ADAPT: an algorithm incorporating PRO-C3 accurately identifies patients with NAFLD and advanced fibrosis

Daniels, Samuel J.; Leeming, Diana J.; Eslam, Mohammed; Hashem, Ahmed M; Nielsen, Mette J.; Krag, Aleksander; Karsdal, Morten A.; Grove, Jane I.; Guha, Indra Neil; Kawaguchi, Takumi; Torimura, Takuji; McLeod, Duncan; Akiba, Jun; Kaye, Philip; de Boer, Bastiaan; Aithal, Guruprasad P.; Adams, Leon A.; George, Jacob

Abstract

Background and Aim: Given the high global prevalence of non-alcoholic fatty liver disease (NAFLD), the need for relevant non-invasive biomarkers and algorithms to accurately stage disease severity is a critical unmet medical need. Identifying those with advanced fibrosis (≥F3) is the most crucial, as these individuals have the greatest risk of adverse, long-term, liver-related outcomes. We aimed to investigate the role of PRO-C3 (a marker of type III collagen formation) as a biomarker for advanced fibrosis in NAFLD.
Methods: We measured PRO-C3 by enzyme-linked immunosorbent assay (ELISA) in two large independent cohorts with extensive clinical phenotyping and liver biopsy; 150 in the derivation and 281 in the validation cohort. A PRO-C3 based fibrosis algorithm that included Age, presence of DiAbetes, PRO-C3 (a marker of type III collagen formation), and plaTelet count (“ADAPT”) was developed. Results: PRO-C3 increased with fibrosis stage (rho 0.50 p<0.0001) and was independently associated with advanced fibrosis (OR=1.05, 95% CI 1.02-1.08, p= 0.003). ADAPT showed areas under the receiver operating characteristics curve (AUROC) of 0.86 (95% CI 0.79 to 0.91) in the derivation and 0.87 in the validation cohort (95% CI 0.83 to 0.91) for advanced fibrosis. This was superior to the existing fibrosis scores, aspartate aminotransferase (AST) to platelet ratio index (APRI), FIB-4 and NAFLD fibrosis score (NFS) in most comparisons.
Conclusion: PRO-C3 is an independent predictor of fibrosis stage in NAFLD. A PRO-C3 based score (ADAPT) accurately identifies patients with NAFLD and advanced fibrosis and is superior to APRI, FIB-4 and NFS.

Citation

Daniels, S. J., Leeming, D. J., Eslam, M., Hashem, A. M., Nielsen, M. J., Krag, A., Karsdal, M. A., Grove, J. I., Guha, I. N., Kawaguchi, T., Torimura, T., McLeod, D., Akiba, J., Kaye, P., de Boer, B., Aithal, G. P., Adams, L. A., & George, J. (2019). ADAPT: an algorithm incorporating PRO-C3 accurately identifies patients with NAFLD and advanced fibrosis. Hepatology, 69(3), 1075-1086. https://doi.org/10.1002/hep.30163

• Journal Article Type: Article
• Acceptance Date: Jul 4, 2018
• Online Publication Date: Jul 16, 2018
• Publication Date: 2019-03
• Deposit Date: Jul 17, 2018
• Publicly Available Date: Jul 17, 2019
• Journal: Hepatology
• Print ISSN: 0270-9139
• Electronic ISSN: 1527-3350
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 69
• Issue: 3
• Pages: 1075-1086
• DOI: https://doi.org/10.1002/hep.30163
• Keywords: Biomarker, Extracellular matrix, Non-invasive score, Non-alcoholic fatty liver disease, PRO-C3
• Public URL: https://nottingham-repository.worktribe.com/output/945158
• Publisher URL: https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.30163
• Additional Information: This is the peer reviewed version of the article, which has been published in final form at https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.30163. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
• Contract Date: Jul 17, 2018