https://orcid.org/0000-0002-7341-9174
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ABSTRACT
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.
Article Highlights
Idiosyncratic drug-induced liver injury (DILI) is an unpredictable and challenging clinical event. There is a critical need for biomarkers to detect it, differentiate DILI from other liver injuries and predict its outcomes to guide clinical management. Multiple novel biomarkers have been studied but failed to reach full qualification and application in clinical practice.
This is the first systematic review to summarize the available evidence on the diagnostic and prognostic applications of biomarkers in DILI.
This review demonstrates significant heterogeneity in study designs and lack of validity for novel biomarkers. Predictive models that combine pre-existing risk scores, liver enzymes, and new biomarkers showed high accuracy for predicting death/transplantation at 6 months following DILI.
This review highlights the need for a concerted effort from a multidisciplinary international collaboration focused on idiosyncratic DILI to design and coordinate the discovery, evaluation, and validation of novel biomarkers that are suitable for use in the clinical phase of drug development as well as clinical practice.
This box summarizes key points contained in the article.
Author Contributions
E Atallah drafted the protocol, designed the search strategy, screened studies for eligibility, extracted data from included studies, assessed the methodological quality of studies and drafted the final review. C Freixo screened studies for eligibility, extracted data from included studies, and contributed to the text of the final review. I Alvarez-Alvarez screened studies for eligibility, extracted data from included studies, assessed the methodological quality of included studies, and contributed to the text of the final review. FJ Cubero, GA Kullak-Ublick, and AL Gerbes provided expert opinion and contributed the text of the final review. GP Aithal provided expert opinion on the whole review, involved in decision making, reviewed and revised the manuscript.
All authors approved the final version of the article, including the authorship list.
Declaration of Interest
GP Aithal has received consulting fees from Pfizer and GlaxoSmithKline paid to the University of Nottingham. C Frexio works as a Pharmaceutical Medicine Physician for Novo Nordisk A/S. I Alvarez-Alvarez holds a Sara Borrell contract (CD20/00083) funded by ISCIII. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Acknowledgement
We acknowledge the support of the Translational Safety Biomarker Pipeline (TransBioLine) consortium (GPA, GKU and ALG members) for their internal review process of the review. This article/publication is supported by COST Action CA17112 Prospective European Drug-Induced Liver Injury Network, supported by COST (European Cooperation in Science and Technology). COST is a funding agency for research and innovation networks. Our Actions help connect research initiatives across Europe and enable scientists to grow their ideas by sharing them with their peers. This boosts their research, career and innovation (www.cost.eu).
Disclaimer
The communication reflects the authors’ view and that neither IMI nor the European Union, EFPIA, or any Associated Partners are responsible for any use that may be made of the information contained therein.
Reviewer Disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Supplementary material
Supplemental data for this article can be accessed here.
Correction Statement
This article has been republished with minor changes. These changes do not impact the academic content of the article.