Epidemiology

• Acetaminophen overdose (intentional and unintentional) is a leading cause of acute liver failure in the United States

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Physiology

• A single dose of >10-15 g can cause acute liver failure in an adult
• The degree of liver damage caused by acetaminophen can be effectively ameliorated in the vast majority of cases when N-acetylcysteine is given (PO or IV) within 4-8 hrs post-ingestion

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Diagnosis

• Acetaminophen Level: post-ingestion level should be used with Rumack-Matthew nomogram

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Clinical Manifestations

• Fulminant Hepatic Failure (FHF) (see Fulminant Hepatic Failure, Fulminant Hepatic Failure)

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Treatment

General Treatment of Acetaminophen Intoxication

• Oral Activated Charcoal (see Activated Charcoal, Activated Charcoal): oral activated charcoal after gastric lavage is also indicated up to 4 hrs after ingestion, but is not helpful later
• Hemodialysis: not indicated for treatment of acetaminophen toxicity, but may be required if acute renal failure develops
• N-Acetylcysteine (Mucomyst, Acetadote, Fluimucil, Parvolex) (see N-Acetylcysteine, N-Acetylcysteine)
  • Indications: while N-acetylcysteine should still be administered to any person with hepatic dysfunction after an acetaminophen overdose (regardless of time from ingestion), starting therapy after 24 hrs is much less likely to prevent progression of liver failure and mortality is significantly higher in this late-treatment group
  • Mechanism: sulfhydryl donor
  • Administration
    • PO (Mucomyst): 140 mg/kg PO x 1 dose, then 70 mg/kg PO q4hrs x 17 doses
    • IV (Acetadote)

  • Efficacy of Prolonged Administration

    • In a small, prospective study, IV N-acetylcysteine demonstrated improved outcomes in patients who had acetaminophen-related liver failure when N-acetylcysteine was continued until clinical improvement and an INR <2 was achieved
    • A retrospective trial also demonstrated the benefit of prolonged N-acetylcysteine infusion

  • Simplified N-Acetlycysteine Infusion Regimen in Acetaminophen Intoxication (Clin Toxicologic, 2016) [MEDLINE]:

The incidence of NAARs was significantly reduced by combining the first two bags of the traditional three-bag regimen and infusing these over 4 h at 50 mg/kg/hr. Simplifying the administration of acetylcysteine may have other benefits such as better utilisation of nursing time and reduced infusion administration errors.
CONCLUSIONS: A two-bag 20 h acetylcysteine regimen was well tolerated and resulted in significantly fewer and milder NAARs than the standard three-bag regimen.

Treatment of Fulminant Hepatic Failure

• Treatment of Cerebral Edema (see Increased Intracranial Pressure, Increased Intracranial Pressure): leading cause of death within the first week after acetaminophen-related fulminant hepatic failure
  • Intracranial Pressure (ICP) Monitoring
  • Therapies to ameliorate cerebral edema have not been demonstrated to improve outcome, independent of liver transplantation
• Treatment of Renal Failure: hemodialysis may be required
• Liver Transplantation: transfer to a liver transplantation center is recommended prior to onset of hepatic encephalopathy
  • Intentional ingestion is not considered an absolute contraindication for hepatic transplantation

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Prognosis

• Risk Factors for Poor Outcome (in absence of hepatic transplantation): degree of transaminase elevation and timing of fall in transaminases do not predict outcome
  • Delay in Starting N-Acetylcysteine: later than 24 hrs post-ingestion
  • Metabolic Acidosis
  • Grade III/IV Hepatic Encephalopathy
  • Acute Renal Failure
  • Rising INR
  • Hypoglycemia: usually late

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References

• Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989;97:439-445 [MEDLINE]
• Anaphylactic shock induced by paracetamol. Eur J Clin Pharmacol. 1990;38(4):389 [MEDLINE]
• Intravenous acetylcysteine in paracetamol-induced fulminant hepatic failure: a prospective controlled trial. BMJ 1991;26:1026-29 [MEDLINE]
• Paracetamol anaphylaxis. Clin Exp Allergy. 1992;22(9):831 [MEDLINE]
• A 7-year experience of severe acetaminophen-induced hepatotoxicity (1987-1993). Gastroenterology. 1995;109:1907-1916 [MEDLINE]
• Acetaminophen and adverse chronic renal outcomes: an appraisal of the epidemiologic evidence. Am J Kidney Dis. 1996;28(1 Suppl 1):S14 [MEDLINE]
• Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med. 2002;137:947-954 [MEDLINE]
• Acetaminophen-induced anion gap metabolic acidosis and 5-oxoprolinuria (pyroglutamic aciduria) acquired in hospital. Am J Kidney Dis. 2005 Jul;46(1):143-6 [MEDLINE]
• Increased anion gap metabolic acidosis as a result of 5-oxoproline (pyroglutamic acid): a role for acetaminophen. Clin J Am Soc Nephrol. 2006 May;1(3):441-7. Epub 2006 Apr 19 [MEDLINE]
• Acetaminophen hepatotoxicity. Clin Liver Dis. 2007;11:525-548 [MEDLINE]

N-Acetylcysteine

• Acetylcysteine for acetaminophen poisoning. N Engl J Med 2008;359:285-92 [MEDLINE]

• Simplification of the standard three-bag intravenous acetylcysteine regimen for paracetamol poisoning results in a lower incidence of adverse drug reactions. Clin Toxicol (Phila). 2016 Feb;54(2):115-9. Epub 2015 Nov 23 [MEDLINE]