Assessment of Pyroptosis-Related Indicators as Potential Biomarkers and Their Association with Severity in Patients with Liver Cirrhosis

Abstract

The diagnosis and management of liver cirrhosis remain challenging due to its diverse clinical manifestations and elusive severity evaluation. Pyroptosis, an identified inflammatory form of cell death, has recently been reported to participate in cirrhosis development. Nonetheless, the clinical significance of pyroptosis in liver cirrhosis remains largely unexplored. Patients and Methods: One hundred and fifty-one liver cirrhosis patients either alone or in combination with various complications and twenty-nine gender-and age-matched healthy controls (HCs) were enrolled in this study. Pyroptosis-related indicators gasdermin D (GSDMD), IL-1ß and IL-18 were measured by IHC in tissue section and by ELISA in serum, respectively, and correlations of their circulating levels with disease severity as well as their potential as biomarkers for monitoring cirrhosis progression were evaluated. Results: Increased levels of the circulating pyroptosis-related indicators GSDMD, IL-1ß and IL-18 were observed in liver cirrhosis patients, especially those with an etiology of viral infection. In addition, all three indicators were positively correlated with disease severity parameters, including Child-Pugh classification, APRI scores and compensated status. Furthermore, receiver operating characteristic (ROC) analysis showed that circulating IL-1ß exerted potential discriminating power for SBP occurrence in liver cirrhosis, but GSDMD possessed differentiating power for SBP in liver cirrhosis with ascites, which yielded area under the ROC curve (AUC) of 0.81 and 0.80, respectively. Conclusion: Liver cirrhosis patients exhibited increased levels of circulating GSDMD, IL-1ß and IL-18, all of which were positively correlated with disease severity. More importantly, the identified circulating IL-1ß and GSDMD exhibited potentials as novel biomarkers for liver cirrhosis patients presenting with SBP.

S100A8-Mediated NLRP3 Inflammasome-Dependent Pyroptosis in Macrophages Facilitates Liver Fibrosis Progression

“…In addition, an in vitro mechanistic study showed that the pyroptosis products IL-1β and IL-18 regulate the activation of hepatic stellate cells (HSCs) and facilitate the development of liver fibrosis [ 14 ]. Notably, patients with liver cirrhosis also exhibited elevated levels of circulating GSDMD, IL-1β, and IL-18 in our previous clinical research [ 15 ]. Therefore, NLRP3 inflammasome-dependent pyroptosis may serve as a crucial mechanism for the development of liver injury and fibrosis.…”

Beta-Cell Pyroptosis – A Burning Flame in Type 1 Diabetes?

“…Research in this area is in demand and may lay the foundation for a better understanding of disease etiology. In addition to being an important mediator of pyroptotic cell death, GSDMD also holds potential as a circulating biomarker, as serum GSDMD levels are elevated in inflammatory diseases [55][56][57]. Whether GSDMD or other gasdermins can serve as circulating biomarkers of ongoing beta-cell pyroptosis should be investigated.…”

Gasdermin D: A Potential New Auxiliary Pan-Biomarker for the Detection and Diagnosis of Diseases

“…GSDMD is the first molecule to be released into the extracellular environment and can trigger the release of IFN-β [29]. As the induction of pyroptosis diminishes, intracellular GSDMD expression and splicing cease, leading to a rapid decrease in total extracellular GSDMD levels, indicating a positive correlation between GSDMD and disease severity [30]. This characteristic makes GSDMD a potential biomarker for disease identification, early diagnosis, and the assessment of therapeutic efficacy and prognosis.…”

“…Biomarkers, with their time-dependent effects, sensitivity, and early warning capabilities, have the potential to contribute to early disease diagnosis, reducing mortality rates, and improving survival and quality of life. Pyroptosis, a critical process in the occurrence and progression of major diseases [30][31][32], plays a significant role. GSDMD, as an effector molecule in pyroptosis, forms membrane pores and rapidly exits into the extracellular environment [13].…”

“…Hepatitis B virus (HBV) has been identified as a major contributor to hepatitis through the activation of NLRP3 by HBV X protein, which is triggered by elevated levels of mitochondrial reactive oxygen species (mito-ROS) [70]. This activation leads to the upregulation of IL-1 and IL-18, mediated by caspase-1 [30,71,72]. Similarly, hepatitis C virus (HCV), another common pathogen causing hepatitis, induces NLRP3 activation through glycoproteins, resulting in ASC-SPECK formation and subsequent cell death via both caspase-1 and caspase-3 pathways [73].…”