Thrombospondin 2 is a key determinant of fibrogenesis in non‐alcoholic fatty liver disease

Thrombospondin 2 (TSP2) plays a vital role in collagen/fibrin formation, bone growth, vascular density regulation, hemostasis, and cell adhesion. Close associations of serum TSP2 with histological severity in non-alcoholic fatty liver disease and chronic hepatitis C were reported. The present study investigated the significance of circulating TSP2 in chronic hepatitis B patients. Eighty-seven biopsy-proven chronic hepatitis B patients were analyzed in cross-sectional Study 1 to search for correlations between serum TSP2 levels prior to liver biopsy and clinicopathological parameters. In longitudinal Study 2, 51 chronic hepatitis B patients with long-term follow-up (mean: 7.5 years) were examined for changes in serum TSP2 levels during nucleos(t)ide analog (NA) therapy along with trends in hepatocarciongenesis. In Study 1, serum TSP2 levels were not significantly associated with portal inflammation or fibrosis. Study 2 revealed that serum TSP2 was significantly decreased after 48 weeks of NA therapy ( P < 0.001). Notably, TSP2 levels at 48 weeks of NA administration (TSP2-48W) were significantly higher in the hepatocellular carcinoma (HCC) (+) group than in the HCC (−) group ( P = 0.043). Kaplan–Meier analysis showed that higher TSP2-48W (≥ 24 ng/mL) was associated with future HCC development ( P = 0.030). Serum TSP2 levels may be a potential predictor of HCC development in hepatitis B patients receiving NA therapy. Longitudinal prospective studies are necessary to validate our findings.

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Serum protein risk stratification score for diagnostic evaluation of metabolic dysfunction–associated steatohepatitis

Lai,

Dillon,

et al. 2024

Hepatology Communications

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Background: Reliable, noninvasive tools to diagnose at-risk metabolic dysfunction–associated steatohepatitis (MASH) are urgently needed to improve management. We developed a risk stratification score incorporating proteomics-derived serum markers with clinical variables to identify high-risk patients with MASH (NAFLD activity score >4 and fibrosis score >2). Methods: In this 3-phase proteomic study of biopsy-proven metabolic dysfunction–associated steatotic fatty liver disease, we first developed a multi-protein predictor for discriminating NAFLD activity score >4 based on SOMAscan proteomics quantifying 1305 serum proteins from 57 US patients. Four key predictor proteins were verified by ELISA in the expanded US cohort (N = 168) and enhanced by adding clinical variables to create the 9-feature MASH Dx score, which predicted MASH and also high-risk MASH (F2+). The MASH Dx score was validated in 2 independent, external cohorts from Germany (N = 139) and Brazil (N = 177). Results: The discovery phase identified a 6-protein classifier that achieved an AUC of 0.93 for identifying MASH. Significant elevation of 4 proteins (THBS2, GDF15, SELE, and IGFBP7) was verified by ELISA in the expanded discovery and independently in the 2 external cohorts. MASH Dx score incorporated these proteins with established MASH risk factors (age, body mass index, ALT, diabetes, and hypertension) to achieve good discrimination between MASH and metabolic dysfunction–associated steatotic fatty liver disease without MASH (AUC: 0.87—discovery; 0.83—pooled external validation cohorts), with similar performance when evaluating high-risk MASH F2-4 (vs. MASH F0-1 and metabolic dysfunction–associated steatotic fatty liver disease without MASH). Conclusions: The MASH Dx score offers the first reliable noninvasive approach combining novel, biologically plausible ELISA-based fibrosis markers and clinical parameters to detect high-risk MASH in patient cohorts from the United States, Brazil, and Europe.

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Thrombospondin 2 is a key determinant of fibrogenesis in non‐alcoholic fatty liver disease

Cited by 5 publications

References 54 publications

Integrated analyses and a novel nomogram for the prediction of significant fibrosis in patients

Integrated analyses and a novel nomogram for the prediction of significant fibrosis in patients

Circulating thrombospondin 2 as a predictor of hepatocellular carcinoma in hepatitis B patients undergoing nucleos(t)ide analog therapy

Serum protein risk stratification score for diagnostic evaluation of metabolic dysfunction–associated steatohepatitis

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