The Elucidating Pathways of Steatohepatitis (EPoS) staging system: A reproducible 7-tiered fibrosis scoring system in MASLD

Background & Aims: Fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD) is histologically staged using the 5-tiered NASH CRN system, which has limited resolution for advanced fibrosis stages that are strongly associated with liver-related outcomes. We developed and validated an expanded histological staging system designed to more accurately reflect the spectrum of MASLD fibrosis. Methods: Nine expert hepatopathologists from the Elucidating Pathways of Steatohepatitis (EPoS) Histopathology Group reviewed MASLD liver biopsies to define, by consensus, the fibrosis stages of a new histological scoring system. To assess validity, correlations with quantitative collagen proportionate area (CPA), enhanced liver fibrosis (ELF) score, and liver stiffness measurement (LSM) were evaluated. To assess inter-observer variability and intra-observer agreement, each pathologist independently reviewed 45 cases (glass slides) using the EPoS staging system. After three months, the same slides were digitized and re-evaluated by each pathologist, blinded to their previous assessments. Results: <0.001). Mean inter-observer agreement for EPoS staging was excellent (κ = 0.84). Agreement remained high on digital evaluation (κ = 0.80), while intra-observer agreement was similarly strong (mean κ = 0.85; range 0.79-0.89). Conclusions: The EPoS fibrosis staging system is a robust expanded scoring method that accurately reflects histological CPA, LSM, and ELF values. EPoS staging may be useful for assessing fibrosis in MASLD natural history studies and therapeutic trials. Digital pathology provides results comparable to glass slides for reproducible fibrosis staging. Impact and implications: The traditional 5-tiered NASH CRN system for staging metabolic dysfunction-associated steatotic liver disease (MASLD)-related fibrosis has limited resolution for advanced stages, which are most strongly associated with liver-related outcomes. The newly developed and validated EPoS expanded 7-tiered staging system provides greater granularity for advanced fibrosis and more accurately reflects fibrosis progression in MASLD. The EPoS system is expected to improve the accuracy of fibrosis staging for patient selection in MASH (metabolic dysfunction-associated steatohepatitis) clinical trials and for assessing changes in fibrosis during both natural disease progression and therapeutic interventions, as well as in routine pathology practice. In addition, we demonstrate that digital pathology slides can be reliably used for reproducible fibrosis staging in MASLD, yielding results comparable to those obtained from glass slides, with direct practical implications for liver biopsy interpretation using scanned images.