Hepatotoxicity and Hepatocarcinogenicity of Herbal Medicines: Clinical and Pharmacoepidemiological Perspectives

Background Herbal medicines are widely used throughout the world especially in developing countries as a complementary or alternative medicine. It is a belief that that the use of herbs is associated with a healthier lifestyle, and that herbal medicines, being “natural”, are therefore harmless. Despite this perception, their effectiveness and safety has most often not been evaluated per modern standards. Many signals of safety issues associated with herbal medicines (HMs) involve proximate reports of general hepatic adverse reactions. The potential for hepatotoxicity as well as hepatocarcinogenicity following use of HMs and related preparations is an issue of critical, and global concern. While the hepatoxicity of certain HMs, or their constituents, is well documented, many questions remain; such as the mechanisms for hepatic damage, risk factors, clinical characteristics of herbal-induced liver injury (HILI), and prevalence of use of implicated herbal substances. For herbal induced liver carcinogenicity (HILC), research on the prevalence, risk factors and mechanisms are largely lacking. Some herbs are known to harbour phytochemicals such as aristolochic acids (AAs,) which may lead to genotoxicity, carcinogenicity,or co-carcinogenicity. For many other HMs, their hepatotoxic/hepatocarcinogenic potential is unknown or unclear.

Another major concern is establishing causality between herbal medicine and hepatotoxicity and/or hepatocarcinogenicity. Although the literature is filled with reports of HILI or HLIC, it is often difficult to draw a conclusion without considering key aspects such as: what was actually ingested; whether the competitive causes had been excluded, and whether the data and information provided are enough to build the body of evidence.

Against this background, robust research and rigorous review of existing literature under a good practice of reporting are required to move forward the knowledge and understanding in this field. This Research Topic aims to contribute to this. A first edition on this Research Topic, published in Frontiers in Pharmacology, focused on experimental research papers seeking to elucidate mechanism involved in HILI. The finished edition comprised of 15 papers involving 101 authors. This second edition of the Research Topic shifts the emphasis to articles discussing aspects of clinical pharmacology, pharmacoepidemiology and pharmacovigilance in HILI, such as the identification, diagnosis, incidence, treatment and prevention of hepatic ADRs associated with use of HMs.

Goal: This second edition of the Research Topic aims will publish high-quality frontier reviews, and clinical or pharmacoepidemiologic research papers contributing to knowledge and understanding of epidemiological, mechanistic, clinical and risk mitigation of HILI and HILC, based on defined hypotheses/research questions. Another goal of this Research Topic is to discuss and try to achieve the consensus of good practice of reporting of HILI or HLIC. Ultimately, the aim is to enhance medical, pharmaceutical and pharmacological understanding in this area that will contribute to protection of the public health.

Scope: This second edition Research Topic focuses on clinical pharmacology, pharmacoepidemiology and public health aspects of HILI as well as HILC. While the focus is herbal medicines causing hepatotoxicity and/or hepatocarcinogenicity, papers relating to other types of traditional medicines or ‘natural health products’ are also welcomed, with the caveat that the pharmacologically relevant components must be clearly defined. Papers describing experimental research relating to HILI or HILC that explain the relevance to the clinical setting are also welcomed.

Details for Authors: Themes of particular interest are listed below. High-quality original research articles and review papers are welcome. Case reports will be considered where they are considered by the editors to make an important contribution to knowledge. All submissions must conform to the journal’s guidelines.

Paper themes of specific interest:
-- appraisals of current systems and protocols to clinically identify and categorize adverse events, including evidence-based synthesis of best practice;
-- good practice of reporting on HILI or/and HILC;
-- analyses of databases holding reports of suspected adverse drug reactions relating to HILI or/and HILC;
-- clinical pharmacology studies relating to HILI or/and HILC;
-- clinical pharmacoepidemiological studies on HILI or/and HILC;
-- systematic review/meta-analysis of hepatic adverse event/ADR data collected in randomised clinical trials involving specific herbal medicines
-- case series of HILI or/and HILC reports exploring clinical characteristics, pathological features and prognosis;
-- comprehensive case reports of suspected HILI or/and HILC not previously documented;
-- causality assessment and benefit-harm evaluation in HILI or/and HILC
-- risk management, risk mitigation and risk communication in HILI or/and HILC
-- pharmacoeconomic analyses in HILI or/and HILC;
-- susceptibility factors for herbal hepatotoxicity or/and hepatocarcinogenicity in population and identification biomarkers;
-- genetic factors associated with, or which place people at risk for, HILI or/and HILC;
-- behavioral factors associated with HILI or/and HILC, including but not limited to patterns of use, sources of product;
-- hepatotoxic or/and hepatocarcinogenic constituents and quality assurance and control for raw materials and finished products for HMs associated with liver injury or/and liver carcinogenicity.

Papers describing specific types of methods used should adhere with the following international guidelines.
Clinical trials – CONSORT statement and relevant extensions, see http://www.consort-statement.org/
Systematic review/meta-analyses – PRISMA statement and relevant extensions, see http://prisma-statement.org/
Case reports – ISoP and ISPE guidelines, see Kelly WN, Arellano FM, Barnes J et al. Guidelines for submitting adverse event reports for publication. Pharmacoepidemiol Drug Saf 2007;16(5):581-7
Observational studies – STROBE statement, see https://www.strobe-statement.org/index.php?id=strobe-home

All papers describing herbal medicines, including traditional Chinese herbal medicines, should refer to the relevant CONSORT statements (see http://www.consort-statement.org/extensions) for guidance on how to describe the herbal product(s)/preparation(s) implicated, including, plant part(s) used, type of extract, and so forth.

All species need to be validated taxonomically (e.g. for plants, by using (preferably) the Royal Botanic Gardens at Kew’s Medicinal Plant Names Service (http://mpns.kew.org/mpns-portal/), or The Plant List (www.theplantlist.org); the full accepted scientific name, including authorities and family, must be included. If there are taxonomic issues, this should be highlighted in the paper.

For pharmacological studies, the concentration/dose range and duration, minimal toxic concentration, model used, and controls (positive or negative) should be included, as well as other basic pharmacological data. All studies involving animals or humans should meet ethics requirements, and provide the name, date and reference number for the ethics committee granting approval.


The four pillars of best practice in ethnopharmacology

With these guidelines we define in detail what constitutes best practice for manuscripts submitted to Frontiers in Pharmacology; Section Ethnopharmacology. They provide a basis for the peer review and build on the general requirements of Frontiers in Pharmacology.

1) Pharmacology

a) The manuscript (MS) must report a substantive body of ethnopharmacological research, to be considered as an independent addition to the literature. In general, we expect that such studies are based on local / traditional uses of plants or other natural substances which need to be spelled out clearly.

b) For pharmacological studies, the model used must be one which is either generally accepted in the field as valid or a credible alternative whose general development, and application in the reported instance, has been justified.

Specifically antioxidant activity must be based on a pharmacologically relevant in vivo or cell based model. Simple in silico and pharmacologically irrelevant assays for antioxidant activity (e.g. the DPPH assay, FRAP (Ferric Reducing Ability of Plasma), ABTS (2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)) are not acceptable as a main tool for assessing an extract or a compound for activity.

c) Similarly, simple screening for anti-microbial effects of crude extracts is no longer state-of-the-art. Authors must follow the widely accepted standards for microbiological testing (cf. Cos et al. 2006 Anti-infective potential of natural products: How to develop a stronger in vitro ‘proof-of-concept’ Journal of Ethnopharmacology 106: 290–302) and subsequent methods papers. Such research is only meaningful if it contributes to our mechanistic understanding of anti-microbial effects, its specificity or identifies novel leads.

d) The dose ranges must be therapeutically relevant. While it will be impossible to define an exact cut-off, the literature in the field is now replete with studies which test extracts at implausibly high doses. Single dose studies will only be of relevance in exceptional circumstances (e.g. in case of specific complex pharmacological models). And of course, positive and negative controls must be included.

e) In order to establish therapeutic benefits, selectivity data are essential. How specific is the effect? Many compounds have non-selective in vitro effects and research on common compounds must be justified in terms of the potential therapeutic benefits. While such research may be relevant and have potential applications, authors will need to assess the specificity of a single compound or an extract rich in a well-studied compound (like rutin, curcumin, or quercitin) and provide evidence for the relevance and novelty of the approach

2) Composition:

a) Botanical:

The identification of the study material must be described well. All species are fully validated using Kew MPNS portal or The Plant List initiative or Plants of the World Online Of course, full botanical documentation is essential (i.e. a voucher specimen deposited in a recognised herbarium). A scan of the voucher(s) is welcome as supplementary material and encourage authors to include the coordinates of the location where the material had been collected.

b) Chemical

- The composition of the study material must be described in sufficient detail. Chromatograms with a characterisation of the dominating compound(s) are preferable. If preparations are used which are available commercially quality parameters provided in pharmacopoeia must be provided. The material under study must be characterised using the methods of the relevant monograph

- If ‘pure’ compounds are used sufficient information on the level of purity must be included. Especially in in vitro models, the authors must be confident that the compounds are stable under the conditions used (for example, they do not degrade due to high concentrations of DMSO). A critical aspect that should be considered is how these assays and extraction protocols are linked to local and traditional uses. In this way, variables such as the solubility of the compound in the traditional preparation and in the analytical extraction protocol should be taken into consideration

- All chemical line structures must be drawn using a internationally accepted structure drawing programme, must be consistent and - if possible and relevant - the stereochemistry needs to be given.

c) Multiherbal preparations:

Very often multiherbal preparations are used. Full information on their composition (in terms of the botanical drugs / species included) and information on the rationale for studying this preparation needs to be included. It is essential that in these cases sufficient details are provided on the botanical (2a) and chemical (2b) characterisation.

3) Basic requirements and research ethics

Frontiers has very well developed guidelines relating to ethical aspects of a MS. Specifically, for Frontiers in Pharmacology (Ethnopharmacology) the following key requirements are essential:

a) The objectives of the research reported must be spelled out clearly and in detail. All MS must critically assess the scientific basis of the work and provide meaningful conclusions, which are based on a clear hypothesis / research question as defined in the introduction. Ethnopharmacological research must assess whether a compound or plant extract has a certain effect and it cannot be about ‘confirming an extract’s or compound’s effects or efficacy’.

b) Research must add new and scientifically substantive knowledge to our understanding of the pharmacology and use of medicinal plants. A key basis for this is a review of literature relevant to the pharmacological activity already reported on the species including possibly related taxa or compounds. This must be up-to-date, and clearly demonstrate the substantive addition to the literature the MS submitted represents. Simply using advanced measurements/techniques/protocols reproducing previous studies of the same plant product will only be accepted in exceptional circumstances (e.g. previously unknown, highly active components are discovered).

c) Compliance with all international ethical standards is essential. In the context of ethnopharmacology, the Convention on Biological Diversity and, most recently, the Nagoya Protocol are of particular relevance (https://www.cbd.int/abs/).

d) Research in ethnopharmacology is based on local and traditional knowledge often passed on orally over generations. Ultimately, research in this field must therefore benefit those populations who are or were the original keeper of this knowledge.

e) The use of animals must be justified in the context of novelty (see also part 1). It is ethically not acceptable to have yet another in vivo study on an already well-studied species, demonstrating some common activity (e.g. an anti-inflammatory effect studied in the rat-paw edema). The same is true for species which are chemically very similar (and generally are rich in common ingredient) to ones already studied pharmacologically. Such studies must ‘meet(s) the standards of rigor’ we expect in ethnopharmacology as defined in the Frontiers’ guidelines.

4) Other specific requirements

a) Studies focusing on local and traditional uses of plants (ethnopharmacological field studies) must be based on substantial, original data. The relevance of the MS in the context of previous studies in the geographical region must be spelled out clearly and it must contribute to the understanding of the therapeutic uses of plant species and inform experimental or clinical studies This includes an adequate presentation and discussion of the data. Also, social science centered studies (e.g. ethnobotanical studies or health system research of local and traditional medical systems) are welcome. This journal subscribes to the ConSEFS standards including any updates.

b) In case of reviews, we expect clearly defined scientific aims (objectives), a comprehensive, critical and specific assessment of the relevant information linking local and other medical uses to the biomedical and bioscientific evidence. Reviews need to define future research needs and priorities. It is essential that the scientific quality of the original articles cited is assessed. If pharmacological studies are reviewed, particular attention must be paid to assessing the quality of the studies.

c) Food plants are commonly reported to have pharmacological effects. Frontiers in Ethnopharmacology focuses on therapeutic benefits of such species and not on the general food/nutritional properties.