Disease-associated hepatocytes are predictive of outcomes and survival in MASLD beyond fibrosis staging

We read with interest the recent article by Lai et al, which evaluated 12 950 patients with metabolic dysfunction-associated steatotic liver disease (MASLD) across multiple international centres with a median follow-up of 47.7 months. The study demonstrated that a Fibrosis-4 (FIB-4) Index Score ≥3.25 or liver stiffness measurement (LSM) ≥20 kPa, or LSM ≥15 kPa when used as a second step following an elevated FIB-4, identified patient subgroups with annual hepatocellular carcinoma (HCC) incidence ≥1%, justifying surveillance in these groups.1 This represents an important advance, as it implements clear cut-offs from non-invasive tests, circumventing the complexity of traditional cirrhosis diagnosis. Current guidelines recommend biannual ultrasound, with optional alpha-fetoprotein screening, only for patients with cirrhosis and generally do not endorse routine surveillance in non-cirrhotic individuals.2 3 While approximately 10%–20% of all HCC cases arise in non-cirrhotic livers, this figure is notably higher in MASLD-related HCC, reaching up to 38%.4 Many of these patients have low FIB-4 and LSM Scores and are therefore missed by current and proposed surveillance criteria. This gap underscores the urgent need for additional biomarkers that may predict HCC development independently of fibrosis, particularly in patients without cirrhosis.