Review for 10.1186/s12876-025-03715-3 (2025)

Title: Higher relative fat mass was associated with a higher prevalence of gallstones in US adults
Version: 2 Date: 06 Feb 2025
Reviewer's report:
Dear Editor,
Thank you for the opportunity to review the manuscript titled "Higher Relative Fat Mass Was
Associated with a Higher Prevalence of Gallstones in US Adults." This study examines the
relationship between relative fat mass (RFM) and the prevalence of gallstones using data from
the National Health and Nutrition Examination Survey (NHANES). The manuscript is well-
structured and provides compelling evidence suggesting that RFM is a more accurate predictor
of gallstone risk than BMI, particularly in younger adults and females. The findings are novel
and have significant clinical relevance, offering potential avenues for improving early detection
and management of gallstones in high-risk populations.
Statistical Comments:
Clarification of RFM and BMI Comparison: The authors compare the performance of RFM
and BMI in predicting gallstones, with RFM showing a higher AUC value (0.674 vs. 0.634).
While the comparison is valuable, a more detailed explanation of the clinical significance of this
difference would be helpful. What are the implications of the relatively small difference in AUC
for clinical decision-making? Should healthcare providers consider RFM as a routine measure
alongside BMI for more accurate risk assessment of gallstones?
Consideration of Confounding Variables: The manuscript appropriately adjusts for various
covariates in the analysis. However, given the complex nature of gallstone disease and its many
risk factors, the authors should further discuss potential residual confounding. For example,
factors like physical activity level, medication use, and family history of gallstones could
influence the results. How might these unmeasured variables impact the associations between
RFM and gallstone prevalence?
Nonlinear Association and Threshold Effect: The authors identify a nonlinear association
between RFM and gallstone prevalence with a threshold effect at RFM = 19.8. This finding
is intriguing but would benefit from a more in-depth discussion. Could there be a biological
or metabolic explanation for this threshold? Furthermore, how might this threshold be used in
clinical practice to identify individuals at higher risk for gallstones? A discussion of how to
implement this threshold in clinical screening could enhance the manuscript.
Clinical Comments:
Clinical Relevance of RFM for Gallstone Prediction: The study’s results indicate that RFM is
a significant predictor of gallstone prevalence, particularly in younger adults and females. The
clinical implications of this finding should be further explored. Could RFM be incorporated
into routine screening practices for individuals at high risk for gallstones, especially those with
obesity or metabolic syndrome? The authors could provide more guidance on how RFM can be
applied in clinical settings to identify individuals who would benefit from preventative measures,
such as dietary changes or earlier interventions.
Potential Impact of RFM Management on Gallstone Prevention: Given the strong association
between higher RFM and gallstones, the authors should discuss potential preventive strategies
targeting RFM reduction. Could lifestyle interventions aimed at reducing body fat, such as
physical activity or dietary changes, help reduce gallstone risk? Are there any pharmacological
approaches that could be explored to target RFM, especially in high-risk populations?
Gender Differences in RFM and Gallstones: The authors find that the association between
RFM and gallstones is more significant in females. This result is consistent with previous
research on gender differences in gallstone disease, but the authors could further explore the
underlying mechanisms. How does gender influence the way RFM impacts gallstone formation,
and are there hormonal or metabolic differences that might explain this finding? A more detailed
discussion of these factors would strengthen the clinical relevance of the study.
Impact of Gut Microbiota on Gallstone Development: Given the emerging evidence on the
influence of gut microbiota in metabolic diseases and obesity-related conditions, the authors
should consider discussing the potential impact of gut microbiota on the development of
gallstones. Research suggests that alterations in gut microbiota composition may affect lipid
metabolism, inflammation, and bile acid production, all of which could contribute to gallstone
formation. The authors are encouraged to cite and integrate the following studies that explore
the relationship between gut microbiota and gallstone risk:
DOI: 10.1016/j.dsx.2024.103110
DOI: 10.1093/nutrit/nuad086
DOI: 10.1186/s13643-023-02299-x
DOI: 10.1038/s41467-021-27758-8
DOI: 10.3389/fcimb.2023.1253447
DOI: 10.3389/fnut.2023.1089909
These references provide insights into how microbiota dysbiosis may influence obesity, bile acid
metabolism, and the inflammatory processes that underlie gallstone formation. By integrating
these studies, the authors can strengthen the manuscript by providing a more comprehensive
discussion of the role of the gut microbiota in gallstone pathogenesis and explore potential
interventions that target microbiota modulation as a preventive strategy for gallstone disease.