John is a sixteen-year-old high school student who is interested in trying out for the school wrestling team. One week before tryouts he badly sprains his back playing touch football. He is in considerable pain and is concerned that he will not be able to make the team. He visits his physician who confirms that the injury is not serious but quite painful. To relieve John’s discomfort, the physician prescribes a mild opiate anti-inflammatory medication (Endocet™ 7.5/500, 24 pills). John is instructed to take two pills three times a day for pain relief. Concerned about his ability to compete for the team, John takes the pills four times a day until he runs out. In addition, he self-medicates with extra strength acetaminophen (Tylenol™), taking three pills every four hours in combination with the Endocet™. On the weekend previous to his injury, John attended a party and overindulged in drinks containing alcohol. Four days after seeing his physician, John becomes severely nauseated, sweaty, and “flulike.” John’s mother notes that he seems sluggish and confused and brings her son to the local emergency room. In the emergency room, the physician carefully reviews John’s history of medication. John’s liver is noted to be tender and mildly enlarged on physical examination. The physician is concerned about possible drug toxicity. John has consumed 4 grams of acetaminophen (from the Endocet™) and 6 grams of acetaminophen by self-medication per day. Thus, John has consumed 10 grams of acetaminophen per day for three days. The maximum recommended dose of acetaminophen is 3 grams per day for an adult. Concerned about hepatic toxicity, the physician orders liver function tests that indicate acute liver failure. A serum acetaminophen assay discloses a potentially toxic amount of the drug. John is treated on an emergency basis with oral N-acetylcysteine and medication to control nausea. He recovers with normalization of liver function tests over the period of several weeks. He does not make the wrestling team.
Discussion
Acetaminophen (better known by its trade name Tylenol™) has gained popularity as an over-the-counter pain medication and aspirin replacement over the last several decades, in part because of the association of Reye’s syndrome with aspirin in children and the reduced level of gastric side effects. Although acetaminophen is generally a safe medication, with a toxic dose (generally considered to be above 8 grams per 8 hours or less) far above the recommended maximum therapeutic dose of 3 grams per day, it is often abused. This is related to a lack of knowledge about potential toxicity and the widespread availability of the drug, which is often combined with other medications and hence is not obvious to the user. It may surprise individuals to learn that acetaminophen is responsible for over half of all cases of drug-induced liver injury, almost 80,000 ER visits, and more than 30,000 hospitalizations per year in the United States. Acetaminophen overdose was responsible for more than 300 deaths in 2010—half accidental, half suicidal and is the second most common cause of acute liver failure requiring transplantation. Ninety-five percent of ingested acetaminophen is detoxified and chemically modified in the liver and ultimately excreted in the urine. About 5 percent of acetaminophen is modified by the cytochrome P-450 enzymes to a toxic intermediate called NAPQI. NAPQI binds to mitochondrial proteins and leads to the formation of reactive oxygen species, which result in hepatocyte death and, if levels are high enough, acute hepatic necrosis. Two factors influence the degree of toxicity. Cytochrome P-450 enzymes are increased by alcohol consumption, leading to the formation of more of the toxic metabolite NAPQI. Liver cells have a detoxifying chemical GSH (reduced glutathione), which binds to NAPQI and renders it harmless. However, large amounts of NAPQI can deplete available glutathione. The drug used to treat John (N-acetylcysteine) replenishes stores of GSH, reducing the toxic effects of NAQPI.
Etiology and Pathogenesis
Drug-induced acute liver injury resulting from acetaminophen overdose.
Questions
1. What metabolic factors influence the toxicity of ingested acetaminophen?
2. What over-the-counter drugs are likely to contain “hidden” acetaminophen? It would be instructive to read the contents of the drugs found in your own medicine cabinet.
3. Given the potential toxicity of acetaminophen, what additional controls on its sales (if any) might be reasonable to control accidental overdosing?