HCC Is the Predominant Liver-Related Event in MASLD: 2-Step Non-Invasive Algorithms to Stratify Risk in Non-Cirrhotic Patients

Background & Aims: Hepatocellular carcinoma (HCC) may develop in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) even in the absence of cirrhosis. Whether the risk of HCC in non-cirrhotic MASLD is substantial to justify surveillance, and which patients may benefit, remains unclear. Methods: Post-hoc analysis conducted on a prospective MASLD cohort. All participants underwent baseline liver stiffness measurement (LSM) using SuperSonic Imagine (SSI) two-dimensional shear wave elastography (2D-SWE) and were surveilled every 6–12 months. Exclusion criteria were less than 6 months follow-up, unavailable LSM-SSI, prior HCC. Primary outcome was HCC, with hepatic decompensation and portal vein thrombosis (PVT) as competing risks. To improve risk stratification, LSM-SSI optimized cut-offs were applied: <7.4 kPa to rule-out advanced fibrosis, ≥15.6 kPa to rule-in cirrhosis, based on recent meta-analytic data, and were integrated in different risk stratification algorithms. Results: Among 352 patients with a median follow-up of 31 (14.1–57.8) months, 257 (73%) had LSM-SSI <7.4 kPa, 67 (19%) between 7.4–15.6 kPa, and 28 (8%) ≥15.6 kPa. During follow-up, 9 (2.6%) developed HCC, 6 (1.7%) decompensation, 2 (0.6%) PVT. No events occurred in patients with LSM-SSI <7.4 kPa. In the 7.4–15.6 kPa group, HCC and decompensation occurred in 3 (4.5%) and 1 (1.5%), respectively. For non-cirrhotic patients (LSM-SSI <15.6 kPa), LSM-SSI was significantly associated with HCC risk (HR 1.542, p<0.0001). Following multivariate analysis, independent HCC predictors were: LSM-SSI (HR 1.052, 95% CI 1.030–1.075, p<0.001), type 2 diabetes mellitus (HR 4.555, 95% Ci 1.091–19.012, p=0.038), and gamma-glutamyl transferase (HR 1.004, 95% CI 1.001–1.006, p=0.003). A two-step non-invasive algorithm combining LSM-SSI and the PLEASE score yielded 100% negative predictive value and 89.5% accuracy in identifying patients for HCC surveillance. Conclusion: HCC is the leading liver-related complication in non-cirrhotic MASLD. LSM-SSI <7.4 kPa effectively excludes highrisk patients. A two-step algorithm further enhances risk stratification and surveillance precision.