world limits our understanding of their potential for hepatotoxicity. An accurate estimate of the incidence of HILI is difficult to ascertain, and the frequencies that are reported using registries, single centre hospital experiences, and population‐based cohorts, make them difficult to compare. However, there is strong evidence to suggest that the rate of HILI is increasing despite decreasing reports of liver injury from anabolic steroids. ⁶ Furthermore, the diagnosis of HILI remains a challenge, and while assessment tools are valuable in determining causality, even the widely applied RUCAM scale – designed to evaluate DILI, falls short of adequately evaluating HILI. ⁴⁰ Future use of pharmacogenetics and chemical analysis has shown promise in predicting those who may be at risk of HILI from specific HDS. It is important that we increase awareness and improve surveillance for potential hepatotoxic HDS as the HDS industry continues to grow in use and popularity over the next decade.

FUNDING INFORMATION

None.

CONFLICT OF INTEREST STATEMENT

The authors declare no competing interest related to this work.

Halegoua‐DeMarzio D, Navarro V. Challenges in herbal‐induced liver injury identification and prevention. Liver Int. 2025;45:e16071. doi: 10.1111/liv.16071