- A disorder characterized by hepatic necrosis following large acetaminophen ingestions. Although patients can be asymptomatic, common presenting symptoms include nausea, vomiting, diaphoresis, malaise, jaundice, confusion, somnolence, coma, and potentially death. A clinical hallmark is the onset of symptoms within 24 hours of ingestion of acetaminophen-containing medications. Ingestion should be treated before symptoms develop if possible.
- Acetaminophen poisoning most often occurs following large, single ingestions of acetaminophen-containing medications. Toxicity is likely to occur with ingestions greater than >12 g in adults and >250 mg/kg in children (1). Poisoning also occurs after acute and chronic ingestions of lesser amounts in individuals who regularly abuse alcohol, are chronically malnourished, or take medications that affect hepatic metabolism of acetaminophen.
- Therapeutic adult doses are 0.5 to 1.0 g q4–6h to a maximum of 4 g/day. Therapeutic pediatric doses are 10 to 15 mg/kg q4–6h, not to exceed 5 doses in 24 hours or 75 g/kg/day.
- System(s) affected: gastrointestinal, cardiovascular, renal/urologic, CNS
- Multisystem organ failure can occur.
- Synonym(s): paracetamol poisoning
Increased risk of hepatic damage in frail elderly patients due to decreased hepatic metabolism and coingestion of other hepatotoxic medications. Keep dose of acetaminophen ≤3,000 mg/day in seniors and patients with liver disease and/or alcohol abuse disorders.
Hepatic damage after ingestion of toxic acetaminophen doses can be less severe in young children, potentially due to larger glutathione stores.
Increased incidence of spontaneous abortion, especially with overdose at an early gestational age. Incidence of spontaneous abortion or fetal death is increased when N-acetylcysteine (NAC) treatment is delayed. IV NAC is generally preferred in pregnancy due to greater bioavailability.
- Predominant age: children and adults
- Predominant sex: no reported association
- Intentional versus unintentional ingestion (52% vs. 48%)
- The annual reported incidence of acetaminophen overdose increased from 2 (95% CI 0.2–7.2) cases per 10,000 patients in 2005 to 3.4 (95% CI 1.1–8.8) in 2010.
- Over 65,000 incidents of acetaminophen exposure (either alone or in combination with other medications) were reported nationwide to poison control centers in 2018.
- >38,000 hospitalizations per year for acetaminophen-related poisonings in the United States, nearly 1/2 were unintentional (mostly involving opioid-acetaminophen combinations)
- <1% of hospitalizations in patients <18 years had coexistent liver toxicity.
Etiology and Pathophysiology
- Accidental or intentional ingestion of acetaminophen medications
- 96% of ingested acetaminophen is metabolized in the liver, only 2–4% is excreted unchanged in the urine. When taken in therapeutic doses, 90–95% of hepatic metabolism results in the formation of benign metabolites. 5–10% of hepatic metabolism is by oxidation through the cytochrome P450 enzyme system (CYP 3A4 and CYP 2E1), resulting in the formation of the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is rapidly conjugated with glutathione to form a nontoxic metabolite. Metabolites are excreted in the urine with a small amount of unchanged drug. Hepatocellular damage occurs when toxic doses of acetaminophen saturate the glucuronidation and sulfation pathways with production of excessive NAPQI. Available glutathione stores become depleted, NAPQI accumulates, and hepatocellular damage occurs.
- Concurrent poisoning with other substances
- Psychiatric illness, history of suicide attempts
- Regular ingestion of large amounts of alcohol
- Possible risk related to previous weight loss surgery
- Poison Control: 1-800-222-1222 for consultations and management guidance
- FDA labeling guidance: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances...
Commonly Associated Conditions
Opioid-acetaminophen combination products
- May initially be asymptomatic, particularly with history of ingestion in preceding 8 hours. Signs and symptoms of poisoning are related to liver toxicity and develop over the first 24 hours following large ingestions; may last up to 8 days
- Symptoms may develop gradually following long-term ingestion of near maximal-therapeutic amounts of acetaminophen. Such patients may present in varying stages, without a history of toxic ingestion.
- Severe symptoms indicate large ingestions or coingestants.
- Stage 1: first 24 hours after ingestion:
- Nausea, emesis, and anorexia
- Stage 2: days 2 to 3 following ingestion
- Right upper quadrant pain
- Typically less nausea, vomiting, diaphoresis, and malaise than in stage 1
- Stage 3: days 3 to 4 following ingestion
- Nausea, vomiting, and malaise reappear.
- Severe poisonings may result in jaundice, confusion, somnolence, and coma.
- Stage 4: 5 or more days after ingestion
- Possible deterioration due to multiorgan failure and death. Symptoms resolve over time in survivors.
- Stage 1: first 24 hours after ingestion:
- Fulminant hepatic failure occurs in <1% of adults and is very rare in children <6 years of age.
- An unexplained rise in liver function tests (LFTs) with negative acetaminophen levels might suggest stage 3 toxicity.
Ingestion or suspected ingestion of acetaminophen-containing product
Varies with time after ingestion; follow vital signs and observe for signs of hepatotoxicity
- Consider presence of coingestants, especially alcohol, opiates, and aspirin.
- Other ingested toxins that produce severe acute hepatic injury, including the mushroom Amanita phalloides and products containing yellow phosphorus or carbon tetrachloride
Diagnostic Tests & InterpretationInitial Tests (lab, imaging)
- Draw plasma acetaminophen levels on all patients ≥4 hours after ingestion (levels prior to 4 hours are not useful). Draw additional levels at 6 and 8 hours if extended release form.
- Alanine transaminase (ALT), aspartate transaminase (AST), prothrombin time (PT)/international normalized ratio (INR), bilirubin, lactate dehydrogenase (LDH)
- With severe poisonings, PT/INR rise in parallel with LFT changes.
- With toxic ingestions, AST (serum glutamic-oxaloacetic transaminase), ALT (serum glutamic-pyruvic transaminase), and bilirubin levels begin to rise in stage 2 and peak in stage 3.
- Improvement in ALT with therapy is an encouraging clinical sign.
- Electrolytes, glucose, BUN, creatinine
- Renal function abnormalities are common in patients with hepatotoxicity.
- Pregnancy screen in females (urine or serum)
- Consider arterial blood gas (ABG).
- Anion-gap metabolic acidosis due to accumulation of 5-oxoproline may rarely be seen.
- Screen for suspected coingestants (aspirin, iron, etc.), especially if suicide gesture/attempt.
- Laboratory abnormalities usually resolve by stage 4.
- Cardiovascular, renal, and pancreatic involvement may present following severe poisonings.
- Diseases or toxic substances that damage the liver (particularly alcohol) may alter laboratory results.
- No specific imaging required
Follow-Up Tests & Special Considerations
During recovery, liver tests should normalize.
Centrilobular hepatic necrosis
- Contact a regional/local poison control center for recommendations. In the United States: 1-800-222-1222
- Give acetylcysteine (NAC) when plasma acetaminophen concentrations measured ≥4 hours after ingestion are in the “possible risk” or higher levels on the Rumack-Matthew nomogram. This corresponds to acetaminophen levels >150 μg/mL (993 μmol/L), >75 μg/mL (497 μmol/L), and >37 μg/mL (244 μmol/L) at 4, 8, and 12 hours after ingestion, respectively. See https://www.mdcalc.com/acetaminophen-overdose-nac-dosing.
- Note: The nomogram does not help determine the need for NAC for sustained-release products or chronic ingestions. If a sustained-released product has been ingested, obtain two serum acetaminophen levels 4 to 6 hours apart. Treat if either level is above the possible toxicity line. For chronic toxicity or patients who present 24 hours postingestion, treat based on clinical effects, LFTs, and the acetaminophen level.
- Start NAC within 8 hours of ingestion for maximal hepatic protection. Patients presenting near 8 hours should empirically receive NAC while waiting for labs.
- All patients with acetaminophen liver injury (even after 8 hours) should receive NAC.
- NAC therapy may be effective up to ≥36 hours after ingestion.
- Give single-dose activated charcoal within 1 to 2 hours (and possibly up to 4 hours) of ingestion (especially in cases of coingestants) (2),(3)[C].
Do not delay NAC administration for use of activated charcoal.
- Ipecac and gastric lavage are no longer recommended for routine use at home or in health care facilities.
- Initiate acetylcysteine (NAC, Mucomyst) within 8 hours of ingestion whenever possible; single-dose activated charcoal (1 g/kg PO) may be effective if given within 1 to 2 hours of ingestion especially if other substances concomitantly ingested. Never delay oral NAC for activated charcoal.
- NAC may be given PO or IV, depending on situation and availability:
- A two bag regimen should be used to administer a total of 300 mg/kg IV NAC (Acetadote, Cetylev) over a 20 hour period to reduce adverse effects of NAC administration. Begin with a 200 mg/kg IV dose over 4 hours. Followed by a 100 mg/kg IV dose over 16 hours (4),(5).
- Oral loading dose of 140 mg/kg, then 70 mg/kg q4h for 17 additional doses (72-hour regimen)
- No treatment regimen has been shown to be superior over the other (2)[A]. However, IV NAC has been shown to decrease the length of hospitalization compared to oral NAC.
- Contraindications: medication allergies
- Oral NAC may cause significant nausea and vomiting due to its sulfur content and is often poorly tolerated; consider nasogastric tube.
- Nausea can be treated with metoclopramide (Reglan), 1 to 2 mg/kg IV, or ondansetron (Zofran), 0.15 mg/kg IV (for age >4 years, usually 4 mg/dose).
- IV NAC (Acetadote) may cause anaphylactoid reactions, (3–6%) including rash, bronchospasm, pruritus, angioedema, tachycardia, or hypotension (higher rates seen in asthmatics and those with atopy) (6)[C].
- Reactions usually occur with loading dose. To prevent this, slow or temporarily stop the infusion; may concurrently treat with antihistamines
- Failure rates of NAC of 3–7% have been observed (6)[C].
- Oral racemethionine (methionine)
- In massive ingestions (levels >1,000 mg/L, acidosis, coma/hypotension), hemodialysis may improve survival (7)[C].
- In January 2016, NAC (Acetadote, Cetylev), an effervescent lemon mint–flavored NAC tablet, was approved by the FDA. Tablets come in strengths of 500 mg and 2.5 g.
Issues For Referral
- Behavioral health evaluation for intentional ingestions
- Child abuse reporting if neglect led to overdose
Admission, Inpatient, and Nursing Considerations
- Toxic and intentional ingestions
- Increased LFTs, acidosis on ABG, elevated creatinine, or other signs of target organ damage merit admission.
- Age- and weight-appropriate IV hydration
- Evaluate all patients at an accredited health care facility—escalate level of care as appropriate depending on potential level of toxicity.
- Evaluate patients with evidence of organ failure, increased LFTs, or coagulopathy for emergency liver transplant (ELT) at a transplant center.
- Restrict activity if hepatic damage is significant.
- Outpatient management is adequate for nontoxic accidental ingestions.
Ask about ingestion by others (i.e., suicide pacts).
No special diet, except with severe hepatic damage
- Counsel patients to avoid acetaminophen (Tylenol, others) or other forms of acetaminophen, particularly if using combination product(s) containing acetaminophen.
- Educate parents/caregivers during well-child visits.
- Anticipatory guidance for caregivers, family, and cohabitants of potentially suicidal patients
- Educate patients on long-term acetaminophen therapy.
- Complete recovery with early therapy
- <1% of adult patients develop hepatic failure. King criteria (pH <7.3, PT >100 s [INR >65], creatinine >3.4 mg/dL [>300 μmol/L]) is associated with a poor prognosis and possible need for liver transplant (8)[C]. Early referral increases the chance for transplant success.
- Hepatic failure is very rare in children <6 years of age.
Rare following recovery from acute poisoning
- Major JM, Zhou EH, Wong HL, et al. Trends in rates of acetaminophen-related adverse events in the United States. Pharmacoepidemiol Drug Saf. 2016;25(5):590–598. [PMID:26530380]
- Mund ME, Quarcoo D, Gyo C, et al. Paracetamol as a toxic substance for children: aspects of legislation in selected countries. J Occup Med Toxicol. 2015;10:43. [PMID:26664414]
- Serper M, Wolf MS, Parikh NA, et al. Risk factors, clinical presentation, and outcomes in overdose with acetaminophen alone or with combination products: results from the Acute Liver Failure Study Group. J Clin Gastroenterol. 2016;50(1):85–91. [PMID:26166142]
- K71.10 Toxic liver disease with hepatic necrosis, without coma
- T39.1X1A Poisoning by 4-Aminophenol derivatives, accidental, init
- T39.1X2A Poisoning by 4-Aminophenol derivatives, self-harm, init
- T39.1X4A Poisoning by 4-Aminophenol derivatives, undetermined, init
- 573.3 Hepatitis, unspecified
- 965.4 Poisoning by aromatic analgesics, not elsewhere classified
- 197356006 Toxic liver disease with hepatic necrosis (disorder)
- 290134002 Accidental cetaminophen poisoning (disorder)
- 290136000 Acetaminophen poisoning of undetermined intent (disorder)
- 70273001 Poisoning by acetaminophen
- Consult Poison Control Center for management recommendations, 1-800-222-1222 in United States.
- Give NAC when plasma acetaminophen concentrations (measured ≥4 hours after ingestion) are in the “possible risk” or higher levels. This corresponds to acetaminophen levels >150 μg/mL (993 μmol/L), >75 μg/mL (497 μmol/L), and >37 μg/mL (244 μmol/L) at 4, 8, and 12 hours after ingestion, respectively.
- Start NAC within 8 hours of ingestion for best chance of hepatic protection. Empirically give NAC in patients presenting near 8 hours while waiting for labs. A two-bag IV dosing regimen over 20 hours is preferred.
- All patients with acetaminophen liver injury (even after 8 hours) should receive NAC.
- If using oral NAC, dilute with a beverage to increase palatability. Serve in a cup with lid and straw.
- For extended release acetaminophen, follow plasma levels at 4, 6, and 8 hours after ingestion. Start NAC if any level is elevated.
Daniella D. Brutman, MD
Steve J. Chacko, MD
- Prescott LF. Paracetamol overdosage. Pharmacological considerations and clinical management. Drugs. 1983;25:290. [PMID:6343056]
- Chiew AL, Gluud C, Brok J, et al. Interventions for paracetamol (acetaminophen) overdose. Cochrane Database Syst Rev. 2018;(2):CD003328. [PMID:29473717]
- Spiller HA, Winter ML, Klein-Schwartz W, et al. Efficacy of activated charcoal administered more than four hours after acetaminophen overdose. J Emerg Med. 2006;30(1):1–5. [PMID:16434328]
- McNulty R, Lim JME, Chandru P, et al. Fewer adverse effects with a modified two-bag acetylcysteine protocol in paracetamol overdose. Clin Toxicol (Phila). 2018;56(7):618–621. [PMID:29219630]
- Wong A, Graudins A. Simplification of the standard three-bag intravenous acetylcysteine regimen for paracetamol poisoning results in a lower incidence of adverse drug reactions. Clin Toxicol (Phila). 2016;54(2):115–119. [PMID:26594846]
- Chiew AL, Isbister GK, Duffull SB, et al. Evidence for the changing regimens of acetylcysteine. Br J Clin Pharmacol. 2016;81(3):471–481. [PMID:26387650]
- Gosselin S, Juurlink DN, Kielstein JT, et al; for EXTRIP Workgroup. Extracorporeal treatment for acetaminophen poisoning: recommendations from the EXTRIP workgroup. Clin Toxicol (Phila). 2014;52(8):856–867. [PMID:25133498]
- McPhail MJ, Farne H, Senvar N, et al. Ability of King’s College Criteria and model for end-stage liver disease scores to predict mortality of patients with acute liver failure: a meta-analysis. Clin Gastroenterol Hepatol. 2016;14(4):516.e5–525.e5. [PMID:26499930]
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