Gut Online First, published on March 23, 2017 as 10.1136/gutjnl-2016-313369 Recent advances in clinical practice Drug-induced liver injury: recent advances Gut: first published as 10.1136/gutjnl-2016-313369 on 23 March 2017. Downloaded from in diagnosis and risk assessment Gerd A Kullak-Ublick,1,2 Raul J Andrade,3 Michael Merz,4 Peter End,4 Andreas Benesic,5,6 Alexander L Gerbes,5 Guruprasad P Aithal7 1Department of Clinical ABSTRACT thereby contributing to the considerable economic Pharmacology and Toxicology, Idiosyncratic drug-induced liver injury (IDILI) is a rare but issues associated with DILI. University Hospital Zurich and University of Zurich, Zurich, potentially severe adverse drug reaction that should be Patients who consume acetaminophen (APAP) at Switzerland considered in patients who develop laboratory criteria for a single dose exceeding 7.5 g experience acute liver 2Drug Safety and liver injury secondary to the administration of a toxicity, notably if plasma concentrations exceed Epidemiology, Novartis potentially hepatotoxic drug. Although currently used 200 or 100 μg/L 4 or 8 hours after ingestion, Pharma, Basel, Switzerland 3 liver parameters are sensitive in detecting DILI, they are respectively. APAP intake at the licensed dose of Unidad de Gestión Clínica de fi ’ Aparato Digestivo, Instituto de neither speci c nor able to predict the patient s 4 g/day over a period of 2 weeks results in eleva- Investigación Biomédica de subsequent clinical course. Genetic risk assessment is tions of alanine aminotransferase (ALT) above 3× Málaga-IBIMA, Hospital useful mainly due to its high negative predictive value, the upper limit of normal (ULN) in one-third of Universitario Virgen de la with several human leucocyte antigen alleles being patients.13 This form of dose-dependent Victoria, Universidad de intrinsic DILI Málaga, Centro de associated with DILI. New emerging biomarkers which APAP-induced toxicity is termed :itis Investigación Biomédica en Red could be useful in assessing DILI include total keratin18 predictable, reproducible in preclinical models and de Enfermedades Hepáticas y (K18) and caspase-cleaved keratin18 (ccK18), much insight has been gained into the underlying Digestivas (CIBERehd), Málaga, macrophage colony-stimulating factor receptor 1, high mechanisms.14 15 Spain 4 mobility group box 1 and microRNA-122. From the In contrast to intrinsic DILI, the onset of idiosyn- Novartis Institutes for cratic DILI (IDILI) BioMedical Research, Novartis numerous in vitro test systems that are available, , which is very rare but nonethe- Campus, Basel, Switzerland monocyte-derived hepatocytes generated from patients less responsible for about 10–15% of acute liver 5Department of Medicine II, with DILI show promise in identifying the DILI-causing failures in the USA,16 is almost impossible to Klinikum Grosshadern of the agent from among a panel of coprescribed drugs. predict. IDILI is characterised by a variable latency University of Munich (KUM), Several computer-based algorithms are available that rely to onset (weeks to months) and a lack of clear dose University of Munich, Munich, 17 Germany on cumulative scores of known risk factors such as the dependency. Drug–protein adducts, formed by 6MetaHeps GmbH, Planegg/ administered dose or potential liabilities such as drugs or their metabolites that interact with host Martinsried, Germany 7 mitochondrial toxicity, inhibition of the bile salt export proteins, are presented as neoantigens by major National Institute for Health pump or the formation of reactive metabolites. A novel histocompatibility complex class II, thereby trigger- Research (NIHR), Nottingham http://gut.bmj.com/ Digestive Diseases Biomedical DILI cluster score is being developed which predicts DILI ing an immunoallergic reaction. Individuals with Research Unit, Nottingham from multiple complimentary cluster and classification underlying hepatic injury such as viral hepatitis or University Hospitals NHS Trust models using absorption–distribution–metabolism– inflammatory conditions may be more susceptible and the University of elimination-related as well as physicochemical properties, to immunoallergic injury.18 Following the initial Nottingham, Nottingham, UK diverse substructural descriptors and known structural insult, additional mechanisms such as inhibition of Correspondence to liabilities. The provision of more advanced scientific and transporters, mitochondrial injury, endoplasmic Dr Gerd A Kullak-Ublick, fl regulatory guidance for liver safety assessment will reticulum and oxidative stress and proin ammatory on September 24, 2021 by guest. Protected copyright. Department of Clinical depend on validating the new diagnostic markers in the cytokines can further amplify the injury mechan- Pharmacology and Toxicology, ongoing DILI registries, biobanks and public–private isms that lead to acute DILI.19 Identification of University Hospital Zurich and University of Zurich, partnerships. host factors that render an individual susceptible is 20 Rämistrasse 100, Zurich 8091, the focus of ongoing pharmacogenetic studies. Switzerland; This review article focuses on IDILI and the subse- [email protected] IMPORTANCE OF DILI DIAGNOSIS quent use of the term DILI essentially implies Received 8 November 2016 Drug-induced liver injury (DILI) accounts for <1% IDILI. Revised 24 February 2017 of cases of acute liver injury seen by gastroenterolo- A major problem in drug development is the fre- Accepted 28 February 2017 gists, but is the most common cause for acute liver quency of adverse hepatic reactions induced by the – failure in the USA and Europe.1 3 According to newer molecular targeted agents (MTAs) in oncol- surveys in France and Iceland, DILI occurs with an ogy. Hepatotoxicity occurs in one-third of patients annual incidence of about 14–19 per 100 000 inha- treated with a protein kinase inhibitor, with fatal bitants.45DILI is also a leading cause of attrition outcome reported for pazopanib, sunitinib and of compounds in drug development and one of the regorafenib.21 Ten per cent of patients treated with two most frequent causes for drug withdrawals, immune checkpoint inhibitors, notably ipilimumab, – restrictions and project terminations (figure 1).6 11 develop liver injury with high rates of recurrent Of 76 drugs withdrawn from the market between liver injury upon rechallenge.21 The epidermal 1969 and 2002, 12 were attributable to liver growth factor receptor (EGFR) tyrosine kinase To cite: Kullak-Ublick GA, damage.12 Whereas liver signals that escape detec- inhibitor (TKI) gefitinib is associated with a 18.5% Andrade RJ, Merz M, et al. Gut Published Online First: tion during drug approval result in postmarketing frequency of hepatotoxicity and casualties have [please include Day Month restrictions (eg, pazopanib, temozolomide and flu- occurred for all EGFR TKIs.22 The oncology popu- Year] doi:10.1136/gutjnl- pirtine in 2013), the risk of false-positive DILI lation that is treated with MTAs is more likely to 2016-313369 adjudication may lead to unnecessary attrition, have multiple comorbidities and comedications and Kullak-Ublick GA, et al. Gut 2017;0:1–11. doi:10.1136/gutjnl-2016-313369 1 Copyright Article author (or their employer) 2017. Produced by BMJ Publishing Group Ltd (& BSG) under licence. Recent advances in clinical practice Figure 1 Impact of idiosyncratic drug-induced liver injury (IDILI) on Gut: first published as 10.1136/gutjnl-2016-313369 on 23 March 2017. Downloaded from drug attrition. Pie charts showing the occurrence of liver test abnormalities in clinical trials with drugs withdrawn or stopped due to DILI. Blue: percentage of study participants with normal liver tests and Red: percentage of patients with possibly drug-related liver enzyme elevations. is therefore at risk for hepatotoxicity. The Food and Drug dietary supplements presents unique challenges to hepatotox- Administration (FDA) issues detailed recommendations in drug icity assessment and its incidence is increasing.33 34 Due to the labels as to liver test monitoring intervals and stopping rules; lack of a reliable diagnostic in vitro test, there is no objective however, intensive postmarketing surveillance of method beyond expert opinion that assesses causality of a given MTA-associated liver injury is required. The standard recom- drug in individual cases. mendations contained in the current FDA Guidance to Industry23 are not applicable to the oncology population and STANDARD OF DIAGNOSIS: ROLE OF CURRENTLY new methods of liver safety assessment are required.24 For the PERFORMED LIVER TESTS IN ASSESSING DILI management of IDILI, a key question is whether a patient in DILI most often presents as an acute viral hepatitis-like syn- whom DILI has been diagnosed will progress to severe liver drome, without symptoms that specifically point to the drug injury with potentially fatal outcome or recover spontaneously aetiology unless rash or other cutaneous manifestations35 after cessation of the causative agent. A diagnostic algorithm reinforce the suspicion of drug toxicity. The clinical spectrum of that allows identification of risk factors and prediction of the DILI can mimic almost every other liver disorder. subsequent clinical course would greatly facilitate the manage- Accompanying blood eosinophilia is uncommon in large series ment of acute DILI. The current lack of predictive safety testing of patients with DILI,36 37 but is clearly suggestive of drug before administration of a potentially hepatotoxic compound allergy. Histopathological