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Characteristics of Idiosyncratic Drug-induced Liver Injury in Children: Results From the DILIN Prospective Study

Molleston, Jean P.*; Fontana, Robert J.; Lopez, M. James; Kleiner, David E.; Gu, Jiezhun§; Chalasani, Naga*; for the Drug-Induced Liver Injury Network

Journal of Pediatric Gastroenterology & Nutrition:
doi: 10.1097/MPG.0b013e31821d6cfd
Original Articles: Hepatologyand Nutrition
Abstract

Background: The spectrum and severity of idiosyncratic drug-induced liver injury (DILI) in children are not well established.

Patients and Methods: The DILIN (Drug-Induced Liver Injury Network) Prospective Study is a longitudinal multicenter study designed to determine the etiologies, risk factors, and outcomes of suspected DILI. Between September 2004 and September 2009, 30 children ages 2 to 18 years with suspected DILI who met eligibility criteria were enrolled and studied for at least 6 months.

Results: Mean age was 14 years; 70% were girls. Antimicrobial (50%) and central nervous system agents (40%) were the most commonly implicated drug classes, with minocycline (4), isoniazid (3), azithromycin (3), atomoxetine (3), and lamotrigine (3) the leading agents. Median time from drug initiation to symptom onset was 32 days. Peak (median) liver chemistries were aspartate aminotransferase 503 U/L, alanine aminotransferase 727 U/L, alkaline phosphatase 331 U/L, and total bilirubin 3.9 mg/dL. Autoantibodies were common (64%). Liver injury pattern was hepatocellular 78%, cholestatic 13%, and mixed 9%. The DILI episode was scored: mild 32%, moderate 44%, severe 20%, and fatal (within 6 months) 4%. Causality assessment was definite 36%, very likely 36%, probable 16%, possible 8%, and unlikely 4%. Seven percent had persistent liver test abnormalities at 6-month follow-up suggesting chronic DILI. Liver biopsies from 12 children most frequently demonstrated chronic hepatitis or bile duct injury.

Conclusions: Idiosyncratic DILI in children is most commonly caused by antimicrobial or central nervous system agents and usually presents with a hepatocellular injury pattern. The majority of patients recover, but morbidity and infrequent mortality are seen.

Author Information

*Indiana University School of Medicine, Indianapolis, IN

Departments of Internal Medicine and Pediatrics, University of Michigan, Ann Arbor, MI

National Cancer Institute, Bethesda, MD

§Duke Clinical Research Institute, Duke University, Raleigh, NC.

Address correspondence and reprint requests to Jean P. Molleston, MD, Indiana University School of Medicine, James Whitcomb Riley Hospital for Children, 702 Barnhill Dr, Room ROC 4210, Indianapolis, IN 46202 (e-mail: jpmolles@iupui.edu).

Received 2 December, 2010

Accepted 23 February, 2011

Dr Chalasani has received consulting fees regarding drug-induced liver injury in the past 12 months from the following companies: Teva Pharmaceuticals, Phenomix, Abbott, KaroBio, J&J, Salix Pharmaceuticals, and Gilead; he has received support from Eli Lilly for research on drug-induced liver disease. Drs Lopez and Molleston receive research support from Roche. Dr Fontana has provided expert consultation for Abbott Laboratories, GlaxoSmithKline, and Vertex Pharmaceuticals. Dr Kleiner and Dr Gu report no conflicts of interest.

The DILIN is supported by the National Institute of Diabetes and Digestive and Kidney Diseases under the following cooperative agreements: 1U01DK065021, 1U01DK065193, 1U01DK065201, 1U01DK065193, 1U01DK065184, 1U01DK065211, 1U01DK065238, and 1U01DK065176. This study was supported in part by the intramural program of the National Institutes of Health, National Cancer Institute. Additional funding was provided by Clinical and Translational Science Awards grants: UL1 RR025761 (Indiana), UL1 RR025747 (UNC), UL1 RR024134 (UPenn), UL1 RR024986 (UMich), UL1 RR024982 (UT-SW), and UL1 RR024150 (Mayo).

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Copyright 2011 by ESPGHAN and NASPGHAN