Gonzalo Matilla‐Cabello

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas

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M. Isabel Lucena

Universidad de Málaga

Raúl J. Andrade

Instituto de Investigación Biomédica de Málaga

Antonio Segovia-Zafra

Instituto de Investigación Biomédica de Málaga

Marina Villanueva-Paz

Instituto de Investigación Biomédica de Málaga

Daniel E. Di Zeo-Sánchez

Instituto de Investigación Biomédica de Málaga

IÁ

Ismael Álvarez‐Álvarez

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas

Hao Niu

Instituto de Investigación Biomédica de Málaga

Joana P. Miranda

University of Lisbon

Leonard J. Nelson

University of Edinburgh

Irina Milisav

University of Ljubljana

Cooperative Institutions

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas

Instituto de Investigación Biomédica de Málaga

Universidad de Málaga

Andalusian Centre for Nanomedicine and Biotechnology

Centro de Investigación Biomédica en Red

Instituto de Salud Carlos III

Hospital Clínico Universitario Virgen de la Victoria

Centre for Biomedical Network Research on Rare Diseases

University of Edinburgh

University of Southern California

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Clinical presentation, causative drugs and outcome of patients with autoimmune features in two prospective DILI registries

Liver International (2023)

Miren García‐Cortés Aida Ortega‐Alonso Gonzalo Matilla‐Cabello Inmaculada Medina‐Cáliz Agustín Castiella

Abstract Background & aims Idiosyncratic drug‐induced liver injury (DILI) with autoimmune features is a liver condition with laboratory and histological characteristics similar to those of idiopathic autoimmune hepatitis (AIH), which despite being increasingly reported, remains largely undefined. We aimed to describe in‐depth the features of this entity in a large series of patients from two prospective DILI registries. Methods DILI cases with autoimmune features collected in the Spanish DILI Registry and the Latin American DILI Network were compared with DILI patients without autoimmune features and with an independent cohort of patients with AIH. Results Out of 1,426 patients with DILI, 33 cases with autoimmune features were identified. Female sex was more frequent in AIH patients than in the other groups ( p = .001). DILI cases with autoimmune features had significantly longer time to onset ( p < .001) and resolution time ( p = .004) than those without autoimmune features. Interestingly, DILI patients with autoimmune features who relapsed exhibited significantly higher total bilirubin and transaminases at onset and absence of peripheral eosinophilia than those who did not relapse. The likelihood of relapse increased over time, from 17% at 6 months to 50% 4 years after biochemical normalization. Statins, nitrofurantoin and minocycline were the drugs most frequently associated with this phenotype. Conclusions DILI with autoimmune features shows different clinical features than DILI patients lacking characteristics of autoimmunity. Higher transaminases and total bilirubin values with no eosinophilia at presentation increase the likelihood of relapse in DILI with autoimmune features. As the tendency to relapse increases over time, these patients will require long‐term follow‐up.

Autoimmune Hepatitis

10.1111/liv.15623

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Control Compounds for Preclinical Drug-Induced Liver Injury Assessment: Consensus-driven systematic review by the ProEuroDILI Network

Research Square (Research Square) (2023)

Antonio Segovia-Zafra Marina Villanueva-Paz A.S. Serras Gonzalo Matilla‐Cabello Ana Bodoque-García

Abstract Idiosyncratic drug-induced liver injury (DILI) is a complex and unpredictable event caused by different drugs, herbal, and dietary supplements. The early identification of human hepatotoxicity at the preclinical stages remains a major challenge, in which the selection of validated in vitro systems and test drugs has a significant impact. This systematic review aims to analyse the compounds used in hepatotoxicity assays and establish a unified list of DILI positive and negative control drugs for validation of in vitro models of DILI, supported by literature and clinical evidence and endorsed by a committee of experts from the COST Action ProEuroDILI Network (CA 17112). This systematic review was performed in accordance with the 2020 PRISMA guidelines. Original research articles focused on investigating DILI occurrence using in vitro human models performing at least one hepatotoxicity assay with positive and negative control compounds were included. A modified version of the "Toxicological Data Reliability Assessment Tool" (ToxRTool) was used to assess the bias of the included studies. A total of 2,936 studies were retrieved from the different databases. Of these, 51 met the inclusion criteria, with 30 categorized as reliable without restrictions. Diclofenac and buspirone were the most commonly used DILI-positive and DILI-negative control drugs, respectively. Although there was a broad consensus on the positive compounds, the selection of negative control compounds remained less clear. Regarding the models used, the 2D monoculture of primary human hepatocytes (PHHs) was the favoured choice. However, there was no clear consensus on the drug concentrations. Short acute exposure times were mostly utilised, and cytotoxicity was the preferred endpoint. The extensive analysis of included studies highlighted the lack of agreement on appropriate control compounds for the in vitro assessment of DILI. Therefore, following comprehensive in vitro and clinical data analysis together with input from the expert committee, an evidence-based consensus-driven list of 10 positive and negative drugs is proposed for validating new in vitro models for improving preclinical drug safety testing regimes.

10.21203/rs.3.rs-3578817/v1

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P16-38: A systematic review of control compounds tested for validation of Drug-Induced Liver Injury (DILI) in vitro models

Toxicology Letters (2023)

Antonio Segovia-Zafra Marina Villanueva-Paz A.S. Serras Gonzalo Matilla‐Cabello A. Bodoque

10.1016/s0378-4274(23)00727-0

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Immunophenotyping to improve the mechanistic understanding of idiosyncratic drug-induced liver injury: clinical implications and future directions

Alejandro Cueto‐Sánchez Daniel E. Di Zeo-Sánchez Antonio Segovia-Zafra Gonzalo Matilla‐Cabello Ana Bodoque-García

The late event onset of a fraction of idiosyncratic drug-induced liver injury (DILI) cases and the link observed by genome-wide association studies (GWASs) of certain human leucocyte antigen (HLA) alleles with DILI due to specific drugs support the crucial role of the immune system (both innate and adaptive) in the pathogenesis of DILI. Recent advances in both flow and mass cytometry have allowed the profiling of all major immune cell types in a given sample. Therefore, determining the lymphocyte populations in samples from patients with DILI would facilitate the development of specific biomarkers for DILI diagnosis and prognosis. To date, a few studies have explored the immune landscape in DILI. In a recent study of leukocyte immunophenotyping using flow cytometry from the Spanish DILI Registry, an important role of adaptive immune response in DILI is suggested. DILI patients had significantly higher levels of T helper 1 (Th1) cells and activated helper and cytotoxic T cells than healthy controls. Furthermore, the increased expression of negative immune checkpoints and ligands in DILI patients could reflect a restoration of the immune homeostasis. Differences in the profile of cytokines in DILI patients from the Drug-Induced Liver Injury Network (DILIN) also suggest an involvement of both innate and adaptive immune systems in DILI development and prognosis. Moreover, several studies based on immunophenotyping of liver infiltrates showed a distinctive pattern of cellular infiltrates in patients with immune checkpoint inhibitors (ICIs)-DILI, with lower levels of plasma cells, CD20+ B cells and CD4+ T cells than in autoimmune hepatitis (AIH) patients. These pioneering studies highlight the importance of immunophenotyping for the mechanistic understanding of DILI. In this review, available data on immunophenotyping in DILI are gathered, and the potential clinical applications of cutting-edge, novel immunophenotyping techniques are discussed.

Immunophenotyping

Mass cytometry

10.37349/edd.2023.00018

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Control compounds for preclinical drug-induced liver injury assessment: Consensus-driven systematic review by the ProEuroDILI network

Journal of Hepatology (2024)

Antonio Segovia-Zafra Marina Villanueva-Paz A.S. Serras Gonzalo Matilla‐Cabello Ana Bodoque-García

Idiosyncratic drug-induced liver injury (DILI) is a complex and unpredictable event caused by drugs, and herbal or dietary supplements. Early identification of human hepatotoxicity at preclinical stages remains a major challenge, in which the selection of validated in vitro systems and test drugs has a significant impact. In this systematic review, we analyzed the compounds used in hepatotoxicity assays and established a list of DILI-positive and -negative control drugs for validation of in vitro models of DILI, supported by literature and clinical evidence and endorsed by an expert committee from the COST Action ProEuroDILI Network (CA17112).

Drug control

10.1016/j.jhep.2024.04.026

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Methods for causality assessment of idiosyncratic drug‐induced liver injury

Liver International (2024)

Miren García‐Cortés Gonzalo Matilla‐Cabello M. Isabel Lucena

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.

Causality

Expert opinion

Judgement

10.1111/liv.16083

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Modeling drug-induced liver injury: current status and future prospects

Expert Opinion on Drug Metabolism & Toxicology (2022)

Daniel E. Di Zeo-Sánchez Antonio Segovia-Zafra Gonzalo Matilla‐Cabello José M. Pinazo-Bandera Raúl J. Andrade

Introduction Idiosyncratic drug-induced liver injury (iDILI) is a challenging and unpredictable multifactorial condition. At present, validated preclinical models for the prediction of the hepatotoxic potential of a given drug are scarce.Areas covered This review intends to sum up the current knowledge about in vitro (including hepatocyte 2D cultures, cocultures with non-parenchymal cells, 3D configurations and non-typical closer to reality in vitro models), in vivo (covering models for immunological and oxidative stress features, humanized mouse-based and non-rodent models) and in silico approaches for iDILI modeling, highlighting the recent advances in each topic.Expert opinion The future strategy for iDILI modeling should be patient-centered. Future animal and cell-based models, with more predictive value, will be easier to design by using a more translational approach based on mechanisms demonstrated in humans. Genetic and epigenetic information gathered from iDILI patients, together with data from in vitro and in vivo studies, could be used to develop sophisticated predictive in silico models to find compounds with iDILI potential. Collecting genetic, metabolic, and biomarker data from patient cohorts might be another option to create a 'fingerprint' characteristic of people at risk, allowing for the development of new, mechanistic strategies to enhance iDILI in vitro evaluation.

Drug Development

Toxicogenomics

Computational model

10.1080/17425255.2022.2122810

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Citations (12)