Determining a healthy reference range and factors potentially influencing PRO-C3 – A biomarker of liver fibrosis
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Background & Aims: Progressive fibrosis has been identified as the major predictor of mortality in patients with non-alcoholic fatty liver disease (NAFLD). Several biomarkers are currently being evaluated for their ability to substitute the liver biopsy as the reference standard. Recent clinical studies in NAFLD/NASH patients support the utility of PRO-C3, a marker of type III collagen formation, as a marker for the degree of fibrosis, disease activity, and effect of treatment. Here we establish the healthy reference range, optimal sample handling conditions for both short- and long-term serum storage, and robustness for the PRO-C3 assay. Methods: PRO-C3 was measured in 269 healthy volunteers and in 222 NAFLD patients. Robustness of the PRO-C3 assay was measured according to Clinical and Laboratory Standards Institute standards and included validation of interference, precision, and reagent stability, whilst sample stability was defined for storage at different temperatures and for 3 freeze-thaw cycles. Fibrosis scoring was based on histological assessments and used as a reference for the diagnostic ability of PRO-C3 to discriminate between patients with different levels of fibrosis. Results: Robustness of the PRO-C3 analysis validated by interference, precision, and reagent stability was found to be within the predefined acceptance criteria. The healthy reference range was determined to be 6.1–14.7 ng/ml. Levels of PRO-C3 were not affected by sex, age, BMI, or ethnicity. Levels of PRO-C3 were able to identify patients with clinically significant fibrosis and advanced fibrosis (AUC = 0.83 (95% CI [0.77–0.88], p <0.0001), and AUC = 0.79 (95% CI [0.73–0.85], p <0.0001), respectively). Conclusions: The assay proved to be robust and sample stability was found to comply with hospital sample handling requirements. PRO-C3 measured in samples from patients with NAFLD/NASH was diagnostic for significant and advanced liver fibrosis. Lay summary: We showed that PRO-C3 levels were stable under conditions conforming with hospital sample-handling requirements. We determined a healthy reference range and showed that PRO-C3 levels were not associated with sex, age, BMI, or ethnicity. Finally, we provide further evidence of an association of PRO-C3 with increasing liver fibrosis.
Originalsprog | Engelsk |
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Artikelnummer | 100317 |
Tidsskrift | JHEP Reports |
Vol/bind | 3 |
Udgave nummer | 4 |
Antal sider | 8 |
DOI | |
Status | Udgivet - 2021 |
Bibliografisk note
Funding Information:
JS has acted as consultant to Boehringer Ingelheim, BMS, Echosens, Genfit, Gilead Sciences, Intercept Pharmaceuticals, Madrigal, Novartis, Novo Nordisk, Nordic Bioscience, Pfizer, Roche, Sanofi, Siemens Healthcare GmbH, Zydus, has received research funding from Gilead Sciences, and has acted as speaker for Falk Foundation MSD Sharp & Dohme GmbH. All outside the submitted work. EE, DGKR, PF, DJL, and MAK, are employees of Nordic Bioscience, a company engaged in the development of biochemical markers. MAK and DJL are stockholders of Nordic Bioscience. LLG has acted as consultant for Novo Nordisk and received funding for research from Novo Nordisk, Gilead, Alexion, and Vingmed, all outside the submitted work. DS is an employee of Bristol Myers Squibb. GA has associations with Shire, Agios, and GlaxoSmithKline, and advises the Medicines and Healthcare products Regulatory Agency (MHRA), all outside the submitted work.
Funding Information:
The biomarker validation studies were funded by Bristol Myers-Squibb , Princeton, NJ, USA. The study was supported by the Danish Research Foundation .
Publisher Copyright:
© 2021 The Author(s)
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