Medical therapy of MASLD – consequences of the paradigm shift from histology to non-invasive tests

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BACKGROUND & AIMS: The recent approval of pharmacological therapies for fibrotic metabolic dysfunction-associated steatohepatitis (MASH) has increased the need for accurate identification of treatment-eligible patients. Current recommendations increasingly rely on non-invasive tests (NITs), including vibration-controlled transient elastography (VCTE), while multiparametric ultrasound (MPUS) may provide additional opportunities for non-invasive assessment. However, agreement between histology and imaging-based approaches remains uncertain. We compared treatment eligibility based on histology, VCTE, and MPUS in two international biopsy-proven cohorts of metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: We analysed two biopsy-proven MASLD cohorts: CAP-IPDMA (n=1029), including VCTE and controlled attenuation parameter (CAP), and iLEAD (n=124), including MPUS. Treatment eligibility was assessed using histologically confirmed F2/F3 MASH and NIT-based recommendations from international expert panels. RESULTS: In CAP-IPDMA, 277/1029 patients (26.9%) met the histological definition of "at-risk MASH". Depending on the VCTE cut-off, 13.2-32.0% qualified for treatment. Overlap between histological "at-risk MASH" and VCTE thresholds was limited, reaching 27.8% when using VCTE 8-15 kPa, and decreasing when narrower or higher thresholds were applied. Among patients identified only by VCTE 8-15 kPa, males had lower median AST and ALT than those fulfilling only the histological indication (35 vs 48 IU/L p=0.034 and 45 vs 62 IU/L p=0.0072, respectively). In iLEAD, 21/124 patients (16.9%) met the histological definition, while 13.7-16.1% were eligible based on SWE thresholds, again with a similarly limited overlap. CONCLUSIONS: Histology and non-invasive tests capture partly distinct patient populations, meaning that both the number and type of patients selected for therapy depend on the chosen modality and cutoffs. As vibration-controlled transient elastography and multiparametric ultrasound become increasingly accessible in clinical practice, prospective validation is essential for establishing reliable non-invasive treatment pathways. IMPACT AND IMPLICATIONS: The current literature reflects a paradigm shift away from biopsy-based approaches toward NIT-based assessment of treatment eligibility in metabolic dysfunction-associated steatotic liver disease (MASLD), which may substantially affect which patients receive newly approved therapies. Our results are important for clinicians, researchers, and guideline developers because histology and current NIT cut-offs identify only partially overlapping patient populations, implying that different diagnostic strategies select different risk profiles. In practice, these findings support thoughtful implementation of NIT-based treatment pathways, the use of repeated measurements, and prospective validation of NIT thresholds to guide clinical care, trial design, and health policy decisions.

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