Biomarkers of idiosyncratic drug-induced liver injury (DILI) - a systematic review

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

Oxidative Stress in Drug-Induced Liver Injury (DILI): From Mechanisms to Biomarkers for Use in Clinical Practice

Idiosyncratic drug-induced liver injury (DILI) is a type of hepatic injury caused by an uncommon drug adverse reaction that can develop to conditions spanning from asymptomatic liver laboratoryabnormalitiestoacuteliverfailure(ALF)anddeath.Thecellularandmolecularmecha- nisms involved in DILI are poorly understood. Hepatocyte damage can be caused by the metabolic activation of chemically active intermediate metabolites that covalently bind to macromolecules (e.g., proteins, DNA), forming protein adducts—neoantigens—that lead to the generation of oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress, which can eventually lead to cell death. In parallel, damage-associated molecular patterns (DAMPs) stimulate the immune response, whereby inflammasomes play a pivotal role, and neoantigen presentation on specific human leukocyte antigen (HLA) molecules trigger the adaptive immune response. A wide array of antioxidant mechanisms exists to counterbalance the effect of oxidants, including glutathione (GSH), superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX), which are pivotal in detoxification. These get compromised during DILI, triggering an imbalance between oxidants and antioxidants defense systems, generating oxidative stress. As a result of exacerbated oxidative stress, several danger signals, including mitochondrial damage, cell death, and inflammatory markers, and microRNAs (miRNAs) related to extracellular vesicles (EVs) have already been reported as mechanis- tic biomarkers. Here, the status quo and the future directions in DILI are thoroughly discussed, with a special focus on the role of oxidative stress and the development of new biomarkers.This work was supported by the MINECO Retos SAF2016-78711, EXOHEP-CM S2017/BMD- 3727, NanoLiver-CM Y2018/NMT-4949, ERAB Ref. EA 18/14, AMMF 2018/117, FIS-FEDER PI16_01748, PI19-00883, UMA18-FEDERJA-194, PY18-3364_PY19 and UCM-25-2019. FJC is a Ramón y Cajal Researcher RYC-2014-15242 and a Gilead Liver Research 2018. The research group belongs to the validated Research Groups Ref. 970935 “Liver Pathophysiology” and 920631 “Lymphocyte immunobiology” and IBL-6 (imas12-associated). This article/publication is based upon work from COST Action “CA17112—Prospective European Drug-Induced Liver Injury Network” supported by COST (European Cooperation in Science and Technology); www.cost.eu; accessed 4 March 2021. CIBERehd is funded by ISCiii

BENEFÍCIO DA HIPOCOAGULAÇÃO APÓS PONTAGEM DO MEMBRO INFERIOR — UMA REVISÃO SISTEMÁTICA DA LITERATURA

Introdução: Após revascularização cirúrgica do membro inferior é habitualmente prescrito antiagregantes plaquetários e a anticoagulação é considerada em casos de risco aumentado de trombose. Realizamos uma revisão sistemática da literatura da evidência existente sobre o uso prolongado de anticoagulantes no pós-operatório de pontagens do membro inferior. Material e métodos: Revisão sistemática da literatura disponível na base de dados Pubmed. Resultados: Os estudos selecionados para a revisão final consistiam em: 6 estudos aleatorizados controlados (e 4 análises post-hoc), 1 estudo prospectivo com controlos históricos e 3 estudos retrospectivos. Conclusão: A eficácia da hipocoagulação depende do conducto utilizado e factores intrínsecos da pontagem. Existe benefício de hipocoagulação nas pontagens com o conduto venoso autólogo mas o nível de INR e os factores de risco para trombose poderão influenciar os resultados. Nas pontagens poderá haver benefício naquelas com calibre diminuído e baixa velocidade média. A incidência de hemorragia major é significativa, sendo essencial a cuidadosa avaliação do risco beneficio na prescrição de hipocoagulação crónica

Epstein-Barr Virus and Astrocytoma

International audienceEpstein-Barr virus (EBV) is an established pathogen linked to a wide range of lymphoproliferative disorders and solid tumors. Astrocytoma is one of the most frequent brain tumors in children, adolescents, and young adults. Astrocyte proliferation usually occurs after brain tissue aggression, which may be of different types, including viral infection. In particular, it has been suggested that EBV may play a role in astrocytoma pathogenesis. This article presents the summarized results of a systematic review of the literature on the relationship between EBV infection and astrocytoma pathophysiology. Although most studies detect the presence of EBV DNA in subsets of astrocytoma tumors, our conclusion is that currently, except for rare cases, there is no clear evidence that EBV plays a role in the development of astrocytoma

Oxidative Stress in Drug-Induced Liver Injury (DILI): From Mechanisms to Biomarkers for Use in Clinical Practice

This work was supported by the MINECO Retos SAF2016-78711, EXOHEP-CM S2017/BMD-3727, NanoLiver-CM Y2018/NMT-4949, ERAB Ref. EA 18/14, AMMF 2018/117, FIS-FEDER PI16_01748, PI19-00883, UMA18-FEDERJA-194, PY18-3364_PY19 and UCM-25-2019. FJC is a Ramón y Cajal Researcher RYC-2014-15242 and a Gilead Liver Research 2018. The research group belongs to the validated Research Groups Ref. 970935 “Liver Pathophysiology” and 920631 “Lymphocyte immunobiology” and IBL-6 (imas12-associated). This article/publication is based upon work from COST Action “CA17112—Prospective European Drug-Induced Liver Injury Network” supported by COST (European Cooperation in Science and Technology); www.cost.eu; accessed 4 March 2021. CIBERehd is funded by ISCiii.Idiosyncratic drug-induced liver injury (DILI) is a type of hepatic injury caused by an uncommon drug adverse reaction that can develop to conditions spanning from asymptomatic liver laboratory abnormalities to acute liver failure (ALF) and death. The cellular and molecular mechanisms involved in DILI are poorly understood. Hepatocyte damage can be caused by the metabolic activation of chemically active intermediate metabolites that covalently bind to macromolecules (e.g., proteins, DNA), forming protein adducts—neoantigens—that lead to the generation of oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress, which can eventually lead to cell death. In parallel, damage-associated molecular patterns (DAMPs) stimulate the immune response, whereby inflammasomes play a pivotal role, and neoantigen presentation on specific human leukocyte antigen (HLA) molecules trigger the adaptive immune response. A wide array of antioxidant mechanisms exists to counterbalance the effect of oxidants, including glutathione (GSH), superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX), which are pivotal in detoxification. These get compromised during DILI, triggering an imbalance between oxidants and antioxidants defense systems, generating oxidative stress. As a result of exacerbated oxidative stress, several danger signals, including mitochondrial damage, cell death, and inflammatory markers, and microRNAs (miRNAs) related to extracellular vesicles (EVs) have already been reported as mechanistic biomarkers. Here, the status quo and the future directions in DILI are thoroughly discussed, with a special focus on the role of oxidative stress and the development of new biomarkers.Ministerio de Ciencia e Innovación (España)Comunidad Autónoma de MadridUniversidad Complutense de MadridInstituto de Salud Carlos IIIUniversidad de MálagaDepto. de Inmunología, Oftalmología y ORLFac. de MedicinaTRUEpu