Selected ABCB1, ABCB4 and ABCC2 Polymorphisms Do Not Enhance the Risk of Drug-Induced Hepatotoxicity in a Spanish Cohort

[Background and Aims] Flawed ABC transporter functions may contribute to increased risk of drug-induced liver injury (DILI). We aimed to analyse the influence of genetic variations in ABC transporters on the risk of DILI development and clinical presentations in a large Spanish DILI cohort. [Methods] A total of ten polymorphisms in ABCB1 (1236T>C, 2677G>T,A, 3435T>C), ABCB4 (1954A>G) and ABCC2 (−1774G>del, −1549A>G, −24C>T, 1249G>A, 3972C>T and 4544G>A) were genotyped using Taqman 5′ allelic discrimination assays or sequencing in 141 Spanish DILI patients and 161 controls. The influence of specific genotypes, alleles and haplotypes on the risk of DILI development and clinical presentations was analysed. [Results] None of the individual polymorphisms or haplotypes was found to be associated with DILI development. Carriers homozygous for the ABCC2 −1774del allele were however only found in DILI patients. Hence, this genotype could potentially be associated with increased risk, though its low frequency in our Spanish cohort prevented a final conclusion. Furthermore, carriers homozygous for the ABCC2 −1774G/−1549A/−24T/1249G/3972T/4544G haplotype were found to have a higher propensity for total bilirubin elevations when developing DILI. [Conclusions] Our findings do not support a role for the analysed polymorphisms in the ABCB1, ABCB4 and ABCC2 transporter genes in DILI development in Spanish patients. The ABCC2 −1774deldel genotype was however restricted to DILI cases and could potentially contribute to enhanced DILI susceptibility.This study was supported, in part, by research grants from the Agencia Española del Medicamento and Fondo de Investigación Sanitaria (PS 09/01384). CIBERehd and Red Genómica del Cáncer are funded by Instituto de Salud Carlos III

Clinical characteristics and outcome of drug-induced liver injury in the older patients: from the young-old to the oldest-old

Old patients with hepatotoxicity have been scarcely studied in idiosyncratic drug-induced liver injury (DILI) cohorts. We sought for the distinctive characteristics of DILI in older patients across age groups. A total of 882 DILI patients included in the Spanish DILI Registry (33% ≥65 years) were categorized according to age: “young” (<65y); “young-old” (65-74y); “middle-old” (75-84y); and “oldest-old” (≥85y). All elderly groups had increasingly higher comorbidity burden (p<0.001) and polypharmacy (p<0.001). There was a relationship between jaundice and hospitalization (p<0.001), and both were more prevalent in the elderly age groups, especially in the oldest-old (88% and 69%, respectively) and the DILI episode was more severe (p=0.029). The proportion of females decreased across age groups from the young to the middle-old, yet in the oldest-old there was a distinct female predominance. Pattern of liver injury shifted towards cholestatic with increasing age among top culprit drugs amoxicillin- clavulanate, atorvastatin, levofloxacin, ibuprofen, and ticlopidine. The best cut-off point for increased odds of cholestatic DILI was 65y. Older patients had increased non-liver related mortality (p=0.030) as shown by the predictive capacity of MELD (OR=1.116; p<0.001), and comorbidity burden (OR=4.188; p=0.001) in the 6-month mortality. Older patients with DILI exhibited an increasingly predominant cholestatic phenotype across a range of culprit drugs other that amoxicillin-clavulanate, with increased non-liver related mortality and require a different approach to predict outcome. The oldest DILI patients exhibited a particular phenotype with more severe DILI episodes and need to be considered when stratifying older DILI populations.The present study has been supported by grants of Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional - FEDER (contract numbers: PI 18/01804; PT17/0017/0020) and Agencia Española del Medicamento. SCReN and CIBERehd are funded by ISCIII. JSC holds a Rio Hortega (CM17/00243) and MR a “Joan Rodes” (JR16/00015) research contract from the National Health System, ISCIII. RAW held a University of Málaga visiting scientist scholarship

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

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%).[Conclusions] AST elevation at onset is a strong predictor of poor outcome and should be routinely assessed in DILI evaluation. Mortality is higher in older patients with hepatocellular damage and patients with underlying hepatic conditions. The Spanish DILI Registry is a valuable tool in the identification of causative drugs, clinical signatures and prognostic risk factors in DILI and can aid physicians in DILI characterisation and management.[Lay summary] Clinical information on drug-induced liver injury (DILI) collected from enrolled patients in the Spanish DILI Registry can guide physicians in the decision-making process. We have found that older patients with hepatocellular type liver injury and patients with additional liver conditions are at a higher risk of mortality. The type of liver injury, patient sex and analytical values of aspartate aminotransferase and total bilirubin can also help predict clinical outcomes.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.Peer reviewe