S2540 Comparison of Hepatocellular Carcinoma Risk in MASH vs MASLD With Normal Liver Enzymes: A Retrospective Cohort Study

Introduction: The incidence of hepatocellular carcinoma (HCC) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) is rising, including in those without cirrhosis or abnormal liver enzymes. Current AASLD guidelines recommend HCC surveillance every 6 months with ultrasound and AFP only for patients with cirrhosis or chronic hepatitis B. However, up to 30%-40% of MASLD-related HCC cases occur in non-cirrhotic livers, challenging these guidelines. Although AFP alone has limited sensitivity and specificity, levels above 200-400 ng/mL may improve diagnostic accuracy when combined with imaging. This study compares HCC risk in patients with metabolic dysfunction-associated steatohepatitis (MASH) versus MASLD with normal liver enzymes. Methods: A retrospective cohort study using the TriNetX US Collaborative Network included adults ≥18 years with MASH (elevated aspartate aminotransferase [AST]/alanine aminotransferase [ALT] >30 U/L plus ≥1 metabolic risk factor: body mass index (BMI) >25, prediabetes/diabetes, hypertension, triglycerides >150 mg/dL, or HDL <40 mg/dL) or MASLD (normal AST/ALT with the same metabolic criteria). Patients with other chronic liver diseases were excluded. Propensity score matching was done for age, sex, race, BMI, A1C, creatinine, and liver function tests. The primary outcome was HCC development; secondary outcomes were AFP >100 and >400 ng/mL. Statistical significance was set at P < 0.05. Results: After propensity score matching, 342,391 patients in Cohort 1 and 342,464 in Cohort 2 were included. Mean age was 49.9 ± 14.8 vs 50.0 ± 14.8 years, White patients 70.2% vs 70.6%, and men 53.2% in both. HCC occurred in 0.088% of Cohort 1 versus 0.050% of Cohort 2 (OR 1.757; 95% CI: 1.457-2.119). AFP >100 ng/mL was found in 0.011% vs 0.008% (OR 1.310; 95% CI: 0.808-2.125), and AFP >400 ng/mL in 0.006% vs 0.004% (OR 1.538; 95% CI: 0.765-3.093). Conclusion: Our study showed that the cohort primarily consisted of middle-aged White male patients. Patients with MASH had a significantly higher risk of developing HCC, demonstrating a 1.8-fold increase compared to MASLD patients with normal liver enzymes. Although AFP elevations were more common in the MASH group, these differences did not reach statistical significance. These findings highlight the need for prospective studies to evaluate surveillance strategies in metabolically high-risk populations, incorporating demographic factors, metabolic disease severity, non-invasive fibrosis scores, and AFP levels to enhance risk stratification and enable early detection of HCC.