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Review

Worldwide Use of RUCAM for Causality Assessment in 81,856 Idiosyncratic DILI and 14,029 HILI Cases Published 1993–Mid 2020: A Comprehensive Analysis

by
Rolf Teschke
1,* and
Gaby Danan
2
1
Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, D-63450 Hanau, Teaching Hospital of the Medical Faculty of the Goethe University, D-60590 Frankfurt/Main, Germany
2
Pharmacovigilance Consultancy, F-75020 Paris, France
*
Author to whom correspondence should be addressed.
Medicines 2020, 7(10), 62; https://0-doi-org.brum.beds.ac.uk/10.3390/medicines7100062
Submission received: 19 August 2020 / Revised: 23 September 2020 / Accepted: 25 September 2020 / Published: 29 September 2020
(This article belongs to the Special Issue Research Topics in Medicines and How Our Board Members Are Engaged in Them)
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Abstract

:
Background: A large number of idiosyncratic drug induced liver injury (iDILI) and herb induced liver injury(HILI) cases of variable quality has been published but some are a matter of concern if the cases were not evaluated for causality using a robust causality assessment method (CAM) such as RUCAM (Roussel Uclaf Causality Assessment Method) as diagnostiinjuryc algorithm. The purpose of this analysis was to evaluate the worldwide use of RUCAM in iDILI and HILI cases. Methods: The PubMed database (1993–30 June 2020) was searched for articles by using the following key terms: Roussel Uclaf Causality Assessment Method; RUCAM; Idiosyncratic drug induced liver injury; iDILI; Herb induced liver injury; HILI. Results: Considering reports published worldwide since 1993, our analysis showed the use of RUCAM for causality assessment in 95,885 cases of liver injury including 81,856 cases of idiosyncratic DILI and 14,029 cases of HILI. Among the top countries providing RUCAM based DILI cases were, in decreasing order, China, the US, Germany, Korea, and Italy, with China, Korea, Germany, India, and the US as the top countries for HILI. Conclusions: Since 1993 RUCAM is certainly the most widely used method to assess causality in IDILI and HILI. This should encourage practitioner, experts, and regulatory agencies to use it in order to reinforce their diagnosis and to take sound decisions.

1. Introduction

Idiosyncratic drug induced liver injury (DILI), in short also termed iDILI, and herb induced liver injury (HILI) are complex diseases and received much attention in recent years [1,2,3,4,5,6,7,8,9]. The present scientometric study comprehensively analyzed the global knowledge base and specific emerging topics of DILI derived from 1995 publications in 79 countries and regions, with an impressive annual growth of reports between 2010 and 2019 and almost 340 studies published in 2020 [1]. In parallel, more and more publications on DILI and HILI cases refer to RUCAM (Roussel Uclaf Causality Assessment Method) for causality assessment [10,11,12,13]. The original RUCAM was first published in 1993 [14] and updated in 2016 [15] with additional information on its use and perspectives [16,17], which is now the preferred version to be used in future cases of DILI and HILI [15]. It is widely recognized that causality assessment in DILI and HILI is a multifaceted approach [7,8,9,15], a real medical challenge, for which a diagnostic quantitative algorithm such as RUCAM is an easy tool for case evaluation [10,11,12,13,14,15,16,17,18] to solve complex conditions [18].
The RUCAM algorithm is a structured, standardized, transparent, liver specific and quantitative diagnostic clinical scale based on key elements of liver injury, which are individually scored and provide a score for five-degree causality grading from unrelated up to highly probable causality levels [15]. Since key elements are specifically described and scored, assessments are objective with little risk of subjectivity [15,16,17] commonly observed if the approach to assess causality lacks scored key elements [19]. RUCAM can help expand our knowledge by enlarging population analysis with prospective and scored causality assessment, allowing for harmonized interpretation of data across populations [20]. In this context, RUCAM should be viewed as a cornerstone approach assessing causality of liver injury cases [15,16,17,21], because robust diagnostic biomarkers are rarely available due to misconducted studies as outlined by EMA (European Medicines Agency: Formerly London, UK, now Amsterdam, Netherlands) [21].
In this review article, current conditions of DILI and HILI cases assessed worldwide using RUCAM were critically analyzed. For the first time, the focus is on reports published from1993 to mid 2020 and the discussion of their potential use to describe specific features of DILI and HILI cases.

2. Literature Search and Source

The PubMed database (1993–30 June 2020) was searched for articles by using the following key terms: Roussel Uclaf Causality Assessment Method; RUCAM; Idiosyncratic drug induced liver injury (iDILI); Herb induced liver injury (HILI). Key terms were used alone or in combination. Limited to the English language, publications from each search terms were analyzed for suitability of this review article. The electronic search was completed on 30 June 2020 and supplemented by a manual literature search, using also the large private archive of the authors when the publication was not yet referenced in PubMed. The final compilation consisted of original papers including individual case reports and case series, consensus reports, and review articles with the most relevant publications included in the reference list of this review.

3. Definitions

RUCAM is presented as an algorithm that requires a few criteria allowing for a final quantitative evaluation. In particular, establishing RUCAM based criteria of liver test thresholds and liver injury patterns was revolutionary at the time of first publication issued from an international consensus meeting of experts, without the requirement of a liver biopsy [14] with same principles preserved in the updated RUCAM [15].

3.1. RUCAM Based Liver Injury

3.1.1. Liver Test Thresholds

A liver injury caused by exogenous compounds such as drugs and herbs is defined by specific threshold values established for the liver tests (LTs) alanine aminotransferase (ALT) and alkaline phosphatase (ALP), with current serum activities considered as relevant for ALT ≥ 5 × ULN (upper limit of normal) and ALP ≥ 2 × ULN [15] provided that ALP is of hepatic origin. The original RUCAM was the first causality assessment method (CAM) ever considering threshold criteria although initially with lower values for ALT [15] as compared to currently used criteria [16]. Of note, serum bilirubin is not part of the diagnostic RUCAM algorithm that uses ALT or ALP as diagnostic liver test. In this context, conjugated bilirubin is a sign of the severity of the liver injury.

3.1.2. Liver Injury Pattern

RUCAM was also the first CAM proposing different patterns of liver injury based on LTs [14] and are included also in the updated RUCAM [15]. To determine the liver injury pattern, the ratio R is to be calculated using the multiple of the ULN of serum ALT divided by the multiple of the ULN of serum ALP, provided the ALP increase is of hepatic origin. For causality assessment purposes, two types of liver injury are defined (independently from histological findings): first a hepatocellular injury with R > 5, and second, a cholestatic/mixed liver injury with R ≤ 5.

3.2. Idiosyncratic Versus Intrinsic Liver Injury

Liver injury is either idiosyncratic, due to the interaction between the exogenous synthetic chemical or phytochemical and a susceptible individual with some genetic factor(s), or it is intrinsic due to chemical overdose [11,12,13]. In the present analysis, idiosyncratic injury is considered, as opposed to intrinsic liver injury most commonly observed with overdosed drugs such as acetaminophen [22].

4. Worldwide Publications of DILI

The current scientometric report from China on knowledge mapping confirmed the high worldwide interest in DILI publications and identified a total of 1995 DILI studies published between 2010 and 2019, although information on the applied method of causality assessment was not provided and will need further clarification [1]. This Chinese analysis on the top 10 countries involved in DILI research listed the US, China, Japan, Germany, UK, Spain, France, the Netherlands, Sweden, and Canada. In addition, many interesting details on DILI were comprehensively discussed with focus on definition, incidence rate, clinical characteristics, etiology or pathogenesis such as the character of the innate immune system, the regulation of cell-death pathways, susceptible HLA (Human Leukocyte Antigen) identification, or criteria and methods of causality assessment, all topics were considered as the knowledge base for DILI research [1].

5. Worldwide Publications of RUCAM Based Idiosyncratic DILI

The worldwide impact of DILI can best be quantified by using liver injury cases assessed for causality with a robust method that allows for establishing causality gradings for each implicated drug and to exclude alternative causes unrelated to drug administration.

5.1. Countries and Regions

In the current analysis, authors from 31 countries worldwide reported on cases of idiosyncratic DILI caused by multiple drugs published from 1993 up to mid 2020 and applied in all cases RUCAM to assess causality (Table 1) [23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180]. Such a table with a comprehensive list of publications over a long period has never been reported before and will facilitate the search for RUCAM based DILI cases caused by individual drugs, considering that databases such as LiverTox may have problems providing real DILI cases [10,74].

5.2. Hospital and Other Sources

RUCAM based DILI cases were mostly published by authors from university hospitals and their affiliated teaching hospitals known for their high reputation (Table 1). Among these were a broad range of departments, which in most cases include departments of Hepatology and Gastroenterology, ensuring careful clinical evaluation of patients with suspected DILI and associated causality assessment for the offending drug(s). To a lesser degree, other departments were contributors, for instance, Pharmacology, or Pharmacy and Pharmaceutical sciences [170].
In addition to hospitals, other sources provided RUCAM based DILI cases (Table 1). Among these were National Institutes of Health from Japan [92] and the US [165], consortia from Spain [115,141], the adverse drug reactions advisory committee (ADRAC) from Sweden [126], regulatory pharmacovigilance and pharmacoepidemiology centers from France [58,59] and Italy [86], drug commission of medical association from Germany [64], committee for drug induced liver injury from China [42]; also, drug reaction reporting database from Spain [65], regulatory agency from Spain [114] health insurance from the US [157], and drug safety departments of drug companies from France [57], Sweden {148], and Switzerland [132]. Some of these played an eminent role in promoting the use of RUCAM in prospective studies, particularly those from Spain [115], Sweden [126], and the US with France and Sweden [148].

5.3. Top Ranking Countries

Among the top 10 countries were in decreasing order China, the US, Germany, Korea, Italy, Sweden, Spain, Japan, Argentina, and Thailand, whereby the top 5 countries provided most of the DILI cases (Table 2). Authors from these 5 countries contributed together 75,133 DILI cases out of a total 81,856 worldwide DILI cases, corresponding to 91.8%. On the lower part of the list ranked the 6 countries Israel, Malaysia, Mexico, Morocco, Saudi Arabia, and Turkey, authors from these low ranking countries provided each one single DILI case assessed for causality using RUCAM, corresponding to 6 cases altogether out of a total of 81,856 DILI cases. Authors from the remaining 20 countries with a ranking from 6 down to 25 contributed 6.723 DILI cases out of overall 81,856 cases corresponding to 8.2%. In essence, RUCAM based DILI cases were mostly published in English language journals, raising the question how DILI cases were assessed and published by the other countries in local journals in languages other than English. Currently, overall 81,856 cases of idiosyncratic DILI assessed for causality by RUCAM have been retrieved via PubMed, all published 1993–June 2020 (Table 1) [23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180].

5.4. Annual Growth Trends of RUCAM Based DILI Case Publications

Analyses of growth trends provided additional information after identification of a total 1995 DILI studies, published between 2010 and 2019 but not stratified for causality assessment using RUCAM [1]. In the frame of the present analysis, only publications of idiosyncratic DILI cases were included if they had been assessed for causality using RUCAM, providing a more homogenous series with established DILI diagnoses.

5.4.1. Published Annual RUCAM Based DILI Cases

Considering the period from 1993 to 2019, annually published cases of RUCAM based idiosyncratic DILI ranged between 0 and 27,224 in 2019, but data of 2020 were not included because case counting stopped by end of June in this particular year (Figure 1). Three phases of trends appeared with respect to published RUCAM based DILI cases: (1) phase 1 with clinical field testing from 1996 to 2004 (2) phase 2 with promotion from 2005 to 2013, and (3) phase 3 of worldwide use from 2014 to 2019.
Phase 1 started after the launch of RUCAM in 1993 [16,47] and the analysis of 94 DILI cases [47], the number of subsequent annual published DILI cases remained small until 2004, reaching 121 cases (Figure 1). This was the period of initial testing the RUCAM algorithm under clinical field conditions with interesting early information provided by 3 reports [58,91,114]. The first report came from Spain, was published in 1996, analyzed a major study cohort of DILI due to amoxicillin and clavulanate, and described their typical clinical features, with Rodríguez as first author and Zimmerman as senior author [114] who actually was involved as an expert from the US in the international consensus meetings [14] but did not promote RUCAM in DILI evaluations in his own country. Of interest was also the retrospective design of this analysis, suggesting that this particular study approach is feasible [114] although a prospective approach is recommended [15]. The second report was from Japan with Japanese patients, published in 2003 by Masumoto et al. [91]. This study favored RUCAM over other CAMs, provided evidence that the performance of the lymphocyte transformation test was poor in line with previous reports, and the RUCAM criteria were viewed as useful for diagnosing DILI in Japanese patients. The third publication came from France, reported in 2004 on details of a patient with DILI by pioglitazone, and showed the feasibility of a good case report to be assessed by RUCAM, evaluated by Arotcarena et al. [58]. All three reports were hallmarks of the first phase of RUCAM based DILI case series devoted to clinical field evaluation that ended in 2004 (Figure 1).
Phase 2 started in 2005 with overall 7695 annually published RUCAM based DILI cases (Figure 1) [115,126,147,148]. Among these were 461 cases provided by Andrade et al. from Spain retrieved from a prospective study involving various drugs [115], additional 784 cases from Sweden were published by Björnsson and Olsson retrieved from a prospective study of DILI by various drugs [126], whereas from the US 2 case reports of DILI by amoxicillin and clavulanate were presented by Fontana et al. [147] as well as a large cohort of DILI caused by ximelagatran occurred in clinical trials was published by Lee et al. [148]. These 4 studies promoted the usefulness of RUCAM evaluating DILI cases [115,126,147,148] by preferring a prospective study design [115,126], evaluating single DILI case reports [147], and correctly assessing suspected DILI cases in clinical trials [148]. Whereas RUCAM had already a firm place among DILI experts in Europe, it seems that experts in the US became more familiar with the use and practicability of RUCAM.
Phase 3 is characterized by the worldwide use of RUCAM for DILI started in 2014 with 11,525 DILI cases (Figure 1), mostly attributed to one study with 11,109 DILI cases provided by Cheetham et al. [157]. Starting in 2015, there was a continuous rise of published RUCAM based DILI cases (Figure 1), likely driven also by the updated RUCAM available online 2015 and published in 2016 [15]. With 27,224 published DILI cases, the maximum level on an annual base was achieved in 2019 (Figure 1). Until end of June 2020, additional 15,153 published DILI cases were counted but not included in Figure 1, corresponding already to more than half of the cases counted in 2019 and representing a good base for 2020 and further years.

5.4.2. Annual RUCAM Based DILI Publications and Growth Trend

Over the years starting from 1993, when RUCAM was launched [14,57], and until 2019 an upward trend of annual RUCAM based DILI publications can be observed with some dips in between (Figure 2). In 2019, 26 publications were counted, and 15 publications from January 2020 until end of June 2020 that were not included in the listing (Figure 2). Overall 158 publications with RUCAM based DILI cases were counted from 1993 until mid 2020 (Table 1).

5.5. Specificities of DILI Case Evaluation

Large study cohorts of RUCAM based DILI cases accumulated many different drugs and provided as expected a global information of the DILI cases due to various drugs without a detailed description of clinical features drug by drug (Table 1). Consequently, typical clinical features of a DILI by a single drug cannot be obtained from large cohorts as opposed to single DILI case reports or case series that included DILI cases due to a single drug (Table 1). In general, studies with a single DILI case or a few cases are more informative because they provide an exhaustive past medical history with clinical details required for a sound case evaluation. In search for typical DILI features by specific drugs, therefore, assistance may be provided by the drug listing (Table 1). In addition, details can be retrieved via the internet, using the search terms drug induced liver injury and the name of the suspected drug, combined with RUCAM or the updated RUCAM.

5.6. Worldwide Top Ranking of Drugs Causing DILI

There is concern how best to establish a top ranking of drugs most commonly implicated in DILI [70,74]. A recent study presented a list with top ranking drugs out of overall 3312 DILI cases evaluated by RUCAM (Table 3) [70]. The RUCAM based DILI cases were retrievd from 15 reports by six national databases of DILI registries and three large medical centers worldwide, which provided the DILI cases under consideration. Contributing countries and regions were in alphabetical order China, Germany, Latin America, Iceland, India, Singapore, Spain, Sweden, and the US. It was found that the databases of national registries and large medical centers are the best sources of drugs implicated in DILI cases. There is also the note that presently DILI cases of the LiverTox database are less suitable for clinical or regulatory purposes as presented on its website because many suspected DILI cases were derived from published cases of poor quality, lacking a robust CAM such as RUCAM [70,74]. Consequently, the majority of LiverTox based cases of assumed DILI could previously not be classified as real DILI [74]. To overcome these diagnostic shortcomings, LiverTox attempted a top ranking of drugs by counting the published DILI cases for each individual drug [74]. It was assumed that the degree of causality probability increases with the number of published DILI reports: the higher the case number the higher the probability. This special approach explains the variability of the top listing presented by liverTox [74] as compared to RUCAM based cohorts [70].

6. Worldwide Publications of HILI Cases Assessed for Causality Using RUCAM

Highlights of liver injury cases have been reported not only for DILI but with increasing frequency also for HILI cases questionable due to lack of a robust CAM [7,8,9]. The problems associated with HILI are specifically addressed in the current analysis, which considers for the first time worldwide HILI cases using RUCAM as a robust algorithm for assessing causality.

6.1. Countries and Regions

Authors from many countries around the world reported on cases of HILI in connection with the consumption of various herbs, all published since 1993 (Table 4) [29,37,38,42,48,100,101,102,103,113,115,116,117,118,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232,233,234,235,236,237,238,239,240,241,242,243,244,245,246,247,248,249,250,251,252,253,254,255]. Specifically considered were patients, who experienced HILI with established causality using RUCAM. Such a table with a comprehensive list of publications over a long period of time will help the search for RUCAM based HILI cases caused by specific herbs or herbal products containing a mixture of several herbs. This list is unique as compared to databases that may have problems providing real HILI cases not confounded by alternative causes or lack of a robust causality assessment.

6.2. Hospital and Other Sources

Most RUCAM based HILI cases were provided by authors from university hospitals and their affiliated teaching hospitals with their departments of Hepatology and Gastroenterology, Medicine or Internal Medicine (Table 3). Rare contributors were other departments like those with focus on Emergency Medicine [255], Clinical Pharmacology and Toxicology in Berlin [209], Pharmacology and Toxicology in Hannover [213], Pharmacy in Singapore [238], Physiology and Pharmacology in Rome [219,221], Anatomical, Histological, Forensic and Orthopedic Sciences in Rome [222], Pediatrics in Seoul [234], and among the contributors were even the Neurology and Headache Center in Essen [212] and Spine and Joint Research Institute in Seoul [235].
Other sources providing RUCAM based HILI cases include the Chinese Academy of Medical Sciences in Beijing [195], School of Chinese Materia Medica in Beijing [199,202], Competence Centre for Complementary Medicine and Naturopathy in Munich [211], Biomedical Research and Innovation Platform South African Medical Research Council in Tygerberg [239], United States Pharmacopeia in Rockville [254], and Center of Pharmacovigilance of Florence [218].

6.3. Top Ranking Countries

Among the countries presenting RUCAM based HILI cases were on top in descending order China and Korea, followed by Germany, India and the US, whereby the top 5 countries provided most of the HILI cases (Table 5). Authors from these 5 countries contributed together 13,808 HILI cases out of a total 14,029 worldwide HILI cases, corresponding to 98.4%. On the lower part of the list ranked the 4 countries Brazil, Colombia, Switzerland, and Turkey, authors from these low ranking countries provided each one HILI case assessed for causality using RUCAM, corresponding to 4 cases altogether out of a total of 14,029 HILI cases. Authors from the remaining 20 countries with a ranking from 6 down to 14 contributed 217 HILI cases out of overall 14,029 cases corresponding to almost 1.6%.

6.3.1. Published Annual RUCAM Based HILI Cases

From 1993 to 2019, published annual cases of RUCAM based HILI ranged between 0 and 11,609 in 2019, while 57 HILI cases of 2020 were not included because case counting stopped by end of June in this particular year (Figure 3). Three phases of trends appeared with respect to published RUCAM based HILI cases: (1) phase 1 with lack of any clinical field testing from 1993 to 2003, (2) phase 2 with slow promotion from 2004 to 2016, and (3) phase 3 of worldwide use from 2017 to 2019.
Phase 1 started after the launch of RUCAM in 1993 [16,47] but without a single published HILI case until 2003 (Figure 3). The lack of published RUCAM based HILI cases during this period might be due to the fact that the value of RUCAM was not yet sufficiently known or to uncertainties whether herbs have the potential to cause liver injury. In addition, the term of herb induced liver injury or its acronym HILI was unknown at that time and therefore not in common use.
During the subsequent phase 2, the number of annual published HILI cases remained small with cases ranging from 2 to 933, considering the years from 2004 until 2016 (Figure 3). In 2008, there were 108 HILI cases, with 18 Spanish cases published by García-Cortés et al. [117,241] and 90 Korean cases published by Kang et al. [227] and Sohn et al. [228]. During 2016, there was a sharp increase with 933 HILI cases, mostly attributed to 866 cases from China published by Zhu et al. [42]. As a reminder and outlined recently, herb induced liver injury with HILI as its acronym was first introduced and proposed as a specific term in the scientific literature only in 2011 [12]. This may explain retarded publications on HILI cases (Figure 3).
Phase 3 started with low HILI case numbers in 2017 and 2018 (Figure 3), considering that the updated RUCAM applicable also to HILI cases was published only in 2016 [15]. With 11,609 the largest HILI case number was published in 2019 (Figure 3) as a consequence of the ongoing worldwide use of RUCAM for assessing causality in suspected HILI cases (Table 4). In particular, contributing countries were in alphabetical order Australia [29], Brazil [183], China [48,196,197,198,199,200,201], Germany [213,214,215], India [217], Italy [222], Korea [103], Spain [115,117,240,241,242], Switzerland [244], and the US [245,246,247,248,249,250,251,252,253,254]. Most of the 11,619 HILI cases published in 2019 were from China [48,196] and Korea [103], with 6971 cases published by Shen et al. [48], 2019 cases reported by Byeon et al. [103], and 1552 cases provided by Chow et al. [196]. However, until mid 2020 only 57 HILI cases were published (Table 4) [202,203,253,254], suggesting for the whole year 2020 at best 100 cases (Figure 3).

6.3.2. Annual RUCAM Based HILI Publications and Growth Trend

Over the years starting from 1993, when RUCAM was launched [14,57] and until 2019, an upward trend of annual RUCAM based HILI publications can be observed with some dips in between (Figure 4). In 2019, 18 publications were counted and 4 publications until end of June 2020 that were not included (Figure 4). For the whole year 2020, therefore, at best perhaps 8 publications can be anticipated (Figure 4). These figures show that a total of 85 publications with RUCAM based HILI cases were reported from 1993 until mid 2020 (Table 2).

6.4. Specificities of HILI Cases

Large study cohorts of RUCAM based HILI cases accumulate many different herbs and provide as expected a global information of many HILI cases without a detailed description of clinical features for specific herbs (Table 4). Consequently, studies with a single or a few HILI cases have many advantages because they focus on a single herb or herbal product causing the liver injury and usually provide an exhaustive past medical history with clinical details required for a sound case evaluation. For interested physicians, regulators, and manufacturers, this listing provides individual cases with herbs causing HILI.

7. Utility of RUCAM

The utility of RUCAM has been confirmed in in many liver injury cases of DILI (Table 1) and HILI (Table 4) published from countries and regions around the world, as outlined in various reports [5,11,15,16,17,18] and briefly summarized (Table 6). In short, the high qualification of RUCAM as an objective diagnostic algoritm to assess causality in liver injury cases of DILI and HILI is the clue of its increasing use (Figure 1, Figure 2, Figure 3 and Figure 4). RUCAM is smoothly applied by clinicians or regulators and obviously without problems (Table 1 and Table 4). The worldwide use allows data comparison among different countries, a unique condition for multifacetted diseases as DILI and HILI are. RUCAM is also applied in epidemiology studies. Finally and most importantly, each individual DILI and HILI case report contain important details of liver injury cases that may be helpful for physicians in care of patients with suspected DILI and HILI.

8. Other CAMs

Apart from the objective diagnostic RUCAM algorithm, a few non-RUCAM based CAMs are known, critically discussed elsewhere in detail [5,15]. In short, they are less accurate than RUCAM, not quantitative as not based on specific elements to be scored individually, not specific for liver injury cases, not structured, not validated, or based on individual arbitrary subjective opinions. In fact, other CAMs are still caught up in the pre-RUCAM and pre-AI era [18] and thereby neglecting the use of diagnostic algorithms such as the original RUCAM [14] or the now preferred updated version [18].

9. Limitation of the Analysis

The current analysis is based on published data of DILI and HILI reports in English, or at least an abstract in English, rather than on unpublished data contained in the original data sets that were not available to the authors of the analysis for re-analysis. Although most of the published DILI and HILI cases provide excellent data, some authors forgot presenting RUCAM based causality gradings or included cases with a possible causality grading in their final evaluations of cases together with a probable or highly probable causality level. Nevertheless, a broad range of different causality gradings was commonly provided in most published cases, respective references allow for detailed information. As being outside the scope of this article, causality gradings for individual reports were not provided (Table 1 and Table 5), but some details of 46,266 DILI cases assessed by RUCAM were published earlier [11]. Problematic are study cohorts with inclusion of both DILI and HILI cases, unless both groups were separately evaluated [48]. As expected, not all of the patients were commonly confirmed as being DILI by RUCAM scoring, but the number of published cases remained accurate. For instance, special conditions are evident in the randomized clinical trial of ximelagatran [148]. In this prospective, report, hepatic findings were analyzed in all suspected cases with regard to causal relationship to ximelagatran by using RUCAM, considered as the most reliable tool to assess causality [148]. Applying RUCAM based on ALT thresholds only is insufficient since 92% of the ximelagatran group did not meet this criterion missing then a final robust causality grading, as opposed to 8% of the study group receiving partially high causality gradings. This study reaffirms the utility of RUCAM to identify cases with real DILI cases in cohorts under real world conditions.

10. Outlook

The perspectives using the updated RUCAM in future DILI and HILI cases are favorable because many authors including those from the US become more familiar with RUCAM and are ready to use this diagnostic algorithm (Table 1, Table 2, Table 3 and Table 4), in line with principles of Artificial Intelligence to solve difficult processes [18]. Moreover, as in the US and many other countries RUCAM was successfully used to assess causality in cases of DILI, there is no need to invent another instrument specifically designed for drug development [255]. The issue of overlooked alternative causes remains a clinical problem and was described already in 1999 by Aithal et al. [256] and guided by RUCAM subsequently confirmed [69,257].
Future DILI and HILI studies should adhere on a prospective study design as strongly recommended in the RUCAM updated in 2016 because a retrospective approach may create concern on the validity of the published results due to incomplete information [15]. Neglecting this recommendation and using instead a retrospective design could be problematic [48]. In addition, attempts to lift RUCAM based causality gradings from possible to probable must be resisted [48]. Discouraged is in particular the use of a non-RUCAM based CAM in addition to RUCAM, because such a combination causes uncertainty due to disputable results of causality gradings. It is not recommended to mix in the same cohort patients with DILI or HILI [48] because this situation will complicate a separate evaluation of DILI or HILI features. However, it is clear that in individual cases RUCAM allows for a distinction between a drug and a medicinal herb when causality gradings are different.

11. Conclusions

The current analysis showed a favorable run of the RUCAM algorithm globally used since its launch in 1993, considering the annually published DILI and HILI cases. Overall 95,885 liver injury cases were published using RUCAM for causality assessment, namely 81,856 iDILI cases and 14,029 HILI cases. The global use of RUCAM assessing causality in cases of DILI and HILI helps compare study results among various countries and facilitates description of typical clinical features, best derived from case reports or small case series. RUCAM solves complex conditions as an algorithm in line with principles of Artificial Intelligence. Top ranking countries providing RUCAM based DILI cases were China, the United States, Germany, Korea, and Italy, whereas most RUCAM based HILI cases were published by authors from China, Korea, Germany, India, and the United States. In term of number of cases published, there is no other causality assessment method that could outperform RUCAM evaluating DILI and HILI cases. This should encourage all the stakeholders involved in DILI and HILI to systematically use RUCAM in order to reinforce their diagnosis and take the right decisions for the benefit of the patients.

Author Contributions

Conceptualization and methodology, R.T. and G.D.; formal analysis and draft preparation, R.T.; review and editing, G.D. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Acknowledgments

The authors are grateful to Sabine Veltens for her professional providing of the figures.

Conflicts of Interest

The authors declared that they have no conflict of interests regarding this invited article.

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Figure 1. Annual cases of DILI assessed for causality by RUCAM and published since 1993.
Figure 1. Annual cases of DILI assessed for causality by RUCAM and published since 1993.
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Figure 2. Annual publications of DILI cases assessed for causality by RUCAM as reported since 1993.
Figure 2. Annual publications of DILI cases assessed for causality by RUCAM as reported since 1993.
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Figure 3. Annual cases of HILI cases assessed for causality by RUCAM and published since 1993.
Figure 3. Annual cases of HILI cases assessed for causality by RUCAM and published since 1993.
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Figure 4. Annual publications of HILI cases assessed for causality by RUCAM as reported since 1993.
Figure 4. Annual publications of HILI cases assessed for causality by RUCAM as reported since 1993.
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Table
Table 1. Worldwide countries with a selection of published DILI cases assessed for causality using RUCAM.
Table 1. Worldwide countries with a selection of published DILI cases assessed for causality using RUCAM.
Country/
DILI Cases, n		First Author/YearDILI
Cases,
n		DrugsComments on RUCAM Based DILI Cases
Argentina
n = 625		Bessone, 2016 [23]197Various drugsDILI caused by a variety of drugs, not allowing individual description of features
Bessone, 2019 [24]114Various drugsIndividual drugs not available for DILI feature characterization
Colaci, 2019 [25]311Various drugsDILI features for single drugs were not presented
García, 2019 [26]3MethotrexateFeature details provided for DILI by methotrexate
Australia
n = 106		Lin, 2014 [27]47Various volatile anaestheticsDILI by anesthetics without individual features of isoflurane, desflurane, or sevoflurane
Ahmed, 2015 [28]1IpilimumabDetailed features of the DILI case
Laube, 2019 [29]1AtorvastatinGood feature presentation of this DILI case
Worland, 2020 [30]57InfliximabFeature presentation of DILI by the drug
Bahrain
n = 25		Sridharan, 2020 [31]25Various antiepileptic drugsNo feature details provided of DILI due to individual drugs
Brazil
n = 4		Becker, 2019 [32]4Various drugsFeatures of DILI caused by some drugs
Canada
n = 4		Yan, 2006 [33]2RofecoxibTwo well described case features of DILI caused by rofecoxib
Nhean, 2019 [34]2DolutegravirCareful described features of DILI
China
n = 35,825		Hou, 2012 [35]300Various drugsNo feature details available for DILI by individual drugs
Lv, 2012 [36]89Various drugsSpecific features of DILI by individual drugs were not presented
Hao, 2014 [37]140Anti-TuberculoticsLacking specific DILI features of any drug
Ou, 2015 [38]231Various drugsNo feature specifics of DILI are available for individual drugs
Zhu, 2015 [39]39Various drugsSpecific features of DILI caused by individual drugs were not provided
Lu, 2016 [40]513Various drugsMissing specific features of DILI caused by individual drugs
Yang, 2016 [41]124Various drugsFeature specifics of DILI caused by individual drugs were not provided
Zhu, 2016 [42]870Various drugsNo specific features of DILI by individual drugs were presented
Naqiong, 2017 [43]157Various statinsCohort consisted of patients with DILI caused by atorvastatin, simvastatin, and rosuvastatin, but specific features were not provided for individual statins
Li, 2018 [44]1IguratmodDetailed feature description of DILI
Song, 2018 [45]1PosaconazoleCareful feature presentation of DILI by this drug
Tao, 2018, [46]290Anti-TuberculoticsCohort included patients with DILI caused by isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin, but specific features were not presented for individual drugs
Liao, 2019 [47]1CefepimeWell described features of DILI by this drug
Shen, 2019 [48]18,956Various drugsCohort comprized patients with DILI, but special DILI features related to individual drugs were not published.
Xing, 2019 [49]133Various drugs No specific feature presentation of DILI by individual drugs
Ma, 2020 [50]1FenofibrateSpecific feature of DILI by this drug presented
Tao, 2020 [51]146Anti-Tuberculotics Lacking feature data of DILI caused by individual drugs
Wang, 2020 [52]155Anti-TuberculoticsCohort included patients with DILI due to not further identified anti-TB regimens, hence attributing specific DILI features to individual drugs was not possible
Yang, 2020 [53]13,678Various drugs No feature details of DILI by individual drugs
Colombia
n = 19		Ríos, 2013 [54]1AlbendazoleDetailed feature description of DILI caused by albendazole
Cano-Paniagua, 2019 [55]18Various drugs Perfect feature description of DILI by drugs in this excellent prospective epidemiology study using the updated RUCAM for causality assessment
Egypt
n = 75		Alhaddad, 2020 [56]75Various drugs Feature details of DILI by individual drugs incompletely provided
France
n = 170		Bénichou, 1993 [57]94Various drugsNo detailed feature description of DILI by the drugs
Arotcarena, 2004 [58]1PioglitazoneFeature description of the case
Moch, 2012 [59]18EtifoxineDetailed features of DILI due to etifoxine treatment
Carrier, 2013 [60]1Methyl-prednisoloneFeatures of DILI well described for the drug
Ripault, 2013 [61]1CrizotinibGood feature details provided for DILI by this drug
Dumortier, 2017 [62]5Methyl-prednisolone Careful feature description of DILI caused by the drug
Meunier, 2018 [63]50NimesulideNo feature description of DILI by this drug
Germany
n = 10,907		Stammschulte, 2012 [64]37FlupirtineCarefully presented features of DILI caused by flupirtine
Douros, 2014 [65]7FlupirtineComprehensive feature presentation of DILI due to flupirtine
Douros, 2014 [66]198Various drugsCohort of patients with DILI associated with the use of various drugs, but special features of DILI by individual drugs were not provided
Buechter, 2018 [67]15Various drugsNo detailed feature presentation of DILI caused by individual drugs
Dragoi, 2018 [68]16DiclofenacCohort of DILI patients with presentation of limited specific DILI features
Teschke, 2018 [69]7278Various drugsCohort of DILI patients without feature specification for individual drugs
Teschke, 2018 [70]3312Various drugsCohort of DILI cases not providing special features of DILI by individual drugs
Weber, 2019 [71]44Various drugsNo specific features of DILI caused by individual drugs provided
Iceland
n = 367		Björnsson, 2012 [72]73StatinsSpecific feature details provided of DILI by statins
Björnsson, 2013 [73]72Various drugsCohort of DILI cases without providing typical features of DILI by single drugs
Björnsson, 2016 [74]222Various drugsThe two assessed cohorts provided no typical features of DILI caused by the evaluated drugs
India
n = 424		Harugeri, 2009 [75] 1MontelukastGood feature presentation of a patient with DILI caused by montelukast
Devarbhavi, 2010 [76]313Various drugsNo feature description of DILI due to individual drugs
Rathi, 2017 [77]82Various drugsCohort of DILI cases but features of DILI by indivual drugs were not presented
Taneja, 2017 [78]2EtodolacDetailed feature presentation of DILI
Das, 2018 [79]24Various drugsCohort with limited feature description of few patients with DILI caused by drugs assessed for causality by RUCAM or other CAMs
Dutta, 2020 [80]1HaloperidolPerfect presented feature details of DILI caused by this drug
Kulkarni, 2020 [81] 1Vitamin APerfect feature details of this DILI case
Israel
n = 1		Gluck, 2011 [82]1AmiodaroneCareful feature description of a patient with DILI caused by a single drug
Italy
n = 1562		Rigato, 2007 [83]1Flavoxate Good feature presentation of a patient with DILI caused by flavoxate
Licata, 2010 [84]46Various drugs including Nimesulide Feature description of patients with DILI by nimesulide but no description for DILI by other drugs
Abenavoli, 2013 [85]1Cyproterone acetateDetailed feature description of a patient with DILI
Ferrajolo, 2017 [86]938Various antibioticsCombined feature presentation of all antibiotics causing DILI in paediatric patients
Licata, 2017 [87]185Various drugsEpidemiology study, hence no feature description of patients with DILI by any drug
Giacomelli, 2018 [88]362NevirapineDetailed feature description of DILI by nevirapine observed in all patients
Licata, 2018 [89]28RivaroxabanPerfect feature description of this DILI cohort
Lovero, 2018 [90]1UstekinumabCareful feature description of DILI caused by this drug
Japan
n = 939		Masumoto, 2003 [91]85Various drugsNo detailed feature description of DILI caused by drugs
Hanatani, 2014 [92]182Various drugs Detailed features of DILI by individual drugs not provided
Niijima, 2017 [93]1IpragliflozinProvided case features of DILI
Ji, 2017 [94]1MethimazolePerfect feature presentation of DILI caused by this drug
Aiso, 2019 [95]270Various drugsGlobal feature description of DILI by all drugs
Kishimoto, 2019 [96]1ClonazepamDetailed feature of DILI by this drug
Hiraki, 2019 [97]1Tegafur-UracilGood feature presentation of DILI caused by the drug
Kakisaki, 2019 [98]398Various drugsPerfect feature description of the cohort
Korea
n = 6528		Choi, 2008 [99]1AlbendazoleDetailed feature description of DILI by albendazole in a case report of a single patient
Suk, 2012 [100]101Various drugsLacking detailed feature description of DILI by individual drugs
Son, 2015 [101]1Various drugs No specific feature description of DILI due to comedication
Woo, 2016 [102]1Various comedicated drugsLacking specific feature description of DILI due to comedication
Byeon, 2019 [103]6391Various drugsMissing specific feature of DILI caused by individual drugs
Kwon, 2019 [104]33NimesulideDetailed feature description of DILI caused by nimesulide, using a prospective study design in this perfect analysis
Malaysia
n = 1		Thalha, 2018 [105]1KombiglyzePerfect feature description of DILI caused by the combination of metformin and saxagliptin
Mexico
n = 1		Lammel-Lindemann, 2018 [106]1CandesartanWell described features of DILI by this drug
Morocco
n = 1		Essaid, 2010 [107]1TadalafilFeature description of DILI due to the drug
Pakistan
n = 264		Abid, 2020 [108]264Various drugsNo specific feature details presented for DILI caused by individual drugs
Portugal
n = 53		Costa-Moreira, 2020 [109]53Various drugs Specific feature details of DILI caused by individual drugs were not provided
Saudi Arabia
n = 1		Alqrinawi, 2020 [110]1MenotropinPerfect feature details of DILI by this specific drug
Serbia
n = 99		Miljkovic, 2010 [111]80Various drugsNo detailed feature description of DILI by individual drugs
Miljkovic, 2011 [112]19Various drugsLacking detailed feature presentation of DILI caused by individual drugs
Singapore
n = 14		Wai, 2006 [113]14Various drugsLimited feature description of DILI
Spain
n = 1181		Rodríguez, 1996 [114]35 Various drugsNo feature details of DILI cases provided for individual drugs
Andrade, 2005 [115] 461Various drugs Limited feature description of DILI case details
Andrade, 2006 [116]28Various drugsPartial feature description of DILI by few drugs
García-Cortés, 2008 [117]225Various drugsLimited feature description of DILI by few drug groups
Lucena, 2011 [118]78Amoxicillin ClavulanateCareful feature description of DILI by the drug combination
Lucena, 2011 [119]9Various drugsFeature description of DILI caused by individual drugs
Robles-Diaz, 2015 [120]25Anabolic and androgenetic steroidsLimited feature description of DILI
Tong, 2015 [121]1MethylphenidateCareful evaluation of feature details provided for this DILI case
Medina-Calitz, 2016 [122]298Various drugsNo specific feature description for DILI by any drug
López-Riera, 2018 [123]17Various drugsLack of specific feature presentation of DILI by any drug
Machlab, 2019 [124]1ApixabamCareful feature description of the DILI case caused by the drug
Zoubek, 2019 [125]3Methyl-prednisolonePerfect feature presentation of DILI
Sweden
n = 1508		Björnsson, 2005 [126]784Various drugsDetailed feature description of DILI by few drugs
De Valle, 2006 [127]77Various drugsLimited feature description of DILI by a few drugs
Björnsson, 2007 [128]77Various drugsLacking substantial feature description of DILI caused by few drugs
Björnsson, 2007 [129]570Various drugs Feature details of DILI presented
Switzerland
n = 68		Goossens, 2013 [130]1IbandronateDetailed description of immune DILI features by ibandronate, a biphosphonate
Russmann, 2014 [131]14RivaroxabanPerfect individual feature presentation of each DILI case
Scalfaro, 2017 [132]49Sacubitril
Valsartan		No feature details of DILI caused by the drugs
Schneider, 2017 [133]1Zoledronic acidFeature details provided for DILI by this drug
Terziroli Beretta-Piccoli, 2018 [134]1Atovaquon/ProguanilDetailed feature description of DILI
Visentin, 2018 [135]2NSAID
Amoxicillin/Clavulanate		Lack of feature details of DILI by individual drugs
Thailand
n = 509		Treeprasertsuk, 2010 [136]80Various antibioticsNo feature details provided for DILI caused by individual drugs in the context of this epidemiology study
Sobhonslidsuk, 2016 [137]383Various drugsMissing feature details of DILI caused by individual drugs
Chayanupatkul, 2020 [138]46Various drugsFeature details of DILI due to individual drugs not provided
Duzenli, 2019 [139]1PhenprobamateDetailed feature description of DILI by this drug
Hussaini, 2007 [140]43Various antibioticsNo feature details of DILI caused by individual drugs
Daly, 2009 [141]51Flucloxacillin Excellent feature details presented for DILI cases
Turkey
n = 1		Spraggs, 2011 [142]61LaptinibExcellent feature description of DILI case
United
Kingdom
n = 263		Islam, 2014 [143]1AnastrazoleFeature presentation of a patient with DILI due to anastrazole
Dyson, 2016 [144]1SofosbuvirFeatures of DILI by this drug provided
Abbara, 2017 [145]105Various anti-TuberculoticsFeature presentation of all DILI cases due to various anti-tuberculosis drugs
Vliegenthart, 2017 [146]1NitrofurantoinFeature description of DILI by the drug
United States
n = 20,311		Fontana, 2005 [147]2Amoxicillin, Amoxicillin/ClavulanateWell described features of DILI caused by the drugs
Lee, 2005 [148] 6448Ximelagatran Perfect presentation of DILI features
Stojanovski, 2007 [149] 1Atomoxetine Good DILI case feature presentation
Lammert, 2008 [150]598Various drugsNo feature presentation of DILI by individual drugs
Singla, 2010 [151] 1Cephalexin DILI features of a single case
Nabha, 2012 [152]1EtravirinePresentation of DILI feature
Sprague, 2012 [153]1Varenicline Careful DILI feature description
Markova, 2013 [154]56BosentanSome global feature description
Marumoto, 2013 [155]4NSAIDLimited feature details of DILI cases
Bohm, 2014 [156]1DaptomycinDILI feature description in this case
Cheetham, 2014 [157]11,109Various drugs No specific feature presentation of any drug under consideration
Lim, 2014 [158]1Various drugsNo presentation of specific features of DILI by 4 drugs used concomitantly or sequentially
Russo, 2014 [159]22StatinsNo individual feature description for DILI caused by various statins
Veluswamy, 2014 [160]1Polamidomide Feature presentation of DILI
Baig, 2015 [161]1RivaroxabanGood feature decription of this DILI case
Hammerstrom, 2015 [162]1Amblodipine Feature presentation of DILI caused by this drug
Stine, 2015 [163]2SimeprevirDetailed feature presentation of the DILI cases
Tang, 2015 [164] 1Bupropion, doxycyclineComplex feature presentation of DILI due to comedication
Unger, 2016 [165]1CiprofloxacinDetailed feature description of DILI by this single drug
Gharia, 2017 [166]1LetrozolePerfect feature presentation of DILI
Nicoletti, 2017 [167]339Various drugsNo specific feature details of DILI caused by individual drugs
Gayam, 2018 [168]3Various drugsFeature details of DILI by the drugs
Hayashi, 2018 [169]493Various drugsLacking specific feature details of DILI by individual drugs
Patel, 2018 [170]1EverolimusSpecific features described for DILI by this drug
Shamberg, 2018 [171]34Various drugsNo specific features of DILI caused by individual drugs presented
Cirulli, 2019 [172]268Various drugsFeature details of DILI by individual drugs not provided
Nicoletti, 2019 [173]197FlucloxacillinSpecific feature details of DILI by flucloxacillin were not provided
Sandritter, 2019 [174]1Various drugs No feature description of DILI by individual drugs
Shumar, 2019 [175]1MemantineDetailed feature description of DILI by this drug
Tsung, 2019 [176]70PembrolizumabFeatures described in detail for DILI caused by this drug
Xie, 2019 [177]1AnastrozoleFeature details of DILI presented
Ghabril, 2020 [178]551Various drugsNo feature details of DILI by individual drugs
Mullins, 2020 [179]99MicafunginFeature details presented of DILI by this drug
Abbreviations: CAMs, Causality Assessment Methods; DILI, Drug induced liver injury; NSAID, Non-steroidal anti-inflammatory drug; RUCAM, Roussel Uclaf Causality Assessment Method.
Table
Table 2. Top ranking of countries providing DILI cases assessed for causality by RUCAM.
Table 2. Top ranking of countries providing DILI cases assessed for causality by RUCAM.
Top Ranking
Countries		Cases,
n		References
1. China35,825[35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53]
2. United States20,311[147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179]
3. Germany10,907[64,65,66,67,68,69,70,71]
4. Korea6528[99,100,101,102,103,104]
5. Italy1562[83,84,85,86,87,88,89,90]
6. Sweden1508[126,127,128,129]
7. Spain1181[114,115,116,117,118,119,120,121,122,123,124,125]
8. Japan939[91,92,93,94,95,96,97,98]
9. Argentina625[23,24,25,26]
10.Thailand509[136,137,138]
11. India424[75,76,77,78,79,80,81]
12. Iceland367[72,73,74]
13. Pakistan264[108]
14. UK263[140,141,142,143,144,145,146]
15. France170[57,58,59,60,61,62,63]
16. Australia106[27,28,29,30]
17. Serbia99[111,112]
18. Egypt75[56]
19. Switzerland68[130,131,132,133,134,135]
20. Portugal53[109]
21. Bahrain25[31]
22. Colombia19[54]
23. Singapore14[113]
24. Brazil4[32]
25. Canada4[33,34]
26. Israel1[82]
27. Malaysia1[105]
28. Mexico1[106]
29. Morocco1[107]
30. Saudi Arabia1[110]
31. Turkey1[139]
Abbreviations: DILI, Drug induced liver injury; RUCAM, Roussel Uclaf Causality Assessment Method.
Table
Table 3. Worlwide top ranking of drugs causing DILI cases with causality assessment by RUCAM.
Table 3. Worlwide top ranking of drugs causing DILI cases with causality assessment by RUCAM.
DrugRUCAM Based DILI Cases (n)
1. Amoxicillin-clavulanate333
2. Flucloxacilllin130
3. Atorvastatin50
4. Disulfiram48
5. Diclofenac46
6. Simvastatin41
7. Carbamazepine38
8. Ibuprofen37
9. Erythromycin27
10. Anabolic steroids26
11. Phenytoin22
12. Sulfamethoxazole/Trimethoprim21
13. Isoniazid19
14. Ticlopidine19
15. Azathioprine/6-Mercaptopurine17
16. Contraceptives17
17. Flutamide17
18. Halothane15
19. Nimesulide13
20. Valproate13
21. Chlorpromazine11
22. Nitrofurantoin11
23. Methotrexate8
24. Rifampicin7
25. Sulfazalazine7
26. Pyrazinamide6
27. Gold salts5
28. Sulindac5
29. Amiodarone4
30. Interferon beta3
31. Propylthiouracil2
32. Allopurinol1
33. Hydralazine1
34. Infliximab1
35. Interferon alpha/Peginterferon1
36. Ketaconazole1
37. Busulfan0
38. Dantrolene0
39. Didanosine0
40. Efavirenz0
41. Floxuridine0
42. Methyldopa0
43. Minocycline0
44. Telithromycin0
45. Nevirapine0
46. Quinidine0
47. Sulfonamides0
48. Thioguanine0
Substantially modified from a previous report [70], which provides references for each implicated drug.
Table
Table 4. Worldwide countries with a selection of published HILI cases assessed for causality using RUCAM.
Table 4. Worldwide countries with a selection of published HILI cases assessed for causality using RUCAM.
Country/
HILI Cases, n		First Author/
Year		HILI Cases,
n		Herbal ProductsComments on RUCAM Based HILI Cases
Australia
n = 2		Smith, 2016 [181]1Garcinia CambogiaCareful feature detail description of HILI by this herb
Laube, 2019 [29]1GinsengFeature presentation of this single HILI case
Austria
n = 2		Stadlbauer, 2005 [182]2Various herbs contained in Tahitian NONI juiceFeatures described for these HILI cases
Brazil
n = 1		Barcelos, 2019 [183]1Senecio brasiliensisComplete feature description of HSOS caused by this herb
China
n = 10,914		Yuen, 2006 [184]7Various herbsNo specific feature description of HILI by individual herbs
Cheung, 2009 [185]3Psoralea corylifoliaWell described features of HILI cases
Chau, 2011 [186]27Various herbsLacking feature presentation of HILI by individual herbs
Lin, 2011 [187]1Gynura segetumPerfect feature presentation of HSOS
Gao, 2012 [188]5Gynura segetumExcellent feature description of HSOS
Lai, 2012 [189]74Various herbs
Polygonum multiflorum		Missing feature presentation of HILI by individual herbs
Dong, 2014 [190]18Various herbsGood feature presentation of HILI
Hao, 2014 [37]8PA containing herbsLacking feature presentation of HILI by individual herbs
Gao, 2015 [191]23Various herbsPerfect feature presentation of HSOS cases
Ou, 2015 [38]130Polygonum multiflorumNo feature description of HILI caused by the herb
Wang, 2015 [192]40 Polygonum multiflorumComprehensive feature description of HILI cases
Zhu, 2015 [193]158Polygonum multiflorum Detailed feature presentation of HILI cases
Zhang, 2016 [194]54Various herbsNo feature details described of HILI by individual herbs
Zhu, 2016 [42]866Various herbsMissing feature details of HILI caused by individual herbs
Li, 2017 [195]1Polygonum multiflorumExcellent description of feature details provided for HILI case
Chow, 2019 [196]1552Various herbsNo feature presentation of HILI by individual herbs but excellent listings
Jing, 2019 [197]145Polygonum multiflorumMissing feature presentation of HILI caused by individual herbs
Li, 2019 [198]1Psoralea corylifoliaPerfect feature presentation of HILI
Ni, 2019 [199]331Polygonum multiflorumFeature description of HILI cases
Shen, 2019 [48]6971Various herbsNo feature details presented for HILI by individual herbs
Tan, 2019 [200]3Swietenia macrophyllaPerfect presentation of feature details for these HILI cases
Zhu, 2019 [201]488Various herbsLacking feature details of HILI caused by individual herbs
Gao, 2020 [202]1PsoraleaFeature description of this HILI case
Xia, 2020 [203]7Swietenia macrophylla, syn skyfruitCareful description of HILI features
Colombia
n = 1		Cárdenas, 2006 [204]1Polygomun multiflorumFeatures well described for this HILI case
France
n = 10		Parlati, 2017 [205]10Aloe veraExcellent feature presentation of the HILI cases
Germany
n = 170		Teschke, 2009 [206]1Ayurveda herbs Complete feature presentation of the HILI case
Teschke, 2011 [207]22Chelidonium majus syn. Greater CelandineComplete feature description provided for HILI cases
Teschke, 2012 [208]21Chelidonium majus syn. Greater CelandineThorough features presented of HILI cases
Douros, 2015 [209]10Various herbsNo detailed features reported of HILI caused by individual herbs
Teschke, 2015 [210]12Camellia sinensis, syn. Green tea, or Lu Cha Feature details presented of HILI cases
Melchart, 2017 [211]26Herbal TCMsWell described features of HILI caused by individual TCM herbs
Diener, 2018 [212]10Petasites hybridusProvided features of HILI by this herb
Anderson, 2019 [213]48Petasites hybridusDescription of HILI features
Gerhardt, 2019 [214]1Chelidonium majus, syn. Greater Celandine HILI features described
Teschke, 2019 [215]19Camellia sinensisCareful feature presentation of HILI cases
India
n = 117		Philips, 2018 [216]94Ayurvedic and other herbs Features not individually described for HILI by various herbs
Philips, 2019 [217]17Various herbs No detailed features presented for HILI cases by individual herbs
Italy
n = 77		Lapi, 2010 [218]1Serenoa repensDetailed feature presentation of HILI
Mazzanti, 2015 [219]19Camellia sinensis, syn. green teaCareful feature description of HILI cases
Sáez-González, 2016 [220]1Chelidonium majusFeature details of the HILI case
Mazzanti, 2017 [221]55Red yeast riceThorough feature presentation of HILI
Osborne, 2019 [222]1Mitragyna speciosa, syn. KratonIndividual feature details not provided for the HILI case
Japan
n = 3		Tsuda, 2010 [223]1SaireitoPerfect feature details presented for the HILI case
Hisamochi, 2013 [224]2Agaricus blazei MurillExcellent presentation of HILI features
Korea
n = 2507		Ahn, 2004 [225]64Various herbsMissing feature presentation of HILI by individual herbs
Seo, 2006 [226]17Various herbsNo individual feature description of HILI by specific herbs
Kang, 2008 [227]66Various herbsLacking feature details of HILI by individual herbs
Sohn, 2008 [228]24Various herbsFeature details of HILI by individual herbs not provided
Kang, 2009 [229]1Corydalis speciosaPerfect feature details provided for this single HILI
Kim, 2009 [230]2Arrowroot, syn. ge GenExcellent presentation of features for these HILI cases
Bae, 2010 [231]1Polygonum multiflorumCareful feature details presented for this HILI case
Yang, 2010 [232]3Aloe vera or arborescensThorough description of features of these HILI cases
Jung, 2011 [233] 25PolygonumExcellent feature presentation of the HILI cases
Kim, 2012 [234]1multiflorumPerfect feature description for this HILI case
Suk, 2012 [100]149Hovenia dulcis, syn. JugujuNo feature description of HILI caused by individual herbs
Lee, 2015 [235]27Various herbsLacking feature details of HILI caused by individual herbs
Lee, 2015 [236]97Various herbsFeature details of HILI cases caused by individual herbs were not provided
Woo, 2015 [102]5Various herbsNo feature details presented for HILI by individual herbs
Cho, 2017 [237]6Various herbsMissing feature details of HILI cases by individual herbs
Byeon, 2019 [103]2019Various herbsNo detailed feature description of HILI by individual herbs
Singapore
n = 25		Wai, 2006 [113]15Various herbsNo detailed features presented for HILI cases by individual herbs
Teo, 2016 [238]10Various herbsMissing feature details of HILI cases
South Africa
n = 47		Awortwe, 2018 [239]47Various herbsFeatures were not provided for cases of HILI caused by individual herbs
Spain
n = 46		Andrade, 2005 [115]9Various herbsNo feature details of HILI by individual herbs
Jimenez-Saenz, 2006 [240]1Camellia sinensisFeature details presented for this HILI case
García-Cortés, 2008 [241]13Various herbsLacking feature details of HILI caused by individual herbs
García-Cortés, 2008 [117]5Various herbsSpecific feature details of HILI by individual herbs not provided
Medina-Caliz, 2018 [242]18Camellia sinensis and other herbsNo specific feature details provided for HILI
Sweden
n = 5		Björnsson, 2007 [243]5Camellia sinensisFeature details provided for HILI cases
Switzerland
n = 1		Ruperti-Repilado, 2019 [244]1Artemisia annuaCareful feature presentation of this HILI case
Turkey
n = 1		Yilmaz, 2015 [245]1Lesser Celandine, syn. PilewortExcellent feature presentation of the HILI case
United States
n = 100		Papafragkakis, 2016 [246]1Chinese skullcap plus Black catechuPerfect feature presentation of this HILI case
Dalal, 2017 [247]1Ayurvedic herbSpecific case features described
Kesavarapu, 2017 [248]1Yogi Detox tea with multiple herbsIndividual specific features not provided for this HILI case caused specifically by a single herb
Kothadia, 2018 [249]19Garcinia CambogiaCareful feature presentation of HILI cases
Surapaneni, 2018 [250]19Camellia sinensisFeature details provided for the HILI case
Imam, 2019 [251]1CurcuminThorough feature description of the HILI case
Yousaf, 2019 [252]9Garcinia CambogiaExcellent feature description of the HILI case
Oketch-Rabah, 2020 [253]29Camellia sinensis extractPerfect feature presentation of HILI by this herb
Schimmel, 2020 [254]20Mitragyna speciosa, syn. KratonFeature details provided for HILI cases
Abbreviations: DILI, Drug induced liver injury; HILI, Herb induced liver injury; HSOS, Hepatic sinusoidal obstruction syndrome; RUCAM, Roussel Uclaf Causality Assessment Method, TCM, Traditional Chinese Medicines; USP, United States Pharmacopeia; WHO, World Health Organizations.
Table
Table 5. Top ranking of countries providing HILI cases assessed for causality by RUCAM.
Table 5. Top ranking of countries providing HILI cases assessed for causality by RUCAM.
Top Ranking
Countries		Cases,
n		References
1. China10,914[37,38,42,48,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203]
2. Korea2507[100,101,102,103,225,226,227,228,229,230,231,232,233,234,235,236,237]
3. Germany170[206,207,208,209,210,211,212,213,214,215]
4. India117[216,217]
5. US100[247,248,249,250,251,252,253,254,255]
6. Italy77[218,219,220,221,222]
7. South Africa47[239]
8. Spain46[115,117,240,241,242]
9. Singapore25[113,238]
10. France10[205]
11. Sweden5[244]
12. Japan3[223,224]
13. Australia2[29,181]
14. Austria2[182]
15. Brazil1[183]
16. Colombia1[204]
17. Switzerland1[245]
18. Turkey1[246]
Abbreviations: HILI, Herb induced liver injury; RUCAM, Roussel Uclaf Causality Assessment Method.
Table
Table 6. Characteristics of RUCAM.
Table 6. Characteristics of RUCAM.
RUCAM Specificities
Basic features
  • Validated method (gold standard) based on cases with positive reexposure test results, providing thereby a robust CAM
  • Worldwide use with 46,266 DILI cases assessed by RUCAM published 2014–2019, outperforming thereby any other CAM in term of number of cases published
  • Assesses causality in DILI and HILI cases validly and reproducibly
  • A typical intelligent diagnostic algorithm in line with artificial intelligence (AI) concepts
  • A diagnostic algorithm for objective, robust causality assessment
  • Assessment is user friendly, cost effective with results available in time and without needing expert rounds that often provide subjective and fragile, arbitrary opinions based on own experience
  • Transparency of case data and clear result presentation
  • Suitable for reevaluation by peers and any of other interested parties such as national regulatory agencies international registries, and pharma companies
  • Mandatory application for DILI cases if to be used for establishing new robust diagnostic biomarkers
  • High causality gradings with complete data
  • With prospective case data collection best results are obtainable
Clearly defined and scored key elements
  • Time frame of latency period
  • Time frame of dechallenge
  • Recurrent ALT or ALP increase
  • Risk factors
  • Individual comedications
  • Exclusion of alternative causes
  • Markers of HAV, HBV, HCV, HEV
  • Markers of CMV, EBV, HSV, VZV
  • Cardiac hepatopathy and other alternative causes
  • Liver and biliary tract imaging
  • Doppler sonography of liver vessels
  • Prior known hepatotoxicity of drug or herb
  • Unintentional reexposure
Other important specificities
  • Laboratory based hepatotoxicity criteria
  • Laboratory based liver injury pattern
  • Hepatotoxicity specific method
  • Structured, liver related method
  • Quantitative, liver related method, based on scored key elements
Abbreviations: AI: Artificial Intelligence; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; CAM: Causality assessment method; CMV: Cytomegalovirus; DILI: Drug induced liver injury; EBV: Epstein Barr virus; HAV: Hepatitis A virus; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HEV: Hepatitis E virus; HILI: herb induced liver injury; HSV: Herpes simplex virus; RUCAM: Roussel Uclaf Causality Assessment Method; VZV: Varicella zoster virus.

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MDPI and ACS Style

Teschke, R.; Danan, G. Worldwide Use of RUCAM for Causality Assessment in 81,856 Idiosyncratic DILI and 14,029 HILI Cases Published 1993–Mid 2020: A Comprehensive Analysis. Medicines 2020, 7, 62. https://0-doi-org.brum.beds.ac.uk/10.3390/medicines7100062

AMA Style

Teschke R, Danan G. Worldwide Use of RUCAM for Causality Assessment in 81,856 Idiosyncratic DILI and 14,029 HILI Cases Published 1993–Mid 2020: A Comprehensive Analysis. Medicines. 2020; 7(10):62. https://0-doi-org.brum.beds.ac.uk/10.3390/medicines7100062

Chicago/Turabian Style

Teschke, Rolf, and Gaby Danan. 2020. "Worldwide Use of RUCAM for Causality Assessment in 81,856 Idiosyncratic DILI and 14,029 HILI Cases Published 1993–Mid 2020: A Comprehensive Analysis" Medicines 7, no. 10: 62. https://0-doi-org.brum.beds.ac.uk/10.3390/medicines7100062

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