Progress made toward understanding best noninvasive tests for NASH, fibrosis diagnosis
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To streamline and validate diagnosis of and clinical trials in nonalcoholic steatohepatitis, one group is on a mission to determine the best noninvasive tests for all physicians to use, according to a presentation.
“As you know, there are many noninvasive tests that are in development, but there are very few that are actually approved for any context of use,” Arun J. Sanyal, MBBS, MD, professor in the department of internal medicine in the division of gastroenterology, hepatology and nutrition at Virginia Commonwealth University School of Medicine, said during The Liver Meeting Digital Experience. “In this cross-sectional analysis of multiple biomarker panels in the same blood sample from a highly phenotyped NAFLD population, multiple biomarkers met a priori criteria for preliminary success. ... There was differential performance across biomarkers for both NASH and for fibrosis making it likely that future combinatorial approaches could be used to enhance diagnostic position.”
NIMBLE collaboration
In the NIMBLE collaboration with the NASH Clinical Research Network (CRN), researchers looked at 1,073 preselected patients with NAFLD (n = 220) or NASH (n = 853) distributed across fibrosis stages: F0 (n = 222; mean age, 47.8 years; 44.6% men; 71.2% white), F1 (n = 114; mean age, 48.1 years; 45.6% men; 59.6% white), F2 (n = 262; mean age, 51.7 years; 38.9% men; 76.2% white), F3 (n = 277; mean age, 54.4 years; 32.9% men; 78.9% white) and F4 (n = 198; mean age, 56.2 years; 30.3% men; 86.2% white). They analyzed results from the following tests performed within 90 days of a liver biopsy: NIS4 (Genfit), the Enhanced Liver Fibrosis score (ELF, Siemens Healthineers), FibroMeter VCTE (FM-VCTE, Echosens), PRO-C3 (Nordic Biosciences) and the One-Way Lipidomics (OWL, OWLiver). Each technique was compared to FIB4 and ALT.
“We have to really parse it down very finely to think about whether we are going to use it for diagnosis, to establish prognosis, for monitoring disease, for predicting treatment response. Each one is sort of considered a different context of use and each one has to be evaluated independently,” Sanyal said. “We felt our immediate focus was to try to identify the population that is at risk for having more liver outcomes.”
The NIS4 test met criteria for diagnosis of NASH and NAFLD Activity Score (NAS) of 4 or greater, while NIS4, ELF and FM-VCTE all met criteria for diagnosis of F2 or higher. ELF and FM-VCTE improved for F3 and F4.
In looking for NASH diagnosis, the group showed NIS4 had an area under the curve (AUROC) of 0.832 vs. ALT’s 0.678, positioning it to be accurate (P < .001). Similarly, NIS4 outperformed ALT for the NAFLD activity score with an AUROC of 0.815 vs. ALT’s 0.726 (P < .001).
The OWL liver panel provides results specifically as a yes or no, so Sanyal explained there is no AUROC for this test, but it did provide 63.3 for sensitivity and 75.4 for specificity.
Sanyal showed that the ELF test performed at 0.828 AUROC (P < .001) and “progressively improved” to 0.855 (P < .001) at cirrhosis level, making it superior to both the baseline and FIB4 as its comparator.
PRO-C3 showed to be superior to the unit line but not to FIB4 and “with increasing fibrosis, the performance declined,” Sanyal said.
The FibroMeter VTCE was performed in 393 patients, showing an AUROC from 0.841 to 0.897 as fibrosis progressed, making it superior to the unit line and to FIB4 (all P < .001). Sanyal noted this subset of patients was the only one to have a FibroScan (Echosens) performed within the pre-set time period.
“Lastly, I want to point out that FIB4 also had fairly robust diagnostic characteristics for these fibrosis-related endpoints,” Sanyal said in his presentation.
Next steps
This initial stage of the NIMBLE study laid the groundwork, Sanyal said, by clarifying sensitivity and specificity for this group of who would most benefit from knowing the status of their disease.
“The basis for looking at all of these were really based on panels whose laboratory analytic robustness is already established and meets regulatory standards, so we think when you take the totality of all of this data, we now have made substantial progress toward meeting the evidence burden for biomarker qualification for enrichment of the diagnostic context of use for people who have NASH with significant fibrosis which is stage 2 or higher,” Sanyal said. “We are very excited about these results.”
In stage 2 of NIMBLE, Sanyal said these biomarkers will be integrated with imaging workstreams to address disease monitoring types of use and build to truly predictive models.
“It is time to include the liver as a critical end organ that is associated with type 2 diabetes. Diabetologists are often focused on kidney disease, heart disease, eye disease, etc, but many of these patients, especially those who progress to bridging fibrosis and cirrhosis, will die of their liver disease,” he said. “Since most of those patients have type 2 diabetes, it behooves us now to increase awareness within the diabetes population but coupled with giving them tools to identify this in their routine practice.”
“NIMBLE is an advanced qualification plan. We want something approved that every doctor can use in the next 2 years,” Sanyal said.
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Sanyal AJ. Primary results of the NIMBLE stage 1-NASH CRN study of circulating biomarkers for nonalcoholic steatohepatitis and its activity and fibrosis stage. Presented at: The Liver Meeting Digital Experience; Nov. 12-15, 2021 (virtual meeting).
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