A new Framework for Advancing in Drug-induced Liver Injury Research

The Prospective European DILI Registry

Einar S. Björnsson; Camilla Stephens; Edmond Atallah; Mercedes Robles-Diaz; Ismael Alvarez-Alvarez; Alexander Gerbes; Sabine Weber; Guido Stirnimann; Gerd Kullak-Ublick; Helena Cortez-Pinto; Jane I. Grove; M. Isabel Lucena; Raul J. Andrade; Guruprasad P. Aithal


Liver International. 2023;43(1):115-126. 

In This Article

Abstract and Introduction


Background & Aims: No multi-national prospective study of drug-induced liver injury (DILI) has originated in Europe. The design of a prospective European DILI registry, clinical features and short-term outcomes of the cases and controls is reported.

Methods: Patients with suspected DILI were prospectively enrolled in the United Kingdom, Spain, Germany, Switzerland, Portugal and Iceland, 2016–2021. DILI cases or non-DILI acute liver injury controls following causality assessment were enrolled.

Results: Of 446 adjudicated patients, 246 DILI patients and 100 had acute liver injury due to other aetiologies, mostly autoimmune hepatitis (n = 42) and viral hepatitis (n = 34). DILI patients (mean age 56 years), 57% women, 60% with jaundice and 3.6% had pre-existing liver disease. DILI cases and non-DILI acute liver injury controls had similar demographics, clinical features and outcomes. A single agent was implicated in 199 (81%) DILI cases. Amoxicillin-clavulanate, flucloxacillin, atorvastatin, nivolumab/ipilimumab, infliximab and nitrofurantoin were the most commonly implicated drugs. Multiple conventional medications were implicated in 37 (15%) and 18 cases were caused by herbal and dietary supplements. The most common single causative drug classes were antibacterials (40%) and antineoplastic/immunomodulating agents (27%). Overall, 13 (5.3%) had drug-induced autoimmune-like hepatitis due to nitrofurantoin, methyldopa, infliximab, methylprednisolone and minocycline. Only six (2.4%) DILI patients died (50% had liver-related death), and another six received liver transplantation.

Conclusions: In this first multi-national European prospective DILI Registry study, antibacterials were the most commonly implicated medications, whereas antineoplastic and immunomodulating agents accounted for higher proportion of DILI than previously described. This European initiative provides an important opportunity to advance the study on DILI.


Interest in the study of idiosyncratic drug-induced liver injury (DILI) has increased considerably during the last two decades. Given the relative rarity of this adverse reaction, it is often not detected during drug development nor in clinical trials and becomes apparent after marketing.[1] DILI due to troglitazone was detected late in the post-marketing phase leading to high mortality from acute liver failure among troglitazone users in the United States and other countries.[2] The devastating consequences of troglitazone hepatotoxicity, along with severe DILI adverse reactions due to other drugs occurring pre- and post-marketing might partly explain the increased interest and funding of research initiatives in this area. In Europe, pioneering prospective studies on DILI have appeared from the Spanish DILI Registry,[3] and other European DILI cohorts have been reported from Sweden,[4] Iceland[5] and Germany.[6] Similarly, the Drug-Induced Liver Injury Network (DILIN) project, sponsored by the National Institutes of Health, has described causative agents, risk factors and outcome of DILI in the United States.[7] In Asian countries, the more recently established Indian Network of Drug-Induced Liver Injury,[8] as well as nationwide studies,[9,10] reflect the growing interest in this public health burden. The European Association for the Study of the Liver (EASL)—Lancet liver commission recently highlighted DILI as an extremely challenging clinical condition due to the wide range of drugs used in clinical practice, the variety of clinical presentations and serious outcomes.[11] The article highlighted the gaps in the DILI field, including the lack of recent information regarding its true prevalence in Europe. However, to date, no multi-national prospective cohort study of DILI has been reported from Europe.

The aim of the current study was to report the clinical presentation, drug aetiologies and outcomes from a European-wide interdisciplinary network of researchers, the Prospective European DILI (Pro-Euro-DILI) Registry.