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.

引言
肝细胞癌（hepatocellular carcinoma, HCC）是癌症相关死亡的主要病因之一。当前国际指南推荐，对所有肝硬化患者及存在乙型肝炎病毒相关危险因素的人群，每6个月行超声筛查以检出早期肝细胞癌。然而目前尚不明确，筛查的获益在不同患者群体及基础疾病相关因素中是否具有可比性。本研究旨在评估英国多族裔人群中，与诊断时肝细胞癌分期及总生存相关的患者自身及疾病相关因素。

方法
本研究为一项多中心回顾性观察研究，纳入了2007年至2020年间来自英国6个医学中心的新诊断肝细胞癌患者。研究采用Cox比例风险回归及多因素logistic回归模型进行分析。

结果
本研究共分析1780例肝细胞癌患者，其中酒精相关肝病（alcohol-related liver disease, ArLD）患者占20.9%，非酒精性脂肪性肝病（non-alcoholic fatty liver disease, NAFLD）患者占29.7%，病毒性肝炎患者占31.0%。筛查与病毒性肝炎患者的生存改善相关，但在酒精相关肝病及非酒精性脂肪性肝病患者中未观察到该关联。在病毒性肝炎患者中，筛查还与确诊时处于早期疾病（巴塞罗那临床肝癌分期0或A期，Barcelona Clinic Liver Cancer, BCLC）相关，但在酒精相关肝病患者中未发现此关联。酒精相关肝病女性患者确诊为早期肝细胞癌的概率是男性患者的2.5倍。非酒精性脂肪性肝病患者在无肝硬化的情况下更易发生肝细胞癌。2型糖尿病与患者死亡率无相关性，但使用二甲双胍可带来生存获益。与其他族裔相比，白人患者的生存情况更优，且确诊时处于晚期肝细胞癌的概率更低。

结论
当前实施的肝细胞癌筛查，在非病毒性及非肝硬化性肝病患者中，早期肝细胞癌检出效果欠佳。性别与族裔会影响确诊时的疾病分期及患者预后。亟需优化肝细胞癌筛查策略以完善风险分层，尤其针对非酒精性脂肪性肝病患者或无肝硬化的人群。