Plasma Biomarkers of Senescence in Cholestatic Liver Disease: A Signature of Risk Stratification and Progression.

The second principal component (PC2) from PCA of 71 plasma analytes best separated PSC patients from healthy controls.

• PC2 comprised 17 analytes and explained 17.1% of variability in the dataset.
• Seventy-one analytes were quantified using Luminex Multiplex Immunoassay or ELISA.
• ANOVA showed significant differences in PC2 between early PSC vs. controls (p = 0.0001), late PSC vs. controls (p < 0.0001), and early vs. late PSC (p < 0.0001).
• Plasma samples from early- and late-stage PSC, PBC, ALD, IBD patients, and healthy controls were analyzed.

Logistic regression using PC2 analytes demonstrated strong discrimination between disease stages in PSC.

• AUC = 0.86 for discrimination of early- versus late-stage PSC.
• AUC = 0.83 for discrimination of controls versus early-stage PSC.
• These results indicate strong clinical discriminatory performance of the PC2 biomarker signature.

The PC2 SASP biomarker signature distinguished cholestatic liver diseases (PBC and ALD) from controls but did not distinguish IBD from controls.

• PC2 analytes distinguished early PBC vs. controls (p = 0.0332), late PBC vs. controls (p < 0.0001), and early vs. late PBC (p < 0.0001).
• PC2 analytes distinguished ALD from controls (p < 0.0001).
• IBD vs. controls was not significantly distinguished by PC2 analytes (p = 0.119), suggesting the signature is more specific to cholestatic/liver conditions than to intestinal inflammation.

Cellular senescence and the senescence-associated secretory phenotype (SASP) are mechanistically implicated in cholestatic liver diseases including PSC and PBC.

• Senescent cholangiocytes exhibit a SASP characterized by profibroinflammatory mediator release.
• Cellular senescence is described as a hallmark of several liver diseases, including PSC and PBC.
• Current cost-effective biomarkers predicting disease progression, particularly for PSC, are limited and often lack mechanistic relevance.

The plasma SASP biomarker signature findings from the PSC cohort were validated by application to additional independent cohorts.

• Findings from the PSC cohort were applied to additional cohorts including PBC and ALD patients.
• The signature tracked disease stage across multiple cholestatic liver disease populations.
• The authors characterize these analytes as representing both mechanistic indicators and potential clinical trial endpoints.