A Novel Risk Prediction Model for Hepatocellular Carcinoma in MASLD: A Multinational, Multicenter Cohort Study

Background & Aims It is unclear that which cardiometabolic risk factors (CMRFs) are significantly associated with hepatocellular carcinoma (HCC) development in metabolic dysfunction–associated steatotic liver disease (MASLD). We aimed to develop and validate a novel CMRF-based HCC risk prediction model in MASLD. Methods This multicenter cohort study recruited 77,677 MASLD patients from 20 medical centers in Korea and other Asian and Western countries (2004–2023). A novel CMRF-based HCC risk prediction model (MASLD-HCC score) was developed based on time-varying Cox multivariable analysis in a training cohort (n = 36,800, Korea), which was validated internally (n = 36,799, Korea) and externally (n = 4078, 11 other Asia and Western countries). Results In the training cohort, 71 (0.2%) patients developed HCC (median follow-up 5.1 years). Overweight/obesity or central obesity and prediabetes/diabetes were independently associated with HCC development, along with age, sex, and platelets. The MASLD-HCC score with these 5 risk factors showed a Harrell’s C-index of 0.84 for HCC development, which was maintained in the internal (C-index 0.83) and external validation cohorts (C-index 0.93), and the model was well calibrated. Decision curve analyses showed that patients had positive net benefits from the model. When stratified by the MASLD-HCC score, the risk of HCC development in the high-risk group was significantly higher than the low-risk group (training: subdistribution hazard ratio [sHR], 11.44; 95% confidence interval [CI], 7.10–18.41; internal validation: sHR, 12.36; 95% CI, 7.72–19.79; external validation: sHR, 56.84; 95% CI, 12.88–250.73; all P < .001). Conclusions Overweight/obesity or central obesity and prediabetes/diabetes with fibrotic burden were significantly associated with the increased HCC risk in MASLD. The MASLD-HCC score may enable physicians to stratify the HCC risk.