Description

• A disorder characterized by hepatic necrosis following large acetaminophen ingestions. Clinical manifestations of acetaminophen toxicity vary with time since ingestion and are generally classified into four stages.
• Single, large ingestions of acetaminophen account for a majority of poisonings. Toxicity can also occur with ingestions of lesser amounts in individuals who regularly abuse alcohol, are chronically malnourished, or take medications impacting hepatic metabolism. Ingestions greater than 12 g in adults and greater than 250 mg/kg in children are likely to cause toxicity.

Epidemiology

• Two-thirds of hospitalizations due to acetaminophen toxicity are due to intentional ingestion. Most (80%) are adults and 70% are women. 50% of poison control calls related to acetaminophen are related to unintentional ingestions in children under 5.
• Second leading factor associated with liver transplantation worldwide
• More than 50,000 emergency department visits, >2,500 hospitalizations, and nearly 500 deaths annually in the United States are associated with acetaminophen ingestion.

Etiology and Pathophysiology

Pharmacokinetics

• 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.

Pathophysiology
Ingestion of supratherapeutic doses of acetaminophen or subtherapeutic ingestions in individuals with compromised liver function can cause acetaminophen poisoning and result in hepatocellular damage. The liver metabolizes 96% of ingested acetaminophen and 2–4% is excreted 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.

Risk Factors

Concurrent poisoning with other substances can impact the hepatic metabolism; 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

General Prevention

• Poison Control: 800-222-1222 for consultations and management guidance
• FDA labeling guidance: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances...

Geriatric Considerations
There is an increased risk of hepatic damage in 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.

Pediatric Considerations
Hepatic damage after ingestion of toxic acetaminophen doses can be less severe in young children, potentially because they have more stores of glutathione.

Pregnancy Considerations
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.

History

Primary questions should focus on what was ingested (extended release, hydrocodone-acetaminophen, co-ingestants, 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

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 right upper quadrant pain.

Differential Diagnosis

• Consider presence of co-ingestants, 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. 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.
  • 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 post-ingestion, 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.

Diagnostic Procedures/Other
Advanced imaging of the liver and/or kidney with ultrasound or CT should 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.

Medication

First Line

• 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 (1).
  • 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.
  • 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% (1).
• Give single-dose activated charcoal within 1 to 4 hours of ingestion (especially in cases of co-ingestants). Do not delay NAC administration for use of activated charcoal.

Second Line
In massive ingestions (levels >1,000 mg/L, severe acidosis, coma/hypotension) or when severe renal failure is present, hemodialysis may improve survival (1).

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.

Follow-up Recommendations

• 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.

Diet

No special diet, except with severe hepatic damage

Patient Education

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 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.

Prognosis

• Complete recovery with early therapy is possible and more likely in stage 4 of toxicity.
• 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.

Complications

Recovery after acute poisoning is complete and sequelae are rare.

ICD-10

• 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

SNOMED

• 197356006 Toxic liver disease with hepatic necrosis (disorder)
• 290134002 Accidental acetaminophen poisoning (disorder)
• 290136000 Acetaminophen poisoning of undetermined intent (disorder)
• 70273001 Poisoning by acetaminophen