Chapter 26-4: Acetaminophen-Induced Hepatotoxicity

TEXTBOOK PRESENTATION

Most patients experience nausea, vomiting, malaise, and abdominal pain. While single overdose ingestion usually is a result of a suicide attempt, up to half of cases occur accidentally.

DISEASE HIGHLIGHTS

1. Maximum recommended dose of acetaminophen is 4 g/day; some experts recommend < 2 g/day in patients with decompensated cirrhosis or continued alcohol ingestion.

2. In the United States, acetaminophen overdose was the leading cause for calls to Poison Control Centers and accounts for 42% of acute liver failure cases.

3. Unintentional overdose, 48%; intentional overdose, 44%; remaining cases are unknown

   1. 38% ingested ≥ 2 acetaminophen preparations simultaneously

   2. 63% used opioid-containing compounds

4. Hepatotoxic effect is due to production of N-acetyl-p-benzoquinone imine (NAPQI)

   1. NAPQI can be rapidly conjugated by hepatic glutathione to nontoxic metabolites.

   2. Once hepatic glutathione stores are depleted by 70–80%, NAPQI binds to hepatocytes causing cellular injury.

      1. Chronic liver disease and chronic alcohol ingestion cause depletion of hepatic glutathione, making acetaminophen toxicity more likely in these patients.

5. Toxicity is acute; transaminases typically increase 24–36 hours after ingestion and peak at 72 hours.

6. Maximal liver injury peaks 3–5 days after ingestion; jaundice, coagulopathy, and encephalopathy can be present.

7. Concurrent lactic acidosis is a poor prognostic marker.

   1. Early lactic acidosis due to inhibition of mitochondrial function by NAPQI

   2. Late lactic acidosis due to tissue hypoxia and decreased lactate clearance from acute liver failure

8. Screening for possible coingested substances and other causes of hepatitis should be considered, particularly if the history is uncertain.

EVIDENCE-BASED DIAGNOSIS

1. AST is often > ALT and can exceed 10,000 international units/L.

2. Precise time and amount of acetaminophen intake are critical for diagnosis and management; a 4-hour acetaminophen level, or as soon after as possible, should be obtained.

3. Time after ingestion and acetaminophen levels should be plotted on the Rumack-Matthew nomogram which is used to guide whether administration of N-acetylcysteine (NAC) should be considered (Figure 26-6).

TREATMENT

1. Activated charcoal

   1. Effective at limiting acetaminophen absorption when given within 4 hours of ingestion

   2. Contraindicated in patients with an unsecured airway or gastrointestinal tract injury

2. NAC is established antidote; the key to effective treatment is administering before ALT elevation.

   1. Hepatotoxicity is < 5–10% when NAC is administrated within 8 hours of overdose; delays beyond 10 hours increase risk to 20–30%.

   2. Liver transplant can be life-saving in patients who progress to severe acute liver disease.

ISOLATED ALKALINE PHOSPHATASE ELEVATION

Figure 26-7 outlines the diagnostic approach ...