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

Abstract

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 inperson 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 lowdose 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. (Hepatology Communications 2021;0:1-13).A cetaminophen (APAP) is the most commonly used analgesic in the United States and throughout much of the world. However, overdose of APAP causes massive centrilobular hepatocyte necrosis that can lead to acute liver failure (ALF) and death. It is overwhelmingly the most common cause of drug-induced ALF in the United States and similarly developed countries, accounting for at least 45%-65% of all cases (1) and possibly even more that go undiagnosed. (2) Although mortality is generally lower in APAP-induced ALF compared to other etiologies, the large number of cases makes APAP overdose the most common cause of ALF-related deaths as well.

Clinical Guideline on Perioperative Management of Patients with Advanced Chronic Liver Disease

“…Although a common misconception, the short-term use of a low dose (2–3 g/day) of acetaminophen is safe in patients with ACLD [ 92 , 94 , 95 , 96 ]. In contrast, NSAIDs should be avoided in all ACLD patients, as they can precipitate AKI and gastrointestinal bleeding due to prostaglandin inhibition and increased bioavailability [ 94 , 97 ].…”

“…Hypoglycemia can occur in patients with decompensated cirrhosis due to depletion in hepatic glycogen stores, impaired gluconeogenesis due to hepatocyte loss, and hyperinsulinemia. Continuous infusion of 10-20% dextrose can mitigate hypoglycemia, alt- Although a common misconception, the short-term use of a low dose (2-3 g/day) of acetaminophen is safe in patients with ACLD [92,[94][95][96]. In contrast, NSAIDs should be avoided in all ACLD patients, as they can precipitate AKI and gastrointestinal bleeding due to prostaglandin inhibition and increased bioavailability [94,97].…”

Effect of changes in metabolic enzymes and transporters on drug metabolism in the context of liver disease: Impact on pharmacokinetics and drug–drug interactions

“…However, a study showed that short-term administration of low-dose paracetamol is likely to be safe in patients with compensated cirrhosis. 140 In liver disease, the changes in individual enzymes that metabolize drugs in each patient are variable and do not closely correlate with clinical impairment as reflected by the Child-Pugh score. However, this is hardly surprising as this score is based exclusively on clinical attributes, and mostly derived from patients with decompensated cirrhosis.…”

“…This effect is initiated by conversion of the drug, mostly via CYP2E1 and CYP1A2, to N‐acetyl‐p‐benzoquinone imine, an intermediate that in high quantity depletes the cells of glutathione. However, a study showed that short‐term administration of low‐dose paracetamol is likely to be safe in patients with compensated cirrhosis 140 …”

The Evolution of Circulating Biomarkers for Use in Acetaminophen/Paracetamol-Induced Liver Injury in Humans: A Scoping Review

“…APAP-protein adducts, measured as protein-derived APAP-cysteine (APAP-CYS) after the removal of free cysteine and proteolysis of the specimen, overcome some major shortcomings of serum APAP, APAP × AT, psi, and similar endpoints that are based on, or incorporate, serum APAP levels. Like APAP, adducts can become detectable in circulation as early as 1 h after a therapeutic dose, with a peak between 3 and 12 h after therapeutic or sub-hepatotoxic doses [81,82] and between 24 and 72 h after overdose [65] (similar to ALT), but they are more stable than APAP and decline slowly, with a half-life of 1-2 days [82-85] (Figure 3). Thus, serum adducts provide a longer diagnostic window than APAP alone.…”