Short-Term Safety of Repeated Acetaminophen Use in Patients With Compensated Cirrhosis

Hepatol Commun. 2022 Feb;6(2):361-373. doi: 10.1002/hep4.1810. Epub 2021 Aug 25.


Current guidelines recommend restricting acetaminophen (APAP) use in patients with cirrhosis, but evidence to support that recommendation is lacking. Prior studies focused on pharmacokinetics (PK) of APAP in cirrhosis but did not rigorously examine clinical outcomes, sensitive biomarkers of liver damage, or serum APAP-protein adducts, which are a specific marker of toxic bioactivation. Hence, the goal of this pilot study was to test the effects of regularly scheduled APAP dosing in a well-defined compensated cirrhosis group compared to control subjects without cirrhosis, using the abovementioned outcomes. After a 2-week washout, 12 subjects with and 12 subjects without cirrhosis received 650 mg APAP twice per day (1.3 g/day) for 4 days, followed by 650 mg on the morning of day 5. Patients were assessed in-person at study initiation (day 1) and on days 3 and 5. APAP-protein adducts and both conventional (alanine aminotransferase) and sensitive (glutamate dehydrogenase [GLDH], full-length keratin 18 [K18], and total high-mobility group box 1 protein) biomarkers of liver injury were measured in serum on the mornings of days 1, 3, and 5, with detailed PK analysis of APAP, metabolites, and APAP-protein adducts throughout day 5. No subject experienced adverse clinical outcomes. GLDH and K18 were significantly different at baseline but did not change in either group during APAP administration. In contrast, clearance of APAP-protein adducts was dramatically delayed in the cirrhosis group. Minor differences for other APAP metabolites were also detected. Conclusion: Short-term administration of low-dose APAP (650 mg twice per day, <1 week) is likely safe in patients with compensated cirrhosis. These data provide a foundation for future studies to test higher doses, longer treatment, and subjects who are decompensated, especially in light of the remarkably delayed adduct clearance in subjects with cirrhosis.

Publication types

  • Controlled Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaminophen / administration & dosage*
  • Acetaminophen / adverse effects*
  • Acetaminophen / blood
  • Adult
  • Alanine Transaminase / blood
  • Analgesics, Non-Narcotic / administration & dosage*
  • Analgesics, Non-Narcotic / adverse effects*
  • Analgesics, Non-Narcotic / blood
  • Biomarkers / blood
  • Drug Administration Schedule
  • Female
  • Glutamate Dehydrogenase / blood
  • HMGB1 Protein / blood
  • Humans
  • Keratin-18 / blood
  • Liver Cirrhosis / blood
  • Liver Cirrhosis / drug therapy*
  • Male
  • Middle Aged
  • Pilot Projects
  • Prospective Studies
  • Young Adult


  • Analgesics, Non-Narcotic
  • Biomarkers
  • HMGB1 Protein
  • HMGB1 protein, human
  • KRT18 protein, human
  • Keratin-18
  • Acetaminophen
  • Glutamate Dehydrogenase
  • Alanine Transaminase