Review for 10.1186/s12876-025-04212-3 (2025)

Title: Association of Alpha-1 Acid Glycoprotein with Hepatic Steatosis and Liver Fibrosis
Among Women: A Population-Based Study
Version: 1 Date: 27 Apr 2025
Reviewer's report:
This study explores the association between serum alpha-1-acid glycoprotein (AGP) levels and
hepatic steatosis and fibrosis among women aged 18–49 years using NHANES 2017–2023 data.
The topic is important and novel, especially given the increasing attention to inflammatory
biomarkers and liver health. The methodology is generally sound, but several key revisions are
necessary to improve the manuscript’s clarity, rigor, and scientific reporting.
In the Abstract, the causal language should be moderated. For example, "AGP may be associated
with hepatic steatosis" is appropriate, but similar moderation is needed when discussing the
findings throughout the text (including in the Discussion and Conclusion).
In the Methods section (Section 2), the authors describe excluding individuals with hepatitis B
or C infection, heavy alcohol intake, and missing data, which is appropriate. However, it would
improve clarity if the authors briefly explain why only women were included (e.g., restriction
to better control confounding by sex hormones and body composition?).
The statistical approach is mostly appropriate. In the section describing regression modeling
(Section 2, Statistical Analysis), the authors should more clearly state whether the survey
design (sampling weights, stratification, and clustering) was fully accounted for in all models,
especially in subgroup and threshold analyses.
Regarding Table 1 and Table 2:
The way characteristics are reported is clear. However, please clarify that some variables (e.g.,
CAP, LSM, AGP) were used as continuous variables but also categorized based on established
thresholds for descriptive purposes.
When presenting p-values, it would be better to avoid reporting them as "<0.0001" repeatedly
— providing exact values would be more informative.
In the Results section:
Table 3 (Ln AGP and CAP association) clearly shows robust associations. However, when
discussing these results in the text, it should be emphasized that the magnitude of association
attenuated after full adjustment (from 82.06 to 11.93), suggesting possible confounding.
The subgroup analysis results in Table 4 should be interpreted more cautiously. Although
interactions were tested, not all subgroup comparisons were statistically significant. Please avoid
overinterpreting borderline p-values (e.g., BMI interaction p=0.0482).
In Table 5 and Figure 3, it is interesting that a threshold effect was detected between Ln AGP
and LSM. However, this result should be framed more cautiously in the Discussion because the
clinical relevance of the inflection point (-0.04 g/L) is unclear.
Figures:
Figure 2 (AGP vs CAP) and Figure 3 (AGP vs LSM) are informative, but legends should be
slightly expanded to mention the covariate-adjusted nature of the plots.
In the Discussion:
The biological plausibility linking AGP to hepatic steatosis is well-discussed. However, the
discussion of fibrosis mechanisms could be shortened slightly — multiple paragraphs seem to
restate similar points.
It would be helpful to include a brief paragraph comparing your findings to previous literature
that assessed systemic inflammation and liver outcomes, even if AGP specifically was not the
focus.
The limitations section is appropriately included but should be strengthened by acknowledging
possible reverse causality in cross-sectional analyses (e.g., could hepatic steatosis itself influence
AGP levels?).
Minor language polishing is needed throughout the manuscript (e.g., minor grammar, tense
inconsistencies, missing articles).
The limitations of this study include its cross-sectional design, which limits causal inference, the
lack of histologic confirmation of hepatic steatosis and fibrosis, potential residual confounding
despite multivariate adjustment, and the absence of medication data (which could influence AGP
levels). Moreover, the threshold effect identified requires cautious interpretation, and larger
longitudinal studies are needed to confirm these findings.