Review for 10.1186/s12876-025-03873-4 (2025)

Title: The non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio
as a predictor of all cause and cardiovascular mortality in United States adults with NAFLD:
a prospective cohort study
Version: 1 Date: 13 Mar 2025
Reviewer's report:
I would like to thank you for the opportunity to review the manuscript titled "The non-high-
density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio as a predictor of all-
cause and cardiovascular mortality in United States adults with NAFLD: a prospective cohort
study." This study investigates the prognostic role of the non-HDL-C to HDL-C ratio (NHHR)
in predicting all-cause and cardiovascular mortality in individuals with non-alcoholic fatty liver
disease (NAFLD). The findings provide valuable insights into how lipid ratios can serve as
predictors of adverse health outcomes in this high-risk population.
After thoroughly reviewing the manuscript, I have provided several comments and suggestions
to improve the clarity, depth, and impact of the study.
Clinical Comments:
Updated Prevalence of NAFLD: The manuscript would benefit from reporting the updated
global prevalence of NAFLD, which is currently estimated to be approximately 30.2%. This
statistic could be cited to better contextualize the significance of the study’s findings and
highlight the growing burden of NAFLD worldwide. The authors are encouraged to reference
the following article to support this updated context:
DOI: 10.1016/j.arcmed.2024.103043
Discussion of Novel Biomarkers: The authors focus on NHHR as a predictive biomarker, but
I encourage them to discuss other novel biomarkers that could offer additional insights into
cardiovascular risk in NAFLD patients. Specifically, biomarkers like the triglyceride-glucose
(TyG) index and the neutrophil to lymphocyte ratio (NLR) are gaining attention for their
role in predicting metabolic and cardiovascular outcomes. The authors should mention these
biomarkers and incorporate their discussion into the manuscript. I recommend that the authors
refer to and use the content of the following articles to inform this discussion:
DOI: 10.1186/s12944-024-02378-5
DOI: 10.1186/s12933-024-02392-y
DOI: 10.3389/fendo.2022.1043169
DOI: 10.1186/s12944-021-01457-1
These biomarkers are increasingly recognized as important predictors of cardiovascular and
metabolic risks, and integrating them into the manuscript would provide a broader perspective on
the utility of inflammatory and metabolic biomarkers in predicting mortality in NAFLD patients.
Clarifying the Mechanisms Linking NHHR to Mortality: The manuscript highlights the
association between NHHR and mortality but could benefit from a deeper exploration of the
pathophysiological mechanisms through which NHHR influences these outcomes. Specifically,
how does an elevated NHHR reflect underlying inflammation, lipid metabolism disturbances,
or atherogenesis in NAFLD? A more detailed discussion of these mechanisms would strengthen
the manuscript's biological and clinical relevance.
Statistical Comments:
Explanation of Non-Linear Relationships: The use of restricted cubic splines (RCS) to assess
non-linear associations between NHHR and mortality is an excellent approach. However, I
suggest providing a clearer explanation of how these non-linear relationships were interpreted
and how the inflection points were determined. It would also be useful to explain the clinical
significance of these points in more detail and how they could influence clinical decision-
making.
Model Adjustments and Confounders: The authors did a good job adjusting for important
covariates, but I recommend discussing how other potential confounders—such as medication
use (e.g., statins, antihypertensives), body fat distribution (e.g., visceral versus subcutaneous
fat), and other inflammatory biomarkers (e.g., C-reactive protein, interleukins)—were handled.
Addressing how these factors were controlled for will help clarify the robustness of the results.
Subgroup Analysis and Stratification: The manuscript discusses subgroup analysis, particularly
in relation to age, sex, and comorbidities like diabetes. However, it would be helpful to expand
on the factors that might contribute to these observed differences in subgroups. For instance, are
there differences in lipid metabolism, endothelial function, or inflammatory response that might
explain the observed associations in specific subgroups?