Acute hepatotoxicity associated with therapeutic doses of intravenous acetaminophen

Abstract

Background: IV acetaminophen at 4 g per day is considered safe, producing no hepatic failure in more than 1400 cases. Oxidation of acetaminophen forms a reactive intermediate that binds to cellular proteins resulting in acetaminophen-protein adducts (APAP-CYS). Serum concentrations of APAP-CYS have been found to correlate with acetaminophen-induced hepatotoxicity. We report a case of hepatotoxicity associated with therapeutic doses of IV acetaminophen, with elevated serum APAP-CYS. Case details: The patient was a 92-year-old, 68 kg woman without known hepatic disease or ethanol abuse. On hospital day 3 she underwent laparoscopic reduction of internal hernias under general anesthesia. Surgery was uncomplicated and postoperatively she was treated with subcutaneous heparin and IV acetaminophen, 1 g every 6 h for almost 4 days (total dose = 13 g). At the start of therapy, transaminases were normal. On hospital day 5, she was noted to have marked transaminase elevations (AST: 4698 IU/L; ALT: 3914 IU/L) with increases in INR (1.68), ammonia (60 mcg/dL), and total bilirubin (1.8 mg/dL). Serum acetaminophen concentration was 15.3 mcg/mL 26 h after her last dose. Acetaminophen was discontinued and IV acetylcysteine was given and continued at the second maintenance dose rate for a second 16-hour infusion, at which time transaminases, INR, ammonia and total bilirubin were all improving. The patient was discharged 2 days later. Serum APAP-CYS concentrations in serum samples obtained during her hospitalization were elevated (peak = 4.81 μM on hospital day 5; expected range for therapeutic dosing <1.1 μM). Case discussion: We have identified a case of acute liver injury associated with therapeutic dosing of IV acetaminophen. The serum APAP-CYS concentrations are consistent with that seen in cases of hepatotoxicity following repeated supratherapeutic acetaminophen ingestion. Several factors that likely contributed to her susceptibility included advanced age, post-operative status, a likely catabolic state and multiple acetaminophen doses over several days. These uncommon circumstances limit the generalizability of risk. We believe the findings are most consistent with acetaminophen-induced liver injury. Conclusion: This case illustrates a potential hazard of IV acetaminophen and demonstrates the potential utility of APAP-CYS adducts in evaluating causality in acute liver injury.

Keywords:

• Acetaminophen
• acetaminophen-protein adducts
• hepatotoxicity
• IV acetaminophen

Disclosure statement

Authors S.A.S. and D.K. report no declarations of interest. Authors K.J.H., V.E.A., J.L.G. and R.C.D were employees of Denver Health while working on this manuscript, Denver Health has research and consulting contracts with McNeil Consumer Healthcare and Cumberland Pharmaceuticals.