What dose of paracetamol (acetaminophen) can cause acute liver injury in otherwise healthy adults?

Dose of Paracetamol That Can Cause Acute Liver Injury

A single acute ingestion of 150 mg/kg or approximately 10 grams (10,000 mg) in adults is considered the threshold for potential hepatotoxicity, but severe liver injury can occur with repeated doses as low as 4 grams per day in high-risk individuals, and even therapeutic doses of 4 grams daily for 14 days cause liver enzyme elevations in 31-41% of healthy adults. 1

Acute Single Ingestion Thresholds

The toxic dose for a single acute ingestion is generally 150 mg/kg or greater, which translates to approximately 10 grams for most adults. 1 However, the relationship between dose and liver injury exists on a spectrum:

• Ingestions exceeding 10 grams in a 24-hour period are considered potentially toxic and require medical evaluation. 1
• Severe hepatotoxicity and mortality have been documented with ingestions ranging from 10-65 grams, with mean doses causing severe hepatotoxicity around 23 grams. 1
• Even with prompt N-acetylcysteine (NAC) treatment, higher plasma paracetamol concentrations at hospital presentation correlate with increased liver injury risk in a dose-dependent manner. 2

The FDA label warns that severe liver damage may occur if an adult takes more than 6 doses in 24 hours or greater than 4000 mg of acetaminophen, the maximum daily amount. 3

Repeated Supratherapeutic Ingestion (RSTI)

This is where the danger becomes particularly insidious, as patients may not realize they are overdosing:

• Repeated ingestions totaling ≥10 grams or 200 mg/kg (whichever is less) over a single 24-hour period require medical evaluation. 1
• Repeated ingestions of ≥6 grams or 150 mg/kg (whichever is less) per 24-hour period for 48 hours or longer are potentially toxic. 1
• Severe hepatotoxicity has been documented with doses as low as 4-5 grams per day when taken repeatedly, particularly in patients with risk factors. 1

A critical 2021 prospective study found that acute liver injury with therapeutic doses (defined as <6 g/day) was associated with more severe liver injury than overdose, occurring exclusively in patients with excess drinking and/or fasting. 4

The "Therapeutic Dose" Problem

Even doses within the recommended maximum can cause liver injury:

• A randomized controlled trial showed that therapeutic doses of 4 grams per day for 14 days caused ALT elevations >3 times normal in 31-41% of healthy adults without risk factors. 1
• The American College of Emergency Physicians documents cases of severe hepatotoxicity with doses of 4-5 grams per day in patients with chronic alcohol consumption. 1
• Severe liver injury has been reported rarely with doses as low as 3-4 grams per day. 1

High-Risk Populations with Lower Toxicity Thresholds

Certain patient populations develop hepatotoxicity at substantially lower doses:

Chronic Alcohol Users

• Multiple case series demonstrate severe hepatotoxicity and mortality (20-33%) in chronic alcoholics taking 2.5-16.5 grams per day (median 6.4 grams per day). 1
• For high-risk individuals, the threshold is lower at >4 grams or 100 mg/kg per day. 1
• The European Association for the Study of the Liver (EASL) recommends limiting paracetamol to 2-3 grams per day maximum in patients with alcoholic liver disease or cirrhosis. 1

Fasting or Malnourished Patients

• Fasting ≥1 day was present in 47.5% of patients with acute liver injury from therapeutic doses versus 26% in overdose patients. 4
• Malnourished patients have depleted glutathione stores, making them more vulnerable to paracetamol toxicity even at therapeutic doses. 1

Pre-existing Liver Disease

• For patients with risk factors such as liver disease or chronic alcohol use, the maximum daily dose should be 2-3 grams per day. 1
• Pre-existing liver disease, including cirrhosis, significantly increases susceptibility to acetaminophen hepatotoxicity. 1

Critical Clinical Pitfalls

Several scenarios dramatically increase overdose risk that clinicians must actively screen for:

Combination Products

• Combination products containing acetaminophen, such as those with opioids like hydrocodone or codeine, significantly increase the risk of unintentional overdose because patients may not realize they are taking acetaminophen from multiple sources. 1
• A large proportion (8.1%) of 5.3 million prescriptions for opioid-paracetamol exceeded the recommended maximum daily dose of paracetamol (4 grams per day), putting over 255,000 beneficiaries at risk. 5
• The FDA label explicitly warns not to use with any other drug containing acetaminophen (prescription or nonprescription). 3

Unintentional vs. Intentional Overdose

• Unintentional paracetamol overdose is associated with increased mortality (38.2%) compared with intentional overdose (25.6%), despite lower admission paracetamol concentrations. 6
• Unintentional overdose patients were significantly older, more likely to abuse alcohol, and more commonly overdosed on compound narcotic/paracetamol analgesics. 6
• Paracetamol hepatotoxicity is the commonest cause of acute liver failure in the UK and accounts for over half of all acute liver failure cases in the United States. 7, 6

Maximum Safe Dosing Recommendations

Based on the totality of evidence, the following dosing limits should be observed:

• The FDA authorizes a maximum daily acetaminophen dose of 4 grams per 24 hours for adults without risk factors; however, recent evidence suggests limiting chronic or repeated use to 3 grams per day to minimize hepatotoxicity risk. 1
• For patients with risk factors (chronic alcohol use, liver disease, fasting, malnutrition), limit to 2-3 grams per day maximum. 1
• The FDA caps the amount of acetaminophen in prescription combination products at 325 mg per dosage unit. 1

When to Suspect Paracetamol Hepatotoxicity

Clinicians should maintain a high index of suspicion in the following scenarios:

• Very high aminotransferase levels (AST/ALT >3,500 IU/L) are highly correlated with acetaminophen poisoning and should raise suspicion even without clear overdose history. 1
• Patients with very high aminotransferase levels should be suspected of acetaminophen toxicity even without a clear history of overdose. 1
• Low or absent acetaminophen levels do not rule out acetaminophen poisoning if the ingestion was remote, occurred over several days, or timing is uncertain. 1