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Cited by 15Drug-Induced Hepatotoxicity and ProtectionPharmacovigilance and Adverse Drug ReactionsDrug-Induced Adverse Reactions

The DOI matches its Crossref record; 63 of the 63 references it cites were found in a registry or an index; 2 of the 69 sources its claims cite were checked for support.

Methods for causality assessment of idiosyncratic drug‐induced liver injury

Open access
García‐Cortés, Miren, Matilla‐Cabello, Gonzalo, Lucena, M. Isabel·2025·Liver International
DOI 10.1111/liv.16083PMC PMC11815608
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Abstract

The diagnosis of idiosyncratic drug‐induced liver injury (DILI) is a challenging task due to the lack of specific features or definitive diagnostic tools. A minimum of clinical and pharmacological information is required, together with laboratory and imaging tests to exclude other causes of liver injury. Several standardized methods have been developed to support clinical judgement and establish causality assessment, the most widely used being the Roussel Uclaf Causality Assessment Method—RUCAM—and structured Expert Opinion. More recently, an evidence‐based, revised RUCAM, Electronic Causality Assessment Method—RECAM—has been developed and, although still a work in progress, may replace RUCAM scoring in the future. International collaborative networks and ongoing research efforts are key to advancing biomarker qualification and validation and developing new in vitro patient‐based methods that will help improve DILI diagnosis and move towards a personalized medicine approach.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes causality assessment methods for idiosyncratic drug-induced liver injury (DILI), focusing on RUCAM, structured expert opinion, and the newer RECAM. It concludes that no single tool captures all DILI phenotypes and that RECAM and expert opinion are currently the most reliable, pending further validation and biomarker development.

Key findings

  • DILI is rare but serious: 14–19 cases per 100,000 population/year, with progression to death or liver transplantation in 4%–10% and chronicity in 8%–17%.
  • RUCAM remains widely used; in 49 published DILI cases with positive rechallenge and 28 controls it showed sensitivity 86%, specificity 89%, positive predictive value 93%, and negative predictive value 78%, but it has ambiguous instructions, arbitrary weighting, and is not suited to herbal and dietary supplements (HDS).
  • RECAM condenses RUCAM into four domains plus a fifth for additional data; in 194 DILI cases from Spanish and DILIN registries, RECAM had better overall agreement with expert opinion (.62 vs. .56 weighted kappa, p = .14) and greater sensitivity at diagnostic extremes, and in 481 DILI plus 100 non-DILI Chinese cases it had higher AUC than RUCAM (.947 vs. .867, p = .0016).
  • A Japanese-adapted RECAM 2023, without deduction for missing hepatitis virus markers, increased highly probable/probable cases from 206/538 (38%) to 421/538 (78%); structured expert opinion is preferred for clinical drug development and atypical DILI but remains subjective and not externally validated.

Methods

  • Narrative review of published causality assessment methods, clinical practice guidelines and position papers, and registry-based comparative studies; no primary patient cohort or new statistical analysis is reported.
  • Synthesizes general adverse drug reaction tools (Naranjo, WHO-UMC), liver-specific tools (RUCAM, Clinical Diagnostic Scale, DDW-J, DILI-CAT, RECAM/RECAM-J), expert opinion processes, and biomarker/in vitro approaches.
  • Reports selected validation and comparison statistics from cited studies, including the Spanish DILI Registry, US DILIN, and Chinese hospital cohorts.

Limitations

  • Stated: there is no gold standard for DILI diagnosis; causality methods cannot replace clinical judgment; no single instrument captures all DILI presentations, especially HDS/multi-ingredient products.
  • Stated: RUCAM has ambiguous instructions, arbitrary weighting, limited applicability to HDS, and inter-/intra-observer variability; RECAM is still a work in progress, has not been tested outside the US and Spain or in HDS cases, and its intra- and inter-rater reliability remains unknown; expert opinion is subjective, has limited reproducibility, and is not externally validated.
  • Evident: as a narrative review, the paper does not report a systematic search strategy, inclusion criteria, or formal quality appraisal of the cited studies.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1111/liv.16083

Cites

63 of 63 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

2 of 69 cited sources checked · 0 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    RECAM was redesigned using data from DILI cases due to single drugs included in prospective registries and, where necessary, expert opinion and literature information.

    “This method was redesigned using data from DILI cases due to single drugs included in these prospective registries and, where necessary, expert opinion and literature information.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Hayashi PH, Lucena MI, Fontana RJ, et al. A revised electronic version of RUCAM for the diagnosis of DILI. Hepatology. 2022; 76(1): 18‐ 31. 35014066 PMC9233102 source
  • Premisecitation

    There is a lack of pathognomonic biochemical parameters, histopathological picture or imaging findings for DILI.

    “and that there is a lack of pathognomonic biochemical parameters, histopathological picture or imaging findings.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] European Association for the Study of the Liver, Andrade RJ, Aithal GP, Bjornsson ES. EASL clinical practice guidelines: drug‐induced liver injury. J Hepatol. 2019; 70(6): 1222‐ 1261. 30926241
  • Premisecitation

    RECAM and RUCAM were applicable not only for conventional drugs but also for herb-induced liver injury.

    “RECAM and RUCAM were also applicable for not only conventional drugs but also herb‐induced liver injury.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Zhao X, Wang Y, Lai R, et al. Validation of the revised electronic version of RUCAM for diagnosis of DILI in Chinese patients. Hepatol Commun. 2024; 8(4): e0235. 38466883 PMC10932528 source
  • Premisecitation

    For DILI-CAT, phenotypic overlap between drugs precluded differentiation, as illustrated by amoxicillin-clavulanate and cefazolin.

    “However, phenotypic overlap between drugs precluded differentiation, as illustrated by amoxicillin‐clavulanate and cefazolin.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Tillmann HL, Suzuki A, Merz M, Hermann R, Rockey DC. A novel quantitative computer‐assisted drug‐induced liver injury causality assessment tool (DILI‐CAT). PLoS One. 2022; 17(9): e0271304. 36174069 PMC9521919 source
  • Premisecitation

    Contrary to expectations, the distinction between hepatocellular and cholestatic/mixed injury was not necessary for latency and dechallenge scoring in RECAM.

    “Contrary to expectations, the distinction between hepatocellular and cholestatic/mixed injury was not necessary for latency (both from drug start & drug stop) and dechallenge scoring.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Hayashi PH, Lucena MI, Fontana RJ, et al. A revised electronic version of RUCAM for the diagnosis of DILI. Hepatology. 2022; 76(1): 18‐ 31. 35014066 PMC9233102 source
  • Probably not a substantial claim. 8
  • It may state two separate claims as one. 34
  • The quote only partly states this claim. 1

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    RECAM covers a dynamic range of −6 to +20 points.

    “This semi‐automated, computerized platform and validated scoring system covers a dynamic range of −6 to +20 points.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [37] Hayashi PH, Lucena MI, Fontana RJ, et al. A revised electronic version of RUCAM for the diagnosis of DILI. Hepatology. 2022; 76(1): 18‐ 31. 35014066 PMC9233102 source

      The Results section, “RECAM warnings and stops” (page unavailable), says RECAM can automatically assign a final score of −6. Our copy does not establish +20 as the upper limit or state that −6 to +20 is the scoring range (searched for +20, 20 points, and maximum score). (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Interpretationcitation

    The MetaHeps® test has shown promise as a confirmatory assay in several studies, but further refinement of methodology and validation is required before implementation in clinical practice.

    “While this test has shown promise as a confirmatory assay in several studies, further refinement of the methodology and validation is required for its implementation in clinical practice.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [59] Fontana RJ, Liou I, Reuben A, et al. AASLD practice guidance on drug, herbal, and dietary supplement‐induced liver injury. Hepatology. 2023; 77(3): 1036‐ 1065. 35899384 PMC9936988 source

      The DILI biomarkers section (page not provided) says that in vitro tests derived from circulating macrophages are being explored and need further validation. It does not name MetaHeps®, describe it as promising in several studies, or call specifically for methodological refinement before clinical use. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [67] Benesic A, Rotter I, Dragoi D, et al. Development and validation of a test to identify drugs that cause idiosyncratic drug‐induced liver injury. Clin Gastroenterol Hepatol. 2018; 16(9): 1488‐ 1494.e5. 29723689 source

  • It may state two separate claims as one.

    Interpretationreasoning

    Causality assessment methods cannot replace clinical judgement, but they can bring consistency to the diagnosis of DILI.

    “These methods cannot replace clinical judgement, but they can bring consistency to the diagnosis of DILI.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Pharmacovigilance-RUCAM needs prospective validation.

    “but as the authors acknowledge, it needs prospective validation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Scalfaro E, Streefkerk HJ, Merz M, Meier C, Lewis D. Preliminary results of a novel algorithmic method aiming to support initial causality assessment of routine pharmacovigilance case reports for medication‐induced liver injury: the PV‐RUCAM. Drug Saf. 2017; 40(8): 715‐ 727. 28508325 source

  • It may state two separate claims as one.

    Premisecitation

    The addition of histological data to the causality assessment process reduces intermediate probabilities and shifts likelihood scores to higher or lower categories, thereby strengthening causality assessment.

    “The addition of histological data to the causality assessment process has been shown to reduce intermediate probabilities (more uncertain degrees of probability) and shift likelihood scores to higher or lower categories, thereby strengthening the causality assessment.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Ahmad J, Barnhart H, Bonacini M, et al. Value of liver biopsy in the diagnosis of drug‐induced liver injury. J Hepatol. 2022; 76(5): 1070‐ 1078. 35074471 PMC9018618 source

  • It may state two separate claims as one.

    Premisecitation

    In that Chinese study, single conventional drugs caused 63% of DILI cases and HDS caused 37%, with P. multiflorum accounting for 21.0% of HDS cases.

    “Single conventional drugs were responsible for the injury in 63% of cases and HDS in the remaining 37% (P. multiflorum accounted for the 21.0% of HDS cases).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Zhao X, Wang Y, Lai R, et al. Validation of the revised electronic version of RUCAM for diagnosis of DILI in Chinese patients. Hepatol Commun. 2024; 8(4): e0235. 38466883 PMC10932528 source

  • It may state two separate claims as one.

    Premisecitation

    The likelihood score describes the likelihood of a given drug being associated with DILI, ranging from A to E, based on the number of published cases; it is more accurate for extensively used drugs and less accurate for recently approved drugs and HDS.

    “Using this repository, Björnsson & Hoofnagle developed ‘The likelihood score’, that describes the likelihood of a given drug being associated with DILI, ranging from A to E. The score is based on the number of cases published in the literature, so it is more accurate for drugs that have been used extensively over a longer period, and less accurate for more recently approved drugs and HDS that have”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Bjornsson ES, Hoofnagle JH. Categorization of drugs implicated in causing liver injury: critical assessment based on published case reports. Hepatology. 2016; 63(2): 590‐ 603. 26517184 source

  • It may state two separate claims as one.

    Premisecitation

    An updated RUCAM was developed to overcome some limitations of the original scale, with modifications including new additional criteria, clarification of ambiguous items, inclusion of herbal-induced liver injury peculiarities, and updating of exclusion criteria, although a degree of subjectivity remains in the exclusion of liver disorders.

    “An ‘updated RUCAM’ was therefore developed to overcome some of the limitations of the original scale. 41 Modifications included new additional criteria, clarification of some ambiguous items, inclusion of the peculiarities of herbal‐induced liver injury, and updating of the list of exclusion criteria, although a degree of subjectivity remains in the exclusion of these liver disorders.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Danan G, Teschke R. RUCAM in drug and herb induced liver injury: the update. Int J Mol Sci. 2015; 17(1): 14. 26712744 PMC4730261 source

  • It may state two separate claims as one.

    Premisecitation

    RECAM showed better overall agreement with expert opinion than RUCAM (.62 vs .56 weighted kappa, p = .14) and had greater sensitivity for extreme causality results.

    “although RECAM showed better overall agreement with expert opinion (.62 vs. .56 weighted kappa, p = .14), and had greater sensitivity for extreme causality results.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Hayashi PH, Lucena MI, Fontana RJ. RECAM: a new and improved, computerized causality assessment tool for DILI diagnosis. Am J Gastroenterol. 2022; 117(9): 1387‐ 1389. 35973138 source

  • It may state two separate claims as one.

    Premisecitation

    Causality assessment methods cannot distinguish valid from invalid cases, convert uncertainty into certainty, prove a drug-event relationship, or quantify a drug's contribution to the development of an adverse event.

    “Indeed, causality assessment methods that rely on case‐by‐case information cannot distinguish valid from invalid cases, convert uncertainty into certainty, prove a drug‐event relationship, or quantify a drug's contribution to the development of an adverse event, as the WHO rightly points out.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] World Health Organization, Uppsala Monitoring Centre. The use of the WHO‐UMC system for standardised case causality assessment. 2013. https://www.who.int/publications/m/item/WHO‐causality‐assessment

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    LiverTox provides comprehensive data on the hepatotoxic risk assessment of over 1000 drugs and 60 HDS.

    “‘LiverTox’ is an open access authoritative website developed by Jay Hoofnagle, who was the driving force, with the support of various DILI experts (http://livertox.nih.gov), which provides comprehensive data on the hepatotoxic risk assessment of over 1000 drugs and 60 HDS”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Bjornsson ES, Hoofnagle JH. Categorization of drugs implicated in causing liver injury: critical assessment based on published case reports. Hepatology. 2016; 63(2): 590‐ 603. 26517184 source

  • It may state two separate claims as one.

    Premisecitation

    In 50 suspected DILI cases, RUCAM reproducibility showed agreement among two experts of 99%, among three experts of 74%, and among four experts of 37%.

    “The reproducibility of the scale was evaluated by four experts in 50 suspected DILI cases, with agreement among two experts of 99%, 74% between three experts, although low agreement among four experts was reached (37%)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Danan G, Benichou C. Causality assessment of adverse reactions to drugs—I. A novel method based on the conclusions of international consensus meetings: application to drug‐induced liver injuries. J Clin Epidemiol. 1993; 46(11): 1323‐ 1330. 8229110 source

  • It may state two separate claims as one.

    Premisecitation

    In that Chinese study, RECAM had better overall diagnostic performance than RUCAM, with a higher AUC (.947 vs .867, p = .0016).

    “The authors found an overall better diagnostic performance of RECAM than RUCAM with a higher AUC (.947 (.926–.964) vs. .867 (.836–.893), p = .0016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Zhao X, Wang Y, Lai R, et al. Validation of the revised electronic version of RUCAM for diagnosis of DILI in Chinese patients. Hepatol Commun. 2024; 8(4): e0235. 38466883 PMC10932528 source

  • It may state two separate claims as one.

    Interpretationreasoning

    Unlike RUCAM, RECAM evaluates one drug at a time without considering comedication, which remains a limitation of current causality assessment methods.

    “Unlike RUCAM, RECAMis evaluating one drug at a time without considering comedication, but a RECAM can be done for each drug. While this may result in different scores and degrees of likelihood, it is possible for some drugs to have the same score on the scale. This remains a limitation of current causality assessment methods.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    DILI can mimic any acute or chronic liver disease, and its phenotypic expression is heterogeneous because drugs do not have a consistent signature.

    “It is known that DILI can mimic any acute or chronic liver disease, that the phenotypic expression in DILI is quite heterogeneous as drugs do not have a consistent signature”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] European Association for the Study of the Liver, Andrade RJ, Aithal GP, Bjornsson ES. EASL clinical practice guidelines: drug‐induced liver injury. J Hepatol. 2019; 70(6): 1222‐ 1261. 30926241

  • It may state two separate claims as one.

    Premisecitation

    Probabilistic methods are limited in DILI scenarios by the need for accurate data from a large cohort of cases and by the lack of methodological evaluation specific to hepatic adverse drug reactions.

    “Despite the exploration of probabilistic methods in the context of hepatotoxicity, the need for accurate data derived from a large cohort of cases to model the probability distribution relevant to each parameter, coupled with the lack of methodological evaluation specific to hepatic adverse drug reactions (ADRs), limits the practicality of this modality in DILI scenarios.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Zapater P, Such J, Perez‐Mateo M, Horga JF. A new Poisson and Bayesian‐based method to assign risk and causality in patients with suspected hepatic adverse drug reactions: a report of two new cases of ticlopidine‐induced hepatotoxicity. Drug Saf. 2002; 25(10): 735‐ 750. 12167069 source

  • It may state two separate claims as one.

    Premisecitation

    RECAM-J 2023, without deduction of missing hepatitis virus markers, increased the sum of highly probable and probable cases to 421 (78%) and was considered useful for the identification of suspected DILI in clinical practice.

    “With this modification, the sum of highly probable and probable cases was increased to 421 (78%) and the RECAM‐J 2023 was considered useful for the identification of suspected DILI in clinical practice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] Tanaka A, Tsuji K, Komiyama Y, et al. RECAM‐J 2023‐validation and development of the Japanese version of RECAM for the diagnosis of drug‐induced liver injury. Hepatol Res. 2024; 54(6): 503‐ 512. 38642343 source
    • Rests on an assumption: Viral hepatitis is not an issue in Japan.

  • It may state two separate claims as one.

    Premisecitation

    The DDW-J scale has not been generalized outside Japan because the DLST is not standardized worldwide and has not been shown to be consistent in diagnosing DILI due to all different types of drugs.

    “However, the DDW‐J scale has not been generalized outside Japan because the DLST is not standardized worldwide and has not been shown to be consistent in diagnosing DILI due to all different types of drugs.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Whritenour J, Ko M, Zong Q, et al. Development of a modified lymphocyte transformation test for diagnosing drug‐induced liver injury associated with an adaptive immune response. J Immunotoxicol. 2017; 14(1): 31‐ 38. 28121193 PMC5505862 source

  • It may state two separate claims as one.

    Premisecitation

    The modified updated RUCAM retains risk factors of unclear value, includes changes that make it more complex and time-consuming, and is not prospectively validated.

    “Nevertheless, this modified scale retains risk factors of unclear value, included changes that make it more complex and time‐consuming, and it is not prospectively validated.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Danan G, Teschke R. RUCAM in drug and herb induced liver injury: the update. Int J Mol Sci. 2015; 17(1): 14. 26712744 PMC4730261 source

  • It may state two separate claims as one.

    Premisecitation

    RUCAM cannot discriminate between drugs with known hepatotoxic potential and the same temporal sequence, in patients with underlying liver disease, progression to fulminant liver failure, liver transplantation or death, or chronicity, or in atypical presentations.

    “In addition, it cannot discriminate between drugs with known hepatotoxic potential and the same temporal sequence, in patients with underlying liver disease, progression to fulminant liver failure, liver transplantation or death, or chronicity, or in atypical presentations, limiting causality assessment.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] García‐Cortés M, Stephens C, Lucena MI, Fernández‐Castañer A, Andrade RJ. Causality assessment methods in drug induced liver injury: strengths and weaknesses. J Hepatol. 2011; 55(3): 683‐ 691. 21349301 source

  • It may state two separate claims as one.

    Premisecitation

    In Japan, missing viral data was common in retrospectively collected DILI cases, and the sum of highly probable and probable cases reached only 206 out of 538 cases (38%).

    “As viral hepatitis is not an issue in Japan, missing viral data was common in retrospectively collected DILI cases in this country, and the sum of highly probable and probable cases reached only 206 out of 538 cases (38%).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] Tanaka A, Tsuji K, Komiyama Y, et al. RECAM‐J 2023‐validation and development of the Japanese version of RECAM for the diagnosis of drug‐induced liver injury. Hepatol Res. 2024; 54(6): 503‐ 512. 38642343 source
    • Rests on an assumption: Viral hepatitis is not an issue in Japan.

  • It may state two separate claims as one.

    Premisecitation

    The Clinical Diagnostic Scale has simplified criteria, but excessive weighting of extrahepatic or hypersensitivity features makes it less valid than RUCAM in DILI assessment.

    “The immunologists Maria and Victorino developed the CDS or Maria and Victorino Scale 34 and although the criteria have been simplified, the excessive weighting of extrahepatic or hypersensitivity features makes it less valid than RUCAM in DILI assessment.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Lucena MI, Camargo R, Andrade RJ, Perez‐Sanchez CJ, Sanchez De La Cuesta F. Comparison of two clinical scales for causality assessment in hepatotoxicity. Hepatology. 2001; 33(1): 123‐ 130. 11124828 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    RECAM diagnostic testing is categorical and menu-driven to reduce interobserver variability.

    “Diagnostic testing is categorical and menu‐driven to reduce interobserver variability.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Hayashi PH, Lucena MI, Fontana RJ, et al. A revised electronic version of RUCAM for the diagnosis of DILI. Hepatology. 2022; 76(1): 18‐ 31. 35014066 PMC9233102 source

  • It may state two separate claims as one.

    Premisecitation

    The DDW-J scale accurately diagnoses DILI and is superior to the Maria and Victorino scale.

    “The Japanese scale was shown to accurately diagnose DILI and was superior to the Maria and Victorino scale.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Watanabe M, Shibuya A. Validity study of a new diagnostic scale for drug‐induced liver injury in Japan‐comparison with two previous scales. Hepatol Res. 2004; 30(3): 148‐ 154. 15588780 source

  • It may state two separate claims as one.

    Premisecitation

    In that Chinese study, the criteria responsible for poorer agreement between RECAM and RUCAM were latency, hepatitis B exclusion criteria, and hepatotoxicity information of the culprit drugs.

    “Criteria responsible for the poorer agreement between the two scales were latency, hepatitis B exclusion criteria, and hepatotoxicity information of the culprit drugs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Zhao X, Wang Y, Lai R, et al. Validation of the revised electronic version of RUCAM for diagnosis of DILI in Chinese patients. Hepatol Commun. 2024; 8(4): e0235. 38466883 PMC10932528 source

  • It may state two separate claims as one.

    Premisecitation

    RUCAM disadvantages include complexity and ambiguous instructions, arbitrary weighting of criteria such as overestimation of rechallenge, lack of evidence-based risk factors, failure to consider ultra-short or long latency periods, excessive penalty for concomitant hepatotoxic drugs, and omission of liver histological findings.

    “However, disadvantages of the RUCAM scale include complexity and ambiguous instructions, arbitrary weighting of the criteria such as an overestimation of rechallenge, which is seldom done, lack of evidence‐based risk factors, failure to consider ultra‐short or long latency periods for drugs with short or long half‐lives, excessive penalty for concomitant hepatotoxic drugs, or omissions such as”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [20] García‐Cortés M, Stephens C, Lucena MI, Fernández‐Castañer A, Andrade RJ. Causality assessment methods in drug induced liver injury: strengths and weaknesses. J Hepatol. 2011; 55(3): 683‐ 691. 21349301 source
    • cites [39] Lewis JH. Causality assessment: which is best‐expert opinion or RUCAM? Clin Liver Dis (Hoboken). 2014; 4(1): 4‐ 8. 30992910 PMC6448723

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    An expert opinion approach has been considered the gold standard, although disagreements between experts have questioned its validity.

    “An expert opinion approach has been considered the gold‐standard, although disagreements between experts have also questioned its validity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Hayashi PH. Drug‐induced liver injury network causality assessment: criteria and experience in the United States. Int J Mol Sci. 2016; 17(2): 201. 26861284 PMC4783935

  • Probably not a substantial claim.

    Interpretationreasoning

    Further validation of genetic testing is required before routine implementation can be recommended in DILI.

    “further validation of genetic testing is required before routine implementation can be recommended”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    The HLA-B*5701 genotype increases the risk of flucloxacillin-induced DILI by 80-fold, but only an estimated one in every 500 carriers of the variant will develop liver injury after exposure to flucloxacillin.

    “For example, the HLA‐B*5701 genotype increases the risk of flucloxacillin‐induced DILI by 80‐fold, but it is estimated that only one in every 500 carriers of the genetic variant will develop liver injury after exposure to this antibiotic.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Daly AK, Donaldson PT, Bhatnagar P, et al. HLA‐B*5701 genotype is a major determinant of drug‐induced liver injury due to flucloxacillin. Nat Genet. 2009; 41(7): 816‐ 819. 19483685

  • It may state two separate claims as one.

    Interpretationcitation

    Liver-specific causality scales do not capture the complexity of HDS-induced liver injury and are therefore not suitable for attributing causality in that context, because HDS products are frequently multi-ingredient and the toxic compound is often not identified or mislabelled.

    “However, it is important to emphasize that the liver‐specific scales do not capture the complexity of HDS‐induced liver injury and are therefore not suitable for attributing causality in this context, as these products are frequently multi‐ingredient and the toxic compound is often not identified or mislabelled.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Medina‐Cáliz I, García‐Cortés M, Gonzalez‐Jimenez A, et al. Herbal and dietary supplement‐induced liver injuries in the Spanish DILI registry. Clin Gastroenterol Hepatol. 2018; 16(9): 1495‐ 1502. 29307848 source
    • cites [5] Bessone F, García‐Cortés M, Medina‐Caliz I, et al. Herbal and dietary supplements‐induced liver injury in Latin America: experience from the LATINDILI network. Clin Gastroenterol Hepatol. 2022; 20(3): e548‐ e563. 33434654 source
    • cites [52] Navarro V, Avula B, Khan I, et al. The contents of herbal and dietary supplements implicated in liver injury in the United States are frequently mislabeled. Hepatol Commun. 2019; 3(6): 792‐ 794. 31168513 PMC6545864 source

  • It may state two separate claims as one.

    Premisecitation

    The MetaHeps® in vitro assay uses blood monocytes from the index patient differentiated to hepatocyte-like cells that exhibit increased cytotoxicity when cultured with the suspected drug, and is a patient-based approach to assess causality in idiosyncratic DILI.

    “The development of an in vitro assay, MetaHeps®, using blood monocytes from the index patient differentiated to hepatocyte‐like cells which exhibit increased cytotoxicity when cultured with the suspected drug, is an interesting patient‐based approach to assess causality in idiosyncratic DILI.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Benesic A, Leitl A, Gerbes AL. Monocyte‐derived hepatocyte‐like cells for causality assessment of idiosyncratic drug‐induced liver injury. Gut. 2016; 65(9): 1555‐ 1563. 26045135 source

  • It may state two separate claims as one.

    Premisecitation

    International DILI consortia have contributed to construction of a polygenic risk score for amoxicillin-clavulanate susceptibility, which may also improve causality assessment.

    “In addition, the international DILI consortia have contributed to the construction of a polygenic risk score for amoxicillin‐clavulanate susceptibility, which may also improve causality assessment.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Nicoletti P, Dellinger A, Li YJ, et al. Identification of reduced ERAP2 expression and a novel HLA allele as components of a risk score for susceptibility to liver injury due to amoxicillin‐clavulanate. Gastroenterology. 2023; 164(3): 454‐ 466. 36496055 PMC9974860 source

  • It may state two separate claims as one.

    Interpretationreasoning

    Genetic determinants of DILI confer a high negative predictive value, so absence of the specific polymorphism can be used to exclude DILI diagnosis, differentiate between suspected culprit drugs taken at the same time, or for differential diagnosis with autoimmune hepatitis.

    “In contrast, these genetic determinants confer a high negative predictive value, so that the absence of the specific polymorphism can be used to exclude the diagnosis of DILI, to differentiate between suspected culprit drugs taken at the same time, or for differential diagnosis with autoimmune hepatitis.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisereasoning

    In response to limitations of expert judgement, the Spanish, LATINDILI and Pro-Euro DILI networks combined evaluation of suspected DILI cases by three experts with further assessment using causality scales, while DILIN developed a structured expert opinion process.

    “In response to these limitations, the Spanish, LATINDILI and Pro‐Euro DILI networks have combined the evaluation of suspected DILI cases by three experts and further assessment using causality scales, while the DILIN has developed a structured expert opinion process.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [9] Björnsson ES, Stephens C, Atallah E, et al. A new framework for advancing in drug‐induced liver injury research. The prospective European DILI registry. Liver Int. 2023; 43(1): 115‐ 126. 35899490 PMC7614006 source
    • cites [38] Fontana RJ, Watkins PB, Bonkovsky HL, et al. Drug‐induced liver injury network (DILIN) prospective study: rationale, design and conduct. Drug Saf. 2009; 32(1): 55‐ 68. 19132805 PMC3637941 source
    • cites [53] Andrade RJ, Lucena MI, Fernandez MC, et al. Drug‐induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10‐year period. Gastroenterology. 2005; 129(2): 512‐ 521. 16083708 source
    • cites [54] Bessone F, Hernandez N, Medina‐Caliz I, et al. Drug‐induced liver injury in Latin America: 10‐year experience of the Latin American DILI (LATINDILI) network drug‐induced liver injury in Latin America. Clin Gastroenterol Hepatol. 2024; S1542‐3565(24)00605‐0. 38992407 source

  • It may state two separate claims as one.

    Premisecitation

    When compared with RUCAM, concordance between expert opinion and RUCAM yielded a correlation coefficient of .42 and low complete inter-rater agreement.

    “When compared with RUCAM, the concordance between the two methods yielded a correlation coefficient of .42 and a low complete inter‐rater agreement.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Rockey DC, Seeff LB, Rochon J, et al. Causality assessment in drug‐induced liver injury using a structured expert opinion process: comparison to the Roussel‐Uclaf causality assessment method. Hepatology. 2010; 51(6): 2117‐ 2126. 20512999 PMC3249230 source

  • It may state two separate claims as one.

    Premisecitation

    International collaborative efforts such as the Safer and Faster Evidence-Based Translation consortium and the Translational Safety Biomarker Pipeline are enabling development and implementation of novel safety biomarkers in clinical trials and early diagnosis of disease, although none have yet been shown to be DILI specific.

    “International collaborative efforts such as the Safer and Faster Evidence‐Based Translation consortium, followed by the Translational Safety Biomarker Pipeline, are enabling the development and implementation of novel safety biomarkers in clinical trials and early diagnosis of disease, although none of these have yet been shown to be DILI specific.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [13] Cueto‐Sanchez A, Niu H, Alvarez‐Alvarez I, et al. Evaluation of diagnostic and prognostic candidate biomarkers in drug‐induced liver injury vs. other forms of acute liver damage. Br J Clin Pharmacol. 2023; 89(8): 2497‐ 2507. 36965054 source
    • cites [62] Church RJ, Kullak‐Ublick GA, Aubrecht J, et al. Candidate biomarkers for the diagnosis and prognosis of drug‐induced liver injury: an international collaborative effort. Hepatology. 2019; 69(2): 760‐ 773. 29357190 PMC6054900

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Interpretationreasoning

    The expert opinion method is hampered by subjectivity and limited reproducibility, making it unsuitable for clinical practice.

    “However, this method is hampered by subjectivity and limited reproducibility, making it unsuitable for clinical practice.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one. The quote only partly states this claim.

    Premisecitation

    Despite inter-observer variability with both instruments, the expert opinion approach resulted in superior inter-rater agreement and improved likelihood score compared with RUCAM.

    “Despite the demonstration of inter‐observer variability with both instruments, the expert opinion approach resulted in superior inter‐rater agreement and improved the likelihood score.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Rockey DC, Seeff LB, Rochon J, et al. Causality assessment in drug‐induced liver injury using a structured expert opinion process: comparison to the Roussel‐Uclaf causality assessment method. Hepatology. 2010; 51(6): 2117‐ 2126. 20512999 PMC3249230 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisereasoning

    The European Association for the Study of the Liver clinical practice guidelines recommend HLA genotyping only in clinical settings where it can assist in the diagnosis and management of hepatotoxicity.

    “Under this premise, the European Association for the Study of the Liver clinical practice guidelines recommend HLA genotyping only in clinical settings where it can assist in the diagnosis and management of hepatotoxicity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] European Association for the Study of the Liver, Andrade RJ, Aithal GP, Bjornsson ES. EASL clinical practice guidelines: drug‐induced liver injury. J Hepatol. 2019; 70(6): 1222‐ 1261. 30926241

  • It may state two separate claims as one.

    Premisecitation

    The US DILIN Expert Opinion process has not been externally validated and requires expert judgement.

    “The US DILIN Expert Opinion process has not been externally validated and requires expert judgement.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Fontana RJ, Watkins PB, Bonkovsky HL, et al. Drug‐induced liver injury network (DILIN) prospective study: rationale, design and conduct. Drug Saf. 2009; 32(1): 55‐ 68. 19132805 PMC3637941 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationcitation

    Further technical and clinical validation of the candidate serum biomarkers FBP1, GSTA1, and LC2 is required.

    “However, further technical and clinical validation of these promising biomarkers is required.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Ravindra KC, Vaidya VS, Wang Z, et al. Tandem mass tag‐based quantitative proteomic profiling identifies candidate serum biomarkers of drug‐induced liver injury in humans. Nat Commun. 2023; 14(1): 1215. 36869085 PMC9984368 source
41 of 41

  • The paper relies on this without support.

    RUCAM has never been developed or tested for use in HDS cases.

    “Furthermore, RUCAM has never been developed or tested for use in HDS cases.”

  • The paper relies on this without support.

    Viral hepatitis is not an issue in Japan.

    “As viral hepatitis is not an issue in Japan”
2 of 2

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting statements about a DILI diagnostic gold standard

    Minor

    One passage says there is no gold standard for verifying DILI diagnosis; another says a positive rechallenge can be considered the gold standard of DILI diagnosis.

1 of 1

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Bessone F, 2024, Drug‐induced liver injury in Latin America: 10‐year experience of the Latin American DILI (LATINDILI) network drug‐induced liver injury in Latin America, Clin Gastroenterol Hepatol, S1542‐3565(24)0

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Related

Metadata

Authors
García‐Cortés, M., Matilla‐Cabello, G., & Lucena, M. I.
Affiliations
  • Centro de Investigación Biomédica en Red (ES)
  • Spanish Clinical Research Network (ES)
Corresponding author
García‐Cortés, Miren
ORCID
Venue
Liver International
Publisher
Wiley
Published
2024-08-21
Volume
45
Issue
3
Pages
e16083-e16083
ISSN
  • 0106-9543 (ISSN-L)
  • 1478-3223
  • 1478-3231
DOI
10.1111/liv.16083
PMC
PMC11815608
OpenAlex
W4401728295
Cited by
15
References
63
Citations by year
2026: 8 · 2025: 6 · 2024: 1
FWCI
0.88
Type
journal article
Language
en
Open access
Licence
Locations
  • Liver International (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Repositorio Institucional de la Universidad de Málaga (University of Málaga) (submittedVersion, cc-by-nc-nd)
Funders
  • Instituto de Salud Carlos III (PI21/01248, PT23/00137)
  • Agencia Estatal de Investigación (PID2022‐140169OB‐C21)
  • Ministerio de Ciencia, Innovación y Universidades (FPU22/03868)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
  • Health Sciences › Medicine › Pharmacology (medical) › Drug-Induced Adverse Reactions
Keywords
idiosyncratic drug-induced liver injury, causality assessment, RUCAM, expert opinion, biomarkers, personalized medicine, drug safety
MeSH terms
Humans, Biomarkers, Chemical and Drug Induced Liver Injury

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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A second model labelled each claim on 2026-11-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (gpt-6-sol).

Statistics and arithmetic are recomputed, not judged.

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