Xenobiotic-Induced Liver Injury in the United States: A 25-Year Retrospective Analysis of National Poison Data System

Xenobiotic-induced liver injury (XILI) remains a challenge in hepatology, with acetaminophen (APAP) as a leading contributor to severe disease. We used national poison center surveillance to characterize long-term trends in XILI and APAP- and alcohol-associated liver injury in the United States.

A retrospective analysis of the National Poison Data System was conducted to identify reported xenobiotic exposures involving individuals aged ≥15 years from 2000 to 2024 with biochemical evidence of hepatocellular injury, defined by aspartate or alanine aminotransferase elevations >100 U/L. Exposures were stratified by sex, age, substance type, exposure intent and acuity, level of care, and medical outcome. Two secondary analyses restricted to single-substance, single-ingredient APAP (APAP-alone) and single-substance alcohol exposures were performed using the same approach.

A total of 220,160 xenobiotic exposures associated with liver injury were identified. Population-adjusted exposure rates increased nearly 4-fold (10.9-52.9 per million). Women accounted for most exposures (54%). More than 80% of exposures required inpatient hospitalization, indicating substantial clinical severity. Medication-related exposures accounted for the majority of cases (men, 85%; women, 94%), with APAP-alone the most frequently implicated xenobiotic (men, 33%; women, 45%). APAP-containing combination products declined by approximately 60% to 85% following regulatory actions in the early 2010s, whereas APAP-alone exposures increased substantially (men, 349%; women, 380%).

Clinically significant XILI has increased substantially over the past 25 years, with APAP-alone emerging as a growing and persistent contributor. These findings underscore the value of poison center surveillance for monitoring hepatotoxic risk and informing targeted prevention strategies in an era of expanding reliance on nonopioid analgesics.