Circulating matricellular fibrosis markers TSP2, IGFBP7, TSP4 and the M2-macrophage marker CD163 in predicting disease stage and progression in primary sclerosing cholangitis

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Background: Primary sclerosing cholangitis (PSC) is a complex liver disease with a lack of biomarkers for the assessment of disease progression. We investigated five serum markers – Thrombospondin-2 and -4 (TSP2/-4), Insulin-like growth factor-binding protein 7 (IGFBP7), Cluster of Differentiation 163 (CD163) and PRO-C3 – as potential indicators of fibrosis and outcome in PSC. Method : We analysed serum marker levels in 142 people with PSC from the University Medical Center Hamburg-Eppendorf using ELISA, alongside liver stiffness measurements, assessments of disease activity and patient outcome. Results were externally validated in 170 patients from Oslo University Hospital Rikshospitalet. Results: In multivariable regression analyses, TSP2, IGFBP7, CD163, TSP4 and PRO-C3 were found to be independently and positively associated with liver stiffness (p<0.001 – 0.014). ROC curve analyses indicated that especially TSP2, IGFBP7, CD163 and PRO-C3 were effective in distinguishing between patients with and without cirrhosis (AUCs 0.87 – 0.90). A newly developed fibrosis score, including a combination of the aforementioned markers, further enhanced the ability to discriminate for cirrhosis, resulting in an AUC of 0.95 (95% CI: 0.92 – 0.98, p<0.0001). In both, the derivation and validation cohorts, patients with baseline serum levels of TSP2 and CD163 indicating advanced fibrosis (stage≥F3), experienced significantly reduced transplant-free survival (Log Rank p<0.001). Conclusion: Circulating TSP2, IGFBP7, CD163, TSP4 and PRO-C3 levels were significantly associated with advanced fibrosis and cirrhosis in people with PSC. Furthermore, especially TSP2 and CD163 serum levels were associated with transplant-free survival, indicating their potential as prognostic biomarkers in PSC. Publication History Article published online: 20 January 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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