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The liver metabolizes more than 90% of the acetaminophen taken to sulfate and glucuronide conjugates,
which are water soluble and eliminated in the urine. In children, sulfation is the primary pathway until the age
of 10-12 years, whereas glucuronidation predominates in adolescents and adults. Hepatotoxicity is the result
of formation of the reactive and toxic metabolite NAPQI by the cytochrome P450 (CYP) system.
Glutathione can bind NAPQI and lead to excretion of nontoxic mercapturate conjugates. As glutathione stores
are diminished, NAPQI is not detoxified, and it covalently binds to the lipid bilayer of hepatocytes, causing
hepatic centrilobular necrosis. Glutathione must be replaced by sulfhydryl compounds from the diet or from
drugs such as the antidote NAC.
See notes given by Dr. Dahms for three pathways of acetaminophen metabolism.
2. Describe which organ system needs to be monitored after significant acetaminophen ingestion and how and
why you would monitor it.
Liver** (pancreas and kidney were also mentioned but are not considered the MOST important)
This can be monitored by:
Serum levels of alanine aminotransferase and bilirubin
Prothrombin time (slower clotting because prothombin which is produced the liver is present in lower
amounts when there is liver damage. Coagulation time increases in instances of liver damage.)
The antidote for APAP poisoning is N -acetylcysteine (NAC). NAC is theorized to work through a number of
protective mechanisms. NAC is a precursor of glutathione and increases the available glutathione to conjugate
NAPQI. It may also enhance sulfate conjugation of any unmetabolized APAP. NAC also functions as an anti-
inflammatory and antioxidant and has positive inotropic effects. NAC increases local nitric oxide
concentrations, and this vasodilatory effect on microcirculatory blood flow enhances local oxygen delivery to
peripheral tissues. These microvascular effects are associated with a decrease in morbidity and mortality even
in the setting of established hepatotoxicity.
1. What daily doses (adult and pediatric) have been noted to induce hepatic dysfunction due to repeated
acetaminophen ingestion?
Most cases of acetaminophen poisoning occur because people take smaller doses over a long period of time.
In this setting, doses of 4000 mg daily can be toxic.
Acetaminophen should be used cautiously on a chronic basis because several case reports show that it may be
hepatotoxic at therapeutic doses.
In children, daily maximum oral dosing is not to exceed 90 mg per kilogram of body weight.
2. How does chronic acetaminophen toxicity differ from the acute overdose with respect to utilization of the
Nomogram?
The nomogram should not be used to assess chronic or repeated ingestions.
3. Since subsequent analysis revealed undetectable serum acetaminophen levels, is any treatment warranted
for this patient?
Chronic acetaminophen ingestions: Patients may give a history of several doses taken over 24 hours or more,
in which case the nomogram cannot accurately estimate the risk of hepatotoxicity. In such cases, we advise
NAC treatment if the amount ingested was more than 150–200 mg/kg or 6–7 g within a 24-hour period, if
liver enzymes are elevated, or if the patient falls within a high-risk group (see above). Treatment may be
stopped 24–36 hours after the last dose of acetaminophen if liver enzymes and PT/INR are normal.