eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Toxicology

Toxicity, Acetaminophen

Author: Germaine L Defendi, MD, MS, FAAP, Associate Clinical Professor, Department of Pediatrics, Olive View-UCLA Medical Center
Coauthor(s): Jeffrey R Tucker, MD, Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut and Connecticut Children's Medical Center
Contributor Information and Disclosures

Updated: Aug 25, 2009

Introduction

Background

Acetaminophen is the most widely used analgesic-antipyretic medication taken by people in the United States and the world.¹  Since the 1950s, its availability in over-the-counter (OTC) preparations and the contraindication of pediatric use for aspirin-containing products has made acetaminophen one of the most commonly used drugs in pediatric medicine.
 
Acetaminophen is available in more than 200 OTC and prescription medications as a single agent or in combination with other pharmaceuticals. Numerous formulations and preparations are also available and include liquids, tablets, caplets, capsules, and suppositories in immediate-release and sustained-release forms.

Acetaminophen, or paracetamol, is also known by its chemical name, N -acetyl-p -aminophenol (APAP). It has an excellent safety profile when administered in proper therapeutic doses, but hepatotoxicity can occur with misuse and overdoses. N -acetylcysteine (NAC) is an effective antidote for acetaminophen-induced hepatotoxicity due to an acute overdose, especially if administered within 8-10 hours after ingestion.²

Pathophysiology

Therapeutic oral doses of acetaminophen are rapidly absorbed by the GI tract, with body serum levels peaking at 0.5-2 hours postingestion. Therapeutic levels are 10-20 mcg/mL (66-132 mcmol/L). Serum peak levels occur after an overdose within 4 hours postingestion for an immediate-release preparation. Co-ingestion with drugs that delay gastric emptying (such as opiates, anticholinergic agents) or ingestion of an APAP extended-release formulation may increase the peak serum level to more than 4 hours postingestion. The elimination half-life of acetaminophen is estimated to be 2-4 hours.
 
Metabolism of acetaminophen is primarily hepatic. The liver metabolizes more than 90% of an acetaminophen dosage to sulfate and glucuronide conjugates, which are water soluble and are then eliminated in the urine. Sulfation is the primary metabolic pathway in children aged 12 years and younger. Glucuronidation predominates in adolescents and adults. Two percent of an acetaminophen dose is excreted unchanged by the kidneys. The remaining acetaminophen is metabolized by the hepatic cytochrome P450 (CYP450) system to form a reactive, highly toxic metabolite known as N -acetyl-benzoquinoneimine (NAPQI). Glutathione binds NAPQI, enabling the excretion of nontoxic mercapturate conjugates in the urine.
 
Therapeutic doses of acetaminophen do not cause hepatic injury; however because hepatic glutathione stores are depleted (by 70-80%) in an acetaminophen overdose, NAPQI cannot be detoxified and covalently binds to the lipid bilayer of hepatocytes, causing hepatic centrilobular necrosis. Necrosis primarily occurs in this hepatic region due to the greater production of NAPQI by these cells. Glutathione stores to enable metabolism of this toxic metabolite are replaced by sulfhydryl compounds from the diet (eg, fruits and vegetables) or from drugs, such as the antidote, NAC.

Age, diet, liver disease, and medical conditions (eg, malnutrition due to prolonged fasting, gastroenteritis, chronic alcoholism, or HIV disease) affect glutathione stores in the body. Ethanol and drugs such as isoniazid (INH), rifampin, phenytoin, phenobarbital, barbiturates, carbamazepine, trimethoprim-sulfamethoxazole, and zidovudine induce CYP2E1 enzymes (part of the CYP450 system). Activation of the cytochrome system increases the production of NAPQI and, therefore, can increase the risk of hepatocellular injury in patients who ingest these agents. Herbal supplements may also play a role in amplifying the risk for acetaminophen-induced hepatic injury.

Frequency

United States

Acetaminophen is the drug most commonly ingested in overdoses. It is also a common co-ingestant. Because of acetaminophen's widespread availability and the underestimation of its potential toxicity, acetaminophen poisoning is the most common cause of acute liver failure and overdose deaths.

Mortality/Morbidity

The proper medical use of the antidote, NAC, has significantly lowered the mortality rate of patients with acetaminophen toxicity. Most patients do not have clinically significant sequelae if they are treated in a timely manner with antidotal therapy and appropriate supportive care.

In acute exposures, mortality and morbidity rates are lower in young children (£ 5 years old) than in older children, adolescents, and adults. The cause for this age-related difference is unclear but may be due to an increased capacity for conjugation with sulphate, an increased supply and regeneration of glutathione stores, lower ingested doses, or a greater likelihood to vomit after an acute ingestion.

Age

Acetaminophen toxicity can present at any age. A therapeutic misadventure typically occurs in patients younger than 1 year when caregivers give improper doses of a medication that contains to a child. An accidental poisoning (unintentional ingestion) can occur in toddlers and young children. Older patients (eg, teenagers and adults) may overdose with intent to do self-harm.

Clinical

History

Patients with acetaminophen-induced hepatotoxicity present in 4 clinical stages.

• Stage 1 (0.5-24 h postingestion)
  • The first stage lasts for 24 hours.
  • Patients have anorexia, nausea, vomiting, malaise, and diaphoresis. These clinical signs are nonspecific, and, hence, patients might inadvertently be given additional doses of an acetaminophen-containing product for treatment.
  • Some patients remain asymptomatic but still have a risk for developing clinically significant toxicity.
  • Neurologic, respiratory, and cardiac symptoms are rare in stage 1. If CNS involvement and/or severe metabolic acidosis (elevated anion gap) are present, consider co-ingestants.
  • Serum studies are typically within normal limits. About 12 hours post-ingestion, subclinical elevation of serum liver transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) occurs.
• Stage 2 (24-72 h postingestion)
  • The second stage begins 24 hours after ingestion and lasts for another 48 hours.
  • Stage 1 symptoms become less evident than before and/or resolve.
  • Patients present with pain and tenderness in the right upper quadrant. Liver enlargement (hepatomegaly) can be present. Some patients may report decreased urinary output (oliguria).
  • Acute pancreatitis has been reported in patients who concurrently drink alcohol.
  • Serum studies reveal elevated ALT and AST levels, prothrombin (PT) times, and bilirubin values. Renal function abnormalities (eg, BUN, creatinine) may also be present.
• Stage 3 (72-120 h postingestion)
  • Stage 3 develops 3-5 days after ingestion.
  • Symptoms seen in stage 1 (eg, anorexia, nausea, vomiting, malaise) reappear along with signs of hepatic failure with jaundice, hypoglycemia, bleeding, or encephalopathy. Renal failure and cardiomyopathy may also occur.
  • Severe toxicity is evident on sera laboratory studies. Lactic acidosis, prolonged PT or international normalized ratio (INR), markedly elevated ALT and AST (>10,000 IU/L), elevated total bilirubin level of more than 4 mg/dL (primarily indirect) and hyperammonemia are reported.
  • Hepatic centrilobular necrosis is diagnosed on liver biopsy. Almost 4% of patients who develop this degree of hepatotoxicity progress to fulminant hepatic failure.
  • Renal involvement from acute tubular necrosis is evident with abnormal renal function studies, proteinuria, hematuria and granular casts on urinalysis. Acute renal failure occurs in 25% of patients with significant hepatotoxicity and in > 50% of those with hepatic failure.
  • Death is most common during stage 3, with multiorgan failure as the primary cause.
• Stage 4 (5-14 d postingestion)
  • Stage 4 occurs 5-14 days after ingestion. This stage can last as long as 21 days.
  • Patients either have a complete recovery of liver function or they die.
  • In patients who recover, the period to normalization may take several weeks. Hepatic histiologic recovery lags behind clinical recovery and can take months to resolve.
  • Acetaminophen-induced hepatotoxicity does not cause chronic hepatic dysfunction.

Physical

Physical findings vary and primarily depend on the stage of hepatotoxicity.

• Stage 1 (0-1 d)
  • Physical findings are nonspecific.
  • Pallor, diaphoresis, and compromised hydration status due to repeated emesis and increased insensible losses may be present.
  • Malaise and fatigue are reported.
• Stage 2 (1-3 d)
  • Abdominal examination reveals tenderness in the right upper quadrant and hepatomegaly.
  • Vital signs show tachycardia and hypotension as indicators of ongoing volume losses.
• Stage 3 (3-5 d)
  • Physical findings reflect clinically significant hepatic injury, such as abdominal pain, jaundice, and GI bleeding due to coagulopathy.
  • Encephalopathy due to severe hepatic injury occurs.
  • Clinical signs and symptoms of multiorgan failure are noted.
• Stage 4 (5-21 d): Physical findings resolve or death occurs.

Causes

Production of N -acetyl-benzoquinoneimine (NAPQI) by the CYP system is the cause of liver toxicity.

• The maximum daily adult dose of acetaminophen is 4 g with a recommended dosage of 352-650 mg every 4-6 hours or 1 g every 6 hours. For children younger than 12 years and/or less than 50 kg in weight, the maximum daily dosage of acetaminophen is 80 mg/kg (not to exceed a cumulative daily dose of 2.6 g). Therapeutic weight-based oral dosing for children is 10-15 mg/kg every 4-6 hours with a maximum of 5 doses per 24-hour period. Weight-based rectal suppository dosing for children is higher at 15-20 mg/kg per dose.
• In adults, the minimum toxic dose of acetaminophen for a single ingestion is 7.5-10 g. Single ingestions of 12 g or higher have high potential for hepatotoxicity.
• In children, the minimum toxic dose of acetaminophen for a single acute ingestion is 150 mg/kg. Medical toxicologists recommend increasing this threshold to 200 mg/kg in healthy children aged 1-6 years. Children in this age group are less susceptible than others to hepatotoxicity due to acute N -acetyl-p -aminophenol (APAP) poisoning because of their relatively larger hepatic mass (ie, ratio of organ weight to total body weight), which efficiently eliminates and detoxifies NAPQI.
• Children who have acutely ingested 250 mg/kg or more of acetaminophen pose significant concern for acetaminophen-induced hepatotoxicity.
• Patients who ingest more than 350 mg/kg develop severe hepatotoxicity, if they are not appropriately treated.
• In June 2009, the US Food and Drug Administration (FDA) announced requirements for nonprescription and prescription medication to provide new information regarding acetaminophen-induced hepatotoxicity.^3,4 Additionally, the FDA is examining possible removal of acetaminophen from some popular analgesic combination products (eg, Vicodin) and possibly lowering the maximum daily dose. The FDA is currently evaluating whether changes need to be made for acetaminophen regarding the following:
  • Safe daily dose for healthy individuals
  • Safe daily dose in chronic liver disease
  • Safe daily dose when used with alcohol
  • Appropriate dose for efficacy
  • Package size restrictions
  • Pediatric dosing
  • Acetaminophen narcotic combinations

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