Journal of Ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE: The global rise in herbal medicine utilizes as an alternative treatment has corresponded with a rise in herb-induced liver injury (HILI). Although numerous systematic reviews existed, their generalizability is limited, and factors associated with HILI remain unclear.
AIM OF THE STUDY: To comprehensively summarize HILI cases reported in English language literature and to investigate the association between potential factors related to HM use and the severity of liver injury.
MATERIALS AND METHODS: A total of 643 patients from 382 studies were included. Global HILI cases rose markedly between 2002 and 2011. Weight management was the most common reason for HM use. Single-herb product users were more likely to develop mild injury compared with mixed-product users. Supplementary product use was associated with higher chances for having cholestasis. Females (64.9%) were generally older at onset and had longer herb use durations, while males showed higher Gamma-Glutamyl Transferase (GGT) levels. Older patients tended to have less severe injury, though with elevated GGT and prolonged herb use. Race significantly influenced International Normalized Ratio, total bilirubin, and overall severity.
CONCLUSION: This study highlights sex, age, race, usage patterns, liver function markers (GGT, INR, TBL), and HM type (herbal preparations and constituents) as key factors in HILI diagnosis and management. Further studies are warranted to confirm these associations.
Liver injury, including physical damage from trauma, infections, or chemical exposure, is a significant clinical concern (Norton and Kobusingye, 2013). As a vital organ involved in metabolism, detoxification, and homeostasis, the liver is also responsible for first-pass metabolism (Rusyn et al., 2021). Therefore, this organ is particularly susceptible to injury that accounts for approximately 5 % of all hospitalized traumatic cases (Taghavi and Askari, 2024). Drug-induced liver injury (DILI) is a primary cause of liver damage, arising from either dose-dependent (intrinsic) or unpredictable (idiosyncratic) mechanisms. Idiosyncratic DILI is commonly categorized into hepatocellular, mixed, and cholestatic patterns (Francis and Navarro, 2024). DILI carries substantial morbidity and mortality risks, including acute liver failure (ALF) with a mortality rate exceeding 50 % (Hosack et al., 2023). The increasing incidence of DILI, particularly in the US, underscores its critical health impact (Devarbhavi et al., 2023). Previously, herbal and dietary supplements (HDS) have been identified as one of the leading causes of idiosyncratic DILI (Katarey and Verma, 2016).
Complementary and alternative medicine (CAM) is defined as a broad set of healthcare practices that are not part of a country's own traditional or conventional medicine and are not yet fully integrated into the dominant healthcare system (World Health Organization, 2019). Herbal medicine (HM) includes individual herbs, herbal substances, prepared herbal formulations, and finished herbal products, such as dietary supplements, that contain active ingredients believed to promote health (World Health Organization, 2019). In this context, dietary supplements are considered HM only if they contain herbal material or plant-derived compounds. Nowadays, HM is recognized as one of the most popular and rapid growing forms of CAM (Eardley et al., 2012; Ernst and White, 2000; Thomas and Coleman, 2004). The increasing use of HM is frequently associated with self-treatment (Welz et al., 2019). People often consider HM a “natural” product perceived to be safer than conventional medicine, with fewer side effects yet effective in treating various illnesses (Samojlik et al., 2013). HM is deeply rooted in diverse cultures, ranging from Ayurveda in India to Traditional Chinese Medicine in China, as well as the rich repertories of indigenous remedies among African and American tribes. This widespread use highlights HM as a cornerstone of ethnopharmacological practices across the world and has inspired extensive research aimed at isolating and discovering new bioactive compounds for modern medicine. The World Health Organization (WHO) has estimated that 70–95 % of the population in developing countries rely on HM for primary care (Cameron et al., 2011). Multiple surveys have shown a high percentage of HM usage worldwide, with 66.2 % of participants in the USA and Australia (Fravel et al., 2023), 75.4 % 12-month prevalence and 86.7 % lifetime prevalence in Germany (Welz et al., 2019), and 87 % of respondents in the Czech Republic as of 2014 (Pokladnikova and Selke-Krulichova, 2018). In recent decades, the popularity of herbal remedies has increased rapidly. According to the WHO, approximately 80 % of the world's population used HM for primary health care in 2008 (World Health Organization, 2013), and this rose to 88 % in 2018 (World Health Organization, 2019). The HM market is expanding, with its global market size is expected to be around 165.13 billion USD in 2023 and reaching 386.7 billion USD by 2032 (Rahui, 2021). Besides beneficial components, HM might be contaminated with heavy metals, adulterated, or contain toxic compounds (Wachtel-Galor and Benzie, 2011). Even with a long history, most herbal plants have not been researched thoroughly, leading to a lack of information regarding their efficacy and safety (Girard and Vohra, 2011). As a result, there is a high chance of adverse effects and poisoning due to inappropriate HM consumption (Wachtel-Galor and Benzie, 2011).
The widespread use of HM coincides with a significant increase in spontaneous reports on herbal-related adverse health effects on the liver (Zhu et al., 2020). A recent prospective study conducted between 2004 and 2013 by the U.S. Drug-induced liver injury network showed the percentage of domestic herb-induced liver injury (HILI) cases increased from 7 % to 20 % (Navarro et al., 2017). In addition, a retrospective cohort study among 5,484,224 people in California revealed HILI to be the second leading cause of ALF, constituting 18.8 % of the total observed cases (Goldberg et al., 2015). In 2019, the top five countries with the most HILI cases, accounting for 98.4 % of the total 14,029 worldwide HILI cases, were China, Korea, Germany, India, and the US (Teschke and Danan, 2020). Nationwide studies in China, South Korea, and Japan indicated that herbs were associated with 26.81 %, 27.5 %, and 15 % of DILI cases, respectively (Aiso et al., 2019; Shen et al., 2019; Suk et al., 2012).
HM is often used for general wellness, disease prevention, or non-specific health promotion. For example, cowpea (Vigna unguiculata (L.) Walp) has been demonstrated to exhibit notable anthelmintic, thrombolytic, and anticancer properties (Sardar et al., 2024). Moreover, the diverse profiles of fatty acids and vitamins present in both dietary and medicinal plants have been found not only to alleviate the adverse effects of chemotherapy-induced intestinal mucositis (Alcorta et al., 2024) but also to modulate the expression of microRNAs associated with cancer, thereby contributing substantially to its prevention and treatment (Şahin et al., 2023). In addition, dietary flavonoids exhibited protective effects against Parkinson's disease while simultaneously enhancing the composition of beneficial gut microbiota (Açar et al., 2023). However, the combination of self-medication, lack of professional oversight, and a lack of awareness regarding potential risks poses a significant threat to liver health, particularly if individuals do not disclose their HM usage to their healthcare practitioners. Therefore, it is crucial to gather more quantitative data on the motivations and factors influencing HM use, as well as to elucidate the relationship between HM and the severity of liver injury. Additionally, establishing a baseline level of consumer awareness about the side effects and risks associated with HM self-medication is essential. As the use of HM increases, the number of published case reports has risen annually, offering deeper insights into HILI's nature. Although several systematic reviews and meta-analyses of HILI have been published (Ballotin et al., 2021; Byeon et al., 2019; N.-H. Lee et al., 2021; W.-J. Lee et al., 2015), updated data on HILI remains essential for informing clinical practice.
Therefore, this meta-analysis aims to comprehensively summarize HILI cases reported in English language literature. We will investigate the association between potential factors related to HM use and the severity of liver injury. Additionally, bibliometric analyses will be conducted to identify trends in HILI research and to supplement the evidence available in this field.
Study design and search strategy: The study protocol was registered with PROSPERO (CRD42024523012) and adhered to the PRISMA 2020 for systematic reviews and meta-analysis (supplementary file 1) as well as BIBLIO checklists for reporting bibliometric analyses (supplementary file 2). A PEO (Population, Exposure, Outcome) framework guided keyword development. The population of interest encompassed all humans consuming HMs with HILI as an outcome. To maximize the identification of relevant studies, inclusion criteria were...
Search strategy and quality assessment: The PRISMA guidelines for search strategy and selection criteria flow diagram (Fig. 1) outlines the study selection process. An initial search across 10 databases yielded 17,758 articles. After removing duplicates and excluding 84 ineligible records from ClinicalTrials and TRID, 14,047 articles remained. Screening titles and abstracts resulted in 557 articles selected for full-text review. Of these, 22 were inaccessible, leaving 535 for full-text assessment. Ultimately, 382 studies met the...
Trends in HILI research: The bibliometric analysis revealed that research on HILI fluctuated between 1975 and 2023, marked by phases of sporadic occurrence, rapid expansion, stabilization, and a recent resurgence. The regression analysis and the observation of studies over the years indicated a rapid increase in the incidence of HILI globally. Notably, there was an exponential growth in HILI cases from 2002 to 2011, which can be explained by the novelty of the field, prompting researchers to report new cases, as...
By utilizing multiple evidence-derived databases, employing diverse methodologies with rigorous quality control, and incorporating comprehensive discussions, our study offers insights that may lay the groundwork for future research. Moreover, it provides essential information that can help medical professionals quickly diagnose and treat HILI. Factors such as the types of herbal medicine (including their herbal preparations and their constituents), sex, age, race, GGT levels, duration of use,...
Hoang An Nguyen: Writing – original draft, Visualization, Software, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Ngoc Vy Le: Writing – original draft, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Nhat Thong Le: Writing – review & editing, Visualization, Software, Formal analysis, Data curation. Hien Thi Thu Do: Writing – review & editing, Supervision, Project administration,...
The authors report there are no competing interests to declare.
During the preparation of this work the authors used chatGPT in order to improve writing and check English grammar. After using this tool/service, the authors cross-reviewed and edited the content as needed and take(s) full responsibility for the content of the published article...
The manuscript was partially supported by the USAID Partnership for Higher Education Reform Activity Research Capacity Subaward: Health Sciences (Subcontract Agreement number: 1006-VNUHCM_INT)...
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper...
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