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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

Suzuki, Ayako; Tillmann, Hans; Williams, James; Hauser, Ronald G.; Frund, Julie; Suzuki, Mizuki; Prior, Fred; Aithal, Guruprasad P.; Lucena, M. Isabel; Andrade, Raúl J.; Tong, Weida; Hunt, Christine M.


Ayako Suzuki

Hans Tillmann

James Williams

Ronald G. Hauser

Julie Frund

Mizuki Suzuki

Fred Prior

M. Isabel Lucena

Raúl J. Andrade

Weida Tong

Christine M. Hunt


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

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

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.

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.

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.


Suzuki, A., Tillmann, H., Williams, J., Hauser, R. G., Frund, J., Suzuki, M., …Hunt, C. M. (2023). 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. Drug Safety, 46(2), 129-143.

Journal Article Type Article
Acceptance Date Nov 6, 2022
Online Publication Date Dec 22, 2022
Publication Date 2023-02
Deposit Date Jul 19, 2023
Journal Drug Safety
Print ISSN 0114-5916
Electronic ISSN 1179-1942
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Volume 46
Issue 2
Pages 129-143
Keywords Pharmacology (medical); Pharmacology; Toxicology
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