Letter to the editor on “Evolutionary changes in metabolic dysfunction-associated steatotic liver disease and risk of hepatocellular carcinoma: A nationwide cohort study”
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Dear Editor,
The study by Jeong et al. [1], published in Clin Mol Hepatol, presents an intriguing investigation into the evolving status of metabolic dysfunction-associated steatotic liver disease (MASLD) and its association with hepatocellular carcinoma (HCC) risk. While the study is a commendable effort to advance our understanding of MASLD-related HCC, several limitations must be considered to critically evaluate its implications.
One of the most pressing concerns with this study is the inability to establish a causal relationship between evolutionary changes in MASLD status and the development of HCC. Although the study demonstrates a significant association between persistent and incident MASLD with increased risk of HCC, the retrospective design of the cohort does not allow definitive conclusions about causality. The observed associations may reflect underlying confounders that are not adequately controlled for in the analysis, particularly given the study’s reliance on observational data from the National Health Insurance Service (NHIS) database. The potential for reverse causality, whereby the presence of undiagnosed early stage HCC could influence metabolic changes, cannot be ruled out. Although the authors adjusted for multiple confounders, the complexity of liver carcinogenesis, especially in the context of metabolic diseases, requires caution in making direct causal inferences.
Second, the study uses a definition of MASLD that combines steatotic liver disease (fatty liver index ≥60) with at least one cardiometabolic risk factor. While this definition is useful for stratifying populations for epidemiologic studies, its applicability as a clinical tool for predicting HCC remains uncertain. A major limitation is the reliance on the fatty liver index, which, although validated in some populations, may not be universally applicable. The performance of the fatty liver index in non-Western populations, such as the Korean cohort studied here, may be influenced by regional differences in body composition, diet, and genetic factors. In addition, MASLD as a concept is still evolving, and there is a lack of consensus on the thresholds and components that define the disease, which may limit the reproducibility of findings in other cohorts.
In addition to the factors controlled for in the analysis, this study did not account for several other potential confounders that may have influenced the observed association between MASLD and HCC. One such factor is the role of genetic predisposition. Variants in genes involved in lipid metabolism, such as PNPLA3, TM6SF2 and MBOAT7, have been shown to influence both the development of MASLD [2] and the progression to HCC [3]. Genetic variation may contribute to an individual's susceptibility to liver disease independent of metabolic risk factors, but these were not included in the study's analysis. Another important confounder is the presence of comorbidities such as chronic viral hepatitis (hepatitis B virus or hepatitis C virus) or hemochromatosis, both of which can accelerate liver damage and increase the risk of HCC independently of metabolic dysfunction. In addition, the study did not include information on liver fibrosis, which is a well-established risk factor for the development of HCC in individuals with MASLD. The degree of liver fibrosis at baseline, which may not have been captured or adequately measured in the administrative data, could significantly influence the risk of HCC, and failure to adjust for this factor may result in an overestimation or underestimation of the association between MASLD and HCC. Additionally, lifestyle factors such as dietary patterns, physical activity, and smoking, which may modulate the progression of MASLD and liver carcinogenesis, were not fully accounted for. These factors are critical because they interact with metabolic risk factors and could either exacerbate or attenuate the development of HCC. Finally, the study did not consider the role of the gut microbiota, which has been increasingly implicated in the pathogenesis of both MASLD and HCC. Dysbiosis, or an imbalance in the gut microbiome, could influence systemic inflammation, insulin resistance, and liver fibrosis, thereby contributing to the risk of HCC in individuals with MASLD [4]. Failure to account for these factors introduces the possibility of residual confounding that could undermine the robustness of the observed associations. Therefore, it is suggested that future research could address these confounding factors to overcome the limitations of the original study analysis.
The study used data from mandatory health screenings, which, while comprehensive, introduce potential biases. First, there may be a selection bias because the participants who regularly undergo health screenings may not be representative of the general population. Those who participate in such screenings are likely to be more health conscious, which could result in an underestimation of the true incidence of MASLD and HCC in the general population. In addition, reliance on administrative health records to identify HCC events introduces the risk of misclassification or underreporting of cases, particularly in individuals who may have had early stage or asymptomatic HCC.
Finally, a notable finding of the study is the increased risk of HCC in individuals with resolved MASLD. While this suggests a persistent, albeit residual, risk of HCC even after resolution of MASLD, the biological mechanisms underlying this phenomenon remain unclear. The study does not address the possibility that other factors, such as previous liver injury or the presence of subclinical fibrosis, may contribute to this increased risk. Furthermore, it remains unclear whether individuals with resolved MASLD, who may have undergone lifestyle changes or pharmacological interventions, retain a similar risk profile to those with persistent MASLD. This raises the question of whether the observed risk in participants with resolved MASLD is truly due to residual metabolic dysfunction or an artifact of the study design.
Notes
Authors’ contribution
Hai Xu wrote the manuscript, Yong Zhou provided methodological and theoretical support, and Huikun Wu revised the manuscript and provided financial support.
Acknowledgements
Hubei International Science and Technology Cooperation Program (2024EHA019).
Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
HCC
hepatocellular carcinoma
MASLD
metabolic dysfunction-associated steatotic liver disease