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BOSTON -- Women with acetaminophen-induced acute liver failure are more likely than men to have severe hepatic encephalopathy, a researcher said here.

Exactly why that should be the case has been a mystery, according to , of the University of California San Francisco.

But retrospective analysis of a large cohort of patients with acute liver failure suggests that at least part of the answer lies in co-medication -- using other drugs at the same time as acetaminophen, Rubin reported at the

The finding is a "very intriguing possible explanation" for the preponderance of women with acetaminophen-induced liver failure, commented , of Massachusetts General Hospital in Boston.

One implication, he told MedPage Today, is that emergency department physicians need to be "very vigilant about the nature of those ingestions" because some of the drugs -- narcotics, for instance -- have antidotes that can be given.

"We do, as a matter of course, do a tox screen" in cases of acute liver failure, said Chung, who was not involved in the study, so the finding is not likely to instigate a specific practice change. But it's a reminder for clinicians, especially when treating women, to "drill down [to find] the co-conspirators" that are causing the liver damage along with acetaminophen, he added.

The findings come from looking at the men and women with acetaminophen-induced liver failure enrolled in the a consortium at 23 centers, from January 2000 through July 2015.

"Women are more likely to have acetaminophen-induced acute liver failure than men," Rubin told MedPage Today. Of the 912 people in the cohort, 76% were women.

Analysis showed that women in the cohort were also more often in need of critical care, such as intubation and treatment with vasopressors and mannitol. Essentially, she said, they looked sicker than men, even though assessment of outcomes showed they were no more likely to die of their illness.

Importantly, analysis of the cohort showed that women were also more likely to present with Grades 3 and 4 hepatic encephalopathy, she said. Specifically, 58% of the women had severe encephalopathy, compared with 42% of the men.

The encephalopathy "manifests as confusion, altered sensorium, and difficulty with movement," she said.

Rubin cautioned that the male-female difference in incidence might be partly a result of presentation bias. "The fact that we find more women (with acetaminophen-induced acute liver failure) might be because they look sicker," she said.

But she and colleagues were curious to see if they could find out why the women were sicker. One hypothesis, she said, was that "co-ingestion" of other drugs might have played a role.

Overall, Rubin said, some 57% of the cohort reported using other drugs, mainly benzodiazepines, oral narcotics or both, along with too much acetaminophen.

But among those with severe encephalopathy -- 92 men and 428 women -- there was a marked difference in the proportion who reported co-ingestion: 42% and 65%, respectively, Rubin reported.

Univariate analysis found significant associations between severe hepatic encephalopathy and:

• Female sex, with an odds ratio of 1.95
• Each year of age, with an odds ratio of 1.02 per year
• Co-ingestion, with an odds ratio of 1.48

In a multivariate analysis, only female sex remained significantly associated with severe encephalopathy, with an odds ratio of 1.87.

But, Rubin said, the investigators noticed a significant interaction between sex and drug use, which permitted them to perform a sub-analysis on the risk of severe encephalopathy by sex. In that analysis, co-ingestion by men was not a factor in hepatic encephalopathy, but for women, the adjusted odds ratio of 1.42 was significant.

That finding raises another question, Rubin said: why women would be more sensitive than men to the effects of co-ingestion of drugs. Future research, she added, should look at possible physiological and neurological explanations.

The study raises "the issue of a sex influence in the outcome of patients with acetaminophen overdose and liver failure," commented Raul Andrade, MD, PhD, of the in Spain.

Andrade, who was not involved in the current study, told MedPage Today that he and his colleaguges have shown that in Spanish patients, female sex is a risk factor for fulminant liver failure due to idiosyncratic hepatic reactions to drugs other than acetaminophen, a finding that has also been in the U.S.

"The explanation behind the higher fragility of women when developing toxic hepatitis is currently unknown, but hormonal factors and the differences in body fat distribution could contribute," he added.

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