USMLE Step 1 Sample Questions

The correct answer is E. Acetaminophen that is not excreted in the urine is metabolized to N-acetyl-p-benzoquinoneimine (NAPQ)

Explanations: Normally, 2% of ingested acetaminophen is excreted in the urine unchanged, and 90% of a therapeutic dose is metabolized to sulfate and glucuronide conjugates in the liver. These conjugates are then also excreted in the urine. The remaining acetaminophen is metabolized into a toxic and highly reactive electrophilic intermediate compound, N-acetyl-p-benzoquinoeimine (NAPQI). In therapeutic doses, the NAPQI is conjugated with hepatic glutathione to form nontoxic compounds of mercaptate and cysteine. These compounds are then excreted through the kidneys. In overdose, the pathways of NAPQI conjugation are saturated and the toxic substance binds to hepatic macromolecules. This irreversible process leads to oxidative injury and centrilobular necrosis of hepatocytes. The treatment for acetaminophen toxicity is N-acetyl cysteine, which is thought to provide cysteine for synthesis of glutathione and may also form an adduct directly with NAPQI. The Rumack-Matthew nomogram plots serum concentration of acetaminophen against time since ingestion in order to determine if treatment with N-acetyl cysteine is indicated. However, although this patient’s acetaminophen level at 13 hours is below the Rumack-Matthew line, it is above a treatment line established by the government in studies of NAC in the 1970’s that were published in 1981. The nomogram is logarithmic and begins four hours after ingestion, which is when absorption is normally complete.

Liver function abnormalities peak at 72-96 hours after an ingestion, with a concomitant increase in prothrombin time.

Gastric decontamination is not recommended after four hours post-ingestion, as it is unlikely to have any effect since absorption should be complete.

Take home message: Excessive amounts of acetaminophen overwhelm the normal pathway for elimination by formation of sulfates and glucuronides. The excess acetaminophen is metabolized to a highly toxic compound, NAPQI. At therapeutic dosages, the liver has adequate glutathione stores for conjugation and elimination of NAPQI. However, in overdose the glutathione stores are rapidly depleted and the NAPQI causes hepatocellular injury. N-acetyl cysteine provides cysteine for glutathione synthesis, allowing conjugation and elimination of toxic levels of NAPQI.