- A disorder characterized by hepatic necrosis following large acetaminophen ingestions. Clinical manifestations of acetaminophen toxicity vary with time since ingestion and are accordingly classified into four stages.
- Single, large ingestions of acetaminophen account for a majority of poisoning, but it can also occur with ingestions of lesser amounts in individuals who regularly abuse alcohol, are chronically malnourished, or take medications impacting hepatic metabolism. Ingestions >12 g in adults and >250 mg/kg in children are likely to cause toxicity.
- Hospitalizations due to acetaminophen toxicity from 1998 to 2011 were 67% due to intentional ingestion, 16% from unintentional ingestion, and 17% unspecified.
- Of the hospitalizations related to acetaminophen toxicity from 1998 to 2011, 83% were primarily adults and 69% were female (95% CI 0.68–0.69%).
- From 2008 to 2012, about 49% of unintentional acetaminophen-related poison-control calls were regarding children aged ≤5 years.
Rates of acetaminophen-related hospitalizations slowly increased prior to 2009. Discharges following toxicity decreased from 119.8 per 100,000 in 2009 to 108.6 per 100,000 in 2011.
- According to 2008 to 2012 data from the American Association of Poison Control, there were an average of 111,632 nationwide acetaminophen-related events per year.
- An estimated average of 10% of these events resulted in liver toxicity, and 1% resulted in death.
Etiology and Pathophysiology
- With oral therapeutic ingestion, acetaminophen is entirely absorbed from the duodenum and reaches peak serum concentrations of 10 to 20 μg/mL after up to 2 hours. This peak may be delayed with toxic ingestions.
- Therapeutic adult doses of acetaminophen are 325 to 1,000 mg q4–6h to a maximum dose 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.
- The elimination half-life of acetaminophen ranges from 2 to 4 hours but may be delayed in extended-release formulation.
Ingestion of supratherapeutic doses of acetaminophen or subtherapeutic ingestions in individuals with compromised liver function causes acetaminophen poisoning and resulting in hepatocellular damage. The liver metabolizes 96% of ingested acetaminophen and 2–4% is excreted unchanged in urine. Therapeutic doses break down into 90–95% benign metabolites and 5–10% of the toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is rapidly conjugated with hepatic stores of glutathione to form a nontoxic metabolite to be excreted in the urine. Toxic ingestions of acetaminophen saturate the glucuronidation and sulfation pathways, depleting glutathione stores and result in accumulations of NAPQI that cause hepatocellular damage.
Concurrent poisoning with other substances impacting hepatic metabolism; a psychiatric illness or history of suicide attempts; regular ingestion of large amounts of alcohol; chronic malnutrition and possible risk related to previous weight loss surgery
- Poison Control: 1-800-222-1222 for consultations and management guidance
- FDA labeling guidance: https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guida...
There is an 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 in patients with liver disease and/or alcohol abuse disorders (1).
Hepatic damage after ingestion of toxic acetaminophen doses can be less severe in young children, potentially because they have more stores of glutathione (1).
There is an increased incidence of spontaneous abortion in pregnant patients with acetaminophen poisoning, especially with overdose at an early gestational age. Abortion incidence and possible fetal death is increased if N-acetylcysteine (NAC) treatment is delayed. IV NAC is generally preferred in pregnancy due to greater bioavailability (1).
Signs and symptoms of poisoning develop over the first 24 hours following large ingestions. Symptoms may develop gradually in those with a history of long-term ingestion near supratherapeutic doses. Presentation of symptoms varies and is divided into four stages (1):
- Stage 1—first 24 hours after ingestion
- Patient may be asymptomatic in first 8 hours following ingestion. Symptoms may include nausea, emesis, anorexia, and diaphoresis. Laboratory results are usually unremarkable at this time.
- Stage 2—days 2 to 3 following ingestion
- Typically less nausea, vomiting, diaphoresis, and malaise than in stage 1; right upper quadrant pain and hepatomegaly may become evident. Elevated aminotransferases are usually seen.
- Stage 3—days 3 to 4 following ingestion
- Stage I symptoms such as nausea, vomiting, and malaise reappear. Severe poisonings may result in jaundice, confusion, somnolence, and coma. Marked liver enzyme elevations which usually peak at this point; prolonged prothrombin time (PT)/international normalized ratio (INR); typically negative acetaminophen levels. Multiorgan failure and death most commonly occur in this stage.
- Stage 4—days 5+ after ingestion
- Possible recovery stage in patients with resolving stage 3 symptoms; recovery may be prolonged, but is typically complete and without long-term sequelae. Laboratory abnormalities typically resolve. Fulminant hepatic failure occurs in <1% of adults and is very rare in children <6 years of age.
Primary questions should focus on what was ingested (extended release, hydrocodone-acetaminophen, coingestant, etc.), how much was ingested, and time of ingestion. Was the ingestion intentional or accidental? Also ask regarding current or history of alcohol abuse, hepatitis, and previous surgeries.
Physical exam findings will likely vary depending on stage of toxicity. In general, a full physical examination is warranted with vitals assessment.
- Assess individual’s general appearance for somnolence, fatigue, pallor, diaphoresis, and signs of dehydration.
- Look for signs of hepatotoxicity: hepatomegaly and RUQ pain.
- Consider presence of coingestants, especially alcohol, opiates, and aspirin.
- Other ingested toxins that produce severe acute hepatic injury include the mushroom Amanita phalloides and products containing yellow phosphorus or carbon tetrachloride. Consider other causes of hepatitis: alcoholic, viral, ischemic.
Diagnostic Tests & Interpretation
Initial Tests (lab, imaging)
- Draw plasma acetaminophen levels on all patients ≥4 hours after ingestion (levels peak at 4 hours). Draw additional levels at 6 and 8 hours if extended-release form was ingested. Poison Control may help guide the frequency of exams, vitals, or any other ancillary testing that may be warranted (1).
- 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.
- Liver function tests: alanine transaminase (ALT), aspartate transaminase (AST), PT/INR, bilirubin, lactate dehydrogenase (LDH)
- With severe poisonings, PT/INR rise in parallel with LFT changes. With toxic ingestions, AST, ALT, and bilirubin levels begin to rise in stage 2 and peak in stage 3. Improvement in ALT with therapy is an encouraging clinical sign.
- Additional labs: electrolytes, glucose, BUN, creatinine, urinalysis, urine drug screen (UDS), serum alcohol, and salicylate.
- Screen for coingestants with the above labs and consider searching for other medications/substances depending on the clinical history. Obtain a pregnancy screen in females (urine or serum) as it can influence management.
- Consider an arterial blood gas (ABG): anion gap metabolic acidosis due to accumulation of 5-oxoproline may rarely be seen.
- Imaging: No specific imaging is required.
Follow-Up Tests & Special Considerations
During recovery, liver tests should normalize and complete restoration of liver function without long-term sequelae is expected.
Advanced imaging of the liver and/or kidney with ultrasound or CT can be considered when acute hepatitis or kidney injury is present to rule out alternative causes. Otherwise, imaging is not required and any abnormal findings, if present, may be nonspecific.
- Immediately contact a local Poison Control center for recommendations. Call (800) 222-1222 in the United States.
- NAC is a benign prodrug that provides cysteine as a substrate to detoxify acetaminophen metabolites and replenish glutathione stored in the liver. NAC administration may reduce mortality from 5% to 0.7%.
- The Rumack-Matthew nomogram (1):
- A plot used to determine if acetaminophen levels are high enough to warrant treatment with NAC during acute toxic ingestions; the nomogram is not intended for sustained-release products or chronic ingestions.
- Give NAC when acetaminophen plasma levels measured ≥4 hours after ingestion are at the “treatment line” or higher on the Rumack-Matthew nomogram.
- Treatment line acetaminophen plasma levels on the nomogram correspond to >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.
- Initiate 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 4 hours of ingestion. Never delay oral NAC for activated charcoal.
- Ipecac and gastric lavage are no longer recommended for routine use at home or in health care facilities (2).
- Empirically start NAC within 8 hours even while awaiting lab results. It may be effective up to ≥36 hours after ingestion.
- NAC may be given PO or IV, depending on situation and availability. IV NAC has been shown to decrease the length of hospitalization compared to PO NAC (2).
- A 2-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.
- Use an oral loading dose of 140 mg/kg and then 70 mg/kg q4h for 17 additional doses (72-hour regimen).
- NAC precautions:
- PO NAC may cause significant nausea and vomiting due to its sulfur content and is often poorly tolerated; consider a nasogastric tube.
- 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). Reactions usually occur with the loading dose. To prevent this, slow or temporarily stop the infusion; may concurrently treat with antihistamines.
- Nausea can be treated with metoclopramide, 1 to 2 mg/kg IV, or ondansetron, 0.15 mg/kg IV.
- NAC failure rates range from 3% to 7% (2).
- Give single-dose activated charcoal within 1 to 4 hours of ingestion (especially in cases of coingestants). Do not delay NAC administration for use of activated charcoal.
In massive ingestions (levels >1,000 mg/L, severe acidosis, coma/hypotension) or when severe renal failure is present, hemodialysis may improve survival (2).
Issues For Referral
- Behavioral health evaluation for intentional ingestions
- Child abuse reporting if neglect led to overdose
Admission, Inpatient, and Nursing Considerations
- Consider hospitalization for toxic ingestions with vital instability and/or laboratory abnormalities. Consider transfer to a psychiatric facility for intentional ingestions when medically stable.
- IV fluids are generally provided for hydration purposes.
- Evaluate all patients at an accredited health care facility. 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.
No special diet, except with severe hepatic damage
Counsel patients to avoid acetaminophen (Tylenol, etc.) or other forms of acetaminophen, particularly if using combination product(s) containing acetaminophen. Educate parents/caregivers during well-child visits regarding appropriate OTC dosing and medication storage. Provide anticipatory guidance for caregivers, family, and cohabitants of potentially suicidal patients. Educate patients on long-term acetaminophen therapy.
- Complete recovery with early therapy is possible and more likely in stage 4 of toxicity (1).
- 10% of adult patients with severe liver complications develop necrosis, hepatic encephalopathy, or require transplant.
- Hepatic failure is rare in children <6 years of age.
Recovery after acute poisoning is complete, and sequelae are rare.
- 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
- 197356006 Toxic liver disease with hepatic necrosis (disorder)
- 290134002 Accidental acetaminophen poisoning (disorder)
- 290136000 Acetaminophen poisoning of undetermined intent (disorder)
- 70273001 Poisoning by acetaminophen
- Immediately consult Poison Control Center for management recommendations by calling (800) 222-1222 (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 (265 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 2-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.
Mark B. Stephens, MD, MS, FAAFP
Grant M. Reed, DO
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