Hepatotoxicty from Combined Use of Acetaminophen and Phenobarbital

Abstract

Purpose: A 48-year-old Caucasian male with known chronic hepatitis C infection presented to the emergency department following an intentional phenobarbital overdose. He had been maintained on phenobarbital for many years, due to an underlying seizure disorder. There was no other evidence of illicit, prescribed or over-the-counter medication use. On presentation, he was unresponsive, hypotensive and bradycardic. The patient was intubated for airway protection and admitted to the intensive care unit. Toxicology screens, acetaminophen levels and aspirin levels were negative except for significantly elevated phenobarbital levels. On admission, his liver transaminases were mildly elevated (but stable and consistent with his prior known HCV). He was treated with supportive care and eventually extubated. Several days later in the hospitalization, he developed right-sided abdominal pain. Evaluation was consistent with severe colitis, which eventually required an uneventful right hemicolectomy. The LFTs remained stable. Post-operatively, he was started back on phenobarbital. His pain medication regimen was intravenous acetaminophen 1,000 mg every 6 hours, as needed. Three days later, the patient was noted to be jaundiced. Liver function tests revealed AST 1690, ALT 1851, alkaline phosphatase 536 and bilirubin 4.7. Ultrasound with Doppler studies demonstrated gallbladder sludge, but no acute liver or biliary pathology. Workup for other causes of acute liver disease including hepatitis A, hepatitis B, autoimmune hepatitis, Wilson disease and alpha-1-antitrypsin deficiency were negative. He was felt to likely have acetaminophen toxicity as the cause of the elevated LFT's. Acetaminophen was discontinued and the transaminases rapidly returned to baseline. This case illustrates several important points regarding acetaminophen hepatotoxicity. First, acetaminophen is metabolized by the cytochrome P450 system into its toxic metabolite, N-acetyl-p-benzoquinone imine. Second, potent inducers of CYP2E1, such as phenobarbital, can significantly increase the levels of the toxic metabolite causing increased risk for acetaminophen hepatotoxicity. Third, this toxicity can even occur within the expected therapeutic levels of acetaminophen. In conclusion, acetaminophen, especially in the intravenous form, should be used with caution in patients taking medications that affect its metabolism due to an increased risk of hepatotoxicity.