Significant Medical Comorbidities Are Associated With Lower Causality Scores in Patients Presenting With Suspected Drug-Induced Liver Injury.

INTRODUCTION: Drug-induced liver injury (DILI) is a diagnosis of exclusion, and it can be challenging to adjudicate when there are multiple comorbidities and concomitant medications. In this study, we tested the hypothesis that comorbidity burden impacts the causality adjudication in patients with suspected DILI. METHODS: We studied consecutive patients with suspected DILI enrolled in the Drug-Induced Liver Injury Network Prospective Study at 2 centers between 2003 and 2017. The comorbidity burden at presentation was determined using the Charlson Comorbidity Index (CCI). We analyzed the association between significant comorbidity (CCI > 75th percentile) and (i) the adjudication of DILI by expert consensus as definite, highly likely, or probable (high-confidence DILI) and (ii) the Roussel Uclaf Causality Assessment Method (RUCAM) scores. RESULTS: Our cohort consisted of 551 patients who were classified as "no comorbidity" (54%, CCI = 0), "mild comorbidity" (29%, CCI = 1 or 2), and "significant comorbidity" (17%, CCI > 2). The probability of high-confidence DILI was significantly lower in patients with significant comorbidity compared with those with mild or no comorbidities (67% vs 76% vs 87%, respectively, P < 0.001). The mean RUCAM scores decreased with increasing comorbidity (no comorbidity 6.6 ± 2, mild comorbidity 6 ± 2.4, and significant comorbidity 5.6 ± 2.7, P < 0.001). In the multiple logistic regression, significant comorbidity had an independent inverse relationship with DILI (odds ratio: 0.37, 95% confidence interval: 0.2-0.69, P = 0.001). DISCUSSION: Higher comorbidity burden impacts the causality assessment in patients with suspected DILI. Further studies are needed to investigate the utility of comorbidity burden as a variable in the DILI causality instruments.

Development and Validation of a Model Consisting of Comorbidity Burden to Calculate Risk of Death Within 6 Months for Patients With Suspected Drug-Induced Liver Injury.

BACKGROUND & AIMS: Patients with drug-induced liver injury (DILI) frequently have comorbid conditions, but the effects of non-liver comorbidities on outcomes are not well understood. We investigated the association between comorbidity burden and outcomes of patients with DILI, and developed and validated a model to calculate risk of death within 6 months. METHODS: A multiple logistic regression model identified variables independently associated with death within 6 months of presenting with suspected DILI (6-month mortality) for 306 patients enrolled in the Drug-Induced Liver Injury Network prospective study at Indiana University (discovery cohort). The model was validated using data from 247 patients with suspected DILI enrolled in the same study at the University of North Carolina (validation cohort). Medical comorbidity burden was calculated using the Charlson Comorbidity Index-patients with scores higher than 2 were considered to have significant comorbidities. RESULTS: Six-month mortality was 8.5% in the discovery cohort and 4.5% in the validation cohort. In the discovery cohort, significant comorbidities (odds ratio, 5.4; 95% confidence interval [CI], 2.1-13.8), Model for End-Stage Liver Disease score (odds ratio, 1.11; 95% CI, 1.04-1.17), and serum level of albumin at presentation (odds ratio, 0.39; 95% CI, 0.2-0.76) were independently associated with 6-month mortality. A model based on these 3 variables identified patients who died within 6 months, with c-statistic values of 0.89 (95% CI, 0.86-0.94) in the discovery cohort and 0.91 (95% CI, 0.83-0.99) in the validation cohort. We developed a web-based calculator for use in the clinic to determine risk of death within 6 months for patients with suspected DILI. CONCLUSIONS: We developed and validated a model based on comorbidity burden, Model for End-Stage Liver Disease score, and serum level of albumin that predicts 6-month mortality in patients with suspected DILI.