Emergency Medicine · Toxicology
The facts most likely to be tested
The toxic metabolite NAPQI (N-acetyl-p-benzoquinone imine) causes centrilobular hepatic necrosis when glutathione stores are depleted.
The Rumack-Matthew nomogram is used to determine the need for treatment based on serum acetaminophen levels drawn at least 4 hours post-ingestion.
N-acetylcysteine (NAC) acts as a glutathione precursor and is the definitive antidote to replenish stores and neutralize NAPQI.
Patients presenting within 1 to 2 hours of ingestion should receive activated charcoal to decrease drug absorption.
The clinical course of toxicity typically progresses from asymptomatic or mild GI upset to right upper quadrant pain and elevated transaminases within 24 to 72 hours.
Fulminant hepatic failure is characterized by coagulopathy (elevated INR), encephalopathy, and metabolic acidosis.
Liver transplantation is indicated for patients meeting King's College Criteria, such as arterial pH < 7.3 or the triad of grade III/IV encephalopathy, INR > 6.5, and creatinine > 3.4 mg/dL.
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A 24-year-old female is brought to the emergency department after being found with an empty bottle of acetaminophen. She reports ingesting the pills 6 hours ago in a suicide attempt. On physical exam, she is currently asymptomatic with stable vital signs. Her initial laboratory workup reveals a serum acetaminophen level of 160 µg/mL. She has no history of liver disease and her baseline liver function tests are within normal limits.
What is the most appropriate next step in management?
Initiate N-acetylcysteine (NAC) therapy
The patient's acetaminophen level falls above the treatment line on the Rumack-Matthew nomogram at the 6-hour mark, necessitating the immediate administration of NAC to prevent hepatotoxicity.
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Etiology / Epidemiology
Most common cause of acute liver failure in the US. Risk increased by chronic alcohol use and CYP450 induction.
Clinical Manifestations
Often asymptomatic initially; Stage 1 presents with nausea/vomiting. Stage 3 manifests as fulminant hepatic failure.
Diagnosis
Obtain Rumack-Matthew nomogram at 4 hours post-ingestion. >150 mcg/mL at 4 hours indicates toxicity.
Treatment
Administer N-acetylcysteine (NAC). Do not delay treatment while awaiting labs if ingestion >8 hours ago.
Prognosis
Monitor PT/INR and lactate for transplant criteria. King's College Criteria predicts mortality.
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Epidemiology & Etiology
Acetaminophen toxicity is the leading cause of drug-induced liver injury. High-risk populations include patients with chronic malnutrition, alcoholism, or those taking enzyme-inducing medications like phenytoin.
Pertinent Anatomy
The liver is the primary site of metabolism. The centrilobular region (Zone III) is most susceptible to toxic injury due to high concentrations of the cytochrome P450 enzyme system.
Pathophysiology
Metabolism via glucuronidation and sulfation is saturated, shunting drug to the CYP2E1 pathway. This produces the toxic metabolite NAPQI, which depletes glutathione stores. Without glutathione, NAPQI causes hepatocellular necrosis.
Clinical Manifestations
Stage 1 (0-24h) is often subclinical or mild nausea/vomiting. Stage 2 (24-72h) shows RUQ pain and rising transaminases. Stage 3 (72-96h) features jaundice, coagulopathy, and encephalopathy.
Diagnosis
The Rumack-Matthew nomogram is the gold standard for determining the need for treatment. Draw serum levels at 4 hours post-ingestion. Levels >150 mcg/mL at 4 hours require treatment.
Treatment
Initiate N-acetylcysteine (NAC) as the antidote to replenish glutathione. Oral NAC is effective but poorly tolerated due to emesis; IV NAC is preferred for severe cases. If ingestion >8 hours, start NAC immediately while awaiting labs.
Prognosis
Monitor PT/INR daily; rising values indicate worsening synthetic function. Use King's College Criteria to determine the need for liver transplantation in patients with severe encephalopathy or acidosis.
Differential Diagnosis
Viral Hepatitis: elevated IgM antibodies
Alcoholic Hepatitis: AST:ALT ratio >2:1
Ischemic Hepatitis: rapid rise/fall of transaminases after shock
Salicylate Toxicity: respiratory alkalosis and metabolic acidosis
Reye Syndrome: associated with aspirin use in children