New sequential combinations of noninvasive fibrosis tests provide an accurate diagnosis of advanced fibrosis in NAFLD

Background & Aims Advanced liver fibrosis is an important diagnostic target in non-alcoholic fatty liver disease (NAFLD) as it defines the subgroup of patients with impaired prognosis. The non-invasive diagnosis of advanced fibrosis is currently limited by the suboptimal positive predictive value and the grey zone (representing indeterminate diagnosis) of fibrosis tests. Here, we aimed to determine the best combination of non-invasive tests for the diagnosis of advanced fibrosis in NAFLD. Methods A total of 938 patients with biopsy-proven NAFLD were randomized 2:1 into derivation and validation sets. All patients underwent liver stiffness measurement with vibration controlled transient elastography (VCTE) and blood fibrosis tests (NAFLD fibrosis score, Fibrosis-4 [FIB4], Fibrotest, Hepascore, FibroMeter). FibroMeter VCTE , which combines VCTE results and FibroMeter markers in a single test, was also calculated in all patients. Results For the diagnosis of advanced fibrosis, VCTE was significantly more accurate than the blood tests (area under the receiver operating characteristic curve [AUROC]: 0.840 ± 0.013, p  ≤0.005). FibroMeter was the most accurate blood test (AUROC: 0.793 ± 0.015, p  ≤0.017). The combinatory test FibroMeter VCTE outperformed VCTE and blood tests (AUROC: 0.866 ± 0.012, p  ≤0.005). The sequential combination of FIB4 then FibroMeter VCTE (FIB4-FM VCTE algorithm) or VCTE then FibroMeter VCTE (VCTE-FM VCTE algorithm) provided an excellent diagnostic accuracy of 90% for advanced fibrosis, with liver biopsy only required to confirm the diagnosis in 20% of cases. The FIB4-FM VCTE and VCTE-FM VCTE algorithms were significantly more accurate than the pragmatic algorithms currently proposed. Conclusion The sequential combination of fibrosis tests in the FIB4-FM VCTE and VCTE-FM VCTE algorithms provides a highly accurate solution for the diagnosis of advanced fibrosis in NAFLD. These algorithms should now be validated for the diagnosis of advanced liver fibrosis in diabetology or primary care settings. Lay summary The evaluation of liver fibrosis is mandatory in non-alcoholic fatty liver disease (NAFLD), as advanced fibrosis identifies the subgroup of patients with impaired prognosis. FibroMeter VCTE is a new fibrosis test combining blood markers and the result of vibration controlled transient elastography (VCTE) into a single diagnostic test. Our results show that FibroMeter VCTE outperforms other blood fibrosis tests and VCTE alone for the diagnosis of advanced fibrosis in a large multi-centric cohort of 938 patients with biopsy-proven NAFLD. Sequential algorithms using a simple blood test or VCTE as a first-line procedure, then FibroMeter VCTE as a second-line test accurately classified 90% of patients.