title: Acute hepatotoxicity associated with therapeutic doses of intravenous acetaminophen.
abstract: BACKGROUND
  IV acetaminophen at 4 g per day is considered safe, producing no hepatic failure in more than 1400 cases. Oxidation of acetaminophen forms a reactive intermediate that binds to cellular proteins resulting in acetaminophen-protein adducts (APAP-CYS). Serum concentrations of APAP-CYS have been found to correlate with acetaminophen-induced hepatotoxicity. We report a case of hepatotoxicity associated with therapeutic doses of IV acetaminophen, with elevated serum APAP-CYS.
  
  
  METHODS
  The patient was a 92-year-old, 68 kg woman without known hepatic disease or ethanol abuse. On hospital day 3 she underwent laparoscopic reduction of internal hernias under general anesthesia. Surgery was uncomplicated and postoperatively she was treated with subcutaneous heparin and IV acetaminophen, 1 g every 6 h for almost 4 days (total dose = 13 g). At the start of therapy, transaminases were normal. On hospital day 5, she was noted to have marked transaminase elevations (AST: 4698 IU/L; ALT: 3914 IU/L) with increases in INR (1.68), ammonia (60 mcg/dL), and total bilirubin (1.8 mg/dL). Serum acetaminophen concentration was 15.3 mcg/mL 26 h after her last dose. Acetaminophen was discontinued and IV acetylcysteine was given and continued at the second maintenance dose rate for a second 16-hour infusion, at which time transaminases, INR, ammonia and total bilirubin were all improving. The patient was discharged 2 days later. Serum APAP-CYS concentrations in serum samples obtained during her hospitalization were elevated (peak = 4.81 μM on hospital day 5; expected range for therapeutic dosing <1.1 μM).
  
  
  METHODS
  We have identified a case of acute liver injury associated with therapeutic dosing of IV acetaminophen. The serum APAP-CYS concentrations are consistent with that seen in cases of hepatotoxicity following repeated supratherapeutic acetaminophen ingestion. Several factors that likely contributed to her susceptibility included advanced age, post-operative status, a likely catabolic state and multiple acetaminophen doses over several days. These uncommon circumstances limit the generalizability of risk. We believe the findings are most consistent with acetaminophen-induced liver injury.
  
  
  CONCLUSIONS
  This case illustrates a potential hazard of IV acetaminophen and demonstrates the potential utility of APAP-CYS adducts in evaluating causality in acute liver injury.
authors.affiliation: a Department of Emergency Medicine and New Mexico Poison and Drug Information Center , University of New Mexico Health Sciences Center , Albuquerque , NM , USA ;
authors.forename: Steven A
authors.initials: SA
authors.lastname: Seifert
authors.affiliation: b Christus St. Vincent Regional Medical Center , Santa Fe , NM , USA ;
authors.forename: Daniel
authors.initials: D
authors.lastname: Kovnat
authors.affiliation: c Rocky Mountain Poison and Drug Center, Denver Health , Denver , CO , USA ;
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Anderson
authors.affiliation: c Rocky Mountain Poison and Drug Center, Denver Health , Denver , CO , USA ;
authors.forename: Jody L
authors.initials: JL
authors.lastname: Green
authors.affiliation: c Rocky Mountain Poison and Drug Center, Denver Health , Denver , CO , USA ;|d Department of Emergency Medicine , University of Colorado School of Medicine , Aurora , CO , USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Dart
authors.affiliation: d Department of Emergency Medicine , University of Colorado School of Medicine , Aurora , CO , USA.
authors.forename: Kennon J
authors.initials: KJ
authors.lastname: Heard
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000097:blood / Q000506:poisoning*; D061605:Administration, Intravenous; D000369:Aged, 80 and over; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000097:blood / Q000506:poisoning*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000628:therapy; D062787:Drug Overdose / Q000188:drug therapy; D005260:Female; D059685:Herniorrhaphy; D006801:Humans; D010535:Laparoscopy; D008111:Liver Function Tests; D010146:Pain / Q000209:etiology
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen
keywords: Acetaminophen; IV acetaminophen; acetaminophen-protein adducts; hepatotoxicity