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
