Assessment of the Frequency, Phenotypes, and Outcomes of Acute Liver Injury Associated with Amoxicillin/Clavulanate in 1.4 Million Patients in the Veterans Health Administration

Introduction: Drug-induced liver injury is a significant health issue, yet the exposure-based incidence remains to be characterized.

Objective: We aimed to assess the frequency, phenotypes, and outcomes of acute liver injury associated with amoxicillin/clavulanate using a large electronic health record system.

Methods: Using the Veterans Health Administration electronic health record system, we developed the framework to identify unexplained acute liver injury, defined by alanine aminotransferase and/or alkaline phosphatase elevation temporally linked to prescription records of amoxicillin/clavulanate, a major culprit of clinically significant drug-induced liver injury, excluding other competing causes. The population was subcategorized by pre-existing liver conditions and inpatient status at the time of exposure for the analysis.

Results: Among 1,445,171 amoxicillin/clavulanate first exposures in unique individuals [92% men; mean age (standard deviation): 59 (15) years], 6476 (incidence: 0.448%) acute liver injuries were identified. Of these, 4427 (65%) had alternative causes, yielding 2249 (incidence: 0.156%) with unexplained acute liver injuries. The incidence of unexplained acute liver injury was lowest in outpatients without underlying liver disease (0.067%) and highest in inpatients with pre-existing liver conditions (0.719%). Older age, male sex, and American Indian or Alaska Native (vs White) were associated with a higher incidence of unexplained acute liver injury. Cholestatic injury affected 74%, exhibiting a higher frequency with advanced age, inpatient exposure, and pre-existing liver conditions. Hepatocellular injury with bilirubin elevation affected 0.003%, with a higher risk at age >45 years. During a 12-month follow-up, patients with unexplained acute liver injury had a higher adjusted overall mortality risk than those without evident acute liver injury.

Conclusions: This framework identifies unexplained acute liver injury following drug exposure in large electronic health record datasets. After validating in other systems, this framework can aid in deducing drug-induced liver injury in the general patient population and regulatory decision making to promote drug safety and public health.