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Therapeutic Acetaminophen Not Linked to Liver Injury in Children

  • Authors: News Author: Laurie Barclay, MD
    CME Author: Penny Murata, MD
  • CME/CE Released: 11/29/2010
  • Valid for credit through: 11/29/2011
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Target Audience and Goal Statement

This article is intended for primary care clinicians and specialists who provide care to children who use therapeutic acetaminophen.

The goal of this activity is to provide medical news to primary care clinicians and other healthcare professionals in order to enhance patient care.

Upon completion of this activity, participants will be able to:

  1. Report whether therapeutic use of acetaminophen in children is linked with signs or symptoms of liver disease, the need for antidote or transplantation, or death.
  2. Report whether therapeutic use of acetaminophen in children is linked with major or minor hepatic adverse events.


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  • Laurie Barclay, MD

    Freelance writer and reviewer, Medscape, LLC


    Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.


  • Brande Nicole Martin

    CME Clinical Editor, Medscape, LLC


    Disclosure: Brande Nicole Martin has disclosed no relevant financial relationships.

CME Author(s)

  • Penny Murata, MD

    Clinical Professor, Pediatrics, University of California, Irvine, California
    Pediatric Clerkship Director, University of California, Irvine, California


    Disclosure: Penny Murata, MD, has disclosed no relevant financial relationships.

CME Reviewer(s)

  • Sarah Fleischman

    CME Program Manager, Medscape, LLC


    Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.

Nurse Planner

  • Laurie E. Scudder, DNP, NP

    Nurse Planner, Continuing Professional Education Department, Medscape, LLC; Clinical Assistant Professor, School of Nursing and Allied Health, George Washington University, Washington, DC


    Disclosure: Laurie E. Scudder, DNP, NP, has disclosed no relevant financial relationships.

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Therapeutic Acetaminophen Not Linked to Liver Injury in Children

Authors: News Author: Laurie Barclay, MD CME Author: Penny Murata, MDFaculty and Disclosures

CME/CE Released: 11/29/2010

Valid for credit through: 11/29/2011


November 29, 2010 — Hepatoxicity after therapeutic dosing of acetaminophen in children is rarely reported in defined-population studies, according to the results of a systematic review reported online November 22 in Pediatrics.

"Use of the drug has recently come under increased scrutiny by the Food and Drug Administration because of the increased recognition of the contribution of acetaminophen to acute liver injury globally," Dr. Laura James, section chief of clinical pharmacology and toxicology at Arkansas Children's Hospital and professor of pediatrics at University of Arkansas for Medical Sciences, told Medscape Medical News when asked for independent comment. "While most experts view acetaminophen to be safe when used as directed, there have been rare reports of toxicity occurring with recommended dosing of the drug. Individual susceptibilities in drug response and toxicity may occur with the use of any drug, including acetaminophen."

Eric J. Lavonas, MD, from Rocky Mountain Poison and Drug Center at Denver Health in Colorado, and colleagues systematically reviewed the medical literature to assess the rate at which liver injury has been reported for children prescribed therapeutic doses of acetaminophen, defined as up to 75 mg/kg per day orally or intravenously or up to 100 mg/kg per day rectally.

Studies in which acetaminophen was given to a defined pediatric population for at least 24 hours were identified from a search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. Trained reviewers also searched these sources for all case reports of liver injury after therapeutic acetaminophen dosing and extracted data from each report. Major and minor hepatic adverse events (AEs) were defined prospectively, and the Naranjo algorithm allowed evaluation of causality.

Among 62 identified studies enrolling a total of 32,414 children, there were no reports (0%; 95% confidence interval [CI], 0.000 - 0.009) of a child showing signs or symptoms of liver disease, having received an antidote or liver transplantation, or having died. A total of 10 children were reported to have major or minor hepatic AEs (0.031%; 95% CI, 0.015 - 0.057), and the highest transaminase value reported was 600 IU/L, with Naranjo scores (2 - 3) suggesting "possible" causation. However, none of the children had other evidence of liver dysfunction.

Among 22 identified case reports, there were 9 cases in which the Naranjo score suggested "probable" causation. The investigators concluded that hepatoxicity after therapeutic dosing of acetaminophen in children is rarely reported in defined-population studies. Although case reports suggest that this phenomenon may occur, few reports contain sufficient data to support a probable causal relationship.

"The limitations of the report are that the study reviewed previously published studies that were not expressly designed to systematically collect laboratory measurements that would detect liver injury," Dr. James said. "The clinical signs and symptoms of liver injury can be subtle until significant liver injury is present. Acetaminophen is a drug with a narrow safety index and thus careful dosing of the drug is a necessity for safe use."

Other limitations noted by the study authors include imperfect indexing strategies of medical databases, publication bias, possible errors introduced by manual search, possible failure to detect liver inflammation in some children, lack of routine blood testing on children without signs or symptoms of liver injury in most studies, and possible differences in clinical trial participants from the general population of children who take acetaminophen. A major limitation that the reviewers pointed out is that incomplete safety reporting is common in published clinical trials.

The reviewers also warn that their findings should not be used to estimate the proportion of children taking acetaminophen who experience elevations in asymptomatic transaminase levels, because if routine screening had been performed in all studies, it would likely have revealed additional cases of hepatic enzyme elevation. They also note that threshold criteria used to define severe liver injury are arbitrary. Because few children in these studies received exactly 75 mg/kg per day of acetaminophen, and many did not receive the drug for longer than 3 to 5 days, this study has limited power to detect infrequent hepatic AEs associated with longer therapy and/or maximal therapeutic dosing.

"Pediatricians should continue to educate families and patients about the safe use of acetaminophen, including informing families about the widespread use of acetaminophen in many over-the-counter products and prescription pain medications," Dr. James concluded. "Ongoing studies will help determine the factors that may contribute to individual susceptibilities to acetaminophen-induced liver injury."

This review was internally funded. The Rocky Mountain Poison and Drug Center, Denver Health receives research funding from McNeil Consumer Healthcare, but the development and analysis of the database described in the review article was not supported by McNeil Consumer Healthcare. The study authors have disclosed no relevant financial relationships. Dr. James is the recipient of 2 National Institutes of Health grants for the study of acetaminophen toxicity. She also has a patent pending for the measurement of acetaminophen protein adducts in human blood samples.

Pediatrics. Published online November 22, 2010. Abstract

Additional Resources
The American Academy of Pediatrics Policy Statement on Acetaminophen Toxicity in Children describes situations and conditions that may contribute to acetaminophen toxicity not associated with suicidal intentions.

Additionally, Mayo Clinic provides a helpful guide for parents that emphasizes the importance of correct acetaminophen dosing in children.

Clinical Context

In 2009, the US Food and Drug Administration addressed the prevention of acetaminophen toxicity from overdosage at a joint meeting of the Drug Safety and Risk Management Advisory Committee, Nonprescription Drugs Advisory Committee, and the Anesthetic and Life Support Drugs Advisory Committee. However, therapeutic acetaminophen use might be linked to hepatic toxicity, as reported by Alonso and colleagues in the December 1995 issue of the Journal of Pediatrics.

This systematic review assesses whether therapeutic acetaminophen use in children is associated with liver injury.

Study Highlights

  • Search of the literature included MEDLINE (1966-2006), EMBASE (1980-2006), Old MEDLINE (1950-1965), the Cochrane Central Register of Controlled Trials (1968-2006), and the reference lists.
  • Study eligibility criteria were defined population studies that reported therapeutic dosing of acetaminophen to an identifiable group of more than 1 child for at least 24 hours and case reports of hepatoxicity developing in a child after a therapeutic dose of acetaminophen.
  • Children aged 0 to 18 years were included.
  • The reasons for acetaminophen use were standard therapy, control intervention, or rescue medication.
  • Therapeutic acetaminophen dose was defined as up to 75 mg/kg (or 4 g) per 24 hours orally or up to 100 mg/kg per 24 hours rectally.
  • Acetaminophen equivalents included benorylate and propacetamol up to 150 mg/kg per day or up to 8 g per day.
  • Major hepatic AE criteria were death from liver failure, liver transplant, or modified Drug-Induced Liver Injury Network criteria (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] level > 5 times the upper limit of normal; alkaline phosphatase level > 2 times the upper limit of normal; jaundice or serum bilirubin level > 2.5 mg/dL plus ALT, AST, or alkaline phosphatase level > 1 time the upper limit of normal).
  • Minor hepatic AE criteria were AST or ALT level between more than 3 and up to 5 times the upper limit of normal and any sign or symptom resulting from liver injury.
  • The Naranjo scale was used to determine the likelihood of a causal relationship between acetaminophen and hepatic AEs.
  • 62 population studies with 32,414 children were identified.
  • 61 studies had prospective data, and 1 study had prospective and retrospective data.
  • No child had signs or symptoms of liver disease, had received antidote or a liver transplant, or had died.
  • 59 studies of 32,213 children reported no major or minor hepatic AEs.
  • 3 studies reported that 10 children had elevated transaminase levels that met major or minor hepatic AE criteria (0.031%) with possible causal link to acetaminophen:
    • 1 study of 100 inpatients reported 3 major and 4 minor events.
    • 1 prospective observational case series of 80 children reported 1 major elevation of AST level and 1 minor elevation of AST and ALT levels.
    • 1 randomized trial of 21 children reported 1 major event in a child who discontinued acetaminophen because of increase in transaminase levels and 1 child who discontinued acetaminophen but whose transaminase levels did not meet AE criteria.
  • The highest transaminase level was 600 IU/L.
  • 22 case reports of hepatic AEs noted outcomes of death in 4 patients, neurologic sequelae in 1, and full recovery in 17 children.
  • Analysis of case reports found possible causation in 13 cases and probable causation in 9 cases, including 1 death.
  • Study limitations included possible incomplete identification of articles, undetected liver inflammation, and inability to assess effect of prolonged acetaminophen use or higher-than-recommended acetaminophen dose.

Clinical Implications

  • Therapeutic use of acetaminophen in children is not linked with signs or symptoms of liver disease, the need for antidote or transplantation, or death.
  • In children using therapeutic acetaminophen, elevated transaminase levels are reported in 0.031%.

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