Epidemiology

Leading cause of acute liver failure

Etiology

Exhaustion of hepatic metabolic pathways causes accumulation of a toxic metabolite of acetaminophen, N-acetyl-p-benzoquinoneimine (NAPQI).
- Glutathione initially inactivates NAPQI, but its reserves are eventually depleted, leading to NAPQI accumulation.
- NAPQI → irreversible oxidative hepatocyte injury → liver cell necrosis
APAP-induced hepatotoxicity
- Defined as peak AST or ALT > 1000 IU/L
- Most commonly caused by APAP overdose
- Occurs rarely at therapeutic doses in patients with:
  - Alcohol consumption
  - Prolonged fasting
  - Chronic liver disease

Phase 1 (0–24 hours):
- Minimal or non-specific symptoms: Nausea, vomiting, anorexia, diaphoresis, pallor.
Phase 2 (24–72 hours):
- “Latent period” where systemic symptoms improve, but subclinical hepatotoxicity begins.
- Right upper quadrant (RUQ pain) and tenderness.
- Rising LFTs (AST, ALT, bilirubin) and PT/INR.
Phase 3 (72–96 hours):
- Peak hepatotoxicity.
- Jaundice, coagulopathy (bleeding/bruising), hepatic encephalopathy (confusion, asterixis).
- Severe cases develop metabolic acidosis, renal failure, and multi-organ dysfunction syndrome (MODS).
Phase 4 (4 days to 3 weeks):
- Resolution of liver injury (for survivors) or progression to death from liver failure.

Initial Test: Serum APAP level drawn at exactly 4 hours post-ingestion (levels drawn <4 hours are uninterpretable due to ongoing absorption).
Confirmatory/Risk Stratification: Plot the 4-hour (or later up to 24 hours) level on the Rumack-Matthew Nomogram.
- Only valid for a single, acute, immediate-release ingestion.
- If the level lies on or above the treatment line (150 mcg/mL at 4 hours), initiate antidote therapy.
Key Labs:
- LFTs: AST/ALT > 10,000 U/L in severe toxicity (highest of any toxic/infectious cause). c
- Coagulation studies: PT/INR (most sensitive indicator of liver synthetic function decline).
- BMP: Creatinine (evaluates for acute kidney injury/hepatorenal syndrome), HCO3- (evaluates for metabolic acidosis).
- Arterial Blood Gas (ABG): pH and lactate (essential for prognosticating liver transplant need).

Feature	Salicylate (ASA)	Acetaminophen (APAP)	Reye Syndrome
Path	Uncouple oxidative phosphorylation (leads to hyperthermia); Direct stimulation of resp center.	Glutathione depletion $\to$ NAPQI $\to$ centrilobular hepatic necrosis.	Mito dysfunction ( $↓$ $β$ -oxidation) $\to$ Microvesicular fatty change in liver
Hx/Trigger	OD; Wintergreen oil	OD (esp. w/ CYP inducers/EtOH)	Child + Virus + ASA
Key Sx	Tinnitus, Hyperthermia, Tachypnea	RUQ pain, Fulminant liver failure	Encephalopathy, Vomiting
Labs/Path	Mixed Resp Alk + Met Acidosis	Zone 3 Necrosis, $↑↑$ AST/ALT	Microvesicular fatty liver, $↓$ Glucose, $↑$ Ammonia
Tx	NaHCO3 (Alkalinize urine), Dialysis	N-acetylcysteine (restore glutathione)	Supportive

Airway, Breathing, Circulation (ABCs): Establish IV access and stabilize.
Activated Charcoal: Administer if patient presents within 4 hours of ingestion and is awake/cooperative with a protected airway.
N-acetylcysteine (NAC):
- Restores glutathione reserves to safely detoxify the toxic metabolite NAPQI.
- Indicated if:
  - APAP level is above the treatment line on the Rumack-Matthew Nomogram.
  - Ingestion history >150 mg/kg (or >7.5 g total) and lab results are not immediately available.
  - Unknown ingestion time + detectable APAP level or elevated transaminases.
  - Late presentation (>8–24 hours post-ingestion) with suspected overdose.
- Consensus stopping criteria (do not stop NAC until all are met):
  - APAP level <10 mcg/mL.
  - INR <2.0.
  - AST/ALT are normal or significantly decreased (by 25–50% from peak).
  - Patient is clinically well.
Refractory/Definitive (Liver Transplantation): c
- Evaluated using King’s College Criteria for APAP toxicity:
  - Arterial pH <7.3 after fluid resuscitation, OR
  - All three of the following: INR >6.5, Creatinine >3.4 mg/dL, and Grade III/IV hepatic encephalopathy.

tags	—
aliases	Acetaminophen toxicity