Drug-induced hepatotoxicity.

Causality assessment of adverse reactions to drugs--I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries.

Drug-induced liver injury (DILI) is an important cause of serious liver disease. The antimicrobial agent flucloxacillin is a common cause of DILI, but the genetic basis for susceptibility remains unclear. We conducted a genome-wide association (GWA) study using 866,399 markers in 51 cases of flucloxacillin DILI and 282 controls matched for sex and ancestry. The GWA showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 x 10(-33)) seen for rs2395029[G], a marker in complete linkage disequilibrium (LD) with HLA-B*5701. Further MHC genotyping, which included 64 flucloxacillin-tolerant controls, confirmed the association with HLA-B*5701 (OR = 80.6, P = 9.0 x 10(-19)). The association was replicated in a second cohort of 23 cases. In HLA-B*5701 carrier cases, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance (OR = 4.1, P = 1.4 x 10(-8)). These findings provide new insights into the mechanism of flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease.

HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin.

Given its rarity, drug-related hepatotoxicity may not be seen during the initial clinical trials of a new medication. After approval, when many more patients are exposed, toxic effects that are very infrequent may emerge. This review explains the difficulties in identifying the cause of hepatotoxic effects in such situations and provides clinical guidance with regard to the detection, evaluation, and possible prevention of drug-related hepatotoxicity.

https://www.nejm.org/doi/pdf/10.1056/nejmra052270

Drug-Related Hepatotoxicity

The occurrence of idiosyncratic drug hepatotoxicity is a major problem in all phases of clinical drug development and the most frequent cause of post-marketing warnings and withdrawals This review examines the clinical signatures of this problem, signals predictive of its occurrence (particularly of more frequent, reversible, low-grade injury) and the role of monitoring in prevention by examining several recent examples (for example, troglitazone) In addition, the failure of preclinical toxicology to predict idiosyncratic reactions, and what can be done to improve this problem, is discussed Finally, our current understanding of the pathophysiology of experimental drug hepatotoxicity is examined, focusing on acetaminophen, particularly with respect to the role of the innate immune system and control of cell-death pathways, which might provide targets for exploration and identification of risk factors and mechanisms in humans

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Idiosyncratic drug hepatotoxicity

• We retrospectively analyzed 63 observations collected in nine French departments of dermatology of an acute pustular dermatosis, recently named in the French literatureacute generalized exanthematous pustulosis(AGEP). Even though 11 of these cases occurred in patients with a history of psoriasis, AGEP appeared distinct from pustular psoriasis based on several slight pathologic differences, drug induction in most cases, and a more acute course of fever and pustulosis, with rapid spontaneous healing. We, therefore, suggest that AGEP is a reaction pattern, perhaps favored by a "psoriatic background." The most frequent causes of AGEP seem to be drug reactions, acute infections with enteroviruses, and hypersensitivity to mercury. With 55 (87%) of 63 cases attributed to drugs in this series, AGEP should be added to the list of cutaneous adverse drug reactions. Among druginduced skin eruptions, AGEP is remarkable by its short time to onset after the administration of the suspected drug ( (Arch Dermatol.1991;127:1333-1338)

Acute generalized exanthematous pustulosis. Analysis of 63 cases.

Causality assessment of adverse reactions to drugs--II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge.

Proposed improvement to the WHO adverse reaction terminology (WHO‐ART)

The weaknesses and the nonreproducibility of most causality assessment methods could be explained, at least in part, by the following reasons: (a) they pretend to be applied to all adverse drug events, and (b) they propose levels for the various criteria but do not clearly define their limits. In order to try and resolve these issues, Roussel Uclaf has organized French consensus meetings with university experts and specialists in industrial or official pharmacovigilance. A consensus has been reached on the definition of adverse reactions, on the limits of the various chronologic criteria and on the evaluation of the clinical context. Most situations have been considered, reducing the individual interpretation and ensuring an excellent reproducibility. On the basis of these results, and using the same method for organizing the meeting, a first international consensus on drug-induced liver disorders has been recently obtained in Paris.

Christian Bénichou

Papers

Causality assessment of adverse reactions to drugs--I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries.

Acute generalized exanthematous pustulosis. Analysis of 63 cases.

Causality assessment of adverse reactions to drugs--II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge.

Proposed improvement to the WHO adverse reaction terminology (WHO‐ART)

Experts' Opinion in Causality Assessment: Results of Consensus Meetings