Study data published in the Lancet Gastroenterology & Hepatology support the efficacy of a novel blood-based biomarker panel for the diagnosis of non-alcoholic steatohepatitis (NASH) and liver fibrosis. The panel — called NIS4 — may present a means to avoid unnecessary liver biopsies in patients at low risk for disease.

This prospective derivation and global validation study enrolled patients with suspected non-alcoholic fatty liver disease (NAFLD) from 3 existing clinical trials: GOLDEN-505, RESOLVE-IT (ClinicalTrials.gov identifier: NCT02704403), and Angers. The discovery cohort (GOLDEN-505) included 239 patients with biopsy-confirmed NASH from 56 hepatology or gastroenterology centers in the United States and Europe. Patient blood samples were collected and assessed for the presence of various NASH-associated biomarkers. The primary outcome was the diagnosis of at-risk NASH, defined by a NAFLD score (NAS) ≥4 and liver fibrosis stage ≥2.

A total of 23 covariates associated with at-risk NASH diagnosis was used to train a logistic bootstrap-based stepwise algorithm that minimized the Akaike information criterion. All 1000 repetitions were assessed; the biomarkers with the strongest associations with at-risk NASH across the greatest proportion of repetitions were selected for panel inclusion. The diagnostic performance of the trained algorithm was then assessed in 2 independent cohorts (RESOLVE-IT and Angers) using area under the receiver operating curve (AUROC) analyses. Accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were reported.  

The NIS4 algorithm included 4 independent NASH-associated biomarkers: miR-34a-5p,


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alpha-2 macroglobulin, YKL-40, and glycated hemoglobin, which together had an AUROC of 0.80 (95% CI, 0.73-0.85) for diagnosis of at-risk NASH in the discovery cohort. The NIS4 results were not influenced by patients’ age, sex, body mass index, or aminotransferase concentrations.

The NIS4 panel was validated in both the RESOLVE-IT (n=475) and Angers (n=227) cohorts, with AUROC values of 0.83 (95% CI, 0.79-0.86) and 0.76 (0.69-0.82), respectively. In the pooled validation cohort (n=702), patients with a NIS4 value <0.36 were classified as not having at-risk NASH, with a sensitivity of 81.5% (95% CI, 76.9%-85.3%), a specificity of 63% (95% CI, 57.8%-68%), and a negative predictive value of 77.9% (72.5%-82.4%). An NIS4 value >0.63 identified at-risk NASH with a sensitivity of 87.1% (95% CI, 83.1-90.3%), specificity of 50.7% (45.3-56.1%), and a positive predictive value of 79.2% (73.1%-84.2%). The NIS4 panel’s diagnostic capabilities were consistent across patient subgroups defined by age, sex, body mass index, and aminotransferase concentrations.

The primary limitation of this research was the lack of patients with cirrhosis in the discovery cohort, and only a few of these patients were included in the pooled validation cohort.

According to study authors, the ability of NIS4 to properly identify patients with cirrhosis requires further analysis. Even so, “[t]his non-invasive test is expected to increase the rate of diagnosis of patients with potentially deleterious outcomes, and thereby benefit those in need of specific management, including regular monitoring and pharmacotherapy,” investigators concluded.

Disclosure: This clinical trial was supported by Genfit. Please see the original reference for a full list of authors’ disclosures.

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Reference

Harrison SA, Ratziu V, Boursier J, et al. A blood-based biomarker panel (NIS4) for non-invasive diagnosis of non-alcoholic steatohepatitis and liver fibrosis: a prospective derivation and global validation study [published online August 4, 2020]. Lancet Gastroenterol Hepatol. doi: 10.1016/S2468-1253(20)30252-1