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A 45-year-old man presented for his annual physical examination. He had no current complaints except for knee pain related to known osteoarthritis for which he took acetaminophen on a regular basis (two 500-mg capsules about every 6 hours, as recommended on the package label, but sometimes more often). His past history was notable for hypertension, for which he took an ACE inhibitor. His family history was notable for hypertension, heart disease in both of his elderly parents, and diabetes in his mother. He reported drinking 1 or 2 beers on social occasions (about once a month). Results of the patient’s physical examination were normal, except for a blood pressure of 142/97 mmHg and obesity (BMI 27.3). His weight has been stable for the past year. Because of his routine use of acetaminophen and his alcohol intake, serum tests for liver enzymes were done. Prothrombin time (PT) and partial thromboplastin time (PTT) values were normal; other values were as follows: gamma-glutamyl transferase (GGT), 45 IU/L; aspartate aminotransferase (AST), 225 IU/L; and alanine aminotransferase (ALT), 246 IU/L. The patient was advised to discontinue the acetaminophen. Results of liver function tests repeated 2 weeks later demonstrated a return to normal levels. |
This patient had been following the package instructions on the dosage for acetaminophen fairly consistently, yet elevations in his liver enzymes developed. It is very likely he was dosing more frequently than he realized or reported, but it is also possible that the enzyme levels became elevated because of concurrent, excess alcohol use or other factors.
Acetaminophen is considered hepatotoxic at doses higher than 140 to 150 mg/kg (as a single dose). The maximum daily dose is 4 g for adults and 90 mg/kg for children. Those clearly at risk for hepatotoxicity are persons who take repeated, high doses of acetaminophen, those who intentionally overdose, and persons who have dementia and accidentally take high and/or frequent doses. In addition, patients with impaired liver function are at risk, even at lower doses.
Increased cytochrome P450 2E1 activity also leads to more rapid accumulation of the toxic metabolite of acetaminophen. Therefore, in patients who are chronic alcohol abusers or who routinely take medications that are metabolized by the P450 system (e.g. barbiturates, phenytoin), toxicities can develop at lower doses.
The risk for drug-related hepatotoxicity is thought to be in the range of 1/10,000 to 1/100,000 treated persons. In most countries, antituberculosis drugs, antibiotics, halothane anaesthetics, and NSAIDs are the most common causes of drug-related hepatotoxicity. However, in the United States and United Kingdom, acetaminophen is the most common cause of drug-related hepatotoxicity.
Unless overt hepatitis or liver failure develops, this toxicity is asymptomatic. Patients with large, intentional overdoses are initially asymptomatic and then begin to have nausea and vomiting. About 12 hours after the overdose, serum levels of transaminase enzymes begin to rise. Subsequently, the patient has right upper quadrant pain, jaundice, coagulopathy, renal failure, and progression to hepatic encephalopathy (as a result of cerebral oedema) as liver failure worsens. Jaundice and right upper quadrant tenderness develop because of liver inflammation. Hypotension, clinical bleeding, and altered mental status may be apparent on physical examination.
Laboratory abnormalities develop as liver failure progresses. Serum AST or ALT levels exceeding 1,000 IU/L, prolonged PT and PTT, elevated bilirubin levels, and a metabolic acidosis develop. Patients with a serum pH level less than 7.30 after fluid resuscitation have a particularly poor prognosis.
Treatment is easier for acute, known overdoses, because the actual time of ingestion can be determined. In the first hour after ingestion of a large dose, activated charcoal administration may be helpful in reducing the absorption of acetaminophen. If gastric emptying is delayed, activated charcoal may be effective up to 4 hours after ingestion. Otherwise, since absorption is generally very rapid, removal of the doses from the stomach (i.e. with gastric lavage or induced vomiting) is not generally attempted or recommended. Such attempts may prevent or delay administration of N-acetylcysteine and should be avoided.
Fluid replacement and correction of electrolyte abnormali-ties are indicated in all patients with an overdose. Supportive care, particularly as liver failure progresses, is indicated.
Treatment with N-acetylcysteine (orally or intravenously) is useful for overdoses that are detected early; it is most effective when given within 8 hours of the ingestion. N-acetylcysteine is metabolized to cysteine, which in turn serves as a precursor for glutathione. The goal is to increase the glutathione available to inactivate NAPQI. However, the damage already done by NAPQI is not reversed by therapy with N-acetylcysteine. The Rumack-Matthew nomogram is used to determine the appropriate dose and timing of N-acetylcysteine therapy. This nomogram is a semi-logarithmic graph of acetaminophen levels plotted against time since ingestion along a line that defines toxicity levels (200 µg/mL at 4 hours after ingestion to 50 µg/mL at 12 hours). If serum levels are below the zone demarcated at 25% above the line of toxicity, treatment with N-acetylcysteine is indicated. Treatment may also be helpful in some chronic ingestions, and consultation with a toxicologist may be helpful in determining whether a given patient might benefit from treatment.
The majority of patients fully recover from an acetaminophen overdose that is detected early enough to prevent liver failure. Nearly all patients who are treated with N-acetylcysteine within 8 to 10 hours of the overdose are protected from hepatotoxicity and hence have an excellent prognosis. Even with some hepatic damage, most patients fully recover and suffer no long-term sequelae.
For patients with hepatotoxicity who develop a progres-sive coagulopathy, renal impairment, hypoglycaemia, a metabolic acidosis with a pH level <7.35, hypotension despite fluid replacement, and encephalopathy, early referral for liver transplantation is critical. Unfortunately, only half the patients who meet criteria for transplantation are able to be treated because they are either too critically ill to undergo transplantation or they die before a suitable organ match is available.
In the future, treatment with agents that block the enzymes leading to the formation of NAPQI or that bind directly with NAPQI may become available. In addition, experimental evaluation of artificial liver support is being studied and may one day provide a way to treat patients who are waiting for liver transplantation.