This multicentre, prospective, observational PREDICT study analyses and characterized the precipitants leading to AD. The PREDICT study included 1,273 patients with AD and focused on the characteristics of precipitants, specifically induction of organ dysfunction/failure and/or systemic inflammation, chronology, intensity, and relationship to outcome in both AD phenotypes (No-ACLF and ACLF). In particular, in proven bacterial infections and severe alcoholic hepatitis, either alone or in combination, accounted for almost all (96-97%) acute decompensation and ACLF. Whilst type of the precipitants was not associated with mortality, the number was. This study identified precipitants that are significantly associated with a distinct clinical course and prognosis of patients with AD. Specific preventative and therapeutic strategies targeting these events may improve outcome in decompensated cirrhosis.

The present study described for the first time three different clinical courses of patients with AD after hospital admission. The first clinical course (pre-ACLF) included patients who develop ACLF and has high probability of death. These patients are characterized by high-grade systemic inflammation. The second clinical course (unstable decompensated cirrhosis) included patients requiring frequent hospitalizations unrelated with ACLF, show low-grade systemic inflammation, but suffer characteristically from complications related to severe portal hypertension. They present lower risk of mortality than patients with pre-ACLF. Finally, the third clinical course (stable decompensated cirrhosis), included two-third of all patients admitted hospital with AD. They do not present severe systemic inflammation or frequent complications related with portal hypertension, rarely require hospital admission and present an extremely low 1-year mortality risk.

The objective of this study was to profile by Omics approaches the chronological relationship between the clinical course of decompensated cirrhosis and the changes in systemic inflammation, metabolic dysregulation, transcriptomics, lipidomics and markers of mitochondrial dysfunction.

The initial results indicate that acute decompensation in cirrhosis and the ACLF syndrome are part of the same disorder driven by systemic inflammation that leads to secondary mitochondrial dysfunction and metabolic dysregulation. The inflammatory markers of the entire PREDICT cohort have been measured (including all the time points of the study). The metabolomics and lipidomics data are already available from all patients at inclusion. The transcriptomic analysis of the patients is also well advanced.

The aims of the study are to better understand the role of microbiome and the gut-liver-axis interactome;) to identify and validate microbiome-based biomarkers and signatures for personalized prediction of decompensation and ACLF, and response to treatment; to design three new tests as easy-to-use tools and point-of-care, smartphone-connected nano-biosensors; and to validate them in a RCT.

So far, the foundations for the completion of the first objective were laid: In the MUCOSA-PREDICT cohort, we analysed the microbiome and the host using many omics techniques. The data are currently being analysed. The second objective is dependent on the final results of analysis ongoing. Still, important progress could be made during this funding period. Regarding the third objective, we use extensive cohorts and cover large parts of the world and many geographic regions of Europe, and we control for this important confounder. To reach the last objective, the protocol of the ALB-TRIAL is close to finalization, with a design to test the biomarker(s) that specifically predict treatment response to albumin.

Changes in serum protein glycosylation occur in several liver diseases and have been the basis for the development of diagnostic and prognostic biomarkers. The goal of this work was to assess if there is an association between changes in protein glycosylation and the severity of ACLF. A second goal was to study if these changes relate to outcome in patients with ACLF.

A pilot study has been started. The serum N-glycomic profile is analysed of specific subsets of patients with different degrees of ACLF and different outcomes. At this day, the glycomic profiles have been analysed. The interpretation of the data and statistical analysis is ongoing.