AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Acetaminophen is the most widely used analgesic-antipyretic medication taken by people in the United States and worldwide. After acetaminophen became available over the counter (OTC) in the 1950s and after subsequent concerns over the association of aspirin use and Reye syndrome in children arose, acetaminophen became 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 combined with other pharmaceuticals. In addition, various formulations are available and include liquids, tablets, capsules, and suppositories.

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

Pathophysiology

The body rapidly absorbs acetaminophen in therapeutic oral doses. Serum levels peak in 0.5-2 hours or 2-4 hours after an overdose. Therapeutic levels are 10-20 mcg/mL. Small-protein binding is 10%, with a volume of distribution of 0.9 L/kg. Metabolism is primarily hepatic; the half-life of acetaminophen is 2-4 hours. Acetaminophen, the parent compound, is nontoxic, but hepatic metabolism leads to formation of the toxic metabolite N-acetyl-benzoquinoneimine (NAPQI).

The liver metabolizes more than 90% of the acetaminophen taken to sulfate and glucuronide conjugates, which are water soluble and eliminated in the urine. In children, sulfation is the primary pathway until the age of 10-12 years, whereas glucuronidation predominates in adolescents and adults. Only 2% of a dose of acetaminophen is excreted unchanged by the kidneys. Hepatotoxicity is the result of formation of the reactive and toxic metabolite NAPQI by the cytochrome P450 (CYP) system.

Glutathione can bind NAPQI and lead to excretion of nontoxic mercapturate conjugates. As glutathione stores are diminished, NAPQI is not detoxified, and it covalently binds to the lipid bilayer of hepatocytes, causing hepatic centrilobular necrosis. Glutathione must be replaced by sulfhydryl compounds from the diet 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. Agents, such as ethanol, isoniazid (INH), rifampin, phenytoin, phenobarbital, barbiturates, and carbamazepine, induce CYP2E1 enzymes. Activation of the CYP system increases the production of NAPQI and increases the risk of hepatocellular injury in patients who take these agents.

Frequency

United States

Acetaminophen, or APAP, is the drug most commonly ingested in overdoses, and it is a common co-ingestant. Because of its widespread availability and because people underestimate its potential toxicity, APAP accounts for the most overdose deaths due to a pharmaceutical agent.

Mortality/Morbidity

• Since the introduction of the antidote NAC, the mortality rate from APAP toxicity has been low. 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 children younger than 6 years old than in older children, adolescents, and adults. The cause for this age-related difference is unclear, but it may be due to an increased capacity for conjugation with sulphate, an increased supply and regeneration of glutathione stores, or low ingested doses.

Age

• In the United States, the primary reason for liver transplantation in children is biliary atresia; the second is acetaminophen-induced hepatic failure.


• See Mortality/Morbidity above.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

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

• Phase 1 (0-24 h)
• • The first phase lasts up to 24 hours.
  • Patients have anorexia, nausea, vomiting, malaise, and diaphoresis. Because these clinical signs are nonspecific, patients might inadvertently be given additional doses of an acetaminophen-containing product for treatment.
  • Some patients remain asymptomatic, but they can still develop clinically significant toxicity.
  • Neurologic, respiratory, and cardiac symptoms are rare in phase 1.
  • Subclinical elevation of serum liver transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) occurs about 12 hours after ingestion.

• Phase 2 (24-72 h)
• • The second phase begins 24 hours after ingestion and lasts for another 48 hours.
  • Phase 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 report having decreased urinary output.
  • Serum studies reveal elevated ALT and AST levels, prothrombin times (PTs), and bilirubin values.

• Phase 3 (72-120 h)
• • Phase 3 develops 3-5 days after ingestion.
  • The symptoms seen in phase 1 (eg, anorexia, nausea, vomiting, malaise) may reappear.
  • Patients have symptoms of hepatic failure with jaundice, hypoglycemia, bleeding, or encephalopathy. Renal failure and cardiomyopathy may also occur.
  • Hepatic centrilobular necrosis is evident on liver biopsy. Almost 4% of patients who develop this degree of hepatotoxicity progress to fulminant hepatic failure.
  • Death may occur because of cerebral edema, sepsis, or multiorgan failure.

• Phase 4 (5-14 d)
• • Phase 4 occurs 5-14 days after ingestion. This phase can last as long as 21 days.
  • Patients either have a complete recovery of liver function or they die.

Physical

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

• Phase 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.

• Phase 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.

• Phase 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.

• Phase 4 (5-21 d): Physical findings resolve or death occurs.

Causes

Production of NAPQI by the CYP system is the cause of liver toxicity.

• The maximum daily adult dose of APAP 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 <50 kg in weight, the maximum daily dosage of acetaminophen is 75 mg/kg. Weight-based dosing for children is 10-15 mg/kg every 4-6 hours with a maximum of 5 doses per 24-hour period.
• In adults, the minimum toxic dose of APAP for a single ingestion is 7.5-10 g.
• In children, the minimum toxic dose of APAP 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 APAP poisoning because of their relatively large hepatic mass (ie, ratio of organ weight to total body weight), which eliminates and detoxifies NAPQI relatively efficiently.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Drug- or toxin-induced hepatitis
Hepatobiliary disease
Inborn errors of metabolism: alpha1-antitrypsin deficiency or fatty acid oxidation abnormalities
Ischemic hepatitis (shock liver)
Reye syndrome
Viral hepatitis due to Epstein-Barr virus or varicella
Vomiting of unclear etiology

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Measurement of acetaminophen, or APAP, serum concentration
• • Obtain a plasma APAP level in patients who have a history of a potentially toxic ingestion, who ingested an unknown amount of APAP, who have altered mental status, or who may have made an active suicidal gesture.
  • Routine assessment of APAP levels is controversial but recommended because deaths from occult APAP overdoses have occurred.
  • Negligible APAP values from an ingestion less than 4 hours old can be used to rule out hepatotoxicity.
  • Any serum concentration based on a sample drawn 4 hours or longer after a single ingestion may be plotted on an acetaminophen toxicity nomogram (Rumack-Matthew nomogram) to estimate the risk of hepatotoxicity.

• Interpretation of APAP values by using the acetaminophen toxicity nomogram (Rumack-Matthew nomogram)
• • The Rumack-Matthew nomogram was developed for single acute ingestions of APAP and is based on observational data that were successfully validated in a large series of patients.
  • With the nomogram, a single level in time is used to predict the risk of hepatotoxicity. It does not help in predicting fulminant hepatic failure or death.
  • Nomogram tracking begins at 4 hours after ingestion and ends at 24 hours after ingestion.
  • The upper line of the nomogram is the probable line. About 60% of patients with values above this line develop hepatotoxicity. The lower line is the possible line, which was added to the nomogram to give a 25% margin of error to allow for variations in measurements of the APAP level or for uncertainty regarding the time of ingestion.
  • The nomogram cannot be used if the patient has a history of multiple APAP ingestions. Its reliability also decreases for ingestions involving extended-release acetaminophen tablets or for co-ingestions of APAP with anticholinergics or opioids.

• Measurement of hepatic ALT and AST levels
• • Hepatic transaminase levels start to rise within 24 hours after ingestion (phase 1) and peak at 48-72 hours after ingestion (phase 2). In severe overdose, transaminase elevation can be detected as early as 12-16 hours after ingestion.
  • Evidence of hepatic injury due to APAP overdose is defined by elevation of the plasma transaminases values >1000 U/L.
  • Additional serum measurements of hepatic function include glucose, PT, and bilirubin may be useful.

• Other laboratory studies
• • Renal function tests of electrolyte, BUN, and creatinine levels can show evidence of renal failure, which often occurs with hepatic failure. Urinalysis to check for proteinuria and hematuria helps in diagnosing acute tubular necrosis (ATN) that can also occur in this clinical setting. Renal injury becomes apparent 2-3 days after an acute APAP ingestion (phase 2). Although renal failure is rare, it can occur independent of hepatic failure.
  • Assess for pancreatic injury by obtaining lipase and amylase levels, especially if the patient has evidence of clinically significant hepatotoxicity and complaints of severe abdominal pain.
  • Hepatic injury can cause coagulopathy; hence, blood products may be needed. Typing and crossmatching should be performed.
  • Order a pregnancy test (based on human chorionic gonadotropin) in all women of childbearing age. APAP crosses the placental barrier. Delayed antidotal treatment in pregnant women has been associated with fetal loss.

Imaging Studies

• Imaging studies can be helpful in some circumstances.
• CT scanning of the head is indicated for patients who present with or who develop altered mental status or encephalopathy. Encephalopathy due to cerebral edema occurs in the late clinical presentation of APAP overdose (phase 3 to 4) and is detectable on CT.
• Ultrasonography is helpful in defining hepatic and/or renal abnormalities as well as in assessing for involvement of other abdominal organs.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Initial appropriate supportive care is essential. Immediate assessment of the patient's airway, breathing and fluid status is critical before treatment for suspected acetaminophen overdose is started. In addition, it is important to access for other potential life-threatening co-ingestions.

• GI decontamination: Consider decontamination with activated charcoal in any patient who presents within 4 hours of ingestion.
• Oral NAC (Mucomyst)
• • The antidote for APAP toxicity is NAC, which has several mechanisms to prevent hepatotoxicity. The oral formulation is the drug of choice for the treatment of either acute, chronic, or late-presenting acetaminophen ingestions.
  • NAC is converted to cysteine, which replenishes glutathione stores. NAC also directly detoxifies NAPQI to nontoxic metabolites. NAC provides a substrate for sulfation, increasing the capacity for nontoxic metabolism. NAC can directly conjugate to NAPQI to reduce toxicity.

  • The National Multicenter study (Smilkstein, 1988) revealed that oral NAC is safe and effective for as long as 24 hours after a toxic ingestion. Treatment with oral NAC effectively prevented hepatotoxicity regardless of the initial plasma acetaminophen level if it was started within 8 hours of the ingestion. Its effectiveness did not depend on whether NAC was started 0-4 or 4-8 hours after ingestion.

• Intravenous NAC (Acetadote)
• • In 2004, the US Food and Drug Administration (FDA) approved an intravenous formulation of NAC for use in adults. In February 2006, this FDA approval was modified to include children (patients <40 kg).

  • Intravenous administration of NAC is recommended for use in selected patients, including those with an altered mental status, GI bleeding and/or obstruction or a history of caustic ingestion, potential fetal toxicity from maternal toxicity, or an inability to tolerate oral NAC because of refractory emesis despite proper use of antiemetics.

  • Pharmaceutical guidelines for intravenous NAC administration differ depending on the patient's body weight and/or on whether the ingestion is acute or chronic. Guidelines for intravenous dosage and administration are discussed in the Medication section below.

Surgical Care

• Surgical evaluation for possible liver transplantation is indicated for patients who have severe hepatotoxicity.
• Criteria for liver transplantation include metabolic acidosis, renal failure, coagulopathy, and encephalopathy.

Consultations

• A medical toxicologist or a regional poison control center may be helpful in treating patients with possible co-ingestions, complicated histories, or atypical presentations.
• Consultation with a hospital-based pediatric gastroenterologist affiliated with a transplant center is needed for patients who have signs of clinically significant hepatotoxicity.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

NAC, antiemetics, and activated charcoal are helpful in the treatment of acetaminophen toxicity.

Drug Category: Antidotes

NAC is the antidote of choice to prevent and treat acetaminophen-induced hepatotoxicity. It is indicated for all ingestions above the possible toxicity line on the Rumack-Matthew nomogram. The FDA has approved both PO (Mucomyst) and IV (Acetadote) formulations. Three treatment protocols are recognized: 72-hour PO, 21-hour IV, and 48-hour IV. For maximum hepatoprotective effect, the antidote should be given within 8-10 hours of the acetaminophen ingestion.

Drug Category: Antiemetic agents

Nausea and vomiting in acetaminophen-induced hepatotoxicity may due to acetaminophen, activated charcoal, or PO NAC. Antiemetic therapy is indicated in patients with these symptoms to enable successful treatment with PO NAC.

Drug Category: Decontamination agents

Consider decontamination with activated charcoal in any patient who presents within 4 hours after the ingestion. Activated charcoal adsorbs APAP, but its use has been controversial because activated charcoal may absorb PO NAC. Although activated charcoal significantly reduces the bioavailability of NAC, the small decrease in the NAC bioavailability is unlikely to reduce the effectiveness of PO NAC as an antidote.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Admit patients with APAP levels above the possible line on the Rumack-Matthew nomogram for treatment with NAC.
• Treat patients with evidence of hepatic failure, metabolic acidosis, encephalopathy, or coagulopathy in an intensive care unit.

Further Outpatient Care

• Patients with APAP levels below the possible line for hepatotoxicity on the Rumack-Matthew nomogram may be discharged home after they are medically cleared.
• If the ingestion occurred with an intent to harm oneself, a complete psychiatric evaluation is indicated before the patient is discharged from the hospital.

In/Out Patient Meds

• Treatment for APAP overdose with antidotal therapy must be managed on an inpatient basis.

Transfer

• Transfer patients with evidence of clinically significant hepatotoxicity to a hospital with transplant services.

Patient Education

• Inform parents and caregivers of the risks associated with acetaminophen overdose and that this drug, though it is safe when dosed properly, can cause harm if misused.
• Educate parents and caregivers about the proper dose of APAP in children based on weight and inform them that various preparations have different concentrations of APAP. Adult formulations of APAP should not be used to treat children.
• Educate parents and caregivers that many OTC cold and cough preparations contain APAP. They should carefully read medication labels before they give these preparations to children.
• Give parents and caregivers information, including the toll-free phone numbers for the National Poison Control hotline (1-800-222-1222) and their regional Poison Control hotline.
• For excellent patient education resources, visit eMedicine's Poisoning Center. Also, see eMedicine's patient education articles, Acetaminophen (Tylenol) Poisoning, Activated Charcoal, and Poison Proofing Your Home.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Special Concerns

• Delayed presentation of an acute single ingestion
• • Until recently, the standard of care for APAP management in the United States was administration of NAC to patients who presented within but not later than 24 hours after ingestion. Data from England suggest that NAC may be beneficial for APAP-induced hepatic failure when patients present more than 24 hours after ingestion. The authors know of no studies conducted to evaluate the use of NAC in patients who present late with hepatotoxicity but without signs of hepatic failure.
  • Medical toxicologists recommend treatment with NAC in patients who present more than 24 hours after ingestion, if unmetabolized APAP is detected in the serum and if hepatic injury is evident. Laboratory findings of hepatic injury or impaired hepatic function include increased ALT and AST levels, elevated total bilirubin values, and prolonged PTs.
  • Continuation of NAC therapy is based on the patient's clinical status, on detectable serum values of APAP, and liver function (PT and ALT, AST, total bilirubin levels). The Rumack-Matthew nomogram is not valid in cases of late presentation and should not be used to guide decisions in these cases.
  • The beneficial effect of NAC in late treatment when liver damage has occurred suggests that additional repair mechanisms may be present. Proposed mechanisms of NAC in this setting include an antioxidant effect, decreased neutrophil accumulation, and improved microcirculatory blood flow with increased oxygen delivery to hepatic tissue.

• Chronic toxicity
• • Chronic APAP toxicity is being recognized in pediatric patients. Chronic APAP toxicity has occurred in young, febrile children with reduced oral intake who were treated with repeated doses of APAP.
  • In chronic APAP toxicity, the importance of fasting, reduced glutathione stores, and enhanced metabolism is unclear. Risk factors for chronic APAP toxicity include sustained administration of high doses, fever, poor oral intake, and young age. The daily dose of APAP for children should not exceed 75 mg/kg/d.
  • The Rumack-Matthew nomogram was developed for single acute exposures for APAP and should not be used to evaluate chronic exposures. Elevated values on liver function testing are better than nomographic measures as predictors of toxicity. Diagnosing chronic APAP toxicity can be difficult because the patient's presentation may appear to reflect the initial illness. In these situations, consider consulting a poison control center or a medical toxicologist in regard to management strategies.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: May 15, 2007