Introduction

Acetaminophen, also known as paracetamol, is a widely used over-the-counter analgesic and antipyretic. While it is generally safe when used within recommended doses, acetaminophen overdose is a common cause of Acute Liver Failure (ALF),(1) leading to significant morbidity and mortality. Acetaminophen poisoning results from both acute overdose and Repeated Supratherapeutic Ingestion (RSTI), which can overwhelm the body’s metabolic pathways and lead to hepatotoxicity.(2) This article explores the epidemiology, pathophysiology, diagnosis, and management of acetaminophen poisoning.

Epidemiology

Acetaminophen poisoning remains one of the most common causes of drug overdose worldwide. In the United States, it is responsible for a large number of overdose-related emergency room visits and hospitalizations each year.(3) Poisoning can occur either intentionally (as part of a suicide attempt) or unintentionally due to misuse, such as exceeding the maximum daily dose or combining acetaminophen-containing products without realizing it. Acute overdose usually involves a single large dose, while chronic toxicity, or RSTI, results from repeated doses exceeding 4 g/day over time.(2)

Pathophysiology 

After ingestion, acetaminophen is rapidly absorbed from the gastrointestinal tract and undergoes extensive first-pass hepatic metabolism. Under normal circumstances, most of the drug is metabolized to non-toxic sulfate and glucuronide conjugates, which are excreted in the urine. However, a minor fraction is oxidized by the cytochrome P450 enzyme system, predominantly CYP2E1, to form N-acetyl-p-benzoquinone imine (NAPQI), a highly reactive intermediate. Under therapeutic doses, NAPQI is detoxified by hepatic glutathione and subsequently excreted. In overdose situations, the capacity of glutathione to detoxify NAPQI is exceeded, leading to the accumulation of NAPQI, which binds to cellular proteins, causing hepatocyte necrosis and liver injury.(4)

Clinical Presentation

Acetaminophen toxicity progresses through four distinct stages, each characterized by specific symptoms and clinical findings that depend on the dose ingested and the time elapsed since ingestion.(4)

Stages of Acetaminophen Toxicity

Stage I: Incubation (0-24 hours)

• Symptoms: Patients may be asymptomatic or experience nonspecific symptoms such as anorexia, nausea, vomiting, and diaphoresis.
• Lab Findings: Generally normal; however, in cases of massive ingestion, early signs of liver enzyme elevation (transaminitis) or lactic acidosis may be observed.

Stage II: Latent Period (24-72 hours)

• Symptoms: Initial symptoms may resolve, but patients can develop right upper quadrant pain. Some may remain asymptomatic.
• Lab Findings: Elevations in liver enzymes (AST/ALT) are common. Nephrotoxicity may also begin to manifest during this stage.

Stage III: Peak Liver Toxicity (72-96 hours)

• Symptoms: Systemic symptoms return, including severe nausea, vomiting, malaise, and signs of hepatic failure such as jaundice, coagulopathy, and encephalopathy. This stage carries the highest risk of mortality due to complications like cerebral edema or septic shock.
• Lab Findings: Transaminases peak during this period; significant liver dysfunction is evident with elevated bilirubin and INR levels. Renal failure may also occur.

Stage IV: Resolution (4 days to 2 weeks)

• Symptoms: Patients may either recover or progress to multiple organ failure. Recovery is marked by a gradual return to normal liver function.
• Lab Findings: Liver function tests begin to normalize if recovery occurs. Persistent elevation of liver enzymes indicates ongoing damage.

Dose Dependency

The severity of toxicity is influenced by the dose ingested:

• Doses above 10 grams or 200 mg/kg (whichever is lower) are considered potentially toxic.
• Ingestions exceeding 30 grams are classified as “massive” and require aggressive treatment strategies.

Diagnosis

 Early diagnosis of acetaminophen poisoning is crucial to prevent hepatotoxicity. The Rumack-Matthew nomogram is commonly used to assess the risk of hepatotoxicity in cases of acute overdose when the time of ingestion is known. Serum acetaminophen levels are plotted against time since ingestion to determine whether treatment is warranted.(5,6)

Rumack-Matthew Nomogram

• The nomogram plots serum acetaminophen levels against the time since ingestion, allowing healthcare providers to determine whether treatment with N-acetylcysteine (NAC) is warranted.

• A serum acetaminophen level of 140-150 μg/mL at 4 hours post-ingestion indicates a need for NAC treatment to mitigate the risk of hepatotoxicity.
• If the time of ingestion is unknown or if the patient has altered mental status, the nomogram cannot be reliably used, and additional assessments are necessary.

Diagnosis in RSTI or Chronic Toxicity

In cases of Repeated Supratherapeutic Ingestion (RSTI) or chronic toxicity, serum acetaminophen levels may be low or undetectable.(6,7) Therefore, diagnosis relies more heavily on:

• Liver Function Tests: Elevated levels of liver enzymes such as AST (aspartate aminotransferase) and ALT (alanine aminotransferase) are indicative of liver injury.
• Coagulation Studies: An elevated International Normalized Ratio (INR) suggests impaired liver function.
• Other laboratory studies may include a complete metabolic panel, blood gas analysis, and testing for salicylate levels to rule out other toxic ingestions.

Clinical Indicators of Hepatotoxicity

• Elevated AST and ALT levels, particularly if they exceed 1000 IU/L, are strongly suggestive of acetaminophen-related hepatotoxicity.
• Total bilirubin levels may rise, indicating cholestasis or liver dysfunction.
• Metabolic disturbances such as hypophosphatemia and metabolic acidosis can also occur as a result of severe liver injury.

Management

The mainstay of treatment for acetaminophen poisoning is the administration of N-acetylcysteine (NAC), an effective antidote that replenishes hepatic glutathione, enhances non-toxic sulfate conjugation, and reduces NAPQI to less toxic forms.

1.    Activated Charcoal:

Activated charcoal is an important intervention in the management of acetaminophen poisoning, particularly when the patient presents within four hours of ingestion. It helps to reduce the absorption of acetaminophen from the gastrointestinal tract, thereby mitigating its potential hepatotoxic effects.(8)

Administration Guidelines

• Timing: Activated charcoal should be administered if the patient presents within 4 hours of ingesting a potentially toxic dose of acetaminophen.
• Dosage: The recommended dose for adults is between 50 to 100 grams, while for children, it is 25 to 50 grams.
• Contraindications: Activated charcoal should not be given if the patient is unable to protect their airway or if there are other contraindications, such as gastrointestinal perforation or severe altered mental status.

Effectiveness

• Acute Ingestion: The greatest benefit from activated charcoal is observed in cases of massive acetaminophen ingestion (generally defined as more than 30 grams).
• Sustained-Release Formulations: For sustained-release formulations of acetaminophen, activated charcoal may still be beneficial even beyond the four-hour window due to prolonged absorption characteristics.

Clinical Considerations

• In patients with suspected acute overdose, especially those with high-risk ingestion (greater than 200 mg/kg or 10 grams), activated charcoal can play a crucial role in reducing peak acetaminophen levels and subsequent liver injury.
• If activated charcoal is administered, it does not preclude the need for further treatment with N-acetylcysteine (NAC), which should be initiated as soon as possible based on serum acetaminophen levels and clinical judgment.

2.    N-acetylcysteine (NAC):

N-acetylcysteine (NAC) is a crucial antidote for acetaminophen overdose, and its administration can occur via two routes: orally or intravenously. The choice of route often depends on the clinical scenario, particularly the patient’s condition and the timing of presentation.(9)

Administration Routes

Intravenous NAC

• Preferred in Acute Overdose: Intravenous NAC is typically favored for acute acetaminophen overdose due to its rapid onset of action and shorter treatment duration.
• Dosing Protocol: The standard intravenous regimen involves:
  • A loading dose of 150 mg/kg infused over 60 minutes.
  • Followed by a maintenance dose of 50 mg/kg over 4 hours, and then 100 mg/kg over the next 16 hours.
• Advantages:
  • Easier administration in patients who may experience significant nausea or vomiting.
  • Reduced risk of dosing errors compared to oral regimens, which require more frequent dosing.

Oral NAC

• Alternative Option: Oral NAC can be used when intravenous administration is unavailable or impractical.
• Dosing Protocol: The oral regimen consists of:
  • A loading dose of 140 mg/kg, followed by 70 mg/kg every 4 hours for a total of 18 doses over 72 hours.
• Disadvantages:
  • Requires more frequent dosing, which can be cumbersome.
  • Higher incidence of gastrointestinal side effects such as nausea and vomiting.

Timing and Effectiveness

• NAC is most effective when administered within 8 hours of acetaminophen ingestion. Delays beyond this window can significantly increase the risk of hepatotoxicity.
• In cases where the serum acetaminophen concentration is above the treatment line on the Rumack-Matthew nomogram, NAC should be initiated promptly, even before laboratory results are available if there is a strong suspicion of overdose.

3.    Liver Transplantation:

Patients with evidence of fulminant hepatic failure, such as encephalopathy and coagulopathy, may require referral to a liver transplant center. The King’s College Criteria, which include factors such as pH, INR, creatinine levels, and encephalopathy grades, are commonly used to assess the need for transplantation.

Prognosis

The prognosis for acetaminophen toxicity is excellent if NAC is administered promptly, ideally within eight hours of ingestion. Even patients who present later may recover with appropriate NAC therapy, but the risk of liver failure and death increases significantly with delayed presentation.(10)

For those requiring liver transplantation, survival rates are lower, particularly in those who meet the King’s College Criteria. Transplant-free survival from acetaminophen-induced acute liver failure is approximately 70%, compared to much lower rates for other causes of acute liver failure.

Prevention

Efforts to reduce acetaminophen overdose have focused on educating the public and healthcare professionals on safe dosing, limiting the availability of high-dose over-the-counter formulations, and incorporating safety packaging to reduce the risk of unintentional overdose. In the United Kingdom, restrictions on over-the-counter sales and the implementation of blister packaging have resulted in a significant decline in overdose cases and the number of liver transplants required due to acetaminophen toxicity.

Conclusion

Acetaminophen poisoning is a leading cause of acute liver failure, with potentially severe outcomes if not treated promptly. Early diagnosis using the Rumack-Matthew nomogram, timely administration of NAC, and appropriate critical care are key components of management. Prevention through public education and regulatory changes remains an important strategy for reducing the burden of acetaminophen toxicity.

References

1.          Fontana RJ. Acute Liver Failure Including Acetaminophen Overdose. Vol. 92, Medical Clinics of North America. 2008.

2.          Mehrpour O, Hoyte C, Nakhaee S, Megarbane B, Goss F. Using a decision tree algorithm to distinguish between repeated supra-therapeutic and acute acetaminophen exposures. BMC Med Inform Decis Mak. 2023;23(1).

3.          Budnitz DS, Lovegrove MC, Crosby AE. Emergency department visits for overdoses of acetaminophen-containing products. Am J Prev Med. 2011;40(6).

4.          Agrawal S, Khazaeni B. Acetaminophen Toxicity [Internet]. StatPearls Publishing; 2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441917/

5.          Agrawal S, Khazaeni B. Acetaminophen Toxicity [Internet]. StatPearls Publishing; 2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441917/

6.          Chun LJ, Tong MJ, Busuttil RW, Hiatt JR. Acetaminophen Hepatotoxicity and Acute Liver Failure. 2009.

7.          OMALLEY.GERALD. Acetaminophen Poisoning [Internet]. MSD Manuals; 2019. Available from: https://www.msdmanuals.com/professional/injuries-poisoning/poisoning/acetaminophen-poisoning

8.          Dart RC, Mullins ME, Matoushek T, Ruha AM, Burns MM, Simone K, et al. Management of Acetaminophen Poisoning in the US and Canada: A Consensus Statement. JAMA Netw Open. 2023;6(8).

9.          Smilkstein MJ, Bronstein AC, Linden C, Augenstein WL, Kulig KW, Rumack BH. Acetaminophen overdose: A 48-hour intravenous N-acetylcysteine treatment protocol. Ann Emerg Med. 1991;20(10).

10.       Alizadeh N, Yaryari A, Behnoush AH, Raoufinejad K, Behnoush B. Late N ‐acetylcysteine for successful recovery of acetaminophen‐related acute liver failure: A case report.  Clin Case Rep. 2023;11(9).