The Evolving Profile of Idiosyncratic Drug-Induced Liver Injury

Funding Information: Conflicts of interest This author discloses the following: Rajender Reddy has received grant/research support from BMS, EXACT Sciences, NASH-TARGET, HCC-TARGET, Intercept, Mallinckrodt, Grifols, Sequana, and BioVie; serves on advisory committee/review panel for Mallinckrodt, NovoNordisk, Genfit, and Spark Therapeutics; and Data and Safety Monitoring Board from Novartis and Astra Zeneca. The remaining authors disclose no conflicts. Publisher Copyright: © 2023 AGA InstituteIdiosyncratic drug-induced liver injury (DILI) is an infrequent but important cause of liver disease. Newly identified causes of DILI include the COVID vaccines, turmeric, green tea extract, and immune checkpoint inhibitors. DILI is largely a clinical diagnosis of exclusion that requires evaluation for more common causes of liver injury and a compatible temporal association with the suspect drug. Recent progress in DILI causality assessment includes the development of the semi-automated revised electronic causality assessment method (RECAM) instrument. In addition, several drug-specific HLA associations have been identified that can help with the confirmation or exclusion of DILI in individual patients. Various prognostic models can help identify the 5%-10% of patients at highest risk of death. Following suspect drug cessation, 80% of patients with DILI fully recover, whereas 10%-15% have persistently abnormal laboratory studies at 6 months of follow-up. Hospitalized patients with DILI with an elevated international normalized ratio or mental status changes should be considered for N-acetylcysteine therapy and urgent liver transplant evaluation. Selected patients with moderate to severe drug reaction with eosinophilia and systemic symptoms or autoimmune features on liver biopsy may benefit from short-term corticosteroids. However, prospective studies are needed to determine the optimal patients and dose and duration of steroids to use. LiverTox is a comprehensive, freely accessible Web site with important information regarding the hepatotoxicity profile of more than 1000 approved medications and 60 herbal and dietary supplement products. It is hoped that ongoing "omics" studies will lead to additional insight into DILI pathogenesis, improved diagnostic and prognostic biomarkers, and mechanism-based treatments.Peer reviewe

Liver safety assessment: required data elements and best practices for data collection and standardization in clinical trials.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.A workshop was convened to discuss best practices for the assessment of drug-induced liver injury (DILI) in clinical trials. In a breakout session, workshop attendees discussed necessary data elements and standards for the accurate measurement of DILI risk associated with new therapeutic agents in clinical trials. There was agreement that in order to achieve this goal the systematic acquisition of protocol-specified clinical measures and lab specimens from all study subjects is crucial. In addition, standard DILI terms that address the diverse clinical and pathologic signatures of DILI were considered essential. There was a strong consensus that clinical and lab analyses necessary for the evaluation of cases of acute liver injury should be consistent with the US Food and Drug Administration (FDA) guidance on pre-marketing risk assessment of DILI in clinical trials issued in 2009. A recommendation that liver injury case review and management be guided by clinicians with hepatologic expertise was made. Of note, there was agreement that emerging DILI signals should prompt the systematic collection of candidate pharmacogenomic, proteomic and/or metabonomic biomarkers from all study subjects. The use of emerging standardized clinical terminology, CRFs and graphic tools for data review to enable harmonization across clinical trials was strongly encouraged. Many of the recommendations made in the breakout session are in alignment with those made in the other parallel sessions on methodology to assess clinical liver safety data, causality assessment for suspected DILI, and liver safety assessment in special populations (hepatitis B, C, and oncology trials). Nonetheless, a few outstanding issues remain for future consideration

Setting up criteria for drug-induced autoimmune-like hepatitis through a systematic analysis of published reports

Funding Information: The authors would like to thank Maria Angeles, secretary for the Department of Medicine, Faculty of Medicine, University of Malaga for expert secretarial assistance. Funding Information: Supported by grants of Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional‐FEDER (contract number: PI19‐00883) Publisher Copyright: © 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.Nitrofurantoin, minocycline, methyldopa and infliximab, have been found to induce autoimmune-like hepatitis (DI-AILH). Evidence for other drugs and herbal and dietary supplements (HDS) is unclear. The aims of the study were to establish criteria to define and review the published evidence of suspected DI-AILH. Search was undertaken in Pubmed using search terms “drug-induced liver injury,” “autoimmune hepatitis,” and “drug-induced autoimmune hepatitis.” DI-AILH was defined as (1) drug as a potential trigger of liver injury with autoimmune features and histological findings compatible with AIH; (2) no or incomplete recovery or worsening of liver tests after discontinuation of the drug; (3) corticosteroids requirement or spontaneous recovery; (4) follow-up without immunosuppression (IS) and no relapse of AIH at least 6 months after discontinuation of IS; and (5) drugs potentially inducing AILH with a chronic course. Cases fulfilling the first four criteria were considered probable DI-AILH with three possible DI-AILH. A total of 186 case reports were identified for conventional drugs (n = 148; females 79%; latency 2.6 months) and HDS (n = 38; females 50%). The most commonly reported agents of DI-AILH were interferons (n = 37), statins (n = 24), methylprednisolone (MPS) (n = 16), adalimumab (n = 10), imatinib (n = 8), and diclofenac (n = 7). Tinospora cordifolia and Khat were the only HDS with probable DI-AILH cases. No relapses of AIH were observed when IS was stopped after interferons, imatinib, diclofenac, and methylprednisolone. Conclusion: Beyond well-recognized nitrofurantoin, methyldopa, hydralazine, minocycline, and infliximab as causes of DI-AILH, interferons, imatinib, adalimumab, and MPS were the best-documented agents leading to probable DI-AILH. Khat and Tinospora cordifolia were the only HDS found to be able to induce DI-AILH. Long-term immunosuppression appears to be rarely required in patients with DI-AILH due to these drugs.Peer reviewe

A revised electronic version of RUCAM for the diagnosis of DILI

Background and Aims: Roussel Uclaf Causality Assessment Method (RUCAM) for DILI has been hindered by subjectivity and poor reliability. We sought to improve the RUCAM using data from the Drug-Induced Liver Injury Network (DILIN) and the Spanish DILI Registry, published literature, and it- erative computer modeling. Approach and Results: RUCAM criteria were updated, clarified, and com- puterized. We removed criteria 3 (risk factors) for lack of added value and cri- teria 4 because we felt it more useful to assess each drug separately. Criteria 6 (drug-specific risk) was anchored to LiverTox likelihood scores. Iterative testing in subsets of 50–100 single-agent, nonherbal cases from both regis- tries was done to optimize performance. We used classification tree analysis to establish diagnostic cutoffs for this revised electronic causality assessment method (RECAM) and compared RECAM with RUCAM for correlation with expert opinion diagnostic categories in 194 DILI cases (98 DILIN, 96 Spanish DILI). Area under receiver operator curves for identifying at least probable DILI were the same at 0.89 for RECAM and RUCAM. However, RECAM diagnostic categories have better observed overall agreement with expert opinion (0.62 vs. 0.56 weighted kappa, p = 0.14), and had better sensitivity to detect extreme diagnostic categories (73 vs. 54 for highly likely or high probable, p = 0.02; 65 vs. 48 for unlikely/excluded, p = 0.08) than RUCAM diagnostic categories. Conclusions: RECAM is an evidence-based update that is at least as capa- ble as RUCAM in diagnosing DILI compared with expert opinion but is better than RUCAM at the diagnostic extremes. RECAM’s increased objectivity and clarity will improve precision, reliability, and standardization of DILI diagnosis, but further refinement and validation in other cohorts are needed.Funding information The Drug-Induced Liver Injury (DILN) Network is structured as a U01 cooperative agreement with funds provided by the National Institute of Diabetes and Digestive and Kidney Diseases (U24-DK065176, U01-DK065201, U01-DK065184, U01-DK065211, U01DK065193, U01-DK065238, U01-DK083023, U01-DK083027, U01-DK082992, U01-DK083020, and U01-DK100928). Additional support is provided by CTSA grants (UL1 RR025761, UL1TR000083, UL1 RR024134, UL1 RR024986, UL1 RR024982, UL1 RR024150), the Intramural Research Program of the National Institutes of Health, the National Cancer Institute (ClinicalTrials.gov number: NCT00345930), and the 2016 American Association for the Study of Liver Disease (AASLD) Innovations Fund. The Spanish DILI Registry is funded by grants from Instituto de Salud Carlos III, cofounded by Fondo Europeo de Desarrollo Regional - FEDER (PI 18/01804 and PT 20/00127) and Agencia Española del Medicamento. Plataforma ISCiii de Investigación Clínica and CIBERehd are funded by ISCIII

N-Acetylcysteine for the Management of Non-Acetaminophen Drug-Induced Liver Injury in Adults : A Systematic Review

Funding Information: The present study has been supported by grants of the Instituto de Salud Carlos III co-founded by Fondo Europeo de Desarrollo Regional–FEDER (contract numbers: PI19/00883, P18‐RT‐3364‐2020), from the Consejería de Economía, Conocimiento, Empresas y Universidad (Junta de Andalucía, Spain) (UMA18‐FEDERJA‐194, PI18‐RT‐3364) and by the Agencia Española del Medicamento. JS-C holds a “Juan Rodés” research contract from the National System of Health, ISCIII (JR21/00066). IA-A holds a Sara Borrell contract (CD20/00083). HN holds a postdoctoral contract from the Junta de Andalucia (POSTDOC_21_00780). CIBERehd and Plataforma ISCIII Ensayos Clínicos (PT20/000127) are funded by ISCIII. This article is based upon work from COST Action “CA17112 - Prospective European Drug-Induced Liver Injury Network” supported by COST (European Cooperation in Science and Technology) ( www.cost.eu ). All authors of this manuscript are members of COST Action CA17112. The funding sources had no involvement in the study design; in the collection, analysis, and interpretation of data; in the writing of the report or in the decision to submit the manuscript for publication. Funding Information: The present study has been supported by grants of the Instituto de Salud Carlos III co-founded by Fondo Europeo de Desarrollo Regional–FEDER (contract numbers: PI19/00883, P18‐RT‐3364‐2020), from the Consejería de Economía, Conocimiento, Empresas y Universidad (Junta de Andalucía, Spain) (UMA18‐FEDERJA‐194, PI18‐RT‐3364) and by the Agencia Española del Medicamento. JS-C holds a “Juan Rodés” research contract from the National System of Health, ISCIII (JR21/00066). IA-A holds a Sara Borrell contract (CD20/00083). HN holds a postdoctoral contract from the Junta de Andalucia (POSTDOC_21_00780). CIBERehd and Plataforma ISCIII Ensayos Clínicos (PT20/000127) are funded by ISCIII. This article is based upon work from COST Action “CA17112 - Prospective European Drug-Induced Liver Injury Network” supported by COST (European Cooperation in Science and Technology) (www.cost.eu). All authors of this manuscript are members of COST Action CA17112. The funding sources had no involvement in the study design; in the collection, analysis, and interpretation of data; in the writing of the report or in the decision to submit the manuscript for publication. Publisher Copyright: Copyright © 2022 Sanabria-Cabrera, Tabbai, Niu, Alvarez-Alvarez, Licata, Björnsson, Andrade and Lucena.Introduction: Idiosyncratic drug-induced liver injury (DILI) is a rare adverse reaction to drugs and other xenobiotics. DILI has different grades of severity and may lead to acute liver failure (ALF), for which there is no effective therapy. N-acetylcysteine (NAC) has been occasionally tested for the treatment of non-acetaminophen drug-induced ALF. However, limited evidence for its efficacy and safety is currently available. Our aim was to elucidate the benefit and safety of NAC in DILI and evaluate its hepatoprotective effect. Methods: We conducted a systematic review to evaluate the management and prevention focused on NAC in idiosyncratic DILI. The main outcomes included mortality due to DILI, time to normalization of liver biochemistry, transplant-free survival, and adverse events. We included clinical trials and observational studies, either prospective or retrospective. Results: A total of 11 studies were included after literature screening. All studies had different methodologies, and some of them had important risk of bias that may lead to interpreting their findings with caution. The majority of the studies proved NAC efficacy in a cohort of patients with ALF due to different etiologies, where DILI represented a subgroup. NAC seemed to improve transplant-free survival; however, its benefit was inconclusive in terms of overall survival. With regard to safety, NAC showed an adequate safety profile. In prevention studies, NAC showed a possible hepatoprotective effect; however, this finding is limited by the lack of studies and presence of bias. Conclusion: NAC treatment seems to have some benefit in non-acetaminophen drug-induced liver failure patients with acceptable safety; however, due to the lack of evidence and limitations detected across studies, its benefit must be corroborated in clinical trials with adequate methodology.Peer reviewe

Liver Safety Assessment: Required Data Elements and Best Practices for Data Collection and Standardization in Clinical Trials

A workshop was convened to discuss best practices for the assessment of drug-induced liver injury (DILI) in clinical trials. In a breakout session, workshop attendees discussed necessary data elements and standards for the accurate measurement of DILI risk associated with new therapeutic agents in clinical trials. There was agreement that in order to achieve this goal the systematic acquisition of protocol-specified clinical measures and lab specimens from all study subjects is crucial. In addition, standard DILI terms that address the diverse clinical and pathologic signatures of DILI were considered essential. There was a strong consensus that clinical and lab analyses necessary for the evaluation of cases of acute liver injury should be consistent with the US Food and Drug Administration (FDA) guidance on pre-marketing risk assessment of DILI in clinical trials issued in 2009. A recommendation that liver injury case review and management be guided by clinicians with hepatologic expertise was made. Of note, there was agreement that emerging DILI signals should prompt the systematic collection of candidate pharmacogenomic, proteomic and/or metabonomic biomarkers from all study subjects. The use of emerging standardized clinical terminology, CRFs and graphic tools for data review to enable harmonization across clinical trials was strongly encouraged. Many of the recommendations made in the breakout session are in alignment with those made in the other parallel sessions on methodology to assess clinical liver safety data, causality assessment for suspected DILI, and liver safety assessment in special populations (hepatitis B, C, and oncology trials). Nonetheless, a few outstanding issues remain for future consideration

Drug-Induced Liver Injury due to Flucloxacillin:Relevance of Multiple Human Leukocyte Antigen Alleles

© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics Some patients prescribed flucloxacillin (~0.01%) develop drug-induced liver injury (DILI). HLA-B*57:01 is an established genetic risk factor for flucloxacillin DILI. To consolidate this finding, identify additional genetic factors, and assess relevance of risk factors for flucloxacillin DILI in relation to DILI due to other penicillins, we performed a genomewide association study involving 197 flucloxacillin DILI cases and 6,835 controls. We imputed single-nucleotide polymorphism and human leukocyte antigen (HLA) genotypes. HLA-B*57:01 was the major risk factor (allelic odds ratio (OR)=36.62; P=2.67×10−97). HLA-B*57:03 also showed an association (OR=79.21; P=1.2×10−6). Within the HLA-B protein sequence, imputation showed valine97, common to HLA-B*57:01 and HLA-B*57:03, had the largest effect (OR=38.1; P=9.7×10−97). We found no HLA-B*57 association with DILI due to other isoxazolyl penicillins (n=6) or amoxicillin (n=15) and no significant non-HLA signals for any penicillin-related DILI

Beneficial effect of ursodeoxycholic acid in patients with acyl-CoA oxidase 2 (ACOX2) deficiency-associated hypertransaminasemia

Background and aims: A variant (p.Arg225Trp) of peroxisomal acyl-CoA oxidase 2 (ACOX2), involved in bile acid (BA) side-chain shortening, has been associated with unexplained persistent hypertransaminasemia and accumulation of C27-BAs, mainly 3?,7?,12?-trihydroxy-5?-cholestanoic acid (THCA). We aimed to investigate the prevalence of ACOX2 deficiency-associated hypertransaminasemia (ADAH), its response to ursodeoxycholic acid (UDCA), elucidate its pathophysiological mechanism and identify other inborn errors that could cause this alteration. Methods and results: Among 33 patients with unexplained hypertransaminasemia from 11 hospitals and 13 of their relatives, seven individuals with abnormally high C27-BA levels (>50% of total BAs) were identified by high-performance liquid chromatography-mass spectrometry. The p.Arg225Trp variant was found in homozygosity (exon amplification/sequencing) in two patients and three family members. Two additional nonrelated patients were heterozygous carriers of different alleles: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). In patients with ADAH, impaired liver expression of ACOX2, but not ACOX3, was found (immunohistochemistry). Treatment with UDCA normalized aminotransferase levels. Incubation of HuH-7 hepatoma cells with THCA, which was efficiently taken up, but not through BA transporters, increased reactive oxygen species production (flow cytometry), endoplasmic reticulum stress biomarkers (GRP78, CHOP, and XBP1-S/XBP1-U ratio), and BAX? expression (reverse transcription followed by quantitative polymerase chain reaction and immunoblot), whereas cell viability was decreased (tetrazolium salt-based cell viability test). THCA-induced cell toxicity was higher than that of major C24-BAs and was not prevented by UDCA. Fourteen predicted ACOX2 variants were generated (site-directed mutagenesis) and expressed in HuH-7 cells. Functional tests to determine their ability to metabolize THCA identified six with the potential to cause ADAH. Conclusions: Dysfunctional ACOX2 has been found in several patients with unexplained hypertransaminasemia. This condition can be accurately identified by a noninvasive diagnostic strategy based on plasma BA profiling and ACOX2 sequencing. Moreover, UDCA treatment can efficiently attenuate liver damage in these patients.Funding information: This study was supported by the following grants: CIBERehd (EHD15PI05/2016); Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain (PI19/00819 and PI20/00189), co-funded by European Regional Development Fund/European Social Fund, “Investing in your future”; “Junta de Castilla y León” (SA074P20); Fundació Marato TV3 (201916–31); AECC Scientific Foundation (2017/2020), Spain; and “Centro Internacional sobre el Envejecimiento” (OLD-HEPAMARKER, 0348_CIE_6_E), Spain. We also acknowledge support from grants PID2019-111669RBI-100, PID2020-115055RB-I00 from Plan Nacional de I+D funded by the “Agencia Estatal de Investigación” (AEI) and the center grant P50AA011999 Southern California Research Center for ALPD and Cirrhosis funded by NIAAA/NIH, as well as support from AGAUR of the “Generalitat de Catalunya” SGR-2017-1112, European Cooperation in Science & Technology (COST) ACTION CA17112 Prospective European Drug-Induced Liver Injury Network. Marta Alonso-Peña was the recipient of a predoctoral fellowship from “Ministerio de Educación, Cultura y Deporte” (BOE-A-2015-9456; FPU-14/00214) and a Mobility Grant for Short Stays from “Ministerio de Ciencia, Innovación y Universidades” (EST17/00186). Ricardo Espinosa-Escudero is the recipient of a predoctoral fellowship from “Junta de Castilla y León” and “Fondo Social Europeo” (EDU/574/2018). The funding sources were not involved in the research design or preparation of the article

Comprehensive analysis and insights gained from long-term experience of the Spanish DILI Registry

Background & aims: Prospective drug-induced liver injury (DILI) registries are important sources of information on idiosyncratic DILI. We aimed to present a comprehensive analysis of 843 patients with DILI enrolled into the Spanish DILI Registry over a 20-year time period. Methods: Cases were identified, diagnosed and followed prospectively. Clinical features, drug information and outcome data were collected. Results: A total of 843 patients, with a mean age of 54 years (48% females), were enrolled up to 2018. Hepatocellular injury was associated with younger age (adjusted odds ratio [aOR] per year 0.983; 95% CI 0.974-0.991) and lower platelet count (aOR per unit 0.996; 95% CI 0.994-0.998). Anti-infectives were the most common causative drug class (40%). Liver-related mortality was more frequent in patients with hepatocellular damage aged ≥65 years (p = 0.0083) and in patients with underlying liver disease (p = 0.0221). Independent predictors of liver-related death/transplantation included nR-based hepatocellular injury, female sex, higher onset aspartate aminotransferase (AST) and bilirubin values. nR-based hepatocellular injury was not associated with 6-month overall mortality, for which comorbidity burden played a more important role. The prognostic capacity of Hy's law varied between causative agents. Empirical therapy (corticosteroids, ursodeoxycholic acid and MARS) was prescribed to 20% of patients. Drug-induced autoimmune hepatitis patients (26 cases) were mainly females (62%) with hepatocellular damage (92%), who more frequently received immunosuppressive therapy (58%).The present study has been supported by grants of Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional – FEDER (contract numbers: PI19/00883, PI16/01748, PI18/00901, PI18/01804, PI-0285-2016, PI-0274-2016, PI-0310- 2018, PT17/0017/0020) and Agencia Española del Medicamento. CIBERehd and Plataforma ISCIII Ensayos Clinicos are funded by Instituto de Salud Carlos III. MRD holds a Joan Rodes (JR16/ 00015)/Acción B clinicos investigadores (B-0002-2019) and JSC a Rio Hortega (CM17/00243) research contract from ISCIII and Consejería de Salud de Andalucía. The funding sources had no involvement in the study design; in the collection, analysis, and interpretation of data; in the writing of the report or in the de- cision to submit the manuscript for publication

A new framework for advancing in Drug-Induced Liver Injury research. The Prospective European DILI Registry

Background & AimsNo multi-national prospective study of drug-induced liver injury (DILI) has originated from Europe. The design of a prospective European DILI registry, clinical features and short-term outcomes of the cases and controls is reported.MethodsPatients 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.ResultsOf 446 adjudicated patients, 246 DILI patients and 100 had acute liver injury due to other etiologies, mostly autoimmune hepatitis (n=42) and viral hepatitis (n=34). DILI patients (mean age 56?years), 57% women, 60% with jaundice and 3.6% pre-existing liver disease. DILI cases and non-DILI 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 medications were implicated in 37 (15%) and 18 cases were caused by herbal and dietary supplements. Most common 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 a liver transplantation.ConclusionsIn 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