Clinical and pathophysiological characteristics of non-acute decompensation of cirrhosis

Abstract

Background & aims: The heterogenous presentation patterns in decompensated cirrhosis confer variable outcomes. While acute decompensation (AD) is well-characterized, the presentation patterns and outcomes of non-acute decompensation (NAD) remain unclear. The aim of this study was to characterize clinical and pathophysiological features of NAD and identify predictors of progression in NAD.

Methods: In this prospective study, patients across the cirrhosis spectrum were enrolled from two centers in India between 2020-2023: compensated cirrhosis (CC; n = 29), NAD (n = 311), AD (n = 201), and healthy controls (n = 10). Clinical and laboratory parameters, cytokine levels (IL-6, TNF, IL-10, MCP-1) and cell death markers (M30, M65, Gasdermin-D, RIPK3, MLKL) were assessed at baseline. Twelve-month overall survival was assessed in all patients. The predictors of progression to AD and mortality were evaluated in patients with NAD.

Results: Survival was lower in patients with NAD (81.7%) than in those with CC (100%), but higher than in those with AD (31.2%) (p <0.001). Despite no significant systemic inflammation, patients with NAD exhibited elevated levels of cell death markers, particularly Gasdermin-D and RIPK3, compared to healthy controls and patients with CC. Both inflammatory and cell death markers were most pronounced in AD. Over 12 months, the cumulative incidence of progression to AD among those with NAD was 55.1%, significantly reducing their survival (68.2% vs. 95.3%, p <0.001). Predictors of such progression to AD included severe ascites, lower IGF-1, albumin, BMI, and higher bilirubin, Gasdermin-D, and RIPK3 levels, as well as higher CTP and MELD scores.

Conclusions: NAD represents a clinically, prognostically and pathophysiologically distinct entity in cirrhosis. Patients with NAD express elevated cell death markers and remain at risk of progression to AD and mortality. Identifying such high-risk patients should prompt interventions to prevent progression. Modulation of cell death is a potentially disease-modifying target in cirrhosis.

Impact and implications: This study highlights non-acute decompensation as a clinically, prognostically and pathophysiologically distinct subset of cirrhosis, underscoring the importance of understanding its progression dynamics. Identifying key predictors of acute decompensation, including ascites severity, low IGF-1 levels, and elevated cell death markers, such as Gasdermin-D and RIPK3, potentially uncovers new therapeutic avenues. These findings are crucial for helping hepatologists and researchers to risk stratify patients and optimize transplant candidacy. Interventions targeting necroptosis and pyroptosis pathways may improve outcomes, providing a significant shift towards precision medicine in cirrhosis care.

Keywords: ACLF; Non-acute decompensation; cell death; cirrhosis; immunity; inflammation.