Supplementary Material for: Current surveillance strategy is less effective for detecting early-stage hepatocellular carcinoma in patients with non-viral and non-cirrhotic liver disease

Introduction
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths. Current international guidelines recommend 6-monthly ultrasound surveillance in all patients with cirrhosis and those with hepatitis B virus-related risk factors to detect early-stage HCC. However, it is unknown whether the benefits of surveillance are comparable across patient groups and underlying disease-related factors. We aimed to evaluate patient- and disease-related factors associated with HCC stage at diagnosis and survival in an ethnically diverse UK population.

Methods
This was a multicentre retrospective observational study including patients with newly-diagnosed HCC between 2007-2020 from six UK centres. Cox proportional-hazards regression and multivariate logistic regression models were used.

Results
1780 HCC patients comprising 20.9% with ArLD, 29.7% with NAFLD and 31.0% with viral hepatitis, were analysed. Surveillance was associated with improved survival in patients with viral hepatitis, but not in patients with ArLD and NAFLD. Surveillance was also associated with early-stage disease (BCLC stage 0 or A) at presentation in viral hepatitis, but not in patients with ArLD. Females with ArLD were 2.5-fold more likely to present with early-stage HCC than males. Patients with NAFLD were more likely to develop HCC in the absence of cirrhosis. Type 2 diabetes was not associated with mortality, but metformin use did show survival benefit. Patients of White ethnicity had improved survival and were less likely to present with late-stage HCC compared to other ethnicities.

Conclusion
HCC surveillance as currently delivered was less effective for detecting early-stage HCC in patients with non-viral and non-cirrhotic liver disease. Gender and ethnicity influences stage at presentation and outcomes. HCC surveillance strategies are needed to refine risk stratification particularly in patients with NAFLD or without cirrhosis.