Background & aims: Non-alcoholic fatty liver disease (NAFLD) is a common liver disorder with non-alcoholic steatohepatitis (NASH) being a more progressive phenotype associated with progression to cirrhosis. Type III collagen is a main component of the fibrotic extracellular matrix. PRO-C3 is a biomarker for detectison of moderate/severe fibrosis and the test is further improved when incorporated into the ADAPT algorithm. Here, we validated PRO-C3 and ADAPT within the CENTAUR screening population.

Methods: PRO-C3 was assessed in plasma from the screening population of the phase IIb CENTAUR study (NCT02217475) in adults with NASH and liver fibrosis. The relation between PRO-C3 and histologic features of NASH was evaluated, as well as the demographics of patients with high and low levels of PRO-C3. The diagnostic ability of PRO-C3 as a stand-alone marker or incorporated into ADAPT to identify patients with F≥2 and NASH was estimated using ROC analysis and logistic regression models.

Results: 517 subjects with matched biopsy and PRO-C3 test were included. Patients with PRO-C3 levels ≥20.2 ng/mL showed increased levels of insulin, HOMA-IR, ALT, AST, alkaline phosphatase, and platelet count compared to patients with low PRO-C3 (p<0.05). PRO-C3 increased stepwise with increasing liver fibrosis, lobular inflammation, hepatocyte ballooning, steatosis, and NAS (p<0.05), and could separate NAFL from NASH (p<0.0001). PRO-C3 was independently associated with fibrosis and NASH when adjusted for clinical confounders. ADAPT outperformed FIB4, APRI, and AST/ALT ratio as predictor of advanced fibrosis and NASH (p<0.001).

Conclusion: PRO-C3 was associated with NAS and fibrosis. ADAPT outperformed other non-invasive scores for detecting NASH. These data support the use of PRO-C3 and ADAPT as diagnostic tools to identify patients with NASH eligible for inclusion in clinical trials.

Lay summary: The PRO-C3 is a serological biomarker associated with liver disease activity and fibrosis, and the test is improved when incorporated into the ADAPT score. Here we showed that ADAPT was better at selecting patients with NASH to be included in clinical trials as compared to other non-invasive scores.

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