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.