Hepatocellular carcinoma risk in ICD-coded non-cirrhotic nonalcoholic fatty liver disease refined by fatty liver index: A nationwide South Korean cohort study

Background/Aims: Hepatocellular carcinoma (HCC) is an increasing global health burden, driven by demographic shifts and the growing prevalence of risk factors such as non-alcoholic fatty liver disease (NAFLD), now referred to as metabolic dysfunction-associated steatotic liver disease (MASLD). Despite the majority of NAFLD patients being in the non-cirrhotic stage, there is a notable lack of data on HCC incidence and risk factors, making it challenging to implement effective public health screening and prevention strategies. Methods: This study conducted a longitudinal analysis of a nationwide cohort of NAFLD patients using big data from the National Health Insurance Service of South Korea to assess HCC incidence and risk factors, focusing on non-cirrhotic patients. NAFLD was identified through ICD-10 codes and refined using a fatty liver index (FLI) score above 30. Results: A total of 529,811 patients were enrolled. After a washout period, 36,760 patients were newly diagnosed with NAFLD. The incidence rate of HCC per 100,000 person-years was 10.00 in healthy controls and 31.66 in NAFLD patients, further divided into 24.87 in non-cirrhotic NAFLD and 721.5 in cirrhotic NAFLD. In the 1:1 Propensity Score Matched analysis, HCC incidence in non-cirrhotic NAFLD was 24.89 per 100,000 person-years compared to 9.72 in matched healthy controls, yielding an adjusted hazard ratio (HR) of 2.69 (95 % CI 1.33–5.44). Multivariate Cox regression analysis indicated that both cirrhotic and non-cirrhotic NAFLD significantly increased the risk of developing HCC, with additional factors such as age, male sex, and type 2 diabetes. A subsequent analysis of non-cirrhotic NAFLD patients confirmed that advanced age and male sex remained significant risk factors for the development of HCC. Conclusions: This study demonstrates that non-cirrhotic NAFLD patients, particularly males and those aged 70–79 years, have a significantly increased risk of HCC compared to healthy controls. Given the applicability of NAFLD concepts to MASLD, our findings could provide insights for identifying high-risk individuals within the MASLD spectrum and developing effective strategies to reduce the risk of HCC.