At what degree of hepatocellular injury does Acetaminophen (Paracetamol) toxicity occur?

From the Guidelines

Acetaminophen can cause significant hepatocellular injury at single ingestions exceeding 7.5-10 grams in adults or 150 mg/kg in children, with severe hepatotoxicity defined as an AST greater than 1,000 IU/L, as indicated by the study published in the Annals of Emergency Medicine 1. The degree of hepatocellular injury is assessed using serum aminotransferase levels (AST, ALT), with mild injury showing elevations 2-5 times the upper limit of normal, moderate injury with elevations 5-10 times normal, and severe injury with elevations exceeding 10 times normal. Some key points to consider in the management of acetaminophen overdose include:

• The use of the Rumack-Matthew nomogram to determine the risk of hepatotoxicity, with treatment with N-acetylcysteine (NAC) recommended for patients with possible or probable risk, as stated in the Level B recommendations of the clinical policy 1.
• The importance of prompt treatment with NAC, ideally within 8 hours of ingestion, to reduce the incidence of severe hepatotoxicity and mortality.
• The definition of severe hepatotoxicity as an AST greater than 1,000 IU/L, and hepatic failure as hepatotoxicity with hepatic encephalopathy, as outlined in the study published in the Annals of Emergency Medicine 1. The mechanism of acetaminophen toxicity involves the depletion of glutathione stores, which normally detoxify NAPQI, a toxic metabolite of acetaminophen, leading to hepatocyte death. Treatment with NAC should be initiated promptly when toxicity is suspected, ideally within 8 hours of ingestion, as it replenishes glutathione stores and can prevent severe liver damage, as recommended by the clinical policy 1.

From the FDA Drug Label

ACETAMINOPHEN ASSAYS - INTERPRETATION AND METHODOLOGY The acute ingestion of acetaminophen in quantities of 150 mg/kg or greater may result in hepatic toxicity. However, following ingestion of a large overdose (150 mg/kg or greater) the glucuronide and sulfate conjugation pathways are saturated resulting in a larger fraction of the drug being metabolized via the P-450 pathway The increased formation of reactive metabolite may deplete the hepatic stores of glutathione with subsequent binding of the metabolite to protein molecules within the hepatocyte resulting in cellular necrosis.

The degree of hepatocellular injury from acetaminophen is associated with ingestion of quantities of 150 mg/kg or greater. At this dose, the glucuronide and sulfate conjugation pathways are saturated, leading to increased formation of a reactive metabolite that can deplete hepatic glutathione stores and cause cellular necrosis 2.

• The plasma or serum acetaminophen concentrations can be used to assess the potential risk of hepatotoxicity, with values above the solid line connecting 200 mcg/mL at least 4 hours with 50 mcg/mL at 12 hours associated with a possibility of hepatic toxicity if an antidote is not administered 2.
• It is essential to note that the reported history of the quantity of a drug ingested as an overdose is often inaccurate and is not a reliable guide to therapy of the overdose 2.

From the Research

Hepatocellular Injury Due to Acetaminophen

• The degree of hepatocellular injury due to acetaminophen can vary, but it is a leading cause of acute liver failure (ALF) worldwide 3.
• Acetaminophen-induced hepatotoxicity can occur due to intentional overdose or unintentional ingestion, and factors such as concomitant use of alcohol and certain medications can increase the risk of liver damage 3, 4.
• The severity of liver injury can be influenced by host factors, including age, duration of acetaminophen use, and excess drinking 5.
• Acute liver injury with therapeutic doses of acetaminophen (≤6 g/d) can occur, especially in patients with risk factors such as fasting, excess drinking, and repeated use of acetaminophen 5.

Treatment and Management

• N-acetylcysteine (NAC) is recommended for all patients with acetaminophen-induced ALF and can reduce mortality if given early after an acute overdose 6, 3, 7.
• The optimal treatment schedule and timing of NAC administration are crucial, with initiation of treatment within 8-24 hours from acetaminophen overdose showing efficacy in reducing mortality 6.
• Liver transplantation may be necessary for patients who are unlikely to survive based on prognostic criteria 3, 7.

Risk Factors and Prevention

• Certain populations, such as children, elderly, and obese patients, may be at higher risk of liver damage due to acetaminophen 6.
• Unintentional overdoses, often due to the use of multiple acetaminophen formulations over many days, can lead to liver injury 4.
• A warning should be issued about the repeated use of non-toxic doses of acetaminophen in patients with risk factors such as excess drinking and/or fasting 5.