Non-invasive quantification of hepatic necrosis from circulating alanine aminotransferase kinetics in acetaminophen-treated mice in vivo
Histological necrosis is the reference measure of hepatotoxicity but can only be obtained at terminal cull. A time course requires independent cohorts at every timepoint. Circulating alanine aminotransferase (ALT) can be sampled repeatedly in the same animal, and is released in liver injury. We asked whether serial ALT kinetics can be used to estimate histological necrosis in vivo. Forty-five…
The study investigated if the measurement of circulating alanine aminotransferase (ALT) kinetics could be used to estimate liver necrosis in live mice treated with acetaminophen. Researchers measured ALT in 45 fasted twelve-week-old male C57BL/6J mice receiving a single intraperitoneal dose of 350 mg/kg acetaminophen over a 48-hour period.
They compared these measurements, represented as cumulative area-under-the-curve (AUC), to histological centrilobular necrosis observed in liver sections as the gold standard, ranging from 0 to 59% with a mean of 32%. A generalised additive model was used to predict necrosis based on cumulative ALT AUC and time since dosing, resulting in an error of 7.7% (95% CI 5.6 to 10.0) when validated without using any animal as a test subject, compared to errors of 5.6 to 10.0% in traditional regression and machine-learning models.
The results indicate that serial ALT kinetics can serve as a calibrated, longitudinal measure of hepatic necrosis in vivo, providing a more stable estimate of within-group variability and supporting a reduction in animal use, as the data from one serially sampled cohort can replace data from separate cohorts at each timepoint.
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