PRO-C3, a Serological Marker of Fibrosis, During Childhood and Correlations With Fibrosis in Pediatric NAFLD

• Type of Material: Article
• Authors: Catherine C Cohen, Emory University; Eduardo Castillo-Leon, Emory University; Alton Farris III, Emory University; Shelley Caltharp, Emory University; Rebecca L. Cleeton, Emory University; Elizabeth M. Sinclair, Emory University; Diane E. Shevell, Bristol Myers Squibb; Morten A. Karsdal, Nordic Bioscience, Fibrosis Biology and Biomarkers; Mette Juul Fisker Nielsen, Nordic Bioscience, Fibrosis Biology and Biomarkers; Diana J. Leeming, Nordic Bioscience, Fibrosis Biology and Biomarkers; Miriam Vos, Emory University
• Language: English
• Date: 2021-07-08
• Publisher: JOHN WILEY & SONS LTD
• Publication Version: Final Published Version
• Copyright Statement: © 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/hep4.1766
• Title of Journal or Parent Work: HEPATOLOGY COMMUNICATIONS
• Volume: 5
• Issue: 11
• Start Page: 1860
• End Page: 1872
• Grant/Funding Information: Supported by the National Institute of Diabetes and Digestive and Kidney Diseases (T32DK108735, T32DK007658).
• Keywords: CHILDREN; LIVER-DISEASE; PROPEPTIDE; BIOPSY; Life Sciences & Biomedicine; SCORES; NONALCOHOLIC STEATOHEPATITIS; Gastroenterology & Hepatology; Science & Technology; STAGE; MORTALITY
• Research Categories: Biology, Cell; Health Sciences, Medicine and Surgery

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease in children and may lead to cirrhosis requiring liver transplant. Thus, prompt diagnosis of advanced fibrosis is essential. Our objectives were to examine PRO-C3 (a neo-epitope pro-peptide of type III collagen formation) levels across childhood/adolescence and associations with advanced fibrosis in pediatric NAFLD. This cross-sectional study included 88 children and adolescents with biopsy-proven NAFLD (mean age: 13.9 ± 2.9 years, 71% male) and 65 healthy participants (11.8 ± 4.5 years, 38% male). PRO-C3, and the bone remodeling biomarkers C-terminal telopeptide of type I collagen (CTX-I; bone resorption) and osteocalcin (N-MID; bone formation), were measured in serum by enzyme-linked immunosorbent assay. Fibrosis was assessed by liver biopsy in participants with NAFLD, who were categorized as having advanced (Ishak score ≥ 3) or none/mild fibrosis (Ishak score ≤ 2). Overall, PRO-C3 was similar in participants with NAFLD (median [interquartile range]: 20.6 [15.8, 25.9] ng/mL) versus healthy participants (19.0 [13.8, 26.0] ng/mL), but was significantly lower in older adolescents ≥ 15 years old (16.4 [13.0, 21.2] ng/mL) compared with children ≤ 10 years old (22.9 [18.1, 28.4] ng/mL; P < 0.001) or 11-14 years old (22.4 [18.3, 31.2] ng/mL; P < 0.001). PRO-C3 was also directly correlated with levels of CTX-I and N-MID (r = 0.64 and r = 0.62, respectively; both P < 0.001). Among participants with NAFLD, PRO-C3 was higher in those with advanced fibrosis (median [IQR]: 28.5 [21.6, 37.6]) compared with none/mild fibrosis (20.3 [18.2, 22.8]; P = 0.020) in models adjusted for age, sex, and body mass index z-score. However, associations were attenuated after additionally adjusting for bone-remodeling CTX-I (P = 0.09) or N-MID (P = 0.08). Conclusion: Collectively, these findings show that PRO-C3 levels are higher in children with advanced fibrosis in NAFLD, but are also influenced by age and pubertal growth spurt, assessed by bone remodeling biomarkers, and therefore may not be a reliable biomarker for liver fibrosis in pediatric NAFLD until late adolescence.