THE PREDICT STUDY

The clinical course of cirrhosis is characterized by recurrent episodes of acute decompensation separated by more or less long periods in which the disease remains compensated under medical treatment. The PREDICT study (1335 patients with acute decompensation not associated with ACLF, 175,000 biological samples) is the second large observational study conducted by the CLIF Consortium. It was designed in 2016, started in 2017 and completed in June 2018, and its data revised and cleaned until March 2019. The objective of the study is to characterize the episodes of acute decompensation and, most importantly, to develop prognostic tools to PREDICT and stratify the type of patients at risk of developing ACLF and die.

The final goal is to provide physio-pathological and clinical bases that justify the paradigm change in the therapeutic guidelines of decompensated liver cirrhosis. This feature is simultaneously being pursued by the PRECIOSA study (prevention of episodes of acute decompensation). The initial results indicate that acute decompensation in cirrhosis and the ACLF syndrome are part of the same disorder: systemic inflammation crisis and secondary metabolic dysregulation. The ACLF syndrome would be the most extreme clinical condition of acute decompensation and its main cause of death. The first findings of the PREDICT Study have been published in 2020 in two different articles in The Journal of Hepatology, the main journal in the field.

Detailed agnostic assessment of precipitating events for acute decompensation (AD) and ACLF: Prevalence, association with AD at enrolment and importance in clinical course severity.

Observational Study Jonel Trebicka (Goethe University Frankfurt. Frankfurt, Germany; EF Clif. Barcelona, Spain)
Javier Fernández (Hospital Clínic Barcelona-IDIBAPS; EF Clif. Barcelona, Spain)

Promoter: EF Clif
Start date: 01/03/2017
End date: 31/01/2020

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 Natural History of AD in cirrhosis: phenotypes, pathophysiology and development of a specific clinical score to PREDICT ACLF development and stable decompensated cirrhosis

Observational Study Jonel Trebicka (Goethe University Frankfurt. Frankfurt, Germany; EF Clif. Barcelona, Spain)
Javier Fernández (Hospital Clínic Barcelona-IDIBAPS; EF Clif. Barcelona, Spain)

Promoter: EF Clif
Start date: 01/03/2017
End date: 30/09/2020

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.

Chronological relationship between the clinical course of AD and the changes in systemic inflammation, metabolic dysregulation, transcriptomics, lipidomics and markers of mitochondrial dysfunction.

Translational Research Richard Moreau (EF Clif. Barcelona, Spain)
Joan Clària (Hospital Clínic Barcelona-IDIBAPS; EF Clif. Barcelona, Spain)
Emmanuel Weiss (INSERM. Paris, France)

Promoter: EF Clif
Start date: 01/01/2019
End date: 31/12/2020

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.

Microbiome-based biomarkers to PREDICT decompensation of liver cirrhosis, ACLF and treatment response.

Observational Study Jonel Trebicka (Goethe University Frankfurt. Frankfurt, Germany; EF Clif. Barcelona, Spain)

Promoter: H2020-EU.3.1.2- 825694
Start date: 01/01/2019
End date: 31/03/2025

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.

Glycomics-based biomarkers for diagnosis and prognosis in Acute-on-Chronic Liver Failure.

Observational study Xavier Verhelst (Ghent University Hospital. Ghent, Belgium)
Hans Van Vlierberghe (Ghent University Hospital. Ghent, Belgium)

Promoter: EF Clif
Start date: 01/01/2020
End date: 30/06/2021

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.