SEVERE LIVER INJURY AFTER INITIATING THERAPY WITH ATOMOXETINE IN TWO CHILDREN JOEL R. LIM, MD, PHILIP R. FAUGHT, MD, NAGA P. CHALASANI, MD, AND JEAN P. MOLLESTON, MD Two children presented with acute hepatitis after starting therapy with atomoxetine (Strattera®). In one child, no competing diagnosis could be identified, and liver injury resolved completely on withdrawal of the medication. In the second child, the evaluation was suggestive of type 1 autoimmune hepatitis; she subsequently improved with removal of atomoxetine and concomitant immunosuppressive therapy. Atomoxetine may cause clinically significant hepatotoxicity either by metabolic idiosyncrasy or by inducing autoimmune hepatitis. (J Pediatr 2006;148:831-4) A tomoxetine (Strattera®) is a selective norepinephrine reuptake inhibitor and is one of the approved medications for attention deficit-hyperactivity disorder (ADHD). Since its introduction in 2002, its use has dramatically increased, and in 2003 alone, almost 3.4 million prescriptions were filled. In 2004, sales were estimated at $US 600 million (www.drugtopics.com). The labeling of atomoxetine was recently modified (late 2004) to include severe liver injury among adverse events, based on a teenager and an adult who were treated for several months and who recovered. 1 We report two cases of liver injury in children who were prescribed atomoxetine. CASE REPORTS Case 1 A 12-year-old Caucasian female with ADHD was evaluated for acute hepatitis. She was admitted a week before to a local hospital for jaundice, abdominal pain, diarrhea, and vomiting. Her only medication on admission was atomoxetine (40 mg in the morning), which she had restarted 3 weeks before admission. She had been on atomoxetine previously for nearly 1 year, but her treatment with atomoxetine was interrupted for 6 weeks because of running out of medication. She had no history of liver disease, exposure to hepatitis, or known hepatotoxins. Her physical examination revealed a height of 153.6 cm (25 th to 50 th percentiles), weight of 40.2 kg (25 th percentile), body mass index of 17.9 (25 th to 50 th percentiles), stable vital signs, conjunctival icterus, right upper quadrant tenderness, and no hepatosplenomegaly. Her initial liver enzymes at the local hospital were aspartate aminotransferase (AST) of 2999 U/L (25-45), alanine aminotransferase (ALT) of 3264 U/L (0-50), total bilirubin (Bili T) of 9.1 mg/dL (0-1) with a direct fraction of 5.5 mg/dL (0-0.2), alkaline phosphatase (A phos) of 231 U/L (74-397), gamma glutamyl transpeptidase (GGT) of 108 U/L (12-43), prothrombin time of 14.1 seconds (10.8 – 13.7), and albumin of 4.3 G/dL (3.5-4.7). The evaluation was negative for infectious hepatitis (EBV VCA IgM of 1:10 and CMV IgM of 1:10) and viral hepatitis A, B, and C. The results of other relevant investigations included serum ceruloplasmin 49.2 mg/dL (normal 14-57 mg/dL), serum -1-antitrypsin of 277 mg/dL (normal 85-215 mg/dL), antinuclear antibody titre of 1:160 (normal 1:40), anti-smooth muscle antibody of 1:20 (normal 1:20), liver kidney microsomal antibody of 1.0 (normal 20), and IgG of 769 mg/dL (normal 638-1453). A triglyceride level of 55 mg/dL (0-150) and a cholesterol level of 164 mg/dL (0-200) were obtained during subsequent visits. A liver biopsy showed an intact hepatic lobular architecture within focal thin fibrous bridging on trichrome. Portal areas contained moderate mixed inflammatory infiltrates mainly lym- ADHD Attention deficit-hyperactivity disorder ALT Alanine aminotransferase A phos Alkaline phosphatase AST Aspartate aminotransferase Bili D Direct bilirubin Bili T Total bilirubin CYP Cytochrome P450 GGT Gamma glutamyl transpeptidase RUCAM Rousell Uclaf Causality Assessment Method From the Division of Pediatric Gastroenter- ology/Hepatology/Nutrition, James Whit- comb Riley Hospital for Children, Indiana University School of Medicine, Indianapolis; and the Departments of Pathology and Laboratory Medicine, and Gastroenterol- ogy and Hepatology, Indiana University School of Medicine, Indianapolis. Submitted for publication Apr 8, 2005; last revision received Oct 21, 2005; accepted Jan 10, 2006. Reprint requests: Joel R. Lim, M.D., Assistant Professor of Clinical Pediatrics, Division of Pediatric Gastroenterology/Hepatology/Nu- trition, James Whitcomb Riley Hospital for Children, Indiana University School of Medi- cine, 702 Barnhill Drive, Room ROC 4210, Indianapolis, Indiana 46202-5225. E-mail: jdlim@iupui.edu. 0022-3476/$ - see front matter Copyright © 2006 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2006.01.035 831