Clinical and Pathophysiological Characteristics of Non-acute Decompensation of Cirrhosis.

Background & Aims: The heterogenous presentation patterns in decompensated cirrhosis confers variable outcomes. While acute decompensation (AD) is well-characterised with poorest prognosis, presentation as non-acute decompensation (NAD) remain unclear. This study aimed to characterize clinical and pathophysiological features of NAD in comparison with healthy (HC), compensated cirrhosis (CC) and AD and identify predictors of progression in NAD.

Methods: A prospective, two-center study enrolled patients across the cirrhosis spectrum from India between 2020-2023: CC (n=29), NAD (n=311), AD (n=201), and HC (n=10). Clinical and laboratory parameters, cytokine levels (IL-6, TNF, IL-10, MCP-1), and cell death markers (M30, M65, Gasdermin-D, Receptor-interacting-protein-kinase; RIPK3, Mixed lineage kinase domain-like; MLKL) were assessed at baseline. Patients were followed for 12 month-survival. The predictors of progression to AD and mortality were evaluated in NAD.

Results: Patients with NAD had a poorer survival (81.7%) compared to CC (100%), but superior to 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 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 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, CTP, MELD, Gasdermin-D, and RIPK3 levels.

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 suggests new therapeutic avenues. These findings are crucial for hepatologists and researchers in risk stratifying patients and optimizing transplant candidacy. Interventions targeting necroptosis and pyroptosis pathways may improve outcomes, providing a significant shift towards precision medicine in cirrhosis care.