Is there a role of N-acetylcysteine (NAC) in acetaminophen (APAP)-induced liver injury?

From the Guidelines

Yes, N-acetylcysteine (NAC) plays a crucial role in the management of acetaminophen (APAP)-induced liver injury.

Mechanism of Action and Clinical Use

• NAC serves as a sulfhydryl group donor, allowing continued nontoxic metabolism of acetaminophen, and can conjugate N-acetyl-p-benzoquinoneimine (NAPQI) into a nontoxic metabolite 1.
• It is recommended to administer NAC as early as possible, but it may still be of value 48 hours or more after ingestion 1.
• The standard dosing regimen for NAC is an initial loading dose of 150 mg/kg in 5% dextrose over 15 minutes, followed by a maintenance dose of 50 mg/kg over 4 hours and then 100 mg/kg over 16 hours 1.

Efficacy and Safety

• Studies have shown that NAC can reduce the risk of hepatotoxicity and mortality in patients with acetaminophen overdose 1.
• A meta-analysis found that NAC was significantly superior to placebo, resulting in lower levels of hepatotoxicity and mortality 1.
• NAC is generally well-tolerated, with common side effects including nausea, vomiting, and rare allergic reactions such as urticaria or bronchospasm 1.

Clinical Guidelines

• The American Association for the Study of Liver Diseases (AASLD) recommends administering NAC in any case of acute liver failure (ALF) in which acetaminophen overdose is a suspected or possible cause 1.
• The clinical policy for managing patients with acetaminophen overdose supports the use of NAC as early as feasible to maximize potential benefit 1.

From the FDA Drug Label

Acetylcysteine solution, USP administered orally, is indicated as an antidote to prevent or lessen hepatic injury which may occur following the ingestion of a potentially hepatotoxic quantity of acetaminophen. Acetylcysteine has been shown to reduce the extent of liver injury following acetaminophen overdose Acetylcysteine probably protects the liver by maintaining or restoring the glutathione levels, or by acting as an alternate substrate for conjugation with, and thus detoxification of, the reactive metabolite.

Yes, there is a role of N-acetylcysteine (NAC) in acetaminophen (APAP)-induced liver injury. NAC is indicated as an antidote to prevent or lessen hepatic injury following acetaminophen overdose, and its effectiveness depends on early oral administration, with benefit seen principally in patients treated within 16-24 hours of the overdose 2, 2. The mechanism of action is thought to be through maintaining or restoring glutathione levels, or acting as an alternate substrate for conjugation with the reactive metabolite. Key points:

• NAC is an antidote for APAP-induced liver injury
• Early administration is crucial for effectiveness
• NAC maintains or restores glutathione levels or acts as an alternate substrate for conjugation with the reactive metabolite

From the Research

Role of N-acetylcysteine in Acetaminophen-Induced Liver Injury

• The provided studies do not directly address the role of N-acetylcysteine (NAC) in acetaminophen (APAP)-induced liver injury 3, 4, 5, 6, 7.
• However, it is known that NAC is used as an antidote for hepatotoxicity due to acetaminophen overdose 6.
• Studies have investigated the use of NAC in non-acetaminophen-related acute liver failure, with some showing improved overall survival, post-transplant survival, and transplant-free survival 3, 4.
• Other studies have examined the use of NAC in specific types of liver injury, such as anti-tuberculosis drug-induced liver injury, and found that it may reduce the length of hospital stay 5.
• A study in pediatric patients with non-acetaminophen acute liver failure found that NAC did not improve 1-year survival and actually had a lower liver transplantation-free survival rate compared to the placebo group 7.

Evidence for NAC in Liver Injury

• The American Association for the Study of Liver Diseases recommends that NAC may be beneficial in non-acetaminophen-related drug-induced liver injury 3.
• A systematic review found that NAC seemed to improve transplant-free survival in non-acetaminophen drug-induced liver failure patients, but its benefit was inconclusive in terms of overall survival 4.
• A randomized controlled trial found that NAC did not shorten the time to normalization of liver biochemistry in patients with anti-tuberculosis drug-induced liver injury, but significantly reduced the length of hospital stay 5.

Limitations and Future Directions

• The current evidence for the use of NAC in liver injury is limited by the lack of studies and presence of bias 4.
• Further research is needed to fully understand the role of NAC in acetaminophen-induced liver injury and to determine its potential benefits and limitations 3, 4, 5, 6, 7.