LAUSR

BACKGROUND AND AIMS Acetaminophen (APAP) induced acute liver failure (ALF) remains the commonest cause of ALF in the western world. Conventional prognostic models utilising markers of liver injury and organ failure to predict mortality lack sensitivity. We have previously demonstrated a microRNA signature that is associated with successful regeneration post-auxiliary liver transplant and recovery from APAP-ALF. We aim to develop microRNA outcome prediction models for APAP-ALF utilising this signature. METHODS We undertook a nested, case-control study using serum samples from 194 patients with APAP-ALF enrolled in the US ALF Study Group registry (1998-2014) at early (day 1-2) and late (day 3-5) time-points. A microRNA qPCR panel of 22 microRNA was utilised to assess microRNA expression at both time-points. Multiple logistic regression was used to develop models which were compared to conventional prognostic models using the DeLong method RESULTS: Individual microRNA confer limited prognostic value when utilised in isolation. However, incorporating them within microRNA-based outcome prediction models increases their clinical utility. Our early time-point model (AUC = 0.78, 95%CI 0.71-0.84) contained a microRNA signature associated with liver regeneration and our late time-point model (AUC = 0.83, 95%CI 0.76-0.89) contained a microRNA signature associated with cell-death. Both models were enhanced when combined with patient MELD score and vasopressor use and outperformed the King's College Criteria. The early time-point model combined with clinical parameters outperformed the ALF Study Group prognostic index and MELD score. CONCLUSIONS Our findings demonstrate that a regeneration-linked microRNA signature combined with readily available clinical parameters can outperform existing prognostic models for ALF in identifying patients with poor prognosis who may benefit from transplantation. LAY SUMMARY We show that blood test markers measuring potential for liver recovery may help improve identification of patients unlikely to survive from acute liver failure who may benefit from liver transplantation.