Diagnostic and Prognostic Assessment of Suspected Drug-induced Liver Injury in Clinical Practice

Raúl J. Andrade; Mercedes Robles-Díaz

Disclosures

Liver International. 2020;40(1):6-17. 

In This Article

Abstract and Introduction

Abstract

Idiosyncratic drug-induced liver injury (DILI) is a challenging liver disorder because it can present with a range of phenotypes, mimicking almost every other hepatic disease, and lacks specific biomarkers for its diagnosis. Hence, a confident DILI diagnosis is seldom possible as it relies on the precise establishment of a temporal sequence between the exposure to a given prescription drug or sometimes hidden herbal product/over the counter medication as well as the exclusion of other aetiologies of liver disease. However, an accurate diagnosis is of most importance, as prompt withdrawal of the causative agent is essential in DILI management. Indeed, DILI can be severe and even fatal or in a fraction of cases evolve to chronic damage, but specific biomarkers for predicting mortality/liver transplantation or a chronic outcome in the very early phases of DILI are not yet available. In this article, we discuss the best diagnostic and prognostic approach of a DILI suspicion by judiciously choosing and interpreting the standard tests currently used in clinical practice.

Introduction

Idiosyncratic drug-induced liver injury (DILI), as opposed to intrinsic DILI, is an unexpected adverse drug reaction that occurs rarely owing to interactions between drug properties and host factors (genetics, alcohol intake, diet, coexisting diseases, associated medications and microbiome among others). The variety of interactions accounts for individual susceptibility, DILI phenotypic expression and outcome.[1] Genetic variations in genes involved in drug metabolism phases 1 (bioactivation), phase 2 (conjugation) and phase 3 (cellular excretion) are believed to affect the accumulation of reactive metabolites to a critical threshold leading to cellular stress that potentially initiates cell damage and active immune responses.[2] Drug chemical properties are probably of most importance in the initiation of mild injury, but once injury begins the responses to injury insult (ie immune response, inflammation, tissue injury and repair) are mainly driven by host factors.[1]

The complexity of the mechanism underlying idiosyncratic DILI and the variability from one subject to another might also explain the particular signature of this adverse hepatic reaction, namely the ability to present with a wide range of phenotypes and severity. Indeed, idiosyncratic DILI is one of the most challenging clinical scenarios in hepatology. This is because of the impressive number of drugs used in clinical practice but also herbs and dietary supplements that have shown hepatotoxic potential, its low frequency compared with other acute or chronic liver disease, the variety of clinical and histological phenotypic presentation and, most importantly, the current absence of specific biomarkers able to distinguish DILI form other liver disorders. All these factors jeopardize the correct assessment of DILI, whose diagnosis still relies on a high degree of suspicion in addition to careful exclusion of alternative aetiologies of liver damage. Idiosyncratic DILI is also the most frequent cause of acute liver failure (ALF) in the USA and Europe. Notably, drug-induced ALF carries a particularly poor prognosis so an early prediction is of paramount importance.[3]

Recent concerted efforts on biomarker discovery and validation in the Innovative Medicines Initiative Safer and Faster Evidence-based Translation (IMI SAFE-T) Consortium[4] have brought hope to the area of new serum biomarkers to improve the diagnostic performance of currently used aminotransferases in patients with DILI. However, despite the identification of promising soluble markers for predicting outcome, the specificity of these new analytes in terms of distinguishing DILI from other hepatic injuries is yet limited.[5] Hence, correct assessment of DILI suspicions requires nowadays the optimization of the current laboratory and imaging tests available for a better diagnostic approach and prognostic prediction. In this article, we aim to discuss the best approach to diagnostic and prognostic DILI assessment in a post-market setting.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....