Pathophysiology

Maximum therapeutic dose: - 4g in adults - 90mg/kg in children Toxicity is with single ingestion of 150 mg/kg or ~7-10 g (adult)

-Metabolism is primarily hepatic -Liver metabolizes more than 90% of dosage to sulfate and glucuronide conjugates, which are water soluble and are then eliminated in the urine -Two percent of an acetaminophen dose is excreted unchanged by the kidneys -Remaining acetaminophen is metabolized by CYP450 system to form a reactive, highly toxic metabolite known as N -acetyl- benzoquinoneimine (NAPQI)\ -Glutathione binds NAPQI, enabling the excretion of nontoxic mercapturate conjugates in the urine

-in excessive NAPQI formation, or reduction in glutathione stores, NAPQI covalently binds to the lipid bilayer of hepatocytes, causing hepatic centrilobular necrosis.

Four Clinical Stages Stage 1 ( h postingestion) -Asymptomatic or with nonspecific signs like anorexia, nausea, vomiting, malaise, and diaphoresis. -If CNS involvement and/or severe metabolic acidosis (elevated anion gap) are present, consider co- ingestants. -Serum studies are within normal limits. About 12 hours post-ingestion, subclinical elevation of serum liver transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) occurs.

Stage 2 (24-72 h postingestion) -Stage 1 symptoms less evident and/or resolved. -Present with pain and tenderness in the RUQ -Hepatomegaly can be present. Some may have oliguria -Elevated ALT and AST levels, prothrombin (PT) times, and bilirubin values. Renal function abnormalities (eg, BUN, creatinine) may also be present.

Stage 3 ( h postingestion) -Stage 1 symptoms reappear along with signs of hepatic failure with jaundice, hypoglycemia, bleeding, or encephalopathy. -Severe toxicity evident on serum studies. Lactic acidosis, prolonged PT or INR, markedly elevated ALT and AST (>10,000 IU/L), elevated total bilirubin level of more than 4 mg/dL (primarily indirect) and hyperammonemia -Hepatic centrilobular necrosis is diagnosed on liver biopsy -Renal involvement from acute tubular necrosis is evident with abnormal renal function studies, proteinuria, hematuria and granular casts on urinalysis -Death is most common during this stage, with multiorgan failure as the primary cause.

Stage 4 (5-14 d postingestion) -this stage can last as long as 21 days. -either a complete recovery of liver function or death -period to normalization may take several weeks for patients who recover -Acetaminophen-induced hepatotoxicity does not cause chronic hepatic dysfunction.

Work-up