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Comparison of ADAPT, FIB4 and APRI as non-invasive predictors of liver fibrosis and NASH within the CENTAUR Screening Population
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August 26, 2021 - Journal of Hepatology - Mette Juul Nielsen, Diana Julie Leeming, Zachary Goodman, Scott Friedman, Peder Frederiksen, Daniel Kring Rasmussen, Pamela Vig, Star Seyedkazemi, Laurent Fischer, Richard Torstenson, Morten Asser Karsdal, Eric Lefebvre, Arun J. Sanyal, Vlad Ratziu
In conclusion we have shown that PRO-C3, a direct NIT of liver fibrosis, is associated with the activity of NASH, and that ADAPT outperformed other indirect non-invasive tests for detecting features of NASH. These data support the use of PRO-C3 and ADAPT as diagnostic tools to identify patients with significant or advanced liver fibrosis associated with NASH who are eligible for inclusion in clinical trials, despite the relatively lower diagnostic accuracy compared to previous reported data.
• It is recommended to screen high-risk populations for NASH; however, accurate non-invasive tests (NITs) are lacking.
• PRO-C3, a direct non-invasive test of liver fibrosis, is associated with the activity of NASH.
• ADAPT, a PRO-C3 based score, outperformed other indirect NITs for detecting features of NASH.
• PRO-C3 and ADAPT are useful tools to identify patients with NASH liver fibrosis eligible for clinical trial inclusion.
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.
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.
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).
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.
The global prevalence of non-alcoholic fatty liver disease (NAFLD) is estimated to be 25% of the population (1). The more severe subtype, non-alcoholic steatohepatitis (NASH), is the progressive form and considered among the top etiologies for hepatocellular carcinoma (HCC) and liver transplantation in the United States. Lack of approved treatment modalities and the growing epidemic of obesity worldwide increase the prevalence of NAFLD, estimated to create a serious health crisis in the next few decades (2). It has recently been recommended by the European Association for the Study of Liver (EASL) to screen high-risk populations for NASH, however, the lack of accurate non-invasive tests (NITs) is hindering effective evaluation of people at risk (3).
Recently, a new definition of fatty liver has been proposed, namely metabolic associated fatty liver disease (MAFLD), as a more appropriate term to describe the liver disease. The diagnosis of MAFLD is based on evidence of hepatic steatosis in addition to one of the following: overweight/obesity, presence of type 2 diabetes, or evidence of metabolic dysfunction regardless of alcohol intake (4).
In the case of chronic liver disease, increased turnover of extracellular matrix (ECM) and an unbalanced formation/degradation process leads to increased liver fibrosis and elevated liver stiffness (5). Collagens are the key players in fibrogenesis and may provide distinct information regarding the nature of fibrosis depending on their localization and function in the ECM (6). Both physiological and pathophysiological relevant proteases are responsible for the generation of ECM protein fragments, so called neo-epitopes, which are found systemically and may be utilized as a biomarker for disease activity when measured in a blood sample (7).
PRO-C3 is a serological biomarker detecting formation of type III collagen, a major scar related collagen that becomes deposited during fibrogenesis by activated myofibroblasts (8). The assay measures the type III collagen formation epitope generated by ADAM-TS2 during release of the N-terminal pro-peptide, in contrast to the classical PIIINP (procollagen III amino terminal propeptide) that measures an internal fragment of PIIINP related to both formation and degradation of type III collagen. PRO-C3 has previously been published as a promising biomarker associated with the degree and change of liver fibrosis (9,10), predict progression of liver fibrosis and outcome (11,12), as well as a pharmacodynamic biomarker in metabolic and biliary liver diseases (13,14). Moreover, PRO-C3 has been incorporated into the composite non-invasive algorithm, ADAPT, which in addition to PRO-C3 includes presence of type 2 diabetes, platelet count, and age (15). ADAPT was able to accurately identify NASH patients with advanced fibrosis superior to other non-invasive algorithms such as FIB4, APRI, and NAFLD fibrosis score (15).
In this study we aimed to investigate the ability of PRO-C3 as a standalone marker and in combination with ADAPT in comparison to standard biomarkers, for the diagnosis of liver fibrosis and correlation to key histological parameters of NAFLD patients within the CENTAUR screening population.

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