Liver Biopsy in Metabolic Dysfunction-Associated Steatohepatitis Clinical Trials: Potential Pitfalls and Solutions

Liver biopsy is the reference standard for the evaluation of inflammation and fibrosis in MASH and is the primary endpoint in steatohepatitis clinical trials. An optimal liver biopsy is generally considered to be obtained with a 16-gauge needle, measure at least 2 cm in length and contain at least 10 complete portal tracts, although these features have not been prospectively validated as mandatory thresholds in MASH trials. Published clinical trials for MASH have not consistently reported sufficient details of liver biopsy quality (needle gauge, length, number of portal tracts) at baseline or post-treatment, and biopsy quality metrics are rarely reported separately by treatment arm. Placebo response rates in clinical trials for MASH varied widely (2% to 34%) and this variation could influence the outcomes of clinical trials. Future MASH trials should report biopsy quality metrics (needle gauge, core length and portal tract count) by treatment arm in supplementary appendices of those publications, treat the 16-gauge/≥ 2 cm/≥ 10 portal tract criteria as preferred acquisition standards rather than required thresholds, and may consider pre-specified sensitivity analyses restricted to biopsies meeting adequacy criteria, recognising that such exclusions may alter the disease spectrum and must be interpreted cautiously. Biopsy quality is a plausible contributor to variability in placebo responses and trial outcomes, but direct evidence that needle gauge, core length, or portal tract number independently affect histologic response rates in randomised MASH trials remains limited. As digital pathology/AI tools mature and NIT-based surrogate endpoints advance toward regulatory qualification, ensuring high quality histologic reference standards remains essential.