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Causality assessment methods in drug induced liver injury: Strengths and weaknesses

García-Cortés, Miren, Stephens, Camilla, Lucena, M. Isabel, Fernández-Castañer, Alejandra, Andrade, Raúl J.·2011·Journal of Hepatology
DOI 10.1016/j.jhep.2011.02.007
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Abstract

Diagnosis of drug-induced liver injury (DILI) remains a challenge and eagerly awaits the development of reliable hepatotoxicity biomarkers. Several methods have been developed in order to facilitate hepatotoxicity causality assessments. These methods can be divided into three categories: (1) expert judgement, (2) probabilistic approaches, and (3) algorithms or scales. The last category is further divided into general and liver-specific scales. The Council for International Organizations of Medical Sciences (CIOMS) scale, also referred to as the Roussel Uclaf Causality Assessment Method (RUCAM), although cumbersome and difficult to apply by physicians not acquainted with DILI, is used by many expert hepatologists, researchers, and regulatory authorities to assess the probability of suspected causal agents. However, several limitations of this scale have been brought to light, indicating that a number of adjustments are needed. This review is a detailed timely criticism to alert the readers of the limitations and give insight into what would be needed to improve the scale. Instructions on how to approach DILI diagnosis in practice are provided, using CIOMS as an aid to emphasize the topics to be addressed when assessing DILI cases. Amendments of the CIOMS scale in the form of applying authoritative evidence-based criteria, a simplified scoring system and appropriate weighting given to individual parameters based on statistical evaluations with large databases will provide wider…

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  • 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”

    From Methods for causality assessment of idiosyncratic drug‐induced liver injury (2025) · cites this paper as [20]

  • 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.”

    From Methods for causality assessment of idiosyncratic drug‐induced liver injury (2025) · cites this paper as [20]

  • RUCAM has been hindered by subjectivity and poor reliability.

    “Roussel Uclaf Causality Assessment Method (RUCAM) for drug-induced liver injury (DILI) has been hindered by subjectivity and poor reliability.”

    From A revised electronic version of RUCAM for the diagnosis of DILI (2022) · cites this paper as [6]

  • Lammert et al. demonstrated that AIH was characterised by a group of both IgG and IgM autoantibodies while DI-ALH was only characterised by IgM, which could be used as a feature to distinguish DI-ALH from AIH.

    “Lammert et al., demonstrated that AIH was characterised by a group of both IgG and IgM autoantibodies while DI-ALH was only characterised by IgM, which could be used as a feature to distinguish DI-ALH from AIH.”

    From Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): An expert opinion meeting report (2023) · cites this paper as [63]

  • Concerns have been raised regarding RUCAM's poor reliability, validity and the lack of clinical evidence for the domain criteria.

    “However, concerns have been raised regarding its poor reliability, validity and the lack of clinical evidence for the domain criteria.”

    From Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): An expert opinion meeting report (2023) · cites this paper as [63]

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Metadata

Authors
García-Cortés, M., Stephens, C., Lucena, M. I., Fernández-Castañer, A., & Andrade, R. J.
Venue
Journal of Hepatology
Publisher
Elsevier BV
Published
2011-09
Volume
55
Issue
3
Pages
683-691
ISSN
0168-8278
DOI
10.1016/j.jhep.2011.02.007
Cited by
169
References
2
Language
en
Licence

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