Clinical and pathophysiological characterization of patients with acutely decompensated cirrhosis and acute-on-chronic liver failure

In the last decade, our understanding of the pathophysiological mechanisms underlying decompensated cirrhosis has greatly increased. Moreover, acute-on-chronic liver failure (ACLF) was defined as a distinct syndrome with specific features. Our research activities aimed to provide a contribution in characterizing patients with acutely decompensated cirrhosis and ACLF from a clinical and a pathophysiological perspective. As a first project, we addressed the clinical issue of predicting in-hospital development of ACLF in patients hospitalized for acute decompensation of cirrhosis. As a second contribution, we performed a reassessment of the whole metabolomic dataset obtained from 831 patients enrolled in the CANONIC study, focusing on amino acids, with the aim to uncover alterations in amino acids metabolic pathways. As a third perspective, we performed a GWAS on 270 patients with acute decompensation and ACLF included in the first clinical study. We categorized patients in 4 groups, according to their clinical presentation and their clinical course. We then performed two comparisons: group 1 vs group 4 (i.e., the most severe vs the mildest clinical courses), and group 1 vs group 2 (i.e., patients with different 1-year outcomes from a common clinical presentation with ACLF or bacterial infection). Three SNPs (rs9354118 on chromosome 6q16.1; rs1146878 on chromosome 13q22.2; rs6479397 on chromosome 9q22.31) were significantly associated with the selected phenotypes, but all of them were located in non-codifying DNA regions. However, their potential role as candidate Cis-Regulatory Elements (cCREs) opened interesting hypotheses on effects on the expression of neighboring genes. Indeed, four of them (FUT9 and UFL1 for SNP rs9354118, LMO7 and ACOD1 for rs1146878) are involved in the modulation of immune system activation and systemic inflammation. The results of the GWAS did not confirm previous findings reported in literature and presented some limitations. However, it provided the basis for further research in this still open issue.