Age-related differences in reporting of drug-associated liver injury: data-mining of WHO Safety Report Database

Abstract

Background/aims: Age-differences in the frequency and manifestations of drug-induced liver injury are not fully characterized. Data-mining analyses were performed to assess the impact of age on liver event reporting frequency with different phenotypes and agents.

Methods: 236 drugs associated with hepatotoxicity were evaluated using the Empirical Bayes Geometric Mean (EBGM) of the relative reporting ratio with 90% confidence interval (EB05 and EB95) calculated for the age groups: 0-17, 18-64, and⩾65years (or elderly), for overall, serious (acute liver failure), hepatocellular, and cholestatic liver injury, using the WHO Safety Report Database.

Results: Overall, cases of age 0-17, 18-64, and 65years or older comprised 6%, 62%, and 32% of liver event reports. Acute liver failure and hepatocellular injury were more frequently reported among children compared to adults and the elderly while reports with cholestatic injury were more frequent among the elderly (p<0.00001). A potential to cause mitochondrial dysfunction was more prevalent among the drugs with increased pediatric reporting frequency while high lipophilicity and biliary excretion were more common among the drugs associated with higher reporting frequency in the elderly.

Conclusion: Age-specific phenotypes and potential drug properties associated with age-specific hepatotoxicity were identified in reported liver events; further analyses are warranted.

Keywords: Acute liver failure; Aging; Cholestatic injury; Data-mining; Drug-induced liver injury; Hepatotoxicity; Lipophilicity; Mitochondrial dysfunction; Pediatric.