ADAPT: An Algorithm Incorporating PRO‐C3 Accurately... : Hepatology (original) (raw)

Original Articles: STEATOHEPATITIS/METABOLIC LIVER DISEASE

ADAPT: An Algorithm Incorporating PRO‐C3 Accurately Identifies Patients With NAFLD and Advanced Fibrosis

Daniels, Samuel J.*,1,2; Leeming, Diana J.1; Eslam, Mohammed3; Hashem, Ahmed M.4; Nielsen, Mette J.1; Krag, Aleksander2,5; Karsdal, Morten A.1; Grove, Jane I.6,7,13; Neil Guha, Indra6,7,13; Kawaguchi, Takumi8; Torimura, Takuji8; McLeod, Duncan9; Akiba, Jun10; Kaye, Philip6,13; de Boer, Bastiaan11; Aithal, Guruprasad P.6,7,13,†; Adams, Leon A.12,†; George, Jacob3,†

1Nordic Bioscience Biomarkers and Research A/SHerlevDenmark

2Institute of Clinical ResearchUniversity of Southern DenmarkOdenseDenmark

3Storr Liver CentreWestmead Institute for Medical Research, University of Sydney and Westmead HospitalWestmeadAustralia

4Department of Systems and Biomedical Engineering, Faculty of EngineeringMinia UniversityMiniaEgypt

5Department of Gastroenterology and HepatologyOdense University HospitalOdenseDenmark

6Nottingham Digestive Diseases CentreUniversity of NottinghamNottinghamUnited Kingdom

7NIHR Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and the University of NottinghamNottinghamUnited Kingdom

8Department of MedicineKurume University School of MedicineKurumeJapan

9Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research (ICPMR)Westmead HospitalSydneyAustralia

10Department of Diagnostic PathologyKurume University HospitalKurumeJapan

11Department of Anatomical Pathology, PathWestFiona Stanley HospitalMurdochAustralia

12Medical SchoolUniversity of Western AustraliaNedlandsAustralia

13Medical Research Council (MRC) Nottingham Molecular Pathology NodeUniversity of NottinghamNottinghamUnited Kingdom

*Address Correspondence and Reprint Requests to:
Samuel J. Daniels, B.Sc.(Hons), M.Sc.
Nordic Bioscience
Herlev Hovedgade 205‐207
2730 Herlev, Denmark
E‐mail: [email protected], Tel: +45‐4452‐5252, Fax: +45‐4452‐5251

†These authors share joint last authorship.

Abstract

Given the high global prevalence of nonalcoholic fatty liver disease (NAFLD), the need for relevant noninvasive 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. We measured PRO‐C3 by enzyme‐linked immunosorbent assay 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, and platelet count (ADAPT) was developed. PRO‐C3 increased with fibrosis stage (Rho 0.50; P < 0.0001) and was independently associated with advanced fibrosis (odds ratio = 1.05; 95% confidence interval [CI] 1.02‐1.08; P = 0.003). ADAPT showed areas under the receiver operating characteristics curve of 0.86 (95% CI 0.79‐0.91) in the derivation and 0.87 in the validation cohort (95% CI 0.83‐0.91) for advanced fibrosis. This was superior to the existing fibrosis scores, aspartate aminotransferase 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.