Consensus position statements for the standardized application of histological grading and staging systems in MASH clinical trials.

BACKGROUND & AIMS: Assessment of histologic disease activity (grading) and fibrosis (staging) is a prerequisite for patient selection and evaluation of treatment response in clinical trials of metabolic dysfunction-associated steatohepatitis (MASH). The lack of universally accepted definitions of histological components required for metabolic dysfunction-associated steatotic liver disease (MASLD) grading and staging, inconsistent histologic interpretations, and the absence of guidelines on how to apply currently used scoring systems, contribute to high interobserver variation and influence supervised machine learning algorithms.

METHODS

The International MASLD Pathology Group (IMPG), comprising 25 expert liver pathologists and one statistician, was established to develop guidance for the histological assessment of liver biopsies in MASH clinical trials and to define standards for liver biopsy processing, as well as to refine criteria for histological MASLD grading and staging. Statements were generated by three IMPG working subgroups and evaluated through a Delphi consensus procedure.

RESULTS

The IMPG working groups issued a total of 278 primary statements, which were evaluated in the first Delphi round, yielding 162 statements with 80% or higher agreement. The remaining 116 statements were discussed and either revised or not further considered. The resulting 33 revised statements were evaluated in a second Delphi round, yielding 192 final statements with 80% or higher agreement.

CONCLUSION

For the first time, the IMPG statements provide guidelines to promote consensus among liver pathologists on the histopathological evaluation and scoring of liver biopsies for MASH clinical trials. Furthermore, they may inform the development of supervised machine learning algorithms for quantitative histology assessments of MASLD.

IMPACT AND IMPLICATIONS: Inter- (and intra-) observer variations in the histological interpretation of key morphological features of metabolic dysfunction-associated steatohepatitis (MASH) limit the precision of histological grading and staging, as well as the diagnosis of the histological subtypes, MASL and MASH. This is thought to account, at least in part, for screening failure and variable placebo response rates in clinical trials, potentially obscuring treatment effects. The International MASLD Pathology Group, consisting of 25 expert liver pathologists, generated consensus statements for histopathological procedures, technical aspects and histological criteria for the diagnosis of MASH, as well as for grading disease activity and staging fibrosis. These may provide a basis for standardized histologic interpretation and the development of AI-based grading and staging algorithms for clinical trials of MASH.