Pathology · Year 2 · from Pathology

Case 1: Acetaminophen Hepatotoxicity

Patient Demographics

  • Age: 22 years old
  • Sex: Female
  • Occupation: College student

Chief Complaint

"Abdominal pain and vomiting for 2 days"

History of Present Illness

A 22-year-old female presents to the emergency department with right upper quadrant abdominal pain, nausea, and vomiting for the past 2 days. Upon further questioning, she admits to ingesting approximately 25-30 extra-strength acetaminophen tablets (500 mg each) approximately 36 hours ago following a breakup with her boyfriend. She initially felt fine but developed nausea and vomiting about 24 hours after ingestion, followed by abdominal pain. She now reports dark urine and feels increasingly unwell. She denies regular alcohol use or prior liver disease.

Physical Examination

  • Vital Signs: BP 98/62 mmHg, HR 108 bpm, RR 22/min, Temp 37.4C
  • General: Ill-appearing young woman, mildly jaundiced
  • HEENT: Icteric sclerae
  • Abdomen: Tender right upper quadrant with hepatomegaly, no rebound or guarding
  • Neurologic: Oriented but mildly confused, mild asterixis present
  • Skin: Jaundice, no petechiae

Diagnostic Workup

Laboratory Studies:

TestResultReference Range
AST8,450 U/L10-40 U/L
ALT7,820 U/L7-56 U/L
Total bilirubin5.8 mg/dL0.1-1.2 mg/dL
INR4.20.8-1.2
Creatinine2.1 mg/dL0.7-1.3 mg/dL
Lactate4.8 mmol/L0.5-2.0 mmol/L
Acetaminophen level85 mcg/mLTherapeutic <20 mcg/mL
Ammonia95 umol/L15-45 umol/L
pH (arterial)7.287.35-7.45

Imaging:

  • Ultrasound: Hepatomegaly with heterogeneous echotexture, patent portal and hepatic veins, no biliary dilation

Pathology Correlation

This case demonstrates predictable, dose-dependent hepatotoxicity from acetaminophen:

Mechanism of Acetaminophen Toxicity:

Normal Metabolism (Therapeutic Doses):

  1. 90% undergoes glucuronidation and sulfation - safe water-soluble metabolites
  2. ~10% is metabolized by CYP2E1 to NAPQI (N-acetyl-p-benzoquinone imine)
  3. NAPQI is rapidly conjugated with glutathione and excreted

Toxic Metabolism (Overdose):

  1. Glucuronidation/sulfation pathways become saturated
  2. Increased shunting to CYP2E1 pathway
  3. Massive NAPQI production
  4. Glutathione stores depleted (below 30% of normal)
  5. Free NAPQI covalently binds hepatocyte proteins
  6. Centrilobular (Zone 3) necrosis - highest CYP2E1 concentration in perivenular hepatocytes

Phases of Acetaminophen Toxicity:

  • Phase 1 (0-24h): Asymptomatic or mild GI symptoms
  • Phase 2 (24-72h): Right upper quadrant pain, rising liver enzymes, INR
  • Phase 3 (72-96h): Peak hepatotoxicity, potential liver failure
  • Phase 4 (>96h): Recovery or death

Histopathology:

  • Centrilobular necrosis - zone 3 hepatocytes (around central vein) most affected
  • Periportal hepatocytes (zone 1) relatively spared
  • Inflammatory infiltrate minimal initially

Risk Factors for Increased Toxicity:

  • Chronic alcohol use (induces CYP2E1)
  • Malnutrition (depleted glutathione)
  • Concurrent CYP-inducing medications

Clinical Image

Gross pathology of liver showing centrilobular necrosis pattern. In acetaminophen toxicity, zone 3 hepatocytes (surrounding central veins) demonstrate coagulative necrosis due to highest concentration of CYP2E1 enzyme responsible for generating the toxic NAPQI metabolite.

Image Source: Wikimedia Commons - "Drug-induced liver injury" License: CC BY-SA 4.0 URL: https://commons.wikimedia.org/wiki/File:End-stage_interstitial_lung_disease_(honeycomb_lung).jpg

Diagnosis

Acute Acetaminophen Hepatotoxicity with Acute Liver Failure

  • King's College Criteria assessment for liver transplant

Treatment

Immediate:

  1. N-acetylcysteine (NAC) - replenishes glutathione stores
  • Most effective within 8 hours but beneficial even at 36 hours
  • Continue until INR normalizing
  1. Supportive care: IV fluids, correct coagulopathy
  2. Monitor for hepatic encephalopathy
  3. Avoid hepatotoxic medications

If Progressing to Liver Failure:

  1. Contact transplant center early
  2. King's College Criteria for transplant listing:
  • pH <7.30 after resuscitation, OR
  • INR >6.5 AND creatinine >3.4 mg/dL AND grade 3-4 encephalopathy
  1. Bridge therapies while awaiting transplant

Psychiatric:

  1. Suicide precautions
  2. Psychiatric evaluation
  3. Social work involvement

Teaching Points

  1. Predictable toxicity follows dose-response relationship (unlike idiosyncratic reactions)
  2. NAPQI is the toxic metabolite; glutathione is the protective mechanism
  3. Centrilobular necrosis (zone 3) reflects hepatic zonation of CYP2E1
  4. N-acetylcysteine is the antidote - provides cysteine for glutathione synthesis
  5. Patients may appear well initially despite lethal ingestions
  6. The Rumack-Matthew nomogram guides treatment decisions based on time and level

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