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Toxicity, Acetaminophen: Differential Diagnoses & Workup

Author: Susan E Farrell, MD, Assistant Professor of Medicine, Harvard Medical School; Education Consultant, Office for Graduate Medical Education, Partners HealthCare Systems; Attending Physician, Department of Emergency Medicine, Brigham and Women's Hospital
Contributor Information and Disclosures

Updated: Sep 23, 2009

Differential Diagnoses

Acute Liver Failure of Unknown Etiology
Pancreatitis
Acute Tubular Necrosis
Toxicity, Mushroom - Amatoxin
Gastritis and Peptic Ulcer Disease
Gastroenteritis
Hepatitis

Other Problems to Be Considered

Vomiting of unclear etiology
Hepatic failure
Hepatorenal syndrome

Workup

Laboratory Studies

  • Acetaminophen serum concentration
    • A serum acetaminophen concentration drawn 4 or more hours after a SINGLE ingestion may be plotted on the Rumack-Matthew nomogram as a guide to the likelihood of potential hepatotoxicity and the indication for NAC therapy. The nomogram is NOT applicable in the cases of multiple or chronic acetaminophen ingestion. It may be less reliable for the prediction of hepatotoxicity in cases of acetaminophen ingestion that also include anticholinergic agents or opioids, or in the case of extended-release acetaminophen formulations. (See Special Concerns for information regarding extended-relief acetaminophen.)
    • A serum acetaminophen concentration should be measured after any intentional overdose because the history of acetaminophen ingestion may not be elicited and the onset of clinical toxicity is delayed after overdose. The risk of morbidity increases when the initiation of NAC therapy is delayed.
  • Transaminase levels
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) begin to rise within 24 hours post ingestion and peak at about 72 hours.
    • Toxicity is defined as serum AST or ALT levels greater than 1000 IU/L.
  • Measures of hepatic function
    • Serum glucose
    • Prothrombin time (PT) and international normalized ratio (INR) are laboratory components predictive of mortality. Elevated PT and INR indicate impaired synthetic liver function.
  • Other serum measures of hepatic damage
    • Serum concentrations of NAPQI-protein adducts have been measured as evidence of acetaminophen-induced hepatotoxicity.3 The peak serum concentrations of NAPQI-adducts correlate with peak AST and ALT concentrations, and they may be diagnostic of acetaminophen-induced hepatotoxicity in late-presenting patients with acute liver failure of unknown etiology. NAPQI-protein adducts are not available in real-time clinical practice and could be obtained only through specialized laboratories.
  • Electrolytes and creatinine
    • Lactate is a laboratory component predictive of mortality.
    • Acute tubular necrosis and renal failure have been shown to coexist with or, rarely, be independent of hepatotoxicity in acetaminophen overdose. One study indicated that this is more likely to occur in persons with a history of ethanol abuse. Renal failure, when it occurs, usually occurs within 2-3 days of overdose.
    • Serum creatinine is a laboratory component predictive of mortality.
    • It is suggested that serum phosphate can be used as an early predictor of outcome in severe acetaminophen-induced hepatotoxicity .4
  • Human chorionic gonadotropin (HCG) in females of childbearing age5
    • Acetaminophen crosses the placenta, and the fetal liver is able to elaborate NAPQI by 14 weeks of gestation.
    • Delay in treating pregnant patients with antidotal therapy is associated with fetal demise.
  • A type and crossmatch should be drawn for the treatment of active bleeding in the face of coagulopathy.
  • Urinalysis: Proteinuria and hematuria may be seen with acute tubular necrosis, usually in conjunction with hepatic failure.
  • Arterial blood gas: pH <7.3 is a laboratory component predictive of mortality.

Imaging Studies

  • CT scan of the head
    • CT scan may reveal cerebral edema in patients with late presentation and encephalopathy.
    • Consider in patients with altered mental status.
  • Ultrasound
    • Ultrasound may reveal mild hepatic enlargement in late presentation.
    • If clinically indicated, this is usually an inpatient procedure.

Other Tests

  • Obtain ECG in order to exclude the presence of cardioactive substances/coingestants

Procedures

  • Gastric lavage: Gastric lavage has no proven efficacy in isolated acetaminophen overdose.

More on Toxicity, Acetaminophen

Overview: Toxicity, Acetaminophen
Differential Diagnoses & Workup: Toxicity, Acetaminophen
Treatment & Medication: Toxicity, Acetaminophen
Follow-up: Toxicity, Acetaminophen
References
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References

  1. US Food and Drug Administration. Public health problem of liver injury related to the use of acetaminophen in both over-the-counter (OTC) and prescription (RX) products. Available at http://www.fda.gov/AdvisoryCommittees/Calendar/ucm143083.htm. Accessed August 5, 2009.

  2. US Food and Drug Administration. Organ-specific warnings; internal analgesic, antipyretic, and antirheumatic drug productus for over-the-counter human use. Federal Register. 2009 Apr 29;74(81). Available at http://edocket.access.gpo.gov/2009/pdf/E9-9684.pdf. Accessed August 5, 2009.

  3. James LP, Capparelli EV, Simpson PM, Letzig L, Roberts D, Hinson JA, et al. Acetaminophen-associated hepatic injury: evaluation of acetaminophen protein adducts in children and adolescents with acetaminophen overdose. Clin Pharmacol Ther. Dec 2008;84(6):684-90. [Medline].

  4. Schmidt LE, Dalhoff K. Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity. Hepatology. Sep 2002;36(3):659-65. [Medline].

  5. Crowell C, Lyew RV, Givens M, Deering SH. Caring for the mother, concentrating on the fetus: intravenous N-acetylcysteine in pregnancy. Am J Emerg Med. Jul 2008;26(6):735.e1-2. [Medline].

  6. [Guideline] Wolf SJ, Heard K, Sloan EP, Jagoda AS. Clinical policy: critical issues in the management of patients presenting to the emergency department with acetaminophen overdose. Ann Emerg Med. Sep 2007;50(3):292-313. [Medline]. [Full Text].

  7. Betten DP, Cantrell FL, Thomas SC, Williams SR, Clark RF. A prospective evaluation of shortened course oral N-acetylcysteine for the treatment of acute acetaminophen poisoning. Ann Emerg Med. Sep 2007;50(3):272-9. [Medline].

  8. [Guideline] Dart RC, Erdman AR, Olson KR, et al. Acetaminophen poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila). 2006;44(1):1-18. [Medline]. [Full Text].

  9. Amato CS, Wang RY, Wright RO, Linakis JG. Evaluation of promotility agents to limit the gut bioavailability of extended-release acetaminophen. J Toxicol Clin Toxicol. 2004;42(1):73-7. [Medline].

  10. Anker AL, Smilkstein MJ. Acetaminophen. Concepts and controversies. Emerg Med Clin North Am. May 1994;12(2):335-49. [Medline].

  11. Bailey B, McGuigan MA. Management of anaphylactoid reactions to intravenous N-acetylcysteine. Ann Emerg Med. Jun 1998;31(6):710-5. [Medline].

  12. Bizovi KE, Aks SE, Paloucek F, Gross R, Keys N, Rivas J. Late increase in acetaminophen concentration after overdose of Tylenol Extended Relief. Ann Emerg Med. Nov 1996;28(5):549-51. [Medline].

  13. Brent J. Are activated charcoal-N-acetylcysteine interactions of clinical significance?. Ann Emerg Med. Dec 1993;22(12):1860-2. [Medline].

  14. Burkhart KK. The acetaminophen nomogram: will it withstand the test of the extended relief formulation?. Acad Emerg Med. Aug 1996;3(8):738-9. [Medline].

  15. Cetaruk EW, Dart RC, Hurlbut KM, Horowitz RS, Shih R. Tylenol Extended Relief overdose. Ann Emerg Med. Jul 1997;30(1):104-8. [Medline].

  16. Chamberlain JM, Gorman RL, Oderda GM, Klein-Schwartz W, Klein BL. Use of activated charcoal in a simulated poisoning with acetaminophen: a new loading dose for N-acetylcysteine?. Ann Emerg Med. Sep 1993;22(9):1398-402. [Medline].

  17. Douglas DR, Sholar JB, Smilkstein MJ. A pharmacokinetic comparison of acetaminophen products (Tylenol Extended Relief vs regular Tylenol). Acad Emerg Med. Aug 1996;3(8):740-4. [Medline].

  18. Ekins BR, Ford DC, Thompson MI, Bridges RR, Rollins DE, Jenkins RD. The effect of activated charcoal on N-acetylcysteine absorption in normal subjects. Am J Emerg Med. Nov 1987;5(6):483-7. [Medline].

  19. FDA. Acetadote (R) IV N-Acetylcysteine prescribing information. Food and Drug Administration MedWatch Web site. 2004. [Full Text].

  20. Gardner CR, Heck DE, Yang CS, et al. Role of nitric oxide in acetaminophen-induced hepatotoxicity in the rat. Hepatology. Mar 1998;27(3):748-54. [Medline].

  21. Larson AM. Acetaminophen hepatotoxicity. Clin Liver Dis. Aug 2007;11(3):525-48, vi. [Medline].

  22. Perry H, Shannon MW. Acetaminophen. In: Haddad LM, Shannon MW, Winchester J, Fletcher J, eds. Clinical Management of Poisoning and Drug Overdose. 3rd ed. WB Saunders Co; 1998:664-74.

  23. Smilkstein MJ. A new loading dose for N-acetylcysteine? The answer is no. Ann Emerg Med. Sep 1994;24(3):538-9. [Medline].

  24. Spiller HA, Krenzelok EP, Grande GA, Safir EF, Diamond JJ. A prospective evaluation of the effect of activated charcoal before oral N-acetylcysteine in acetaminophen overdose. Ann Emerg Med. Mar 1994;23(3):519-23. [Medline].

  25. Spiller HA, Winter ML, Klein-Schwartz W, Bangh SA. Efficacy of activated charcoal administered more than four hours after acetaminophen overdose. J Emerg Med. Jan 2006;30(1):1-5. [Medline].

  26. Stork CM, Rees S, Howland MA, Kaplan L, Goldfrank L, Hoffman RS. Pharmacokinetics of extended relief vs regular release Tylenol in simulated human overdose. J Toxicol Clin Toxicol. 1996;34(2):157-62. [Medline].

  27. Vassallo S, Khan AN, Howland MA. Use of the Rumack-Matthew nomogram in cases of extended-release acetaminophen toxicity. Ann Intern Med. Dec 1 1996;125(11):940. [Medline].

  28. Whyte IM, Francis B, Dawson AH. Safety and efficacy of intravenous N-acetylcysteine for acetaminophen overdose: analysis of the Hunter Area Toxicology Service (HATS) database. Curr Med Res Opin. Oct 2007;23(10):2359-68. [Medline].

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Further Reading

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Keywords

acetaminophen toxicity, paracetamol, N-acetyl-p-aminophenol, APAP, analgesic agent, antipyretic agent, N-acetyl-p-benzoquinone-imine, NAPQI, hepatocellular death, hepatocellular necrosis, centrilobular liver necrosis, N -acetylcysteine, NAC, fulminant hepaticfailure, hepatic encephalopathy, renal failure, coagulopathy, diaphoresis, acetaminophen toxicity, acetaminophen overdose, APAP toxicity, APAP overdose, hepatotoxicity, acetaminophen poisoning, APAP poisoning

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Contributor Information and Disclosures

Author

Susan E Farrell, MD, Assistant Professor of Medicine, Harvard Medical School; Education Consultant, Office for Graduate Medical Education, Partners HealthCare Systems; Attending Physician, Department of Emergency Medicine, Brigham and Women's Hospital
Susan E Farrell, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Medical Toxicology, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Medical Editor

Miguel C Fernández, MD, FAAEM, FACEP, FACMT, Associate Clinical Professor; Medical and Managing Director, South Texas Poison Center, Department of Surgery/Emergency Medicine and Toxicology, University of Texas Health Science Center at San Antonio
Miguel C Fernández, MD, FAAEM, FACEP, FACMT is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, American College of Occupational and Environmental Medicine, Society for Academic Emergency Medicine, and Texas Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart & St. Joseph's Hospitals
John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists
Disclosure: Nothing to disclose.

Managing Editor

Michael J Burns, MD, Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center
Michael J Burns, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.

 
 
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