Dear Editor,
We appreciate the comprehensive and balanced perspective provided by Dr. Lee and Dr. Wu in their editorial regarding our study [
1,
2]. Their commentary raises critical points that help delineate the current boundaries of aspirin use for hepatocellular carcinoma (HCC) prevention in metabolic dysfunction-associated steatotic liver disease (MASLD).
We agree that universal aspirin use for HCC prevention remains premature, particularly given the lack of high-level evidence, such as data from randomized controlled trials [
3,
4]. Concern about gastrointestinal bleeding represents a significant clinical threshold; however, our cohort primarily comprised a non-cirrhotic population with low baseline risk of bleeding. In such a low-risk setting, the threshold for a favorable net clinical benefit may be lower than in cases of advanced liver disease [
4,
5]. Our study serves as an evidentiary bridge by identifying a specific population in which the chemopreventive benefits may outweigh potential harms.
Regarding the use of the fatty liver index (FLI) to define MASLD, we acknowledge that it is an indirect surrogate for a histologic or imaging-based diagnosis. Nevertheless, we chose a threshold of FLI ≥30 to reflect the unique metabolic profile of East Asian populations, who often develop MASLD (i.e., non-obese MASLD) despite lower BMI levels [
6-
8], and to account for the high incidence of liver-related outcomes in these subgroups. While increasing the FLI threshold to 60 may improve specificity, our sensitivity analyses confirmed that the protective association of aspirin remained robust across different MASLD definitions. We believe that in large-scale epidemiologic research, such validated non-invasive indices are essential for translating complex clinical phenotypes into actionable population-level data.
The authors also raised a valid concern regarding “healthy user bias”, suggesting that aspirin users might engage in better health-seeking behaviors. While this is an inherent challenge in observational studies, we attempted to mitigate it by adjusting for a wide range of comorbidities and socioeconomic factors. Furthermore, the fact that the protective association remained consistent in our genomic risk score analysis, which is less susceptible to behavioral confounding, supports that the observed benefit is not merely a reflection of a healthier lifestyle but has a biological basis [
9].
Regarding the dose-response relationship, we acknowledge that a clear association was not fully evident in our study, partly due to inherent limitations in the statistical power of certain subgroup analyses. Nevertheless, we believe that the duration of aspirin exposure remains a critical factor, particularly when considering the complex interplay between the anti-inflammatory threshold of aspirin and individual metabolic rates [
10]. Our main and sensitivity analyses consistently demonstrated a sustained trend toward a protective benefit with prolonged aspirin exposure. However, given the limited statistical power of certain subgroup analyses and the absence of detailed dose-graded data in our study, we are unable to draw firm conclusions regarding a dose-dependent effect. Instead, prior studies suggesting a potential dose–response relationship may provide useful context, particularly as higher aspirin doses are also associated with an increased risk of bleeding [
11]. These considerations highlight the need for future investigations to define optimal dosing strategies that balance chemopreventive benefits and safety of aspirin in MASLD.
The authors also pointed out the potential for immortal time bias. To address this, we employed a landmark-based sequential trial design that approximates target trial emulation [
12]. By allowing for dynamic cohort entry and utilizing multiple landmark intervals, we demonstrated that the inverse association between aspirin and HCC risk was consistent regardless of the follow-up start point. This methodological rigor suggests that the observed effects are likely biological rather than a result of temporal bias.
Ultimately, the transition from epidemiologic observation to clinical practice requires a comprehensive approach. Future research should prioritize identifying high-risk subgroups through validated biomarkers or polygenic risk scores to enable a personalized precision-prevention strategy. We sincerely appreciate Dr. Lee and Dr. Wu’s thoughtful discussion. We hope our work stimulates multicenter prospective studies that evaluate hepatic, cardiovascular, and safety outcomes to establish the role of aspirin in the long-term management of MASLD.
FOOTNOTES
-
Authors’ contributions
Hyunjae Shin: conceptualization, writing - original draft; Moon Haeng Hur: writing - review and editing; Yoon Jun Kim: supervision, writing - review and editing. All authors approved the final version of the manuscript.
-
Acknowledgements
This study was supported by the Research Supporting Program of the Korean Association for the Study of the Liver and the Korean Liver Foundation and research grants from Dong-A ST Co. (Seoul, Korea) and Yuhan Corporation (Seoul, Korea)
-
Conflicts of Interest
Hyunjae Shin: Nothing to declare; Moon Haeng Hur: Nothing to declare; Yoon Jun Kim: Receives research grants from BTG, Boston Scientific, AstraZeneca, Gilead Sciences, Samjin, BL&H, and Bayer, and lecture fees from Roche, Abbvie, Eisai, Boston Scientific, BMS, BTG, Bayer, MSD, Novo Nordisk, GreenCross Cell, Boehringer Ingelheim, and Gilead Sciences.
Abbreviations
metabolic dysfunction-associated steatotic liver disease
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