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Special Issue "Drug, Herb, and Dietary Supplement Hepatotoxicity"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (29 February 2016).

Special Issue Editors

Prof. Dr. Rolf Teschke
E-Mail Website
Guest Editor
Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Teaching Hospital of the Goethe University Frankfurt/Main, Germany
Tel. +49-6181/21859
Interests: alcoholic liver disease; alcoholic liver injury; alcohol metabolism; microsomal ethanol-oxidizing system; drug induced liver injury; herb induced liver injury; herbal traditional Chinese medicine (TCM); dietary supplements; causality assessment
Special Issues and Collections in MDPI journals
Dr. Raúl J. Andrade
E-Mail Website
Guest Editor
Liver Unit Gastroenterology Service, Institute for Biomedical Research of Malaga (IBIMA), Virgen de la Victoria University Hospital and School of Medicine, Malaga, Spain; “Centro de Investigación Biomédica en Red de Enfermedades Digestivas y Hepáticas” (CIBERehd), Spain
Interests: drug induced liver injury; pharmacogenomics; toxicogenomics; causality assessment; dietary supplements; regulatory issues

Special Issue Information

Dear Colleagues,

Drugs, herbs, and dietary supplements share the common feature of potential hepatotoxicity in a few susceptible individuals. Most of these hepatotoxic reactions are idiosyncratic and, hence, difficult to predict. Treatment commonly consists of the cessation of the incriminated product, but causality attribution may be cumbersome due to the current absence of valid diagnostic biomarkers. To aid diagnosis in hepatotoxicity cases, diagnostic tools are available, such as the CIOMS (Council for International Organization of Medical Sciences) scale, which is also called RUCAM (Rousell Uclaf Causality Assessing Method) and is based on specific diagnostic items with individual scoring, and the DILIN (Drug Induced Liver Injury Network) method, which is expert based. Whereas hepatotoxicity by synthetic drugs is fairly well recognized in clinical practice, hepatoxicity by herbs, herbal drugs, and dietary supplements are rarely suspected. The aim of this Special Issue is to provide a broad overview on these hepatotoxicity entities with their challenges and highlights. We therefore ask experts in the field to contribute their views on this emerging and fascinating topic. Since various topics are still controversial and disputed, we expect and appreciate lively discussions, in addition to well-settled issues, which are relevant to the clinical setting and require balanced statements.

Prof. Dr. Rolf Teschke
Prof. Dr. Raúl J. Andrade
Guest Editors

Manuscript Submission Information

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Keywords

  • Drug induced liver injury
  • Drug hepatotoxicity
  • Herb induced liver injury
  • Herbal hepatotoxicity
  • Liver injury by dietary supplements
  • Hepatotoxicity
  • Drugs
  • Herbs
  • Herbal traditional Chines medicine
  • Dietary supplements
  • Pharmacogenomics
  • Toxicogenomics
  • Prognosis
  • Chronicity

Published Papers (13 papers)

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Editorial

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Open AccessEditorial
Drug, Herb, and Dietary Supplement Hepatotoxicity
Int. J. Mol. Sci. 2016, 17(9), 1488; https://doi.org/10.3390/ijms17091488 - 06 Sep 2016
Cited by 13
Abstract
The past decade has witnessed drugs, herbs, and dietary supplements share the common feature of potential liver injury in a few susceptible individuals.[...] Full article
(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)

Research

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Open AccessArticle
Herb-Induced Liver Injury in the Berlin Case-Control Surveillance Study
Int. J. Mol. Sci. 2016, 17(1), 114; https://doi.org/10.3390/ijms17010114 - 15 Jan 2016
Cited by 14
Abstract
Herb-induced liver injury (HILI) has recently attracted attention due to increasing reports of hepatotoxicity associated with use of phytotherapeutics. Here, we present data on HILI from the Berlin Case-Control Surveillance Study. The study was initiated in 2000 to investigate the serious toxicity of [...] Read more.
Herb-induced liver injury (HILI) has recently attracted attention due to increasing reports of hepatotoxicity associated with use of phytotherapeutics. Here, we present data on HILI from the Berlin Case-Control Surveillance Study. The study was initiated in 2000 to investigate the serious toxicity of drugs including herbal medicines. Potential cases of liver injury were ascertained in more than 180 Departments of all 51 Berlin hospitals from October 2002 to December 2011. Drug or herb intake was assessed through a standardized face-to-face interview. Drug or herbal aetiology was assessed based on the updated Council for International Organizations of Medical Sciences scale. In ten of all 198 cases of hepatotoxicity included in the study, herbal aetiology was assessed as probable (once ayurvedic herb) or possible (Valeriana five times, Mentha piperita once, Pelargonium sidoides once, Hypericum perforatum once, Eucalyptus globulus once). Mean age was 56.4 ± 9.7 years, and the predominant pattern of liver injury was hepatocellular. No cases of acute liver failure or death were observed. This case series corroborates known risks for ayurvedic herbs, supports the suspected association between Valeriana use and liver injury, and indicates a hepatotoxic potential for herbs such as Pelargonium sidoides, Hypericum perforatum or Mentha piperita that were rarely associated with liver injury before. However, given that possible causality does not prove clinical significance, further studies in this field are needed. Full article
(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)
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Review

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Open AccessReview
Case Characterization, Clinical Features and Risk Factors in Drug-Induced Liver Injury
Int. J. Mol. Sci. 2016, 17(5), 714; https://doi.org/10.3390/ijms17050714 - 12 May 2016
Cited by 25
Abstract
Idiosyncratic drug-induced liver injury (DILI) caused by xenobiotics (drugs, herbals and dietary supplements) presents with a range of both phenotypes and severity, from acute hepatitis indistinguishable of viral hepatitis to autoimmune syndromes, steatosis or rare chronic vascular syndromes, and from asymptomatic liver test [...] Read more.
Idiosyncratic drug-induced liver injury (DILI) caused by xenobiotics (drugs, herbals and dietary supplements) presents with a range of both phenotypes and severity, from acute hepatitis indistinguishable of viral hepatitis to autoimmune syndromes, steatosis or rare chronic vascular syndromes, and from asymptomatic liver test abnormalities to acute liver failure. DILI pathogenesis is complex, depending on the interaction of drug physicochemical properties and host factors. The awareness of risk factors for DILI is arising from the analysis of large databases of DILI cases included in Registries and Consortia networks around the world. These networks are also enabling in-depth phenotyping with the identification of predictors for severe outcome, including acute liver failure and mortality/liver transplantation. Genome wide association studies taking advantage of these large cohorts have identified several alleles from the major histocompatibility complex system indicating a fundamental role of the adaptive immune system in DILI pathogenesis. Correct case definition and characterization is crucial for appropriate phenotyping, which in turn will strengthen sample collection for genotypic and future biomarkers studies. Full article
(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)
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Open AccessReview
Herbal Hepatotoxicity: Clinical Characteristics and Listing Compilation
Int. J. Mol. Sci. 2016, 17(5), 588; https://doi.org/10.3390/ijms17050588 - 27 Apr 2016
Cited by 40
Abstract
Herb induced liver injury (HILI) and drug induced liver injury (DILI) share the common characteristic of chemical compounds as their causative agents, which were either produced by the plant or synthetic processes. Both, natural and synthetic chemicals are foreign products to the body [...] Read more.
Herb induced liver injury (HILI) and drug induced liver injury (DILI) share the common characteristic of chemical compounds as their causative agents, which were either produced by the plant or synthetic processes. Both, natural and synthetic chemicals are foreign products to the body and need metabolic degradation to be eliminated. During this process, hepatotoxic metabolites may be generated causing liver injury in susceptible patients. There is uncertainty, whether risk factors such as high lipophilicity or high daily and cumulative doses play a pathogenetic role for HILI, as these are under discussion for DILI. It is also often unclear, whether a HILI case has an idiosyncratic or an intrinsic background. Treatment with herbs of Western medicine or traditional Chinese medicine (TCM) rarely causes elevated liver tests (LT). However, HILI can develop to acute liver failure requiring liver transplantation in single cases. HILI is a diagnosis of exclusion, because clinical features of HILI are not specific as they are also found in many other liver diseases unrelated to herbal use. In strikingly increased liver tests signifying severe liver injury, herbal use has to be stopped. To establish HILI as the cause of liver damage, RUCAM (Roussel Uclaf Causality Assessment Method) is a useful tool. Diagnostic problems may emerge when alternative causes were not carefully excluded and the correct therapy is withheld. Future strategies should focus on RUCAM based causality assessment in suspected HILI cases and more regulatory efforts to provide all herbal medicines and herbal dietary supplements used as medicine with strict regulatory surveillance, considering them as herbal drugs and ascertaining an appropriate risk benefit balance. Full article
(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)
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Open AccessReview
Hepatotoxicity Induced by “the 3Ks”: Kava, Kratom and Khat
Int. J. Mol. Sci. 2016, 17(4), 580; https://doi.org/10.3390/ijms17040580 - 16 Apr 2016
Cited by 33
Abstract
The 3Ks (kava, kratom and khat) are herbals that can potentially induce liver injuries. On the one hand, growing controversial data have been reported about the hepatotoxicity of kratom, while, on the other hand, even though kava and khat hepatotoxicity has been investigated, [...] Read more.
The 3Ks (kava, kratom and khat) are herbals that can potentially induce liver injuries. On the one hand, growing controversial data have been reported about the hepatotoxicity of kratom, while, on the other hand, even though kava and khat hepatotoxicity has been investigated, the hepatotoxic effects are still not clear. Chronic recreational use of kratom has been associated with rare instances of acute liver injury. Several studies and case reports have suggested that khat is hepatotoxic, leading to deranged liver enzymes and also histopathological evidence of acute hepatocellular degeneration. Numerous reports of severe hepatotoxicity potentially induced by kava have also been highlighted, both in the USA and Europe. The aim of this review is to focus on the different patterns and the mechanisms of hepatotoxicity induced by “the 3Ks”, while trying to clarify the numerous aspects that still need to be addressed. Full article
(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)
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Open AccessReview
Hepatotoxicity by Dietary Supplements: A Tabular Listing and Clinical Characteristics
Int. J. Mol. Sci. 2016, 17(4), 537; https://doi.org/10.3390/ijms17040537 - 09 Apr 2016
Cited by 36
Abstract
Dietary supplements (DS) are extensively consumed worldwide despite unproven efficacy. The true incidence of DS-induced liver injury (DSILI) is unknown but is probably under-diagnosed due to the general belief of safety of these products. Reported cases of herbals and DS-induced liver injury are [...] Read more.
Dietary supplements (DS) are extensively consumed worldwide despite unproven efficacy. The true incidence of DS-induced liver injury (DSILI) is unknown but is probably under-diagnosed due to the general belief of safety of these products. Reported cases of herbals and DS-induced liver injury are increasing worldwide. The aim of this manuscript is to report a tabular listing with a description of DS associated with hepatotoxicity as well as review the phenotype and severity of DSILI. Natural remedies related to hepatotoxicity can be divided into herbal product-induced liver injury and DS-induced liver injury. In this article, we describe different DS associated with liver injury, some of them manufactured DS containing several ingredients (Herbalife™ products, Hydroxycut™, LipoKinetix™, UCP-1 and OxyELITE™) while others have a single ingredient (green tea extract, linoleic acid, usnic acid, 1,3-Dimethylamylamine, vitamin A, Garcinia cambogia and ma huang). Additional DS containing some of the aforementioned ingredients implicated in liver injury are also covered. We have also included illicit androgenic anabolic steroids for bodybuilding in this work, as they are frequently sold under the denomination of DS despite being conventional drugs. Full article
(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)
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Open AccessReview
The Honolulu Liver Disease Cluster at the Medical Center: Its Mysteries and Challenges
Int. J. Mol. Sci. 2016, 17(4), 476; https://doi.org/10.3390/ijms17040476 - 31 Mar 2016
Cited by 19
Abstract
In 2013, physicians at the Honolulu Queen’s Medical Center (QMC) noticed that seven liver disease patients reported the use of OxyELITE Pro (OEP), a widely consumed dietary supplement (DS). Assuming a temporal association between OEP use and disease, they argued that OEP was [...] Read more.
In 2013, physicians at the Honolulu Queen’s Medical Center (QMC) noticed that seven liver disease patients reported the use of OxyELITE Pro (OEP), a widely consumed dietary supplement (DS). Assuming a temporal association between OEP use and disease, they argued that OEP was the cause of this mysterious cluster. Subsequent reexamination, however, has revealed that this QMC cohort is heterogeneous and not a cluster with a single agent causing a single disease. It is heterogeneous because patients used multiple DS’s and drugs and because patients appeared to have suffered from multiple liver diseases: liver cirrhosis, liver failure by acetaminophen, hepatotoxicity by non-steroidal antiinflammatory drugs (NSAIDs), resolving acute viral hepatitis by hepatitis B virus (HBV), herpes simplex virus (HSV), and varicella zoster virus (VZV), and suspected hepatitis E virus (HEV). Failing to exclude these confounders and to consider more viable diagnoses, the QMC physicians may have missed specific treatment options in some of their patients. The QMC physicians unjustifiably upgraded their Roussel Uclaf Causality Assessment Method (RUCAM) causality scores so that all patients would appear to be “probable” for OEP. However, subsequent RUCAM reassessments by our group demonstrated a lack of causality for OEP in the evaluated QMC cases. The QMC’s questionable approaches explain the extraordinary accumulation of suspected OEP cases at the QMC in Hawaii as single place, whereas similar cohorts were not published by any larger US liver center, substantiating that the problem is with the QMC. In this review article, we present and discuss new case data and critically evaluate upcoming developments of problematic regulatory assessments by the US Centers for Disease Control and Prevention (CDC), the Hawaii Department of Health (HDOH), and the Food and Drug Administration (FDA), as based on invalid QMC conclusions, clarifying now also basic facts and facilitating constructive discussions. Full article
(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)
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Open AccessReview
Scientific and Regulatory Perspectives in Herbal and Dietary Supplement Associated Hepatotoxicity in the United States
Int. J. Mol. Sci. 2016, 17(3), 331; https://doi.org/10.3390/ijms17030331 - 03 Mar 2016
Cited by 38
Abstract
In the United States (US), the risk of hepatotoxicity linked to the widespread use of certain herbal products has gained increased attention among regulatory scientists. Based on current US law, all dietary supplements sold domestically, including botanical supplements, are regulated by the Food [...] Read more.
In the United States (US), the risk of hepatotoxicity linked to the widespread use of certain herbal products has gained increased attention among regulatory scientists. Based on current US law, all dietary supplements sold domestically, including botanical supplements, are regulated by the Food and Drug Administration (FDA) as a special category of foods. Under this designation, regulatory scientists do not routinely evaluate the efficacy of these products prior to their marketing, despite the content variability and phytochemical complexity that often characterizes them. Nonetheless, there has been notable progress in the development of advanced scientific methods to qualitatively and quantitatively measure ingredients and screen for contaminants and adulterants in botanical products when hepatotoxicity is recognized. Full article
(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)
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Open AccessReview
The Latin American DILI Registry Experience: A Successful Ongoing Collaborative Strategic Initiative
Int. J. Mol. Sci. 2016, 17(3), 313; https://doi.org/10.3390/ijms17030313 - 29 Feb 2016
Cited by 22
Abstract
Drug induced liver injury (DILI) is a rare but well recognized serious adverse reaction. Pre-marketing studies may not detect liver injury, and DILI becomes very often apparent after the drug is launched to the market. Specific biomarkers for DILI prediction or diagnosis are [...] Read more.
Drug induced liver injury (DILI) is a rare but well recognized serious adverse reaction. Pre-marketing studies may not detect liver injury, and DILI becomes very often apparent after the drug is launched to the market. Specific biomarkers for DILI prediction or diagnosis are not available. Toxic liver reactions present with a wide spectrum of phenotypes and severity, and our knowledge on the mechanisms underlying idiosyncratic reactions and individual susceptibility is still limited. To overcome these limitations, country-based registries and multicenter research networks have been created in Europe and North America. Reliable epidemiological data on DILI in Latin America (LA), a region with a large variety of ethnic groups, were however lacking. Fortunately, a LA network of DILI was set up in 2011, with the support of the Spanish DILI Registry from the University of Malaga. The primary aim of the Latin DILI Network (LATINDILIN) Registry was to prospectively identify bona fide DILI cases and to collect biological samples to study genetic biomarkers. Physicians involved in the project must complete a structured report form describing the DILI case presentation and follow-up which is submitted to a Coordinator Center in each country, where it is further assessed for completeness. During the last four years, several LA countries (Argentina, Uruguay, Chile, Mexico, Paraguay, Brazil, Ecuador, Peru, Venezuela and Colombia) have joined the network and committed with this project. At that point, to identify both our strengths and weaknesses was a very important issue. In this review, we will describe how the LATINDILI Registry was created. The aims and methods to achieve these objectives will be discussed in depth. Additionally, both the difficulties we have faced and the strategies to solve them will be also pinpointed. Finally, we will report on our preliminary results, and discuss ideas to expand and to keep running this network. Full article
(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)
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Open AccessReview
Herbal Medicine in Mexico: A Cause of Hepatotoxicity. A Critical Review
Int. J. Mol. Sci. 2016, 17(2), 235; https://doi.org/10.3390/ijms17020235 - 15 Feb 2016
Cited by 19
Abstract
In Mexico, herbal products are commonly used as therapeutic tools. The analysis of several publications reveals that there are dozens of different herbs and herbal products used for different reasons, some of which have been implicated in causing toxic liver disease. However, methodological [...] Read more.
In Mexico, herbal products are commonly used as therapeutic tools. The analysis of several publications reveals that there are dozens of different herbs and herbal products used for different reasons, some of which have been implicated in causing toxic liver disease. However, methodological aspects limit the attribution of causality, and the precise incidence and clinical manifestations of herb-induced liver injury have not been well characterized. This review outlines the history of traditional herbal medicine in Mexico, critically summarizes the mechanisms and adverse effects of commonly used herbal plants, and examines the regulatory issues regarding the legal use of these products. Full article
(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)
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Open AccessReview
Hepatotoxicity by Drugs: The Most Common Implicated Agents
Int. J. Mol. Sci. 2016, 17(2), 224; https://doi.org/10.3390/ijms17020224 - 06 Feb 2016
Cited by 48
Abstract
Idiosyncratic drug-induced liver injury (DILI) is an underreported and underestimated adverse drug reaction. Information on the documented hepatotoxicity of drugs has recently been made available by a website that can be accessed in the public domain: LiverTox (http://livertox.nlm.nih.gov). According to critical analysis of [...] Read more.
Idiosyncratic drug-induced liver injury (DILI) is an underreported and underestimated adverse drug reaction. Information on the documented hepatotoxicity of drugs has recently been made available by a website that can be accessed in the public domain: LiverTox (http://livertox.nlm.nih.gov). According to critical analysis of the hepatotoxicity of drugs in LiverTox, 53% of drugs had at least one case report of convincing reports of liver injury. Only 48 drugs had more than 50 case reports of DILI. Amoxicillin-clavulanate is the most commonly implicated agent leading to DILI in the prospective series. In a recent prospective study, liver injury due to amoxicillin-clavulanate was found to occur in approximately one out of 2300 users. Drugs with the highest risk of DILI in this study were azathioprine and infliximab. Full article
(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)
Open AccessReview
Drug-Induced Liver Injury Network Causality Assessment: Criteria and Experience in the United States
Int. J. Mol. Sci. 2016, 17(2), 201; https://doi.org/10.3390/ijms17020201 - 04 Feb 2016
Cited by 28
Abstract
Hepatotoxicity due to drugs, herbal or dietary supplements remains largely a clinical diagnosis based on meticulous history taking and exclusion of other causes of liver injury. In 2004, the U.S. Drug-Induced Liver Injury Network (DILIN) was created under the auspices of the U.S. [...] Read more.
Hepatotoxicity due to drugs, herbal or dietary supplements remains largely a clinical diagnosis based on meticulous history taking and exclusion of other causes of liver injury. In 2004, the U.S. Drug-Induced Liver Injury Network (DILIN) was created under the auspices of the U.S. National Institute of Diabetes and Digestive and Kidney Diseases with the aims of establishing a large registry of cases for clinical, epidemiological and mechanistic study. From inception, the DILIN has used an expert opinion process that incorporates consensus amongst three different DILIN hepatologists assigned to each case. It is the most well-established, well-described and vigorous expert opinion process for DILI to date, and yet it is an imperfect standard. This review will discuss the DILIN expert opinion process, its strengths and weaknesses, psychometric performance and future. Full article
(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)
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Open AccessReview
RUCAM in Drug and Herb Induced Liver Injury: The Update
Int. J. Mol. Sci. 2016, 17(1), 14; https://doi.org/10.3390/ijms17010014 - 24 Dec 2015
Cited by 139
Abstract
RUCAM (Roussel Uclaf Causality Assessment Method) or its previous synonym CIOMS (Council for International Organizations of Medical Sciences) is a well established tool in common use to quantitatively assess causality in cases of suspected drug induced liver injury (DILI) and herb induced liver [...] Read more.
RUCAM (Roussel Uclaf Causality Assessment Method) or its previous synonym CIOMS (Council for International Organizations of Medical Sciences) is a well established tool in common use to quantitatively assess causality in cases of suspected drug induced liver injury (DILI) and herb induced liver injury (HILI). Historical background and the original work confirm the use of RUCAM as single term for future cases, dismissing now the term CIOMS for reasons of simplicity and clarity. RUCAM represents a structured, standardized, validated, and hepatotoxicity specific diagnostic approach that attributes scores to individual key items, providing final quantitative gradings of causality for each suspect drug/herb in a case report. Experts from Europe and the United States had previously established in consensus meetings the first criteria of RUCAM to meet the requirements of clinicians and practitioners in care for their patients with suspected DILI and HILI. RUCAM was completed by additional criteria and validated, assisting to establish the timely diagnosis with a high degree of certainty. In many countries and for more than two decades, physicians, regulatory agencies, case report authors, and pharmaceutical companies successfully applied RUCAM for suspected DILI and HILI. Their practical experience, emerging new data on DILI and HILI characteristics, and few ambiguous questions in domains such alcohol use and exclusions of non-drug causes led to the present update of RUCAM. The aim was to reduce interobserver and intraobserver variability, to provide accurately defined, objective core elements, and to simplify the handling of the items. We now present the update of the well accepted original RUCAM scale and recommend its use for clinical, regulatory, publication, and expert purposes to validly establish causality in cases of suspected DILI and HILI, facilitating a straightforward application and an internationally harmonized approach of causality assessment as a common basic tool. Full article
(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)
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