Letter: Beyond advanced fibrosis—The critical need for assessing NITs performance in identifying F2–F3 fibrosis

I read with interest the study conducted by McPherson et al,¹ which aimed to evaluate the concordance between non-invasive fibrosis tests (NITs)-based clinician fibrosis assessment and histology in patients with metabolic dysfunction-associated steatotic liver disease. While the manuscript title suggests that the authors assessed the reliability of experienced hepatologists in staging liver fibrosis using combinations of NITs, the study goal was actually to differentiate advanced fibrosis (stages F3–F4) from F0 to F2. This focus is understandable, given the increased risk of adverse hepatic and extrahepatic outcomes associated with F3–F4.^{2, 3} However, the study could have been further strengthened by incorporating a separate analysis of the accuracy of hepatologists in identifying patients with F2–F3 fibrosis. The results of such an investigation would have been particularly relevant for trials of investigational drugs. Accordingly, at-risk metabolic dysfunction-associated steatohepatitis (MASH), defined as a non-alcoholic fatty liver disease activity score of four or more with at least one point in each of its components, combined with F2–F3 fibrosis, currently represents the target study population in most phase IIb/III clinical trials.^{4, 5} Unfortunately, accurately diagnosing at-risk MASH remains a significant challenge in both research settings and clinical practice.⁵ The accuracy of NITs tends to decrease when distinguishing between adjacent fibrosis stages, particularly in the intermediate range.⁶ Therefore, a specific analysis of F2–F3 fibrosis in the study by McPherson et al¹ would have been highly valuable.

Another observation is that while integrating physical examination findings, biochemical markers, radiographic imaging and endoscopic results can improve the accuracy of NITs in detecting F3–F4 fibrosis,⁷ the same level of improvement may not be observed for earlier fibrosis stages (F2–F3). Shedding light on this additional issue in the study by McPherson et al¹ would have provided critical information, considering that in most clinical trials, over half of the patients in the screening population are excluded, with incompatible histological features being the most common reason for screening failure.⁵ Within a clinical trial framework, a comprehensive examination of NIT combinations across all fibrosis stages is expected to yield substantial benefits in the future. Beyond the methodology employed by McPherson et al,¹ which is limited to distinguishing stages F3–F4 from F0 to F2, the incorporation of a more granular examination of F2–F3 fibrosis has the potential to facilitate the exclusion of individuals with non-at-risk MASH or cirrhosis, thereby enriching clinical trial populations. Such an approach would have relevant implications for reducing the overall costs associated with the screening process by decreasing screen failure rates.

Yusuf Yilmaz: Conceptualization; writing – original draft; writing – review and editing; supervision; investigation; methodology.

No financial support was received for the present study.

The author declare no conflict of interest.

This article is linked to McPherson et al papers. To view these articles, visit https://doi.org/10.1111/apt.18061 and https://doi.org/10.1111/apt.18209.