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Acetaminophen (APAP) is the leading cause of acute liver failure (ALF) worldwide, either following intentional overdose or unintentional ingestion (therapeutic misadventure).
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Spontaneous survival is more common in APAP-induced ALF compared to non-APAP etiologies.
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N-acetylcysteine is recommended for all patients with APAP-induced ALF and liver transplantation should be offered early to those who are unlikely to survive based on described prognostic criteria.
Acetaminophen (APAP or N-Acetyl-p-Aminophenol) and Acute Liver Failure
Section snippets
Key points
Epidemiology of acetaminophen overdose and acetaminophen-induced acute liver failure
APAP has been a major cause of overdose-related ALF and death in the United States (40%–50% of cases) and in the United Kingdom (40%–70% of cases).5, 6, 7, 8, 13, 14, 15, 16 In the United States, APAP overdose is the leading reason for calls to the Poison Control Centers (>100,000 per year) and accounts yearly for more than 56,000 emergency room visits, 2600 hospitalizations, and ∼450 deaths due to ALF.5 In the US ALF Study Group, APAP overdose accounted for 42% (275/662) of ALF cases; with
Pharmacology and mechanism of acetaminophen-induced hepatotoxicity and liver failure
The therapeutic dose of APAP is 325 to 1000 mg/dose (10–15 mg/kg/dose in children), given every 4 to 6 hours, with a maximum recommended daily dose of 3250 mg.1, 31 Peak concentrations of APAP are achieved within 90 minutes of oral ingestion, and the therapeutic serum concentrations range from 10 to 20 μg/mL.1, 3, 32 Peak serum concentration, however, after an overdose is generally noted within 4 hours, but may be delayed beyond 4 hours in cases of overdose of extended-release preparations or
Ingested dose and other factors influencing acetaminophen-induced hepatotoxicity
The total ingested dose of APAP is the most important factor determining the development and severity of APAP hepatotoxicity. In addition, the pattern of use and various factors (eg, chronic alcohol consumption, age, concurrent use of certain medications, genetic factors, preexisting liver disease, and nutritional status) also can influence the susceptibility to APAP hepatotoxicity through several mechanisms, including reduced capacity for glucuronidation or sulfation, excessive CYP activity,
The 4 Classic Stages of Acetaminophen Hepatotoxicity
Timely recognition of APAP overdose is likely to prevent subsequent morbidity and mortality. The early manifestations of APAP overdose are frequent, mild, and nonspecific, and include nausea, vomiting, malaise, and abdominal pain. At large, these symptoms do not reliably predict subsequent hepatotoxicity. Nevertheless, a study of 291 patients suggested that an increase in episodes of vomiting at first presentation appears to be a risk indicator of subsequent hepatotoxicity.56 The clinical
Evaluations for patients with acetaminophen-induced hepatotoxicity and liver failure
General approach promptly begins with careful history taking and physical examination. If encephalopathy is present, the history may be unavailable or can be provided only by the family. The precise time and amount of APAP intake, as well as serum APAP level, should be obtained. The Rumack-Matthew nomogram is a valuable tool for predicting the risk of hepatotoxicity in patients with single acute overdose ingestion who present to a health care facility within 24 hours; however, it is not
Management of acetaminophen-induced liver failure
ALF is considered a “hepatology emergency,” in that early discussion with a transplant team or rapid transfer to an experienced center that has LT availability is advisable once stabilized (even if the patient has not deteriorated).75 As ALF often leads to infections and multiple organ failure, intensive care unit admission should be considered as early as possible. The general principles of the management of APAP-induced ALF do not differ from those for other causes of ALF. Careful monitoring
Mechanism of Actions and Clinical Efficacy
NAC, a GSH precursor, is an established antidote for APAP overdose and should be given in all patients with APAP hepatotoxicity, as well as in patients at significant risk for developing hepatotoxicity. The key to effective treatment is to initiate therapy before the onset of liver injury, as indicated by ALT elevation. When given early after acute APAP overdose, NAC provides cysteine for the replenishment and maintenance of hepatic GSH stores and thus presenting more substrate for the
Selection of Patient and Prognostic Systems
Although APAP-induced ALF is associated with more favorable outcomes compared with all other causes of ALF, it still has a high mortality (∼30%) without LT.8, 11, 36, 74 LT is life-saving in patients with APAP overdose who progress to severe ALF. The decision to proceed with LT in APAP-induced ALF is challenging and involves balancing the inherent risks associated with delay in listing and LT against the potential for spontaneous recovery from medical therapy alone, the risk of major surgery in
References (134)
- et al.
Acetaminophen-related hepatotoxicity
Clin Liver Dis
(2013) - et al.
A review of acetaminophen poisoning
Crit Care Clin
(2012) Acetaminophen (APAP) hepatotoxicity-Isn't it time for APAP to go away?
J Hepatol
(2017)- et al.
Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure
Hepatology
(1995) - et al.
Outcome after wait-listing for emergency liver transplantation in acute liver failure: a single centre experience
J Hepatol
(2009) - et al.
Liver transplantation for acute liver failure: a Spanish perspective
Transplant Proc
(2010) - et al.
Etiologies and outcomes of acute liver failure in Germany
Clin Gastroenterol Hepatol
(2012) - et al.
Fulminant hepatic failure: outcome after listing for highly urgent liver transplantation-12 years experience in the Nordic countries
Liver Transpl
(2002) - et al.
Epidemiology and results of liver transplantation for acute liver failure in Chile
Transplant Proc
(2003) - et al.
Late increase in acetaminophen concentration after overdose of Tylenol extended relief
Ann Emerg Med
(1996)
Acetaminophen hepatotoxicity
Clin Liver Dis
Role of the inflammasome in acetaminophen-induced liver injury and acute liver failure
J Hepatol
Innate immune system plays a critical role in determining the progression and severity of acetaminophen hepatotoxicity
Gastroenterology
Multicenter, randomized, double-blind, active-controlled, parallel-group trial of the long-term (6-12 months) safety of acetaminophen in adult patients with osteoarthritis
Clin Ther
Acute versus chronic alcohol consumption in acetaminophen-induced hepatotoxicity
Hepatology
The temporal profile of increased transaminase levels in patients with acetaminophen-induced liver dysfunction
Ann Emerg Med
Acetaminophen from liver to brain: new insights into drug pharmacological action and toxicity
Pharmacol Res
Risk factors and outcomes of acute kidney injury in patients with acute liver failure
Clin Gastroenterol Hepatol
False positive acetaminophen concentrations in patients with liver injury
Clin Chim Acta
Acute liver failure
Clin Liver Dis
Measurement of serum acetaminophen-protein adducts in patients with acute liver failure
Gastroenterology
An immunoassay to rapidly measure acetaminophen protein adducts accurately identifies patients with acute liver injury or failure
Clin Gastroenterol Hepatol
Sulfate depletion after acetaminophen administration and replenishment by infusion of sodium sulfate or N-acetylcysteine in rats
Biochem Pharmacol
Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine
Lancet
Improved outcome of paracetamol-induced fulminant hepatic failure by late administration of acetylcysteine
Lancet
American Gastroenterological Association Institute technical review on initial testing and management of acute liver disease
Gastroenterology
The Australasian Clinical Toxicology Investigators Collaboration randomized trial of different loading infusion rates of N-acetylcysteine
Ann Emerg Med
Management of anaphylactoid reactions to intravenous N-acetylcysteine
Ann Emerg Med
Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial
Lancet
Acetaminophen-induced hepatotoxicity: a comprehensive update
J Clin Transl Hepatol
Trends in outpatient prescription drug use and related costs in the US: 1998-2003
Pharmacoeconomics
Acetaminophen and the U.S. Acute Liver Failure Study Group: lowering the risks of hepatic failure
Hepatology
Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States
Ann Intern Med
Paracetamol overdose and hepatotoxicity at a regional Australian hospital: a 4-year experience
Intern Med J
Outcomes of liver transplantation for paracetamol (acetaminophen)-induced hepatic failure
Liver Transpl
Liver transplantation for acute liver failure: results from the NIH Acute Liver Failure Study Group
Hepatology
Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study
Hepatology
Etiology and prognosis of fulminant hepatitis in adults
Liver Transpl
Etiologies of acute liver failure
Semin Liver Dis
Acute liver failure in Scotland: changes in aetiology and outcomes over time (the Scottish Look-Back Study)
Aliment Pharmacol Ther
Overdose pattern and outcome in paracetamol-induced acute severe hepatotoxicity
Br J Clin Pharmacol
Liver transplant associated with paracetamol overdose: results from the seven-country SALT study
Br J Clin Pharmacol
Risk factors, clinical presentation, and outcomes in overdose with acetaminophen alone or with combination products: results from the Acute Liver Failure Study Group
J Clin Gastroenterol
Patients with acute liver failure listed for superurgent liver transplantation in France: reevaluation of the Clichy-Villejuif criteria
Liver Transpl
Etiology and outcome of acute liver failure: experience from a liver transplantation centre in Montreal
Can J Gastroenterol
Acute liver failure in Spain: analysis of 267 cases
Liver Transpl
Etiology and outcome of fulminant hepatic failure managed at an Australian liver transplant unit
J Gastroenterol Hepatol
Aetiology and prognostic factors in acute liver failure in India
J Viral Hepat
Etiology and prognosis of fulminant hepatitis and late-onset hepatic failure in Japan: summary of the annual nationwide survey between 2004 and 2009
Hepatol Res
Fulminant hepatic failure in an African setting: etiology, clinical course, and predictors of mortality
Dig Dis Sci
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Conflict of Interest: The authors have nothing to disclose.