Acetaminophen (APAP or N-Acetyl-p-Aminophenol) and Acute Liver Failure

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Key points

  • Acetaminophen (APAP) is the leading cause of acute liver failure (ALF) worldwide, either following intentional overdose or unintentional ingestion (therapeutic misadventure).

  • Spontaneous survival is more common in APAP-induced ALF compared to non-APAP etiologies.

  • 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.

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

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    Conflict of Interest: The authors have nothing to disclose.

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