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

Abstract

Objective: Systemic 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.

Design: 249 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.

Results: Patients 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.

Conclusion: Previous 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.

Keywords: inflammation; liver cirrhosis; portal hypertension.

Figure 1

Kaplan-Meier curve for fatal ACLF development stratified into (A) compensated vs recompensated patients; (B) patients with CLIF-C AD score <50 vs ≥50; (C) compensated patients with undetectable levels of IL-1α and CLIF-C AD score <50 vs compensated patients with detectable levels of IL-1α and CLIF-C AD score ≥50; and (D) recompensated patients with undetectable levels of IL-1β and/or CLIF-C AD score <50 vs recompensated patients with detectable levels of IL-1β and CLIF-C AD score ≥50. ACLF, acute-on-chronic liver failure; AD, acutely decompensated; CLIF-C, European Foundation for the study of chronic liver failure consortium; IL, interleukin.

Figure 2

(A) Schematic of animal models for acute decompensation, recompensated and compensated cirrhosis. (B) Hepatic gene expression of IL-1α in the acute decompensation model. (C) Circulating levels of IL-1α in the acute decompensation model. (D) Gene expression of IL-1α in the liver and PBMC in compensation and recompensation models. (E) Circulating levels of IL-1α in the compensation and recompensation models. (F) Gene expression of IL-1β in the liver and PBMC in compensation and recompensation models. (G) Circulating levels of IL-1β in the compensation and recompensation models. (H) Heat map of gene expression of upstream and downstream signalling of IL-1α and IL-1β in PBMC and liver in compensation and recompensation models. *P<0.05 vs comp, **P<0.005 vs comp. AD, acutely decompensated; BDL, bile duct ligation; Comp, compensated; d21, day 21; d28, day 28; IL, interleukin; LPS, lipopolysaccharide; PBMC, peripheral blood mononuclear cell; Recomp, recompensated.