Hepatocellular carcinoma risk in ICD-coded non-cirrhotic nonalcoholic fatty liver disease refined by fatty liver index: A nationwide South Korean cohort study - 08/05/25

Doi : 10.1016/j.clinre.2025.102612

Chang Hun Lee ^a,^b,^{^{#
Chang Hun Lee and Min Gu Kang contributed equally to this work as first authors.}}, Min Gu Kang ^c,^{^{#
Chang Hun Lee and Min Gu Kang contributed equally to this work as first authors.}}, Shinyoung Oh ^b,^d,^e, In Sun Gwak ^e, Chen Shen ^b,^e, Ha Ram Oh ^b,^e, Young Ran Park ^b,^e, Jong Seung Kim ^b,^c, Ji Hyun Park ^b,^e,^⁎
^a Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jeonbuk National University Medical School, Jeonju, South Korea
^b Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital Jeonju, South Korea
^c Department of Medical Informatics, Jeonbuk National University Medical School, Jeonju, South Korea
^d Department of Medicine, Jeonbuk National University Graduate School, Jeonju, South Korea
^e Division of Endocrinology and Metabolism, Department of Internal Medicine, Jeonbuk National University Medical School, Jeonju, South Korea

^⁎Corresponding author: Division of Endocrinology and Metabolism, Department of Internal Medicine, Jeonbuk National University Medical School, 20 Geonji-ro, Deokjin-gu, Jeonju, Jeonbuk, 54907, Republic of Korea.Division of Endocrinology and Metabolism, Department of Internal MedicineJeonbuk National University Medical School20 Geonji-ro, Deokjin-guJeonjuJeonbuk54907Republic of Korea

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Highlights

•	NAFLD, now referred to as MASLD, is the most common chronic liver disease, but data on HCC risk and surveillance in non-cirrhotic population remain limited.
•	This nationwide study from South Korea demonstrates that non-cirrhotic NAFLD patients have a significantly higher risk of HCC compared to healthy controls. Furthermore, among non-cirrhotic NAFLD patients, male sex and age 70-79 years were identified as independent risk factors for HCC.
•	Non-cirrhotic NAFLD accounted for a significant proportion of total NAFLD-HCC cases, emphasizing the need for targeted surveillance in this population.

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Abstract

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.

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