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Acetaminophen-induced liver injury, failure more common in women

Acetaminophen-induced acute liver injury and failure are more common in women than men, according to recently published data. Women also have greater critical care needs and have an increased risk for severe hepatic encephalopathy, potentially related to increased use of sedatives.

“The reasons for increased prevalence and severity of [drug-induced liver injury] in women are not clear, though may relate to greater use of hepatotoxic medications in women and differential drug metabolism by sex,” Jessica B. Rubin, MD, MPH, from the University of California San Francisco, and colleagues wrote. “Despite apparent sex differences in the prevalence and progression of other etiologies of [acute liver failure (ALF)], less is known regarding the natural history of acetaminophen-induced ALF in men and women.”

To evaluate potential sex differences in presentation and clinical course of acetaminophen-induced acute liver injury (ALI) and ALF, the researchers reviewed patient data from the prospective Acute Liver Failure Study Group from Jan. 1, 2000, to Sept. 27, 2016.

The study included 250 patients with acetaminophen-induced ALI (170 women) and 912 patients with ALF (694 women).

Women with acetaminophen-induced ALF were more likely to have psychiatric disease (60% vs. 48%; P < .01) and take psychiatric medication (42% vs. 25%; P < .001) compared with men, although the distribution of psychiatric illnesses did not differ by sex. Men, however, were more likely to have a history of IV drug use (15% vs. 7%; P < .01) and heavy alcohol use (39% vs. 19%; P < .01).

Indications

Acetaminophen overdose occurred unintentionally in 53% of patients and due to suicide attempts in 40%. The rates of suicide attempts did not differ by sex. Among those using acetaminophen for therapeutic purposes, 77% of patients self-initiated and 23% followed a physician recommendation, the rates of which were similar in men and women.

“Women in the current study were more likely to have psychiatric disease, including anxiety and depression,” Rubin and colleagues wrote. “Prior data from this cohort evaluating detailed psychiatric history found that rates of psychiatric illness in acetaminophen-induced ALF patients were higher than in the general population, in both intentional and unintentional overdoses.”

Of the 15% who provided indications for acetaminophen use, 42% reported use for chronic pain and 28% for acute pain. There was no difference by sex in reported indication or total dose.

Compared with men, a greater proportion of women had co-ingestions with opioids, benzodiazepines or diphenhydramine (70% vs. 52%; P < .001) among both those with and without a history of suicide attempts. The prevalence of co-ingestions was lower in those with a history of suicide attempts (43% vs. 65%; P < .001).

Complication risk factors

Among those with ALF, women were more likely to have hepatic encephalopathy grade 3 or 4 at baseline (58% vs. 42%) and at the 7-day follow-up (68% vs. 58%; P < .01) and more likely to be intubated at baseline (60% vs. 45%; P < .001) and follow-up (67% vs. 59%; P = .03), compared with men.

Women were also more likely to use vasopressor at baseline (26% vs. 19%; P = .04), mannitol at baseline (13% vs. 6%; P < .01) and follow-up (22% vs. 17%; P = .09), and antibiotics at follow-up (14% vs. 9%; P = .06), compared with men.

The researchers found that female sex correlated with an increased risk for severe hepatic encephalopathy at both baseline (OR = 1.95; 95% CI, 1.43-2.67) and follow-up (OR = 1.6; 95% CI, 1.17-2.2), with co-ingestion as a significant covariate at baseline (OR = 1.64; 95% CI, 1.24-2.18).

After adjusting for age, co-ingestion, alanine aminotransferase levels and baseline MELD, women had a significantly higher risk for hepatic encephalopathy at baseline (OR = 1.78; 95% CI, 1.28-2.51) and follow-up (OR = 1.66; 95% CI, 1.17-2.35) compared with men.

Co-ingestion among women significantly increased the risk for severe hepatic encephalopathy at baseline (OR = 1.81; 95% CI, 1.26-2.59) and follow-up (OR = 1.86; 95% CI, 1.28-2.69), whereas there was no significant increased risk for men.

“A striking finding in the current study was the higher prevalence of co-ingestions in women, most notably with combination opioid-acetaminophen products. These results have important public health implications in light of the current opioid epidemic in the U.S., particularly among younger Americans,” the researchers wrote. “More transparency in medication labeling as well as greater patient education regarding combination drug ingredients may help to reduce the morbidity and mortality associated with acetaminophen hepatotoxicity.” – by Talitha Bennett

Disclosure: The authors report no relevant financial disclosures.