Background

• APAP toxicity may be caused by a single large overdose or repeated supratherapeutic dosing, rarely by chronic low doses (≤ 3-4 g/day). Severe liver toxicity (peak AST or ALT >1000 IU/L) develops in virtually all patients who ingest doses in excess of 350 mg/kg.
• Accounts for up to half of all cases of acute liver failure in U.S.

Etiology/Risk Factors

• Normal metabolism: supratherapeutic doses (>4g) lead to oxidation to a reactive intermediate (NAPQI) and glutathione depletion. NAPQI binds to cellular proteins, leading to hepatocyte necrosis. Zone 3 hepatocytes are rich in CYP2E1 and are most susceptible to injury (characteristic “centrilobular pattern” of hepatic necrosis).
• Conditions that predispose to APAP toxicity: 
  • States of decreased glucuronidation, sulfation, glutathione depletion, or CYP450 system induction.
  • Chronic alcohol use induces CYP2E1, depletes glutathione.
  • Medications that induce CYP450 (rifampin, phenytoin, phenobarbital, carbamazepime, INH).
  • Pregnancy, prolonged fasting, or Gilbert’s syndrome.

Evaluation

• Always consider alternative causes of severe liver toxicity/liver failure: toxins, viral (HBV +/- HDV, HAV, HEV, rarely VZV, HSV, CMV, EBV), vascular (ischemic hepatitis, Budd-Chiari), other (Reye’s syndrome, acute fatty liver of pregnancy, autoimmune hepatitis, acute biliary obstruction).
• Clinical presentation: where time 0 = time of ingestion. 
  • 0-24 hours: +/- nausea, vomiting, abdominal pain, malaise. Labs may be normal.
  • 24-72 hours: RUQ pain, +/- nonspecific symptoms.
  • 72-96 hours: LFT elevation, may develop jaundice, HE, hyperammonemia, lactic acidosis, ARF. Transaminases elevation peaks at 3-5 days.
  • 4d-2wks: recovery, if it occurs. Thought to be complete w/o chronic liver dysfunction.
• Labs – serum acetaminophen level (repeat at 4h if unsure of time of ingestion), chem 10, BUN/Cr, coags, pH, lipase/amylase, UA.
  • Monitor and treat for glucose and electrolyte dyscrasias.
  • Recheck acetaminophen level and ALT when patient is finishing treatment course (see below).
• Use Rumack-Matthew nomogram to determine risk of hepatotoxicity.
• Limitations of the treatment nomogram:
  • Useful only in acute ingestions when the time of ingestion is known.
  • Not valid for patients presenting 24 hours after acute overdose, if unknown time of ingestion, history of staggered overdose, history of repeated supratherapeutic ingestion.
  • Does not account for patients at higher risk of toxicity (chronic alcohol use, malnourishment).

Management

• Activated charcoal: consider giving at 1g/kg (max dose 50g) within 2-4 hours of known ingestion. Contraindicated if concern for airway protection, unless patient is already intubated.
• Start NAC if: 
  • Serum APAP concentration (drawn at least 4 hours after ingestion) is above the treatment line on the treatment nomogram.
  • Serum APAP concentration is unavailable or will not return within 8 hours of time of ingestion.
  • Time of ingestion is unknown and serum APAP level >10 mcg/mL.
  • ANY evidence of hepatotoxicity with history of ingestion.
• PO NAC (72 hr) preferred over IV (21 hr) due to lower risk of anaphylaxis but is poorly tolerated.
• Indications for IV NAC: GIB, pregnant, fulminant hepatic failure, unable to tolerate PO, encephalopathy.
• NAC administration: PO 72 hour protocol vs. 21 hour IV protocol.
  • 72h PO protocol: loading dose 140mg/kg PO, then 17 doses 70 mg/kg PO q4h.
  • IV protocol (Acetadote):
    • Loading dose: 150 mg/kg (maximum: 15g) over 1 hour.
    • Second dose: 50 mg/kg (maximum: 5g) infused over 4 hours.
    • Third dose: 100 mg/kg (maximum: 10g) infused over 16 hours.
  • Extension of NAC therapy: use if ALT remains high or serum acetaminophen still detectable as treatment course is finishing.
    • Continue at 6.25mg/kg/hr and recheck ALT, INR, and acetaminophen levels every 12h until ALT decreasing/normal, acetaminophen undetectable, and INR <2.
• Adverse effects of NAC therapy:
  • Nausea/vomiting.
  • For urticaria/angioedema: stop infusion and administer IV Benadryl. May consider re-starting after resolution of reaction.
  • If patient develops bronchospasm or hemodynamic instability (10-20% develop anaphylactoid reactions) during IV therapy, discuss PO administration or alternatives with poison control.
• Alert poison control (1-800-222-1222) and consider consultation with hepatology.
• If NAC unavailable, consider hemodialysis for acetaminophen clearance.
• FFP should only be used in instances of active hemorrhage or prior to procedures. Prophylactic administration has no mortality benefit and can interfere with clinical evaluation.
• If patient develops acute liver failure, alert hepatology for consideration of transplantation and continue IV protocol as above except NAC administration should continue at final rate 6.25mg/kg/h until transplantation or resolution of encephalopathy and coagulopathy (INR <2).
  • According to King’s College Criteria, acetaminophen-induced ALF defined as:
    • Arterial pH <7.3, OR
    • INR >6.5, Cr >3.4, AND severe encephalopathy.
• Consider referral to hepatology for consideration of transplant if the patient continues to have a 12-hr lactate >3.5 despite fluid resuscitation or a 2-4 day phosphate >3.7.

Key Points

• Begin NAC for all suspected cases of acetaminophen overdose and call Poison Control (1-800-222-1222).
• Prognosis very favorable if NAC is given within 8h of ingestion, but still helpful when given late (48-72 hours after ingestion).

• Mortality <1% when NAC given early.
• Monitor for anaphylactoid reaction during NAC administration.

Chun LJ, Tong MJ, Busuttil RW, Hiatt JR. Acetaminophen hepatotoxicity and acute liver failure. J Clin Gastroenterol. 2009 Apr;43(4):342-9.

Hodgman MJ, Garrard AR. A review of Acetaminophen Poisoning. Crit Care Clin 28 (2012) 499-516.

Larson AM. Acetaminophen hepatotoxicity. Clin Liver Dis. 2007 Aug;11(3):525-48, vi.

Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, Reisch JS, Schiødt FV, Ostapowicz G, Shakil AO, Lee WM; Acute Liver Failure Study Group. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005 Dec;42(6):1364-72.

Lee WM, Hynan LS, Rossaro L, Fontana RJ, Stravitz RT, Larson AM, Davern TJ 2nd, Murray NG, McCashland T, Reisch JS, Robuck PR; Acute Liver Failure Study Group. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology. 2009 Sep;137(3):856-64, 864.e1. Epub 2009 Jun 12.

Lewis RK, Paloucek FP. Assessment and treatment of acetaminophen overdose. Clin Pharm. 1991 Oct;10(10):765-74.

Prescott LF. Paracetamol overdosage. Pharmacological considerations and clinical management. Drugs. 1983 Mar;25(3):290-314.

Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics 1975; 55:871.

Zed PJ, Krenzelok EP. Treatment of acetaminophen overdose. Am J Health Syst Pharm. 1999 Jun 1;56(11):1081-91.