Clinical Spotlight is a HistoIndex newsletter series that explores topics in MASH, clinical diagnostics, and chronic liver disease management. Each edition provides commentary based on evidence from relevant publications and the latest research developments.
The emergence of FDA-approved treatments for metabolic dysfunction-associated steatohepatitis (MASH) with moderate-to-advanced fibrosis (F2–F3) marks an important milestone in hepatology. However, with expanding treatment availability comes a major clinical challenge: accurately identifying which patients truly qualify for therapy.
While histological assessment remains the diagnostic gold standard for at-risk MASH (F2-F3), liver biopsies are performed in only a minority of patients in routine clinical practice. Non-invasive tests (NITs) have become the practical cornerstone of patient selection because they are fast, scalable, and reduce the need for invasive procedures.
However, real-world evidence from multiple studies reveals major limitations, which raise concerns whether current NIT algorithms are sufficiently reliable for identifying patients eligible for approved MASH therapies.
The misclassification gap: underdiagnosis and overtreatment
Current eligibility frameworks for resmetirom (the first medication approved for the treatment of MASH) are highly sensitive to the NIT criteria applied, resulting in substantial variability in the size of the treatment-eligible population. A recent study estimated that anywhere from 2.3 to 8.3 million U.S. adults could be considered eligible for resmetirom, depending solely on which NIT thresholds are used, representing a more than threefold discrepancy¹. Similarly, in a real-world multicenter German cohort, the proportion of patients deemed eligible for treatment varies from as low as 6% to as high as 30% depending on which NIT-based criteria is applied².
NIT-based algorithms may also misclassify patients when benchmarked against histology. A study by Kaya et al.3,5 evaluated two widely used NIT-based diagnostic strategies – CAP+LSM and CAP+FAST – in a biopsy-confirmed cohort of 266 Turkish MASLD patients. Both algorithms missed more than 60% of biopsy-eligible patients, indicating substantial underdiagnosis and potential delays in treatment for patients with progressive disease. Simultaneously, roughly 40% of patients who did not meet histologic criteria were incorrectly flagged as treatment eligible, highlighting a parallel risk of overtreatment.
The dual problem of underdiagnosis and overtreatment is also highlighted in the German Steatotic Liver Disease (SLD) registry. When Messer et al.² directly compared NITs with biopsy in patients who had both assessments available, they found that 47 of 150 patients (31.3%) who would have been considered ineligible by the non-invasive criteria were actually eligible based on histology, indicating substantial underdiagnosis. Conversely, 9 of 112 patients (8.0%) classified as eligible by NITs did not meet histologic criteria, reflecting a lower but still relevant risk of overtreatment.
The risks of underdiagnosis and overtreatment are also underscored in a recent Spanish study. Oliveira et al.⁴ found that currently proposed non-invasive eligibility frameworks missed 44–60% of patients with F2/F3 liver disease while incorrectly classifying 23–41% of ineligible patients as treatment candidates.
Taken together, these findings suggest that current NIT-based eligibility frameworks frequently result in both underdiagnosis and overtreatment, limiting their reliability as standalone tools for treatment selection.
Economic and Clinical Implications
At the population level, the dual failure of NITs – simultaneously excluding eligible patients and including ineligible ones – carries both economic and clinical consequences.
The financial implications are substantial. With lifetime resmetirom treatment costs projected to exceed $300,000 per patient³, even modest rates of overdiagnosis could result in major healthcare spending on patients unlikely to benefit from therapy. In publicly funded healthcare systems, inaccurate prescribing also risks undermining the sustainability of broad treatment access. This concern is particularly relevant in middle-income countries such as Türkiye, where MASLD prevalence may reach up to half of the adult population³.
Beyond economics, there are also important clinical implications. Missing eligible populations may delay treatment during a critical therapeutic window before progression to cirrhosis, when outcomes are significantly more difficult to alter. Conversely, exposing patients without clinically significant fibrosis to long-term therapy despite uncertain benefit, is also a serious consequence of diagnostic misclassification.
Biopsy Still Matters
While NITs remain valuable for risk stratification and initial assessment, accumulating evidence across Turkish, Spanish, German, and U.S. cohorts suggests they frequently fail to accurately identify patients eligible for approved MASH therapies.
The gap between NIT-based eligibility algorithms and biopsy-confirmed disease underscores an important limitation: screening tools are not always sufficient for treatment selection and are not yet ready to function as standalone gatekeepers for high-cost, conditionally approved therapies.
Determining eligibility for long-term treatment requires greater diagnostic precision. Therefore, liver biopsy continues to play an essential role in selected cases – particularly when NIT results are discordant or diagnostic uncertainty persists – by minimizing misclassification and avoiding unnecessary economic and clinical consequences.
References
1.Le, Phuc, et al., Hepatology communications 9.7 (2025): e0755.
2.Messer et al., Z Gastroenterol 2025
3.Adali & Akdogan, Hepatology Forum 2025
4.Olveira et al., Clin Gastroenterol Hepatol 2025
5.Kaya, Eda, et al., Hepatology Forum. Vol. 6. No. 3. 2025