Yasaman Yali, MD,

Credit: University of Amsterdam

Investigators have found no single biomarkers or multimarkers are able to be used to detect nonalcoholic steatohepatitis (NASH) or clinically significant fibrosis.¹

A team, led by Yasaman Yali, MD, Epidemiology and Data Science, Amsterdam Public Health, University of Amsterdam, evaluated the diagnostic accuracy of 17 biomarkers and multimarker scores for detecting NASH and clinically significant fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). The team also identified the optimal cutoffs as screening tests in clinical trial recruitment.

Current Practices

The current reference standard used to detect NASH and staging fibrosis is a liver biopsy. However, this is considered invasive and resource intensive.

While non-invasive biomarkers are needed, there have been few studies comparing the biomarkers in a single cohort.

In the Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) project, the investigators examined adult patients with biopsy-confirmed NAFLD from 13 European countries between January 6, 2010 and December 29, 2017.

Each participant had paired liver biopsy and serum samples.

The investigators excluded patients with excessive alcohol consumption, as well as those with evidence of other chronic liver diseases.

The team looked at various target conditions, such as the presence of NASH with clinically significant fibrosis or the presence of advanced fibrosis. They also identified thresholds for each biomarker for reducing the number of biopsy-based screen failure when they recruited patients with both NASH and clinically significant fibrosis for future trials.

Biomarkers

The 1430 patients with NAFLD in the LITMUS metacohort with serum samples were narrowed down to 966 participants, 35% (n = 335) of which had biopsy-confirmed NASH and clinically significant fibrosis. Of this group, 28% (n = 271) had advanced fibrosis.

The results show no single biomarker or multimarker score significantly reached the predefined area under the curve (AUC) of 0.80 acceptability thresholds for patients with NASH and clinically significant fibrosis (AUCs ranging from 0.61; 95% confidence interval [CI], 0.54–0.67] for FibroScan controlled attenuation parameter to 0.81; 95% CI, 0.75–0.86 for SomaSignal), with accuracy mostly similar to FIB-4.

SomaSignal (AUC, 0.90; 95% CI, 0.86–0.94), ADAPT (AUC, 0.85; 95% CI, 0.81–0.89), and FibroScan liver stiffness measurement (AUC, 0.83; 95% CI, 0.80–0.86) reached acceptable accuracy for detecting advanced fibrosis.

Histological screen failure rates could be reduced to 33% in trials with 11 of 17 markers in patients who were marker positive with a biopsy evaluating eligibility.

For NASH and clinically significant fibrosis, the best screening performance was found in SomaSignal (number needed to test [NNT] to find one true positive was 4; 95% CI, 4–5), then ADAPT (NNT = 6; 95% CI, 5–7), MACK-3 (NNT = 7; 95% CI, 6–8), and PRO-C3 (NNT = 9; 95% CI, 7–11).

“None of the single markers or multimarker scores achieved the predefined acceptable AUC for replacing biopsy in detecting people with both NASH and clinically significant fibrosis,” the authors wrote. “However, several biomarkers could be applied in a prescreening strategy in clinical trial recruitment. The performance of promising markers will be further evaluated in the ongoing prospective LITMUS study cohort.”