Comparison of ADAPT, FIB-4 and APRI as non-invasive predictors of liver fibrosis and NASH within the CENTAUR screening population

Abstract

Background & Aims: The development of accurate non-invasive tests to detect and measure the extent of fibrosis and disease activity in patients with non-alcoholic steatohepatitis (NASH)the progressive phenotype of non-alcoholic fatty liver disease (NAFLD) is of great clinical importance. Herein, we aimed to validate the performance of PRO-C3 and ADAPT for the detection of moderate/ severe fibrosis 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 standalone marker or incorporated into ADAPT, to identify patients with F> − 2 and NASH was estimated using receiver-operating characteristic analysis and logistic regression models. Results: A total of 517 individuals with matched biopsy and PRO-C3 measurements were included. Patients with PRO-C3 levels > − 20.2 ng/ml showed increased levels of insulin, HOMA-IR, alanine aminotransferase (ALT), aspartate aminotransferase (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 NAFLD activity score (p <0.05), and could distinguish between NAFL and NASH (p <0.0001). PRO-C3 was independently associated with fibrosis and NASH when adjusted for clinical confounders. ADAPT outperformed Fibrosis-4, AST-to-platelet ratio index, and AST/ALT ratio as a predictor of advanced fibrosis and NASH (p <0.001). Conclusion: PRO-C3 was associated with NAFLD activity score 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. Clinical trial number: NCT02217475 Lay summary: PRO-C3 is a serological biomarker associated with liver disease activity and fibrosis. Its performance for the detection of disease activity and fibrosis is improved when it is incorporated into the ADAPT score. Herein, we showed that ADAPT was better at selecting patients with non-alcoholic steatohepatitis for inclusion in clinical trials than other noninvasive scores.

Systematic Review with Meta-Analysis: Diagnostic Accuracy of Pro-C3 for Hepatic Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease

“…The study flow diagram is shown in Figure 1 . Seven of the included studies were full text reports [ 28 , 29 , 30 , 41 , 43 , 44 , 45 ] and one was an abstract [ 42 ].…”

“…Seven out of the eight studies were designed as diagnostic accuracy studies, while one was an exercise intervention trial that reported Pro-C3 values and liver biopsies at baseline [ 44 ]. Included patients were mostly from Western countries (United States and Europe); two studies also included participants from Asia and Australia [ 29 , 30 ].…”

“…One study reported accuracy data for NASH, and reported a sensitivity of 55% and sensitivity of 82% at a threshold of 14.7 ng/mL [ 30 ]. Two studies reported accuracy data of Pro-C3 in detecting fibrotic NASH, defined as NAS ≥ 4 plus F ≥ 2, and estimated sensitivity at 66% and 68%, and specificity at 68% and 73%, for thresholds of 14.5 and 12.6, respectively [ 28 , 45 ].…”

“…This may be attributed to the paradigm that fibrosis progression results from repetitive periods of inflammation, as in NASH, alternated with periods of ‘repair’ of the extracellular matrix (ECM) [ 51 ]. The three studies that evaluated Pro-C3 accuracy for NASH used different criteria to establish NASH and, therefore, cannot be accurately compared [ 28 , 30 , 45 ]. All three studies used a NAFLD activity score (NAS) of ≥4 with at least 1 point each for steatosis, hepatocyte ballooning and hepatic inflammation to define NASH.…”

“…This marker has been studied in patients with fibrosis related to chronic hepatitis C [ 25 ], after liver transplantation, tumor fibrosis in pancreatic ductal adenocarcinoma [ 26 ] and lung fibrosis in patients with systemic sclerosis [ 27 ]. Several studies have assessed the performance of Pro-C3 in NAFLD, mostly as a single marker and sometimes as part of a diagnostic biomarker panel [ 28 , 29 , 30 , 31 ]. To date, it is unknown for which target condition within the NAFLD spectrum; in which context of use (i.e., in primary, secondary or tertiary care); and at what diagnostic threshold, that Pro-C3 has optimal performance.…”