Dear Editor,
We sincerely appreciate Dr. Baek’s thoughtful and balanced editorial commentary on our study entitled “
Aspirin and hepatocellular carcinoma risk in metabolic dysfunction-associated steatotic liver disease: a nationwide cohort study with genetic risk analysis” [
1,
2]. We are grateful for the opportunity to further clarify the interpretation of our findings.
We fully agree with the editorial’s central premise that, despite accumulating observational evidence, aspirin cannot yet be universally recommended for hepatocellular carcinoma (HCC) prevention in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). In particular, we acknowledge the important concern regarding bleeding risk, which remains the most critical barrier to the clinical application of aspirin for chemoprevention. As noted by Dr. Baek, prior studies have reported heterogeneous results regarding gastrointestinal bleeding among aspirin users with chronic liver disease, underscoring the need for careful patient selection and long-term safety evaluation [
3-
5]. Regarding this issue, we would like to clarify that the primary aim of our study was not to advocate routine aspirin use for HCC prevention, but rather to explore whether a protective association exists in the MASLD population, where effective chemopreventive strategies are currently lacking. Given the inherent limitations of claims-based data, detailed bleeding outcomes could not be robustly captured in our analysis. We therefore drew cautious conclusions, emphasizing the need for further validation before clinical adoption.
The editorial also appropriately raises concerns regarding the disease definition and population heterogeneity, particularly regarding the use of fatty liver index (FLI) for diagnosing MASLD. We agree that FLI does not perfectly reflect the severity of histological steatosis or fibrosis compared to other modalities [
6,
7]. Nevertheless, in large-scale population-based studies where direct imaging or biopsy information is unavailable, FLI is a widely adopted and pragmatic approach to define steatotic liver disease at the population level, enabling the investigation of epidemiologic associations in real-world settings [
8,
9]. In the current study, FLI was not intended to serve as a diagnostic substitute or a precise marker of disease severity, but rather as a feasible surrogate for defining MASLD in a nationwide cohort.
With respect to the landmark analysis and duration of aspirin exposure, we concur that long-term use appears to be a critical determinant of any potential chemopreventive effect [
10,
11]. As discussed in the editorial, the lack of statistical significance at certain landmark intervals likely reflects both limited event numbers and the intrinsic selection characteristics of landmark designs. However, landmark analyses were primarily implemented to minimize immortal time bias and to explore duration-dependent patterns rather than to provide definitive effect estimates. Importantly, similar directional trends were consistently observed across sequential target trial emulation analyses and alternative landmark approaches, supporting an inverse association between aspirin use and HCC rather than an incidental finding driven by a single analytic framework. In addition, complementary genetic analyses provided independent support for the observed association using an orthogonal causal framework. Taken together, we believe that these findings are compatible with prior evidence supporting the protective effect of aspirin against HCC.
Lastly, we strongly agree that the clinical implication of aspirin use in MASLD must be considered within the broader context of cardiovascular risk, liver disease stage, and individual bleeding susceptibility. Our study was intended to provide hypothesis-generating evidence by integrating population-based epidemiologic data with complementary genetic analyses, thereby strengthening causal inference while acknowledging unavoidable limitations.
In conclusion, we sincerely appreciate Dr. Baek’s insightful discussion, which appropriately balances enthusiasm with clinical prudence. We hope that our study contributes to a more nuanced understanding of aspirin’s potential role in MASLD-related hepatocarcinogenesis and stimulates future prospective studies focusing on optimal patient selection, duration of therapy, and long-term safety.
FOOTNOTES
-
Authors’ contributions
MH Hur, HJ Shin, and YJ Kim drafted and reviewed the correspondence equally.
-
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
Moon Haeng Hur: Nothing to declare; Hyunjae Shin: Nothing to declare; Yoon Jun Kim: 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, Green Cross Cell, Boehringer Ingelheim, and Gilead Sciences.
Abbreviations
metabolic dysfunction-associated steatotic liver disease
REFERENCES
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Citations
Citations to this article as recorded by
- Reply to correspondence on “Aspirin and hepatocellular carcinoma risk in metabolic dysfunction-associated steatotic liver disease: nationwide cohort study with genetic risk analysis”
Yang-Hyun Baek
Clinical and Molecular Hepatology.2026; 32(3): e439. CrossRef
