Risk of Acute Liver Failure in Patients With Drug-Induced Liver Injury: Evaluation of Hy’s Law and a New Prognostic Model

Few studies have evaluated the ability of laboratory tests to predict risk of acute liver failure (ALF) among patients with drug-induced liver injury (DILI). We aimed to develop a highly sensitive model to identify DILI patients at increased risk of ALF. We compared its performance with that of Hy’s Law, which predicts severity of DILI based on levels of alanine aminotransferase or aspartate aminotransferase and total bilirubin, and validated the model in a separate sample. We conducted a retrospective cohort study of 15,353 Kaiser Permanente Northern California members diagnosed with DILI from 2004 through 2010, liver aminotransferase levels above the upper limit of normal, and no pre-existing liver disease. Thirty ALF events were confirmed by medical record review. Logistic regression was used to develop prognostic models for ALF based on laboratory results measured at DILI diagnosis. External validation was performed in a sample of 76 patients with DILI at the University of Pennsylvania. Hy’s Law identified patients that developed ALF with a high level of specificity (0.92) and negative predictive value (0.99), but low level of sensitivity (0.68) and positive predictive value (0.02). The model we developed, comprising data on platelet count and total bilirubin level, identified patients with ALF with a C statistic of 0.87 (95% confidence interval [CI], 0.76–0.96) and enabled calculation of a risk score (Drug-Induced Liver Toxicity ALF Score). We found a cut-off score that identified patients at high risk patients for ALF with a sensitivity value of 0.91 (95% CI, 0.71–0.99) and a specificity value of 0.76 (95% CI, 0.75–0.77). This cut-off score identified patients at high risk for ALF with a high level of sensitivity (0.89; 95% CI, 0.52–1.00) in the validation analysis. Hy’s Law identifies patients with DILI at high risk for ALF with low sensitivity but high specificity. We developed a model (the Drug-Induced Liver Toxicity ALF Score) based on platelet count and total bilirubin level that identifies patients at increased risk for ALF with high sensitivity

Population-Representative Incidence of Drug-Induced Acute Liver Failure Based on an Analysis of an Integrated Health Care System

BACKGROUND AND AIMS: Medications are a major cause of acute liver failure (ALF) in the US, but no population-based studies have evaluated the incidence of ALF from drug-induced liver injury. We aimed to determine the incidence and outcomes of drug-induced ALF in an integrated healthcare system that approximates a population-based cohort. METHODS: We performed a retrospective cohort study using data from the Kaiser Permanente Northern California (KPNC) healthcare system between January 1, 2004 and December 31, 2010. We included all KPNC members ≥18 y old with ≥6 months of membership and hospitalization for potential ALF. The primary outcome was drug-induced ALF (defined as coagulopathy and hepatic encephalopathy without underlying chronic liver disease), determined by hepatologists who reviewed medical records of all KPNC members with inpatient diagnostic and laboratory criteria suggesting potential ALF. RESULTS: Among 5,484,224 KPNC members between 2004 and 2010, 669 had inpatient diagnostic and laboratory criteria indicating potential ALF. After medical record review, 62 (9.3%) were categorized as having definite or possible ALF, and 32 (51.6%) had a drug-induced etiology (27 definite, 5 possible). Acetaminophen was implicated in 18 events (56.3%), dietary/herbal supplements in 6 (18.8%), antimicrobials in 2 (6.3%), and miscellaneous medications in 6 (18.8%). One patient with acetaminophen-induced ALF died (5.6%; .06 events/1,000,000 person-years) compared to 3 patients with non-acetaminophen induced ALF (21.4%; .18/1,000,000 person-years). Overall, 6 patients (18.8%) underwent liver transplantation, and 22 patients (68.8%) were discharged without transplantation. The incidence rates of any definite drug-induced ALF and acetaminophen-induced ALF were 1.61 events/1,000,000 person-years (95% confidence interval, 1.06–2.35) events and 1.02 events/1,000,000 person-years (95% confidence interval, 0.59–1.63), respectively. CONCLUSIONS: Drug-induced ALF is uncommon, but over-the-counter products and dietary/herbal supplements are its most common causes