Delicate and thin fibrous septa indicate a regression tendency in metabolic dysfunction-associated steatohepatitis patients with advanced fibrosis

Abstract Background and Aims: Metabolic dysfunction-associated steatohepatitis (MASH)-related fibrosis is reversible. However, the dynamic morphology change in fibrosis regression remains unclear. We aim to explore the morphological characteristics of fibrosis regression in advanced MASH patients. Methods Clinical and histological data of 79 biopsy-proved MASH patients with advanced fibrosis (F3-F4) were reviewed. The second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) image technology was used to quantitively identify the R (regressive) septa from P (progressive) septa and PS (perisinusoidal) fibrosis. Non-invasive tests were used to compare the fibrosis level of the with and without R septa groups. Transcriptomics was used to explore hub genes and the underlying mechanism of the formation of R septa. Results The R septa were different from the P septa and PS fibrosis in detail collagen quantitation identified by SHG/TPEF technology. The R septa were found in MASH fibrosis-regressed patients, which met the definition of the “Beijing classification”. Therefore, patients were divided into two groups according to septa morphology: with R septa (n = 10, 12.7%), and without R septa (n = 69, 87.3%). Patients with R septa had lower values in most non-invasive tests, especially for liver stiffness (12.3 vs. 19.4 kPa, p = 0.010), and FAST (FibroScan®-AST) score (0.43 vs. 0.70, p = 0.003). Transcriptomics analysis showed the expression of five hub fibrogenic genes including Col3A1, BGN, Col4A1, THBS2 and Col4A2 in the with R septa group were significantly lower. Conclusions The R septa can be differentiated from the P septa and PS fibrosis by quantitative assessment of SHG/TPEF, and it represents a tendency of fibrosis regression in MASH patients.