Review for 10.1186/s12876-025-03620-9 (2025)

Title: The Serum Hepcidin and the Hepcidin/Ferritin ratio in NAFLD: A Systematic Review
and Meta-Analysis
Version: 3 Date: 30 Nov 2024
Reviewer:  Ehsan Amini-Salehi
Reviewer's report:
Dear Editor,
Thank you for inviting me to review the manuscript titled "The Serum Hepcidin and the
Hepcidin/Ferritin ratio in NAFLD: A Systematic Review and Meta-Analysis." This is a well-
organized and relevant study addressing the potential association of serum hepcidin and
hepcidin/ferritin ratio with NAFLD, a topic of clinical and scientific interest. The study provides
insights into iron metabolism in NAFLD, including its potential use as a biomarker for early
detection. While the research is comprehensive, there are areas that could benefit from further
clarity and improvement.
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General Comments:
1. Title and Abstract:
The title and abstract clearly summarize the study objectives and findings. However, the abstract
could briefly acknowledge the limitations (e.g., heterogeneity of the included studies) to provide
a balanced perspective.
2. Introduction:
The introduction effectively outlines the importance of iron metabolism in NAFLD. However,
a concise description of how this study fills gaps in the existing literature would strengthen the
rationale.
3. Language and Grammar:
The manuscript is well-written but would benefit from minor grammatical revisions, particularly
in the results and discussion sections, for clarity and fluency.
4. Conclusion:
The conclusion emphasizes the significance of findings but does not provide actionable
recommendations for clinicians. Adding this aspect would enhance the manuscript's utility.
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Clinical Comments:
1. Relevance of Hepcidin as a Biomarker:
The manuscript discusses hepcidin's potential role but lacks detail on its practical applicability
for clinical decision-making. For example, at what threshold levels could it be diagnostically
significant?
2. NAFLD Subtypes:
The study does not explore differences in hepcidin levels among NAFLD subtypes, such as
NASH versus simple steatosis. Including this analysis or acknowledging its absence would be
valuable.
3. Obesity and Hepcidin Interaction:
While the link between obesity and hepcidin is discussed, the clinical implications (e.g., how
obesity might confound hepcidin as a biomarker) are not fully explored.
4. Ferritin as a Confounder:
Since ferritin is an acute-phase reactant, its elevation in inflammatory states could confound the
findings. This potential bias should be more explicitly addressed in the discussion.
5. Clinical Guidelines:
The study should suggest how its findings might be incorporated into existing NAFLD
diagnostic guidelines or pathways for future research.
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Statistical Comments:
1. Heterogeneity:
The high heterogeneity (I² > 50%) in the meta-analysis warrants a more detailed exploration of
sources beyond subgroup analysis, such as publication year, geographical location, or study size.
2. Sensitivity Analysis:
While sensitivity analysis is performed, the manuscript should include a summary of its findings
to reassure readers about the robustness of the results.
3. Publication Bias:
Although Begg’s and Egger’s tests indicate no publication bias, a funnel plot would provide a
more intuitive visualization.
4. Meta-Regression:
The meta-regression focuses only on assay methods. Including additional variables, such as
study quality or participant demographics, could yield further insights.
5. Statistical Reporting:
Confidence intervals and p-values are reported but should be complemented with a discussion
of effect sizes' clinical relevance, particularly for subgroup analyses.
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General Suggestions for Improvement:
• Figures and Tables:
Figures 2–5 are clear but could include annotations or arrows to highlight key findings for readers
unfamiliar with meta-analysis methods.
• Limitations:
The limitations section should more explicitly discuss the reliance on case-control studies and
the challenges in establishing causality.
• Future Directions:
Adding a section on how findings could guide prospective studies, particularly for standardizing
hepcidin assay methods, would increase the manuscript's impact.
• Ethical Considerations:
Since the study involves data extraction from previously published works, a brief statement
clarifying adherence to ethical standards (e.g., PRISMA guidelines) would be helpful.