Mathematical modelling of chronic acetaminophen metabolism and liver injury.

Acetaminophen (APAP) overdose is the leading cause of acute liver injury in the USA and the UK. Increasingly, liver injury is caused by sustained overuse rather than a single-time overdose. We have recently developed a mathematical model, the Model of APAP-induced Liver Damage (MALD), to predict the outcome of patients with APAP-induced liver damage. The model is based on a single-time overdose and uses measurable markers of liver injury to estimate time since overdose and overdose amount, two variables critical for survival. Here, we extend the model to study liver injury from chronic APAP use. We find that there is a threshold in the model, such that liver injury occurs rapidly or not at all, even with chronic use. Fits of synthetic data derived from chronic use overdose scenarios to MALD lead to accurate predictions of outcome, even when liver injury is the result of sustained overuse.