Noninvasive Tests Accurately Identify Advanced Fibrosis due to NASH: Baseline Data From the STELLAR Trials

Abstract

Accurate noninvasive tests (NITs) are needed to replace liver biopsy for identifying advanced fibrosis caused by nonalcoholic steatohepatitis (NASH). We analyzed screening data from two phase 3 trials of selonsertib to assess the ability of NITs to discriminate advanced fibrosis. Centrally read biopsies from the STELLAR studies, which enrolled patients with bridging fibrosis and compensated cirrhosis, were staged according to the NASH Clinical Research Network classification. We explored associations between fibrosis stage and NITs, including the nonalcoholic fatty liver disease fibrosis score (NFS), fibrosis-4 (FIB-4) index, Enhanced Liver Fibrosis (ELF) test, and liver stiffness by vibration-controlled transient elastography (LS by VCTE). The performance of these tests to discriminate advanced fibrosis, either alone or in combinations, was evaluated using areas under the receiver operating characteristic curve (AUROCs) with 5-fold cross-validation repeated 100 times. Of the 4,404 patients screened for these trials, 3,202 had evaluable biopsy data: 940 with F0-F2 fibrosis and 2,262 with F3-F4 fibrosis. Significant differences between median values of NITs for patients with F0-F2 versus F3-F4 fibrosis were observed: −0.972 versus 0.318 for NFS, 1.18 versus 2.20 for FIB-4, 9.22 versus 10.39 for ELF, and 8.8 versus 16.5 kPa for LS by VCTE (all P < 0.001). AUROCs ranged from 0.75 to 0.80 to discriminate advanced fibrosis. FIB-4 followed by an LS by VCTE or ELF test in those with indeterminate values (FIB-4 between 1.3 and 2.67) maintained an acceptable performance while reducing the rate of indeterminate results. Conclusion: Among patients being considered for enrollment into clinical trials, NITs alone or in combination can reduce the need for liver biopsy to discriminate advanced fibrosis caused by NASH. The predictive value of these tests for general screening will require confirmation in a real-world population. (Hepatology 2019;70:1521-1530).Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUROC, area under the receiver operating characteristic curve; BMI, body mass index; CI, confidence interval; CRN, Clinical Research Network; ELF, Enhanced Liver Fibrosis;; IQR, interquartile range; LS, liver stiffness; NAFLD, nonalcoholic fatty liver disease; NFS, nonalcoholic fatty liver disease fibrosis score; NIT, noninvasive test; NPV, negative predictive value; PPV, positive predictive value; TE, transient elastography; VCTE, vibration-controlled transient elastography.

A diabetologist’s perspective of non‐alcoholic steatohepatitis (NASH): Knowledge gaps and future directions

“…For instance, in a recent study by Siddiqi et al in 1,904 patients enrolled in the NIDDK NASH Clinical Research Network recruited from 2004 through 2018, FIB‐4 and the NAFLD fibrosis score (NFS) outperformed other non‐invasive models for detecting advanced fibrosis, although their area under the curve (AUC) was only 0.80 for FIB‐4 and 0.78 for NFS. Similar results were reported by Anstee et al, using baseline data from the STELLAR Trials in 3,202 patients with evaluable biopsies. The performance of individual NITs with single thresholds derived from the literature to discriminate advanced fibrosis (F3‐F4) from less severe disease (F0‐F2) had an AUC of 0.74 for NFS, 0.78 for FIB‐4, and 0.80 for both Enhanced Liver Fibrosis (ELF) and for imaging by vibration controlled elastography (VCTE; FibroScan).…”

Ethnic influence on nonalcoholic fatty liver disease prevalence and lack of disease awareness in the United States, 2011–2016

“…Furthermore, potentially there is a large number of people in this study who may actually have NASH. However, since liver biopsy is truly the gold standard for diagnosing NASH and fibrosis, which is an impractical and costly diagnostic method to use on population level, further study is needed to understand the natural history of NAFLD within the different ethnicities especially as better non‐invasive tests for NAFLD become available .…”

Limitations of non-invasive tests for assessment of liver fibrosis

“…Although this was a high F3-F4 prevalence cohort by selection, there was no single threshold for their serum and imaging NITs that could balance optimal sensitivity and specificity. 126 VCTE thresholds for advanced fibrosis will need to be validated in other NAFLD clinical trials performed in diabetic and multi-ethnic cohorts. Similar studies are also required to determine the diagnostic utility of SWE in advanced NAFLD.…”