Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system.
Medications are a major cause of acute liver failure (ALF) in the United States, 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 health care system that approximates a population-based cohort.



We performed a retrospective cohort study using data from the Kaiser Permanente Northern California (KPNC) health care system between January 1, 2004, and December 31, 2010. We included all KPNC members age 18 years and older with 6 months or more 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.



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 events (18.8%), antimicrobials in 2 events (6.3%), and miscellaneous medications in 6 events (18.8%). One patient with acetaminophen-induced ALF died (5.6%; 0.06 events/1,000,000 person-years) compared with 3 patients with non-acetaminophen-induced ALF (21.4%; 0.18/1,000,000 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) and 1.02 events/1,000,000 person-years (95% confidence interval, 0.59-1.63), respectively.



Drug-induced ALF is uncommon, but over-the-counter products and dietary/herbal supplements are its most common causes.
Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: david.goldberg@uphs.upenn.edu.
David S
DS
Goldberg
Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Kimberly A
KA
Forde
Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Dean M
DM
Carbonari
Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, Pennsylvania.
James D
JD
Lewis
Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania.
Kimberly B F
KB
Leidl
Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania.
K Rajender
KR
Reddy
Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; HealthCore, Inc, Wilmington, Delaware.
Kevin
K
Haynes
Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Jason
J
Roy
Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania.
Daohang
D
Sha
Division of Research, Kaiser Permanente Northern California, Oakland, California.
Amy R
AR
Marks
Division of Research, Kaiser Permanente Northern California, Oakland, California.
Jennifer L
JL
Schneider
Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Rutgers Biomedical and Health Sciences, Newark, New Jersey.
Brian L
BL
Strom
Division of Research, Kaiser Permanente Northern California, Oakland, California.
Douglas A
DA
Corley
Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Division of Infectious Diseases, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Vincent
V
Lo Re
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002140:California / Q000453:epidemiology; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis / Q000453:epidemiology* / Q000628:therapy; D016208:Databases, Factual; D019033:Delivery of Health Care, Integrated / Q000706:statistics & numerical data*; D019587:Dietary Supplements / Q000009:adverse effects; D005260:Female; D006801:Humans; D015994:Incidence; D017114:Liver Failure, Acute / Q000175:diagnosis / Q000453:epidemiology* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D004366:Nonprescription Drugs / Q000009:adverse effects; D028321:Plant Preparations / Q000009:adverse effects; D011379:Prognosis; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors
D004366:Nonprescription Drugs; D028321:Plant Preparations
Acetaminophen; Acute Liver Failure; Drug-Induced Liver Injury