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[ES] La hipótesis sobre la que se fundamentó este proyecto de Tesis Doctoral fue que la deficiencia de la enzima ACOX2, y la consiguiente acumulación de intermediarios hepatotóxicos del metabolismo de los ABs, puede estar implicada en la etiopatogenia de otros casos de hipertransaminasemia persistente de causa no filiada, lo que sería clínicamente relevante si tenemos en cuenta que hasta en un 15% de los pacientes en los que se detecta una elevación persistente de transaminasas en sangre, la causa del trastorno permanece sin identificar. Con estos antecedentes, se plantea como objetivo global de esta Tesis Doctoral investigar la prevalencia de la Hipertransaminasemia Asociada a Deficiencia de ACOX2 (HADA) entre los pacientes con hipertransaminasemia idiopática y su respuesta al ácido ursodesoxicólico, dilucidar su mecanismo patogénico y desarrollar, caracterizar y validar modelos experimentales para el estudio de esta alteración. Para alcanzarlo, se proponen los siguientes objetivos parciales: Objetivo 1: Estudiar los mediadores implicados en la regulación de ACOX2. Objetivo 2: Analizar la prevalencia de HADA en una cohorte de pacientes con hipertransaminasemia no filiada e identificar las bases genéticas del trastorno. Objetivo 3: Evaluar la utilidad del ácido ursodesoxicólico como tratamiento de los pacientes con HADA e investigar su acción farmacológica en esta alteración. Objetivo 4: Desarrollar modelos in vitro de células hepáticas con deficiencia de ACOX2 y expresión de otras variantes genéticas descritas para esta enzima, para evaluar su repercusión funcional. Objetivo 5: Desarrollar y caracterizar modelos murinos de déficit de Acox2, como herramienta para evaluar in vivo la repercusión de esta deficiencia sobre la toxicidad hepática aguda provocada por fármacos.

Introduction: Drug-induced liver injury due to chemotherapy is an important cause of morbidity in cancer patients, although its clinical manifestations are poorly understood. Objective: The objective of the present study was to determine the characteristics (forms of presentation, severity, and type of injury) of hepatotoxicity due to chemotherapy in children treated for cancer. Patients and method: A total of 22 oncological patients were included in the study, after ruling out other causes of increased transaminases (infectious, metabolic, autoimmune, or hereditary), according to the CIOMS causality scale, it is concluded that it was a possible, probable or definite episode of hepatic injury by drugs. Results: All children had more than one episode of hepatotoxicity, and a total of 98 episodes are analysed. Methotrexate was the most commonly implicated drug. The histological pattern of predominant damage was hepatocellular. Only 2 episodes were classified as serious. Conclusions: Idiosyncratic hepatotoxicity due to chemotherapy is frequent, with a tendency to relapse with re-exposure. Although it does not usually have important consequences, the high frequency makes it advisable to establish standardised safety algorithms with very strict monitoring of liver enzymes during high periods of risk in chemotherapy. Resumen: Introducción: La lesión hepática inducida por fármacos debida a quimioterapia es una causa importante de morbilidad en enfermos oncológicos aunque sus manifestaciones clínicas son poco conocidas. Objetivo: El objetivo del presente estudio fue determinar las características (formas de presentación, gravedad y tipo de lesión) de la hepatotoxicidad por quimioterapia en niños tratados por cáncer. Pacientes y método: Se incluyó en el estudio a un total de 22 enfermos oncológico en los que, tras descartar otras causas de aumento de transaminasas (infecciosa, metabólica, autoinmune o hereditaria), se concluye, según la escala de causalidad CIOMS, que se trata de un episodio posible, probable o definido de lesión hepática por fármacos. Resultados: Todos los niños tuvieron más de un episodio de hepatotoxicidad, en total se analizan 98 episodios. Metotrexato fue el fármaco implicado con mayor frecuencia. El patrón histológico de daño predominante fue hepatocelular. Solo 2 episodios fueron clasificados de graves. Conclusiones: La hepatotoxicidad idiosincrásica por quimioterapia es frecuente, la tendencia es a la recidiva con la reexposición y, aunque no suele tener consecuencias importantes, la elevada frecuencia hace aconsejable establecer algoritmos de seguridad estandarizados con controles muy estrictos de enzimas hepáticas durante los períodos de alto riesgo de quimioterapia.

The identification of specific HLA risk alleles in drug-induced liver injury (DILI) points toward an important role of the adaptive immune system in DILI development. In this study, we aimed to corroborate the role of an adaptive immune response in DILI through immunophenotyping of leukocyte populations and immune checkpoint expressions. Blood samples were collected from adjudicated DILI (n = 12), acute viral hepatitis (VH; n = 13), acute autoimmune hepatitis (AIH; n = 9), and acute liver injury of unknown etiology (n = 15) at day 1 (recognition), day 7, and day >30. Blood samples from patients with nonalcoholic fatty liver disease (NAFLD; n = 20) and healthy liver controls (HLCs; n = 54) were extracted at one time point. Leukocyte populations and immune checkpoint expressions were determined based on cell surface receptors, except for CTLA-4 that was determined intracellularly, using flow cytometry. At recognition, DILI demonstrated significantly higher levels of activated helper T-cell (P < 0.0001), activated cytotoxic T-cells (P = 0.0003), Th1 (P = 0.0358), intracellular CTLA-4 level in helper T-cells (P = 0.0192), and PD-L1 presenting monocytes (P = 0.0452) than HLC. These levels approached those of HLC over time. No significant differences were found between DILI and VH. However, DILI presented higher level of activated helper T-cells and CTLA-4 than NAFLD and lower PD-L1 level than AIH. Our findings suggest that an adaptive immune response is involved in DILI in which activated CD4+ and CD8+ play an important role. Increased expression of negative immune checkpoints is likely the effect of peripheral tolerance regulation. The present study has been supported by grants of Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional – FEDER (contract numbers: PI19/00883, PI16/01748, P18-RT-3364-2020, and PT20/000127). CIBERehd and Plataforma ISCiii Ensayos Clínicos are funded by Instituto de Salud Carlos III. Funding for open access charge: Universidad de Málaga/CBUA. The funding sources had no involvement in the study design; in the collection, analysis, and interpretation of data; in the writing of the report, or in the decision to submit the manuscript for publication.

Drug-induced liver injury (DILI) encompasses the unexpected damage that drugs can cause to the liver. DILI may develop in the context of an immunoallergic syndrome with cutaneous manifes- tations, which are sometimes severe (SCARs). Nevirapine, allopurinol, anti-epileptics, sulfonamides, and antibiotics are the most frequent culprit drugs for DILI associated with SCARs. Interestingly, alleles HLA-B*58:01 and HLA-A*31:01 are associated with both adverse reactions. However, there is no consensus about the criteria used for the characterization of liver injury in this context, and the different thresholds for DILI definition make it difficult to gain insight into this complex disorder. Moreover, current limitations when evaluating causality in patients with DILI associated with SCARs are related to the plethora of causality assessment methods and the lack of consensual complementary tools. Finally, the management of this condition encompasses the treatment of liver and skin injury. Although the use of immunomodulant agents is accepted for SCARs, their role in treating liver injury remains controversial. Further randomized clinical trials are needed to test their efficacy and safety to address this complex entity. Therefore, this review aims to identify the current gaps in the definition, diagnosis, prognosis, and management of DILI associated with SCARs, proposing different strategies to fill in these gaps. Instituto de Salud Carlos III: PI18/01804 Instituto de Salud Carlos III: PI19-00883; Instituto de Salud Carlos III: PT 20/00127; Instituto de Salud Carlos III: UMA18-FEDERJA-194; Instituto de Salud Carlos III: PY18-3364; Consejería de Salud de Andalucía: PI-0310-2018, PEMP-0127-2020; Instituto de Salud Carlos III: Rio Hortega CM17/00243; Instituto de Salud Carlos III: Sara Borrell CD20/00083; Instituto de Salud Carlos III: Sara Borrell CD21/00198.

Introduction: Idiosyncratic drug-induced liver injury (DILI) is an unpredictable event, and there are no specific biomarkers that can distinguish DILI from alternative explanations or predict its clinical outcomes. Areas covered: This systematic review summarizes the available evidence for all biomarkers proposed to have a role in the diagnosis or prognosis of DILI. Following a comprehensive search, we included all types of studies in humans. We included DILI cases based on any threshold criteria but excluded intrinsic DILI, commonly caused by paracetamol overdose. We classified studies into diagnostic and prognostic categories and assessed their methodological quality. After reviewing the literature, 14 studies were eligible. Expert Opinion: Diagnostic studies were heterogeneous with regard to the study population and outcomes measured. Prognostic models were developed by integrating novel biomarkers, risk scores, and traditional biomarkers, which increased their prognostic ability to predict death or transplantation by 6 months. This systematic review highlights the case of need for non-genetic biomarkers that distinguish DILI from acute liver injury related to alternative etiology. Biomarkers with the potential to identify serious adverse outcomes from acute DILI should be validated in independent prospective cohorts with a substantial number of cases. This paper was funded by the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 821283 (www.imi.europa.eu). This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. Translational Safety Biomarker Pipeline (TransBioLine): Enabling develop- ment and implementation of novel safety biomarkers in clinical trials and diagnosis of disease’ — ‘TransBioLine’ (‘action’). Grant Number: 821283.