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Cell death markers in patients with cirrhosis and acute decompensation
Stewart Macdonald1, Fausto Andreola1, Patrik Bachtiger1
1Liver Failure Group, Institute for Liver and Digestive Health, University College London, London, United Kingdom.
Insights
Cell death markers, caspase-cleaved keratin 18 (cK18) and keratin 18 (K18), increase with cirrhosis severity. Non-apoptotic cell death is prominent in acute decompensation (AD) and acute on chronic liver failure (ACLF).
Area of Science:
- Hepatology
- Cellular Biology
- Biomarker Discovery
Background:
- Cirrhosis progression to acute decompensation (AD) and acute on chronic liver failure (ACLF) involves complex pathophysiology.
- Understanding the role of cell death is crucial for managing liver disease severity and outcomes.
- Plasma-based biomarkers offer a non-invasive approach to assess cellular processes in liver disease.
Purpose of the Study:
- To investigate the role of cell death in patients with cirrhosis experiencing AD and ACLF.
- To evaluate plasma biomarkers of apoptosis and total cell death, specifically caspase-cleaved keratin 18 (cK18) and keratin 18 (K18).
- To correlate cell death markers with disease severity, clinical parameters, and predict progression from AD to ACLF.
Main Methods:
- Analysis of plasma samples from the CANONIC study cohort (N=337), including AD and ACLF patients, healthy volunteers, and stable cirrhosis patients.
- Measurement of cK18 and K18 using enzyme-linked immunosorbent assay (ELISA) to determine apoptotic and total cell death.
- Histological confirmation of hepatic cell death using Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining in a subset of AD patients.
Main Results:
- Plasma concentrations of cK18 and K18 significantly increased, while the cK18:K18 apoptotic index decreased with increasing AD and ACLF severity.
- Increased cell death markers were associated with alcohol etiology and prior history of alcohol abuse, but not underlying infection.
- Cell death markers correlated with systemic inflammation and hepatic failure markers (ALT, bilirubin) but not extrahepatic organ injury.
Conclusions:
- Hepatic cell death is a significant feature of AD and ACLF, with its magnitude correlating with clinical severity.
- Non-apoptotic cell death pathways become predominant as AD and ACLF severity increases.
- Cell death markers, including cK18 and K18, improve the predictive performance of the CLIF-C AD score for AD to ACLF progression.
Abstract:
The aims of this study were to determine the role of cell death in patients with cirrhosis and acute decompensation (AD) and acute on chronic liver failure (ACLF) using plasma-based biomarkers. The patients studied were part of the CANONIC (CLIF Acute-on-Chronic Liver Failure in Cirrhosis) study (N = 337; AD, 258; ACLF, 79); additional cohorts included healthy volunteers, stable patients with cirrhosis, and a group of 16 AD patients for histological studies. Caspase-cleaved keratin 18 (cK18) and keratin 18 (K18), which reflect apoptotic and total cell death, respectively, and cK18:K18 ratio (apoptotic index) were measured in plasma by enzyme-linked immunosorbent assay. The concentrations of cK18 and K18 increased and the cK18:K18 ratio decreased with increasing severity of AD and ACLF (P < 0.001, respectively). Alcohol etiology, no previous decompensation, and alcohol abuse were associated with increased cell death markers whereas underlying infection was not. Close correlation was observed between the cell death markers and, markers of systemic inflammation, hepatic failure, alanine aminotransferase, and bilirubin, but not with markers of extrahepatic organ injury. Terminal deoxynucleotidyl transferase dUTP nick-end labeling staining confirmed evidence of greater hepatic cell death in patients with ACLF as opposed to AD. Inclusion of cK18 and K18 improved the performance of the CLIF-C AD score in prediction of progression from AD to ACLF (P < 0.05).
Conclusion:
Cell death, likely hepatic, is an important feature of AD and ACLF and its magnitude correlates with clinical severity. Nonapoptotic forms of cell death predominate with increasing severity of AD and ACLF. The data suggests that ACLF is a heterogeneous entity and shows that the importance of cell death in its pathophysiology is dependent on predisposing factors, precipitating illness, response to injury, and type of organ failure. (Hepatology 2018;67:989-1002).