Acetaminophen-induced Acute Liver Failure Is More Common and More Severe in Women

Abstract

Background & aims: Acetaminophen overdose is the leading cause of acute liver injury (ALI) and acute liver failure (ALF) in the developed world. Sex differences in acetaminophen-induced hepatotoxicity have not been described.

Methods: We collected data from the Acute Liver Failure Study Group cohort, a national registry of 32 academic medical centers in North America of adults with ALI or ALF, including 1162 patients with acetaminophen-induced ALI (n = 250) or acetaminophen-induced ALF (n = 912) from January 2000 through September 2016. We analyzed data on patient presentation, disease course, demographics, medical and psychiatric history, medication use, substance use, and details of acetaminophen ingestion. Sex differences in continuous and categorical variables were evaluated by Wilcoxon rank-sum and χ² analysis or the Fisher exact test. Our primary aim was to evaluate sex differences in the presentation and clinical course of acetaminophen-induced acute liver injury or liver failure, and our secondary goal was to compare overall and transplant-free survival between sexes.

Results: Most patients with acetaminophen-induced ALI (68%) or ALF (76%) were women. Higher proportions of women than men had psychiatric disease (60% of women vs 48% of men, P < .01) and had co-ingestion with sedating agents (70% of women vs 52% of men, P < .01)-more than half of which were opioids. Higher proportions of women had severe hepatic encephalopathy (HE) (68% of women vs 58% of men), and required intubation (67% of women vs 59% of men, P values <.03). Higher proportions of women used vasopressors (26% of women vs 19% of men, P = .04) or mannitol (13% of women vs 6% of men, P < .01); proportions of male vs female patients with transplant-free survival were similar (68%). On adjusted analysis, women had higher risk of severe HE (adjusted odds ratio [AOR], 1.66; 95% CI, 1.17-2.35). We found a significant interaction between sex and co-ingestion of sedating agents (P < .01); co-ingestion increased odds of severe HE in women 2-fold (AOR, 1.86; 95% CI, 1.28-2.69; P < .01) but not in men (AOR; 0.62; 95% CI, 0.34-1.13; P = .12).

Conclusions: In an analysis of the Acute Liver Failure Study Group cohort, we found acetaminophen-induced ALI and ALF to be more common among women. Women have greater critical care needs than men, and increased risk for severe HE, which could be due in part to increased use of sedatives. Future studies should investigate sex differences in acetaminophen metabolism and hepatotoxicity, particularly among users of opioids.

Keywords: ALFSG; APAP; Gender; Narcotics; Paracetamol; Tylenol.

Figure 1

Co-ingestion with sedating medications in acetaminophen-induced ALF (A) Proportion with co-ingestion, by type. (B) Proportion with any sedating medication use, by sex.

Figure 2

Clinical characteristics in acetaminophen-induced ALF by sex at (A) study entry (B) during cumulative 7-day follow up.

Figure 3

Clinical outcomes for acetaminophen-induced ALF at 21 days, by sex.