Abstract
BackgroundThere is a clear need for better biomarkers of drug-induced-liver-injury (DILI).AimsWe aimed to evaluate the possible prognostic value of ActiTest and FibroTest proteins apoliprotein-A1, haptoglobin and alpha-2-macroglobulin, in patients with DILI.MethodsWe analyzed cases and controls included in the IMI-SAFE-T-DILI European project, from which serum samples had been stored in a dedicated biobank. The analyses of ActiTest and FibroTest had been prospectively scheduled. The primary objective was to analyze the performance (AUROC) of ActiTest components as predictors of recovery outcome defined as an ALT <2x the upper limit of normal (ULN), and BILI <2x ULN.ResultsAfter adjudication, 154 patients were considered to have DILI and 22 were considered to have acute liver injury without DILI. A multivariate regression analysis (ActiTest-DILI patent pending) combining the ActiTest components without BILI and ALT (used as references), apolipoprotein-A1, haptoglobin, alpha-2-macroglobulin and GGT, age and gender, resulted in a significant prediction of recovery with 67.0% accuracy (77/115) and an AUROC of 0.724 (P<0.001 vs. no prediction 0.500). Repeated apolipoprotein-A1 and haptoglobin remained significantly higher in the DILI cases that recovered (n = 65) versus those that did not (n = 16), at inclusion, at 4–8 weeks and at 8–12 weeks. The same results were observed after stratification on APAP cases and non-APAP cases.ConclusionsWe identified that apolipoprotein-A1 and haptoglobin had significant predictive values for the prediction of recovery at 12 weeks in DILI, enabling the construction of a new prognostic panel, the DILI-ActiTest, which needs to be independently validated.
Highlights
An increase in total bilirubin (BILI) levels along with clinically relevant increases in aminotransferase activity is the signal currently considered most specific for and predictive of severe drug-induced liver injury (DILI) (“Hy’s law”) [1]
We analyzed cases and controls included in the Innovative Medicines Initiative (IMI)-Safer and Faster Evidence-based Translation (SAFE-T)-DILI European project, from which serum samples had been stored in a dedicated biobank
Repeated apolipoprotein-A1 and haptoglobin remained significantly higher in the DILI cases that recovered (n = 65) versus those that did not (n = 16), at inclusion, at 4–8 weeks and at 8–12 weeks
Summary
An increase in total bilirubin (BILI) levels along with clinically relevant increases in aminotransferase activity is the signal currently considered most specific for and predictive of severe drug-induced liver injury (DILI) (“Hy’s law”) [1]. In alanine transaminase (ALT), without BILI elevations are more sensitive, but are not sufficiently specific for DILI. These current standard biomarkers are not ideal for thoroughly monitoring disease progression and resolution, and they do not allow to clinical outcomes of liver injury to be reliably predicted. There is a clear need for better biomarkers of drug-induced-liver-injury (DILI)
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