Letter to the editor: RECAM for the diagnosis of DILI—Is it time to incorporate additional pharmacological criteria?
Authors: Emanuel Raschi, Paolo Caraceni
Journal: Hepatology (2022)

To the editor, We read with great interest the practice‐changing work by Hayashi et al., who updated, refined, and computerized Roussel Uclaf Causality Assessment Method (RUCAM) criteria for the diagnosis of Drug‐Induced Liver Injury (DILI). This revised electronic version, called RECAM, adopted an evidence‐based approach and was found to perform even better than RUCAM, especially at diagnostic extremes, thus making it attractive also for clinicians without consolidated experience in DILI diagnosis.[1] We commend the authors for simplifying this user‐friendly approach (from the original seven RUCAM criteria, five RECAM domains were retained) while considering comprehensive alternative causes, liver histology, atypical viral testing, and presence of severe skin reactions. Our attention was drawn by the revised criterium (formerly six in RUCAM) on “Previous Information on Hepatotoxicity of the Drug,” which was anticipated to domain three in RECAM. To reduce subjectivity, the implicated medication is anchored to LiverTox likelihood scores, with the opportunity to manually score drugs not listed in this Bookshelf website. Although this automated assignment clarifies one of the most ambiguous domains of RUCAM, the provided literature support does not necessarily imply that the drug is hepatotoxic per se in a given patient. In other words, the assessment of DILI in the individual subject should be independent, at least partially, on drug notoriety, which is especially influenced by the time on the market: up to three points are assigned to class A/B drugs, namely consolidated agents with ≥50/12 published DILI cases.[2] We concur with the authors that literature support cannot be disregarded, and we put forward a pharmacological proposal to implement this criterium. Although DILI is unpredictable, physiochemical and pharmacokinetic properties have been identified as plausible risk factors, including reactive metabolites, hepatic metabolism, and dual inhibition of mitochondria and bile salt export pump.[3] A recent review of 3,312 DILI cases found that most implicated drugs (61.1%) assessed with RUCAM are metabolized through cytochrome P450 isoforms.[4] These parameters can be extracted and automated from publicly available sources (e.g., European public assessment report) and also combined with unpublished pharmacovigilance data, namely hepatic reactions recorded in spontaneous reporting systems, thus offering a global real‐time picture from the real world.[5] This “bedside‐to‐bench” approach, partially adopted to rank drugs for their torsadogenic liability (www.crediblemeds.org), can provide additional pharmacological substantiation to refine RECAM, thus supporting automated prediction and assessment of DILI in digital clinical practice. CONFLICT OF INTEREST Emanuel Raschi reports personal fee from Novartis for consultancy on DILI. Paolo Caraceni is part of the speakers’ bureau for Grifols SA, Octapharma SA, Kedrion Biopharma SpA, Mallinkrodt SA, Gilead SA, and Takeda SA outside the submitted work.