Drug-induced liver injury (DILI) is termed "idiosyncratic" when it occurs in a small proportion of patients on drug treatments. It is currently unpredictable and cannot be explained by the pharmacological properties of the drug. In addition to jeopardizing patient safety, it is major cause for withdrawal of successfully launched drugs and for discontinuation of drugs in development. The ability to predict individuals at risk of developing idiosyncratic DILI is of high importance. The identification of DILI risk factors and understanding their role in DILI could subsequently facilitate this task. This would enable patients without DILI risk to securely benefit from an effective treatment (including medications with black box warnings for DILI), while ensuring patient safety to those at increased risk by providing alternative medications. The underlying mechanism of idiosyncratic DILI is not fully understood, but it is believed that this condition is the precipitation of interactions between drug properties and host factors in a susceptible individual. This article summarizes the currently known mechanisms of DILI focusing on drug-induced cellular stress and immune responses. In addition, determinants of susceptibility and risk modulators are discussed, paying attention to drug properties, host factors, and their interactions.

IntroductionData on positive rechallenge in idiosyncratic drug-induced liver injury (DILI) are scarce. We aim to analyse the clinical presentation, outcome and drugs associated with positive rechallenge in two DILI registries.MethodsCases from the Spanish and Latin American DILI registries were included. Demographics, clinical characteristics and outcome of cases with positive rechallenge according to CIOMS/RUCAM and current definitions were analysed.ResultsOf 1,418 patients with idiosyncratic DILI, 58 cases had positive rechallenge (4.1%). Patients with positive rechallenge had shorter duration of therapy (p=0.001) and latency (p=0.003). In patients with rechallenge, aspartate transaminase levels were increased (p=0.026) and showed a prolonged time to recovery (p=0.020), albeit no differences were seen in terms of fatal outcomes. The main drug implicated in rechallenge was amoxicillin-clavulanate (17%). The majority of re-exposure events were unintentional (71%). Using both existing definitions of positive rechallenge, there were four cases which exclusively fulfilled the current criteria and five which only meet the historical definition. All cases of positive rechallenge, irrespective of the pattern of damage, fulfilled the criteria of either alanine transaminase (ALT) ≥3 times the upper limit of normal (ULN) and/or alkaline phosphatase (ALP) ≥2 times ULN.ConclusionsEpisodes of rechallenge were characterised by shorter duration of therapy and latency, and longer time to resolution, but did not show an increased incidence of fatal outcome. Based on our findings, ALT ≥3 times ULN and/or ALP ≥2 times ULN, regardless of the pattern of damage, is proposed as a new definition of rechallenge in DILI.

In the current article the aims for a constructive way forward in Drug-Induced Liver Injury (DILI) are to highlight the most important priorities in research and clinical science, therefore supporting a more informed, focused, and better funded future for European DILI research. This Roadmap aims to identify key challenges, define a shared vision across all stakeholders for the opportunities to overcome these challenges and propose a high-quality research program to achieve progress on the prediction, prevention, diagnosis and management of this condition and impact on healthcare practice in the field of DILI. This will involve 1. Creation of a database encompassing optimised case report form for prospectively identified DILI cases with well-characterised controls with competing diagnoses, biological samples, and imaging data; 2. Establishing of preclinical models to improve the assessment and prediction of hepatotoxicity in humans to guide future drug safety testing; 3. Emphasis on implementation science and 4. Enhanced collaboration between drug-developers, clinicians and regulatory scientists. This proposed operational framework will advance DILI research and may bring together basic, applied, translational and clinical research in DILI.

Background: Severe cutaneous adverse reactions can manifest in a wide spectrum of heterogeneous clinical presentations, including drug reaction with eosinophilia and systemic symptoms (DRESS), a severe idiosyncratic drug reaction. DRESS is characterized by presence of rash, fever, eosinophilia and/or lymphopenia, and liver injury but there is no consensus for the definition of this condition. We aimed to evaluate clinical phenotype, outcome and causative agents associated with DRESS.

Idiosyncratic drug induced liver injury (DILI) is a rare adverse drug reaction that poses major challenges to healthcare practitioners and regulatory agencies. We aimed to update the clinical characteristics and outcomes of DILI patients, and the drugs frequently implicated in hepatotoxicity in Spain. We analyzed 915 DILI cases (842 single episodes, 55 re-challenges, 18 double-episodes due to different drugs) in 857 patients included in the Spanish DILI Registry from 1994 to 2015. Cases were adjudicated using expert clinical judgment/RUCAM scale and compared according to pattern of liver damage (hepatocellular, HC; cholestatic, Chol or mixed, Mix). The cohort median age was 57 years (range: 11-90 y) with a mean body mass index of 25.8 ± 3.8 kg/m2. Male gender predominated (52%). HC, Chol and Mix patterns of liver damage were identified in 65%, 18% and 17% of cases, respectively. More than half of the cases were of moderate severity (58%). Patients with Chol and Mix pattern were older (median 64 y and 62 y, respectively) than HC patients (median 52 y), p<0.001. Anti-infectives, central nervous system, cardiovascular and anti-inflammatory agents were the most commonly implicated therapeutic classes accounting for 37%, 14%, 11% and 9% of cases, respectively. Amoxicillin/clavulanate remains the agent responsible for the highest number of DILI (21% of cases). Substantial increase in anabolic androgenic steroid-induced hepatotoxicity was observed in recent years. A cluster of DILI cases reported to the registry (i.e. ebrotidine, tetrabamate, nimesulide, amoxicillin-clavulanate, Exolise®, Epistane®) contributed to adoption of regulatory measures. The pioneering prospective Spanish DILI Registry proved to be very valuable for in-depth clinical phenotyping of hepatotoxicity, providing consistent figures in clinical characteristic outcomes and implicated drugs. It also constitutes an important tool for public health promotion in postmarketing drug surveillance.

Most drug-induced liver injury (DILI) patients develop symptoms while on drug treatments; however in some instances DILI develops after drug cessation. The reasons behind this delayed onset are currently unknown. In this study we aimed to determine drug-properties and host-factors potentially involved in DILI with delayed onset. 413 DILI cases from the Spanish DILI Registry were classified according to time of first symptom appearance, during (no delay onset, NDO) or after (delay onset, DO) causative agent treatment. The drugs were divided into two groups: drugs with (WP) or without potential (WOP) to induce delayed onset. Only oral drugs with at least three cases in the registry were selected. Amoxicillin-clavulanate (AC) cases were analyzed independently. A total of 11 WP and 33 WOP drugs were found, corresponding to 204 and 209 cases, respectively. Ninety-four (46%) cases, of which 83% were due to AC, presented DO between 2-52 days after treatment cessation. The WP drug cases, omitting AC cases, showed shorter duration of treatment (11 vs 54 days, p=0.0001), time to onset (14 vs 40 days, p=0.0001) and higher mean dosage (744 vs 374 mg, p=0.0001) than the cases induced by WOP drugs. The DO cases showed lower incidence of comorbidities (p=0.0001). In terms of drug properties, the WP drugs showed lower ratio of hepatic metabolism (p=0.0190) and higher proportion of parental drug excretion (p=0.0015). The interactions analyzed showed that drugs with mitochondrial liability have stronger effect on delayed onset in younger patients, females and absence of cardiac diseases. Delayed onset potential appears associated with higher drug dose, shorter treatment and less comorbidities. The fact that drugs with low hepatic metabolism are more frequently associated with delayed onset suggests that additional mechanism(s) outside hepatic metabolism influence the probability of delayed onset.