Herb-induced liver injury (HILI) with 12,068 worldwide cases published with causality assessments by Roussel Uclaf Causality Assessment Method (RUCAM): an overview

Introduction

Herb-induced liver injury (HILI) is a rare adverse reaction associated with the consumption of herbal products like herbal medicines or more specifically regulatory approved herbal drugs and presents clinical features similar to those of drug-induced liver injury (DILI) (1-3). Validated specific biomarkers are not commonly available to diagnose either HILI, perhaps with the exception of a few herbs (4), or DILI (5) with the required degree of likelihood. It is therefore necessary to use a strong and reliable causality assessment method (CAM) such as RUCAM (Roussel Uclaf Causality Assessment Method) to diagnose liver injury (1-6). The original RUCAM was validated and established in 1993 (7,8) with an update in 2016 (9).

A substantial variability was observed among countries whenever liver injury cases had been evaluated using published data (6,10). Their common analytical basis was the use of RUCAM in liver injury cases. However, a systematic worldwide analysis of liver injury cases based on causality assessment by RUCAM was restricted so far to DILI in a study of 46,266 cases presented as case reports or case series published from 2014 to early 2019 (6). No such systematic evaluation of RUCAM based HILI cases worldwide focusing on countries is available.

This analysis presents for the first time an overview on the international literature with focus on the worldwide use RUCAM in HILI cases and critically evaluates the quality of the published reports with respect to completeness of case data and the proportion of highly probable and probable causality gradings. The case evaluation was extended to lower gradings with the most likely alternative cause. Finally, the extent of published reports of HILI cases not assessed for causality using RUCAM was evaluated and compared with well assessed HILI cases showing high causality gradings.

Literature search and source

The PubMed database was used to identify publications for the following terms: Herb induced liver injury; Herbal medicine; Herbal traditional medicine; HILI; Traditional Chinese medicines; TCM; RUCAM; Roussel Uclaf Causality Assessment Method. Search terms were used either alone or combined with other terms. Articles in English were preferred and checked for the suitability to be included in the review article. This excluded, for instance, reports from China published in Chinese language but allowed inclusion of Chinese reports published in English language journals with transparent data accessible for peer review. Search period ended on 14 March 2020.

Definitions

Only herbs causing HILI were considered, which include a variety of herbal products and more specifically herbal traditional medicines with herbal traditional Chinese medicines (TCMs) or traditional occidental medicines (TOM) in general, and regulatory approved herbal drugs. This definition excludes a priori any of the so called herbal dietary supplements (HDS) from the present analysis.

Countries with RUCAM based HILI cases, RUCAM specificities, and HILI epidemiology

Countries worldwide and regions

Scientists from countries throughout the world including regions of Asia, Europe, North America, South America, South Africa, and Australia published HILI cases after assessment for causality using RUCAM (Table 1), referencing in particular in alphabetical order to reports from Australia (11,12), Austria (13), Brazil (14), China with reports from 2006 until 2019 (15-36), China with more recent reports of 2020 (37,38), and Colombia (39), France (40), Germany (41-49), India (50,51), Italy (52-54), and Japan (55,56), followed by Korea (57-71), Singapore (72,73), South Africa (74), Spain (75-80), Sweden (81), Switzerland (82), Turkey (83), and finally the US (84-91).

Table 1 Worldwide countries with a selection of published HILI cases assessed for causality using RUCAM, occasionally reported together with DILI cases
Full table

The current analysis of scientists favoring the use of RUCAM showed that China is on top with 24 publications on RUCAM based HILI cases, followed by Korea with 15 reports, Germany with 9 reports, the US with 7 reports, and Spain with 6 reports, whereas the remaining countries provided less than 3 reports. Among the reports, the number of HILI cases may vary from 1 to 6,971. Considering all RUCAM based cases, the total number of 12,068 HILI cases worldwide includes 443 cases from non-Asian countries versus 11,625 cases from Asian countries. Therefore, non-Asian countries contributed with 3.7% to the worldwide cases as opposed to Asian countries with 96.3%. This difference could be partly due to the known high herbal consumption in Asian countries as compared with non-Asian countries but the exact data of herbal consumption is unknown.

HILI assessed for causality by RUCAM

For the majority of the listed HILI reports (Table 1), the original RUCAM of 1993 was used, with providing the accurate reference (7,8), but recent publications applied more frequently the updated RUCAM, first available since 2016 (9). In addition, other patients with clinically assumed HILI have likely been assessed for causality using RUCAM in a private practice or clinical setting without submitting these cases to publications. These unquantifiable cases would subsequently increase the number of the listed cases (Table 1). Occasionally, another CAM was used in addition to RUCAM, conditions that might disturb results of causality gradings and prevent comparison with HILI cohorts using RUCAM alone.

In a few reports, the highest causality grading for HILI was erroneously reported as certain or definite (Table 1); none of these terms are used in RUCAM publications (7-9) as any biological result including those of a human disease cannot be classified higher as highly probable, there is nothing certain or definite in any biological setting.

Causality gradings and case data quality

The variability of RUCAM based causality gradings is of interest (Table 1) and merits further comments (Table 2). From the initially published 12,068 HILI cases, only 11,404 cases (94.5%) contained sufficient data on RUCAM based causality gradings (Table 2). Consequently, in 5.5% of the cases causality gradings were not provided although RUCAM was applied in these cases. Regrettably, this omission invalidates the conclusions proposed in these case reports of this small HILI subgroup and represents waste of time, financials, and energy of scientists, editors, and reviewers. In more detail, based on 11,404 assessable HILI cases, causality gradings were highly probable in 4.2% of the cases, probable in 15.5% of the cases, possible in 70.3% of the cases, and other gradings like unlikely or excluded in 10.0% of the cases (Table 2). Unquestionable, HILI cases best qualified for further case characterization regarding specific herbs are those with a highly probable or a probable causality grading, both represent 19.7% of the assessable cases (Table 2). High causality gradings were commonly achieved under the following conditions: first, data are derived from studies with a prospective design, allowing for straight forward collection of data sets and their completeness; second, single cases were assessed prospectively, asking for all RUCAM based specific elements in advance at time of first suspected diagnosis and ensuring complete data and high gradings upon final evaluation; third, cases with causality not meeting highly probable or probable gradings may have been deleted prior to publication to provide cohort homogeneity. In line with these considerations, HILI cases with possible causality gradings are mostly the result of insufficient data, obtained from retrospective studies or single cases. It has repetitively and strongly been proposed that RUCAM works best in a prospective setting of data collection to ensure complete data with chances of high causality gradings (6-9,92-95). Of note, among the assessable cases and based on case numbers, best values for highly probable causality gradings were provided in China with 447 cases representing 4.2% of all assessable cases in this country (Table 2).

Table 2 Worldwide countries with a selection of published HILI cases assessed for causality using RUCAM providing various causality gradings
Full table

RUCAM specificities

RUCAM with its favored specificities has seemingly a good run worldwide as evidenced by assessing causality in 46,266 DILI cases (6) and now confirmed in 12,068 HILI cases (Table 1), with many details and proposals ensuring its correct application, providing appropriate case data quality and allowing for high causality gradings (6-9,92-95). For DILI, a RUCAM-DILI Case Quality (RDCQ) system has been proposed (6) that can be translated into HILI as well because many essentials apply to both DILI and HILI. RUCAM is objective, structured, validated, quantitative, transparent, user friendly, and specifically designed for liver injury by assessing liver specific elements, for which individual scores are attributed (9). Authors used RUCAM smoothly in their 12,068 HILI cases (Table 1) and 46,266 DILI cases (6). Problems were not reported, confirming its user-friendly use (9).

Summing up the individual element scores of RUCAM provides a final score and resulting causality grading: score ≤0, excluded causality; 1–2, unlikely; 3–5, possible; 6–8, probable; ≥9, highly probable (9). For future HILI case characterization, only cases with probable or highly probable causality gradings should be included in study cohorts. The updated RUCAM should be the preferred version with all its specificities to be used in future cases of both HILI and DILI (9). The aim of RUCAM is to clearly specify causality gradings using scores of assessed key elements rather than applying obscure percentages of causality ranges, leaving room for arbitrary modifications as known from the recent study from China and the US that published causality upgrading from possible to probable gradings likely in order to increase the power of conclusions (34). In addition, and as confirmed in court for another US study, intentional uptonings of RUCAM scores from possible to probable gradings invalidate published conclusions as outlined in detail (96,97) and recently (10), disregarding ethics commonly prevailing within the scientific community (6).

Actually and in retrospect, RUCAM is now to be seen as part of the recently promoted artificial intelligence (AI) ideas which calls for using algorithms to prevent arbitrary opinions, concepts early recognized already at the time of the introduction of RUCAM in the DILI and HILI community in 1993 (7,8). In fact, RUCAM is an objective diagnostic algorithm that overcomes previous attempts of causality assessment by the vague and subjective global introspection (GI) approach (94,95). GI is not liver specific, not structured, and not based on specific elements to be scored individually, and there is good evidence that RUCAM outperforms any other CAM, which are still caught up in the pre-RUCAM and pre-AI era and thereby neglecting the use of preferred diagnostic algorithms. It is said that most of these CAMs will not survive the next years unless all RUCAM specificities are incorporated one by one into the other CAMs.

As an important specificity, RUCAM was the first CAM that ever recognized the importance of various types of liver injury for a robust causality assessment (7-9). Based on thorough case analyses, three types of liver injury pattern emerged that showed striking differences of their clinical features and courses, with focus on challenge, dechallenge, and reexposure characteristics (9). Using results from laboratory analyses of alanine aminotransferase (ALT) and alkaline phosphatase (ALP) and not from liver histology, these three types were classified as hepatocellular injury, cholestatic liver injury, and mixed liver injury. Due to the variability of their clinical features, specific key items and individual scores had to be defined for each of the three liver injury types. Subsequent analyses led to the conclusion that for the causality assessment, only two instead of three RUCAM versions are necessary, one for the hepatocellular injury and the other one for the cholestatic liver injury and the mixed liver injury with its predominant cholestatic features, with details outlined earlier (9). Types of liver injury were randomly mentioned in the HILI reports under consideration (Table 1).

In line with recommendations presented in the updated RUCAM, liver injury is defined by increased serum activities of liver tests (LTs) with the following thresholds (9): ALT of at least 5× upper limit of normal (ULN) and/or of ALP of at least 2× ULN provided ALP is of hepatic origin, both best assessed simultaneously on the day of first presentation of suspected liver as outlined in 2016 (9). In the original RUCAM of 1993, ALT thresholds of 2× ULN were lower (7,8) but these values should not be applied anymore to ensure exclusion of cases reflecting unspecific, clinically not relevant liver injury, liver adaptation, more frequent cause of liver injury such as nonalcoholic steatohepatitis (NASH), or simple LT abnormality. In the current analysis, some HILI reports were assessed with low threshold values (Table 1), which increased the total number of suspected HILI cases. The current ALT and ALP threshold values of 2016 (9) are also considered as relevant in China (98). For sake of comparability, in future publications of HILI, these thresholds should be used and mentioned in the method section. In fact, actual threshold information is often lacking in HILI publications (Table 1).

Another specificity of RUCAM is the optional rather than mandatory inclusion of results from unintentional reexposure tests, but prerequisite for case inclusion is the application of strict criteria before and during reexposures (9). In detail, to classify a reexposure test as positive, criteria are required. For the hepatocellular injury, ALT levels before reexposure (designated as baseline ALT or ALTb) and reexposure ALT levels (designated as ALTr). The reexposure test is positive if ALTb is <5× ULN and ALTr is ≥2× ALTb, negative if one or both criteria are not fulfilled, and uninterpretable if data are lacking for one or both criteria. For the cholestatic or the mixed liver injury, the criteria and interpretation of results are similar, with ALT replaced by ALP (9). A positive reexposure test result is a hallmark of DILI and HILI and recognized by a maximum achievable score of 3 in RUCAM (9). Clearly, reexposure test is unintentional since intentional test is unethical due to high risks of severe outcome of liver injury. Results of reexposure tests using defined criteria have rarely been reported in the HILI cases under consideration (Table 1). However, high causality gradings in HILI are easily achievable without the need of these tests. In other studies, claimed positive reexposure test results from reexposures have rarely been confirmed following reassessment due to absence of strict criteria (99,100). For instance, among 34 HILI cases with initially reported positive reexposure tests, 61.8% of the cases actually fulfilled established test criteria, with negative tests in 17.6% and uninterpretable tests in 20.6% of the cases (100).

RUCAM considers alternative causes in a transparent approach (9). This is needed because many published HILI cases are not true HILI but such cases have to be attributed to alternative causes (101). Cohorts with inclusion of true HILI cases and liver diseases unrelated to herbal use but due to alternative causes lead inevitably to wrong descriptions of HILI features and conclusions. DILI cohorts show also flaws in the assessment of alternative causes (102,103).

Simultaneous use of RUCAM with other CAMs reported in few cases (Table 1) should be discouraged because it clouds the results of causality gradings. Modification of RUCAM also mentioned in a few publications (Table 1) should also be discouraged because the changes have not been validated. Clearly, RUCAM assesses causality for the herbal product in toto and cannot differentiate between the toxicity of the phytochemicals or the components willingly added to the products such as chemical drugs as adulterants or accidently contaminated by impurities, heavy metals, or toxins.

Obviously, RUCAM is unable to replace methods of herb authentication, an important issue as in some HILI cases where the used herbs had been misidentified. RUCAM also has no extra key element for quality issues of the herbal product (9), resulting from batch to batch variability, plant circadian clock system, biotic or abiotic plant stress, seasonal variation, or non-optimum area of harvest (104).

Cohorts of HILI and DILI

Opposed to European reports, Asian reports often and regretfully included a mix of HILI and DILI cases (Table 1), conditions not facilitating a characterization of HILI features resulting in high confusion in the offending products (Table 3). This analysis extends the previously one of HILI and DILI cases that were not based on RUCAM (105). In future studies a clear separation of HILI cases from DILI cases is indispensable. Difficult to reconcile is also the tendency to identify liver injury by herbs as DILI rather than correctly as HILI as outlined in some reports (Table 1). This may lead to confusion. Consequently and by definition, herbs cause HILI and not DILI, and HILI cases cannot be subsumed under the DILI cases.

Table 3 Selected countries with published HILI cases assessed for causality using RUCAM, reported together with RUCAM based DILI cases
Full table

In Asian countries analyzing the ratio of HILI to DILI (Table 1) provides variable results, best explained by differences in the primary study design favoring either HILI or DILI (Table 3). In European countries, however, RUCAM based HILI cases prevail over RUCAM based DILI cases (Table 3). Clearly, the number of reports is small, but both HILI and DILI cases were drawn from the same ethnic population allowing for a more robust comparison.

On a worldwide base, the 12,068 HILI cases (Table 1) are substantially lower as compared with the reported 46,266 DILI cases (6). However, this divergence should not lead to the erroneous conclusion that risks of liver injury are much higher for patients using conventional drugs than those consuming herbal medicines because the population exposed to each product category is unknown.

HILI epidemiology

Best data of HILI epidemiology can be achieved using a prospective study design that ensures completeness of case data, whereby all cases should be assessed for causality using the updated RUCAM including LT thresholds and causality gradings of probable and highly probable.

Valid data on HILI epidemiology have rarely been reported and are available for a few countries only, but some critical issues remain (34,46,68,71). For instance, a low HILI prevalence was found in a large retrospective single center study from Korea in 27/4,769 patients (0.6%) with musculoskeletal disorders receiving TCMs (68), with confirmed results through a thorough reevaluation as published by the same group (106). In Korea again, HILI prevalence has been reported from a nationwide multicenter and prospective study with 6/1,001patients (0.6%) (71). These results from one single country as presented by two different groups are surprising and require comments. With 0.6%, identical data of HILI prevalence were achieved (68,71,106), although one group used a retrospective design commonly known for its low case quality (68,106), whereas the other group followed a prospective study design (71). The case definition in both groups using HILI cases was ALT thresholds of at least 3× ULN (68,71,106). With higher ALT threshold of ≥5× ULN, HILI case numbers approached the zero range (71). HILI epidemiology is seemingly not a problem in Korea (68,71,106), a situation similar to Germany considering low TCM-related HILI incidence data (46). In the latter report, liver injury data were collected from a prospective, hospital-based and large-scale study of 21,470 patients who had no liver disease prior to treatment with herbal TCM. Among these, 26 patients (0.12%) experienced HILI defined as ALT values of ≥5× ULN but causality as assessed by the updated RUCAM (9) was probable in only 8 cases, possible in 16 patients and excluded in 2 cases (46).

In China with around 1.4 billion inhabitants, HILI epidemiology is more complex (34,107). In particular, valid epidemiology data of HILI are not available for the population although herbal TCMs are constituents of the Chinese health system. An earlier disputable epidemiology analysis was not RUCAM based and used mixed cohorts of liver injury by drugs, herbs, or complementary and alternative medicines (106). Instead, improvements brought were evident in a recent report focusing on incidence and etiology of DILI in mainland China, which in fact considered both HILI and DILI (34). It was now recognized that the use of RUCAM as a valuable diagnostic algorithm can help assess causality in liver injury cases (34). However, the cohorts still included under the term of DILI not only DILI but also liver injury cases caused by herbal TCM and HDS, again presenting the shortcomings of the earlier study (106), not allowing for characterization of HILI epidemiology features (34). Nevertheless, some progress is recognizable because other critical shortcomings have been well identified in the text under the limitation section (34). A new version of this study is promised and will hopefully be published with inclusion of the updated RUCAM of 2016, then without major flaws and after a careful peer review preventing letters to the editor. With the current data and methods, no valid statement is reasonable on HILI epidemiology in China (34). Nevertheless, China is well prepared to present valid data on HILI cases, all assessed by RUCAM to distinguish incidence from prevalence, considering major differences in definitions as outlined earlier (10).

RUCAM based HILI cases without confirmed causality

There are few HILI cohorts with cases, which lost their initially claimed causality after reassessment with RUCAM (Table 4) (108-112). These cohorts share the common feature of being initially submitted as spontaneous reports to regulatory agencies or governmental institutes, which inappropriately handled the causality assessment of these cases (108). Shortcomings included the failure to initiate a formal and robust causality assessment approach or the use of diagnostic methods that were not validated for liver injury preventing any firm conclusion. However and in spite of these methodological issues, some regulatory agencies including the one in Germany announced a restricted market availability for a previously authorized herbal drug because of the risk of liver injury. Despite formal request, the German regulatory agency BfArM (Bundesinstitut für Arzneimittel und Medizinprodukte) refused access to anonymized case data in order to reassess the cases with RUCAM. However, anonymized case details were readily obtained from the involved manufacturers. Assessments with RUCAM showed insufficient data quality and many confounders such as preexisting liver disease or comedication, leading then to the conclusion that the initially claimed HILI was not substantiated. Finally, via a recent court decision against the German regulatory ban of kava (Piper methysticum) and in support of case analyses mainly from the group of the first author (R Teschke), the controversy has now hopefully been settled. According to a comprehensive report published 2015, the administrative court of Cologne in Germany ruled that the available data do not support the alleged liver injury of kava, the herbal anxiolytic drug and traditional herb in Oceania (113). Overall, the number of cases seemed insignificant for the court when compared with the known exposure data of 450 million daily doses in ten years. As the German regulatory agency came under scientific fire, it removed its statements of 2002 from its internet home page, but the file has been preserved by the first author available upon request.

Table 4 RUCAM based HILI reports with negative or rare causality
Full table

Based on these discussions with the German regulatory agency BfArM and to avoid similar disturbances in the future, manufactures of herbal drugs or other herbal medicines are encouraged to submit suspected HILI cases to regulatory agencies only if suspected cases were assessed for causality with the updated RUCAM (9). If regulatory agencies reach different causality gradings, they will have to explain the divergent results.

There was, however, good news from European Medicines Agency (EMA), formerly located in the UK and now in the Netherlands (Table 4) that HILI cases attributed to black cohosh were reassessed using RUCAM and denied causality for a variety of reasons in virtually all cases (Table 4) (112).

Published HILI cases lacking causality assessment by RUCAM

Regretfully, some otherwise promising and promotional HILI cases did not benefit from causality assessment by RUCAM (Table 5) as shown in reports originating from Argentina (114), Austria (115), Belgium (116), Canada (117,118), China (107,119-121), France (121,122), Germany (118,123-131), Italy (132,133). Japan (134), the Netherlands (135), New Zealand (136), South Africa (137), Thailand (138), and the US (139-154). RUCAM could have provided substantial support for published conclusions and provided more power to HILI related issues.

Table 5 Selection of HILI reports lacking causality assessment using RUCAM
Full table

Proposals for improved case management with RUCAM

RUCAM has an excellent run internationally in assessing causality for HILI cases, attributed to its well accepted use worldwide and outperforming over other CAMs. Quality of RUCAM based HILI cases is fairly good but not optimal in some cases. Therefore, in future studies the following points should be considered:

• Recommendations as outlined in the updated RUCAM should strictly be followed when assessing HILI cases. These include prospective study design, adherence to LT thresholds, laboratory-based case classification as hepatocellular injury or cholestatic injury, and application of the criteria for assessing cases with an unintentional reexposure. For case presentation, HILI cohorts must be separated from DILI cohorts, the use of the updated RUCAM should be mentioned. Combined application of RUCAM with other CAMs is discouraged. RUCAM based causality gradings must be attributed to each HILI case, and for final evaluation characterization and decision only cases with a probable or highly probable causality gradings should be taken into consideration.
• Regulatory causality assessments are problematic in most HILI cases due to lacking use of a robust CAM such as RUCAM. Manufacturers and physicians that intend submitting spontaneous reports of assumed HILI to regulatory agencies are well advised to attach a RUCAM sheet with all relevant case data, scores of each key data element, and the final score with a causality grading. This allows regulatory reassessments and fair discussions with the stakeholders, preventing premature regulatory decision going public, potential loss of regulatory reputation, fruitless discussions in scientific journals, and court hearings.
• The HILI community will lose information on HILI characteristics, if HILI case evaluations do not include the use of a robust CAM such as RUCAM. These HILI cases are without scientific value and a waste of time and energy of the authors, aside from financial aspects if studies were supported by governmental funds gathered from taxpayers.
• The recommendations listed above should be included in national guidelines on diagnosis of HILI. This will ensure comparability of HILI case features among various countries in West and East.

Conclusions

The current analysis presents details of 80 publications on a total number of 12,068 RUCAM based HILI cases from various countries around the world, in line with the user-friendly application of RUCAM smoothly used by reporting physicians and scientists. Among the assessable 11,404/12,068 HILI cases available for further evaluation, causality gradings were highly probable in 4.2% of the cases, probable in 15.5%, possible in 70.3%, and lower graded in 10.0%. To improve the reporting of RUCAM based HILI cases in the future, recommendations include the strict adherence to the instructions outlined in the updated RUCAM and, in particular, to follow a prospective study design to ensure completeness of case data commonly allowing for high causality gradings. In an additional HILI group published in 4 reports, regulatory causality assessments were evidently problematic in virtually all HILI cases due to lacking use of a robust CAM such as RUCAM, but this primarily seems a specific problem of the German regulatory agency, not so of EMA that perfectly evaluated HILI cases using RUCAM. Apart from the 80 reports dealing with RUCAM based HILI cases, there were also 39 publications of HILI cases that did not benefit from causality assessments by a robust CAM like RUCAM. Conclusions derived from these reports have to be used with caution and are not helpful for the HILI community. In conclusion, RUCAM is well accepted in the world to assess causality in suspected HILI cases but additional efforts are now required to increase the quality of the reporting system.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Gastroenterology and Hepatology for the series “Liver Injury by Herbal Products”. The article has undergone external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tgh-20-149). The series “Liver Injury by Herbal Products” was commissioned by the editorial office without any funding or sponsorship. RT served as the unpaid Guest Editor of the series and serves as an unpaid editorial board member of Translational Gastroenterology and Hepatology from Aug 2019 to Jul 2021. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and solved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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