Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation

Abstract

ObjectiveSystemic inflammation predisposes acutely decompensated (AD) cirrhosis to the development of acute-on-chronic liver failure (ACLF). Supportive treatment can improve AD patients, becoming recompensated. Little is known about the outcome of patients recompensated after AD. We hypothesise that different inflammasome activation is involved in ACLF development in compensated and recompensated patients.Design249 patients with cirrhosis, divided into compensated and recompensated (previous AD), were followed prospectively for fatal ACLF development. Two external cohorts (n=327) (recompensation, AD and ACLF) were included. Inflammasome-driving interleukins (ILs), IL-1α (caspase-4/11-dependent) and IL-1β (caspase-1-dependent), were measured. In rats, bile duct ligation-induced cirrhosis and lipopolysaccharide exposition were used to induce AD and subsequent recompensation. IL-1α and IL-1β levels and upstream/downstream gene expression were measured.ResultsPatients developing ACLF showed higher baseline levels of ILs. Recompensated patients and patients with detectable ILs had higher rates of ACLF development than compensated patients. Baseline CLIF-C (European Foundation for the study of chronic liver failure consortium) AD, albumin and IL-1α were independent predictors of ACLF development in compensated and CLIF-C AD and IL-1β in recompensated patients. Compensated rats showed higher IL-1α gene expression and recompensated rats higher IL-1β levels with higher hepatic gene expression. Higher IL-1β detection rates in recompensated patients developing ACLF and higher IL-1α and IL-1β detection rates in patients with ACLF were confirmed in the two external cohorts.ConclusionPrevious AD is an important risk factor for fatal ACLF development and possibly linked with inflammasome activation. Animal models confirmed the results showing a link between ACLF development and IL-1α in compensated cirrhosis and IL-1β in recompensated cirrhosis.

Liver transplantation for acute‐on‐chronic liver failure predicts post‐transplant mortality and impaired long‐term quality of life

“…It seems intuitive that the highly dynamic nature of ACLF, which is frequently complicated by infections, evokes comparable phenomena in patients. In this respect, Monteiro et al have recently linked decompensated cirrhosis to persistent alterations of immune regulation, 34 which may outlast the LT phase and concomitantly affect mechanisms of immune activation, the individual's response to immunosuppressive therapy and ultimately the risk for serious infections in the post‐transplant phase. Our data further suggest that the post‐operative course of ACLF‐LT, which is frequently characterized by recurrent interventions, repeated rounds of anti‐infective therapy and prolonged hospitalization in an ICU environment, 10 favours the emergence of 3‐ and 4‐MRGN pathogens that may ultimately contribute to post‐transplant mortality.…”

Long-term Outcome of Autologous Hematopoietic Stem Cell Infusion in Cirrhosis: Waning Effect over Time

“… 16 The beneficial effect of this study, when compared with our research, could be due to the patient population having had a lower Child-Pugh score, and the majority of the patients being without ascites. So, it could be hypothesized that if stem cells are used early in the course of the natural history of cirrhosis, when the inflammatory milieu 17 of the liver is still less hostile to the mobilized or infused stem cells, the regenerative power of the cells could be better. This theory needs to be validated in a prospective randomized trial with paired-biopsies taken pre- and post-stem cell infusion to document increase in the number of stem cells in the liver tissue.…”

Hepatic inflammasome activation as origin of Interleukin-1α and Interleukin-1β in liver cirrhosis

“…In this model, bile duct ligation in rats was used to induce liver cirrhosis and lipopolysaccharide to induce AD as described previously. 2 Gene expression of both IL-1α and IL-1β is significantly higher in liver tissue compared with PBMC in recompensated cirrhosis. In compensated cirrhosis, gene expression of IL-1α, but not IL-1β, is significantly increased in liver tissue compared with PBMC (figure 1A,B).…”