Risk of liver-related events in metabolic dysfunction-associated steatohepatitis (MASH) patients with fibrosis: A comparative analysis of various risk stratification criteria

Background: International regulatory agencies recommend testing drug therapy for patients with noncirrhotic high-risk metabolic dysfunction-associated steatohepatitis (MASH) because they are at risk of liver-related events(LRE). We aimed to compare the risk of LRE in MASLD patients stratified for F2-F4 fibrosis and MASH. Methods: 1938 consecutive patients with biopsy-proven MASLD were enrolled. High-risk MASH was defined as MASH with F2-F4 fibrosis. LSM was measured by transient elastography. LRE were recorded during follow-up. Cox multivariate models were used to assess the association between high-risk MASH or F2-F4 fibrosis without MASH, of LSM(≥8 or ≥10 Kpa) and of AGILE 3+ with LRE. The diagnostic performance for the prediction of LRE was assessed using the area under the receiver operating characteristic(AUROC) curves. Results: The observed 5-year actuarial rate of LRE was 0.4%,0.2%,5.1% and 6.6% in patients with F0-F1 fibrosis without MASH, F0-F1 fibrosis with MASH, F2-F4 fibrosis without MASH, and high-risk MASH, respectively. At multivariate Cox regression analysis using F0-F1 fibrosis without MASH as reference, both F2-F4 fibrosis without MASH (adjusted hazard ratio[aHR] 9.96) and high-risk MASH (aHR 10.14) were associated with LRE. In the 1074 patients with available LSM, LSM≥10 KPa(aHR 6.31) or AGILE 3+ >0.67 (aHR 27.45) independently predicted the development of LRE and had similarly acceptable 5-year AUROC to high-risk MASH and F2-F4 fibrosis(0.772,0.818,0.739, and 0.780, respectively). Conclusions: The risk of LRE is similar in patients with high-risk MASH and with F2-F4 fibrosis without MASH. The use of LSM≥10 KPa or AGILE 3+ >0.67 could be an accurate option to identify MASLD patients worthy to be included in clinical trials.