Title: Effect of Allostatic Load on hepatic steatosis and Fatty Liver-Associated Liver Fibrosis
Version: 5 Date: 19 May 2025
Reviewer's report:
This manuscript addresses an important and underexplored link between systemic stress
(measured by allostatic load index, ALI) and liver disease progression. The authors utilize
NHANES 2017–2020 data to investigate associations between ALI and both hepatic steatosis
and fibrosis, supported by subgroup and mediation analyses. The revised version shows
substantial improvement in clarity, methodological transparency, and analytical rigor. I
commend the authors for their detailed revisions and thoughtful responses to prior critiques.
Major Comments:
Clarity on the Directionality of Findings (Causal Inference):The authors appropriately
acknowledge the limitations of causal inference in a cross-sectional design and have tempered
language throughout. I appreciate the discussion of temporal ambiguity and reverse causation.
However, consider rephrasing the Conclusion section slightly to reinforce this limitation (e.g.,
“Our findings support an association between ALI and hepatic outcomes, but longitudinal
studies are needed to establish causality.”)
Integration of CAP and LSM Limitations: The use of transient elastography (CAP and LSM)
is well-justified and aligned with current noninvasive standards, but the authors should briefly
mention that measurement accuracy can vary by BMI, diabetes status, and operator variability.
A short sentence in the Methods or Limitations would strengthen transparency.
Interpretation of FIB-4 Null Findings: The manuscript acknowledges the absence of association
between ALI and FIB-4 in adjusted models. While the explanation is adequate, it may benefit
from a clearer summary in the Discussion (e.g., “This discrepancy may reflect age and
platelet-dependent biases in FIB-4 estimation, particularly in older populations with chronic
comorbidities.”)
Potential for Bidirectional Interaction (Steatosis # ALI): The authors touch on the intriguing
possibility of a bidirectional relationship between ALI and steatosis. This is an insightful idea—
consider expanding the Discussion slightly to propose how this cycle might be tested in future
longitudinal or mechanistic studies.
Minor Comments:
Terminology Consistency: There is still some variation between “unstable load,” “allogeneic
load,” and “allostatic load index.” Please standardize consistently to “Allostatic Load Index
(ALI)” across the manuscript.
Subgroup Analysis Detail: Figures 2 and 3 are informative, but adding a brief interpretation
of key subgroup interactions (e.g., age, comorbidities) in the Results would help readers better
appreciate clinical relevance.
Language and Grammar: While improved overall, several minor language issues persist (e.g.,
“those comments are all valuable and very helpful” could be revised to “The comments were
valuable and helpful…”). Consider one final proofreading pass with a native English editor.
Table Presentation: Tables are detailed and useful but dense. For publication, consider whether
Tables 5–7 might be better suited as supplemental materials, focusing the main text on Tables
1–4 and key subgroup results.
Title: Effect of Allostatic Load on hepatic steatosis and Fatty Liver-Associated Liver Fibrosis
Version: 5 Date: 19 May 2025
Reviewer's report:
This manuscript addresses an important and underexplored link between systemic stress
(measured by allostatic load index, ALI) and liver disease progression. The authors utilize
NHANES 2017–2020 data to investigate associations between ALI and both hepatic steatosis
and fibrosis, supported by subgroup and mediation analyses. The revised version shows
substantial improvement in clarity, methodological transparency, and analytical rigor. I
commend the authors for their detailed revisions and thoughtful responses to prior critiques.
Major Comments:
Clarity on the Directionality of Findings (Causal Inference):The authors appropriately
acknowledge the limitations of causal inference in a cross-sectional design and have tempered
language throughout. I appreciate the discussion of temporal ambiguity and reverse causation.
However, consider rephrasing the Conclusion section slightly to reinforce this limitation (e.g.,
“Our findings support an association between ALI and hepatic outcomes, but longitudinal
studies are needed to establish causality.”)
Integration of CAP and LSM Limitations: The use of transient elastography (CAP and LSM)
is well-justified and aligned with current noninvasive standards, but the authors should briefly
mention that measurement accuracy can vary by BMI, diabetes status, and operator variability.
A short sentence in the Methods or Limitations would strengthen transparency.
Interpretation of FIB-4 Null Findings: The manuscript acknowledges the absence of association
between ALI and FIB-4 in adjusted models. While the explanation is adequate, it may benefit
from a clearer summary in the Discussion (e.g., “This discrepancy may reflect age and
platelet-dependent biases in FIB-4 estimation, particularly in older populations with chronic
comorbidities.”)
Potential for Bidirectional Interaction (Steatosis # ALI): The authors touch on the intriguing
possibility of a bidirectional relationship between ALI and steatosis. This is an insightful idea—
consider expanding the Discussion slightly to propose how this cycle might be tested in future
longitudinal or mechanistic studies.
Minor Comments:
Terminology Consistency: There is still some variation between “unstable load,” “allogeneic
load,” and “allostatic load index.” Please standardize consistently to “Allostatic Load Index
(ALI)” across the manuscript.
Subgroup Analysis Detail: Figures 2 and 3 are informative, but adding a brief interpretation
of key subgroup interactions (e.g., age, comorbidities) in the Results would help readers better
appreciate clinical relevance.
Language and Grammar: While improved overall, several minor language issues persist (e.g.,
“those comments are all valuable and very helpful” could be revised to “The comments were
valuable and helpful…”). Consider one final proofreading pass with a native English editor.
Table Presentation: Tables are detailed and useful but dense. For publication, consider whether
Tables 5–7 might be better suited as supplemental materials, focusing the main text on Tables
1–4 and key subgroup results.
Please review this paper.
user
Title: Effect of Allostatic Load on hepatic steatosis and Fatty Liver-Associated Liver Fibrosis
Version: 5 Date: 19 May 2025
Reviewer's report:
This manuscript addresses an important and underexplored link between systemic stress
(measured by allostatic load index, ALI) and liver disease progression. The authors utilize
NHANES 2017–2020 data to investigate associations between ALI and both hepatic steatosis
and fibrosis, supported by subgroup and mediation analyses. The revised version shows
substantial improvement in clarity, methodological transparency, and analytical rigor. I
commend the authors for their detailed revisions and thoughtful responses to prior critiques.
Major Comments:
Clarity on the Directionality of Findings (Causal Inference):The authors appropriately
acknowledge the limitations of causal inference in a cross-sectional design and have tempered
language throughout. I appreciate the discussion of temporal ambiguity and reverse causation.
However, consider rephrasing the Conclusion section slightly to reinforce this limitation (e.g.,
“Our findings support an association between ALI and hepatic outcomes, but longitudinal
studies are needed to establish causality.”)
Integration of CAP and LSM Limitations: The use of transient elastography (CAP and LSM)
is well-justified and aligned with current noninvasive standards, but the authors should briefly
mention that measurement accuracy can vary by BMI, diabetes status, and operator variability.
A short sentence in the Methods or Limitations would strengthen transparency.
Interpretation of FIB-4 Null Findings: The manuscript acknowledges the absence of association
between ALI and FIB-4 in adjusted models. While the explanation is adequate, it may benefit
from a clearer summary in the Discussion (e.g., “This discrepancy may reflect age and
platelet-dependent biases in FIB-4 estimation, particularly in older populations with chronic
comorbidities.”)
Potential for Bidirectional Interaction (Steatosis # ALI): The authors touch on the intriguing
possibility of a bidirectional relationship between ALI and steatosis. This is an insightful idea—
consider expanding the Discussion slightly to propose how this cycle might be tested in future
longitudinal or mechanistic studies.
Minor Comments:
Terminology Consistency: There is still some variation between “unstable load,” “allogeneic
load,” and “allostatic load index.” Please standardize consistently to “Allostatic Load Index
(ALI)” across the manuscript.
Subgroup Analysis Detail: Figures 2 and 3 are informative, but adding a brief interpretation
of key subgroup interactions (e.g., age, comorbidities) in the Results would help readers better
appreciate clinical relevance.
Language and Grammar: While improved overall, several minor language issues persist (e.g.,
“those comments are all valuable and very helpful” could be revised to “The comments were
valuable and helpful…”). Consider one final proofreading pass with a native English editor.
Table Presentation: Tables are detailed and useful but dense. For publication, consider whether
Tables 5–7 might be better suited as supplemental materials, focusing the main text on Tables
1–4 and key subgroup results.
assistant