Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This comprehensive narrative review provides a timely and well-organized synthesis of current evidence on the diagnosis and management of metabolic-associated fatty liver disease (MAFLD) in children with severe obesity. The authors address a critical and growing clinical challenge, offering practical screening algorithms and management strategies based on recent guidelines and landmark studies. The manuscript is highly relevant, especially given the rising prevalence of severe obesity and its association with accelerated progression to advanced liver disease in pediatric populations. The review effectively highlights the unique diagnostic and therapeutic challenges in pediatric MAFLD, particularly in the context of severe obesity. The proposed screening algorithm, which recommends initiating alanine aminotransferase (ALT) testing in children aged 9-11 years with obesity and in younger children with severe obesity or additional risk factors, is evidence-based and clinically useful.

 

Hereby are some points needed to be amended, towards improving the manuscript’s quality:

1. The authors should clarify the rationale for retaining the term MAFLD instead of MASLD (Metabolic Dysfunction-Associated Steatotic Liver Disease) throughout the manuscript, given the recent consensus update. A brief discussion on the implications of this terminology shift for pediatric practice would strengthen the introduction and discussion.
2. The manuscript would benefit from a more explicit discussion of the limitations of non-invasive diagnostic tools (e.g., ultrasound, transient elastography) in children with severe obesity, especially regarding accuracy and reproducibility. The authors mention these limitations, but a deeper exploration of their clinical impact would be valuable.
3. The review could further elaborate on the evidence for bariatric surgery in adolescents with severe obesity and MAFLD, including indications, long-term outcomes, and risks. The authors note the need for more research, but a summary of current best practices would be helpful for clinicians.
4. The abstract and introduction are clear, but the abstract could more concisely highlight the main findings and clinical relevance.
5. The manuscript's tables and figures are well-presented, but ensuring all abbreviations are defined upon first use (e.g., ALT, MAFLD, MASLD) will improve readability for a broader audience.
6. The discussion section could briefly compare the current findings with similar studies in the field to contextualize the novelty and significance of the proposed algorithms.
7. The manuscript would benefit from a brief discussion of the potential impact of new noninvasive biomarkers (e.g., TyG-WC, lipid-derived indices) on future screening and management strategies.
8. Please mention and discuss the association of sympathetic nervous system overdrive and MASLD / MAFLD, its potential therapeutic target in adults, and how could this be implemented in adolescence (please read and refer to https://pubmed.ncbi.nlm.nih.gov/39750025/)

 

Author Response

Reviewer 1:
1. This comprehensive narrative review provides a timely and well-organized synthesis of current
evidence on the diagnosis and management of metabolic-associated fatty liver disease (MAFLD) in
children with severe obesity. The authors address a critical and growing clinical challenge, offering
practical screening algorithms and management strategies based on recent guidelines and landmark
studies. The manuscript is highly relevant, especially given the rising prevalence of severe obesity and
its association with accelerated progression to advanced liver disease in pediatric populations. The
review effectively highlights the unique diagnostic and therapeutic challenges in pediatric MAFLD,
particularly in the context of severe obesity. The proposed screening algorithm, which recommends
initiating alanine aminotransferase (ALT) testing in children aged 9-11 years with obesity and in
younger children with severe obesity or additional risk factors, is evidence-based and clinically useful.
Response: We thank the Reviewer for the very positive and insightful evaluation of our
manuscript. We appreciate the recognition of its clinical relevance, clarity, and the practical value
of the proposed evidence-based screening algorithm for pediatric MAFLD, particularly in children
with severe obesity.
Hereby are some points needed to be amended, towards improving the manuscript’s quality:
1. The authors should clarify the rationale for retaining the term MAFLD instead of MASLD
(Metabolic Dysfunction-Associated Steatotic Liver Disease) throughout the manuscript, given the
recent consensus update.
Response: In accordance with the Editor’s request, the terminology throughout the manuscript has
been updated from MAFLD to MASLD.
A brief discussion on the implications of this terminology shift for pediatric practice would strengthen
the introduction and discussion.
Response: We thank the Reviewer for this helpful comment. In response, we have added a brief
discussion on the implications of the terminology shift for pediatric practice to both the
Introduction (lines 50-53) and the Discussion sections (lines 408-412).
2. The manuscript would benefit from a more explicit discussion of the limitations of non-invasive
diagnostic tools (e.g., ultrasound, transient elastography) in children with severe obesity, especially
regarding accuracy and reproducibility. The authors mention these limitations, but a deeper
exploration of their clinical impact would be valuable.
Response: Thank you for this noteworthy suggestion. In response, we have added a new
paragraph highlighting this aspect in Discussion (lines 175-185) to emphasize the limitations of
non-invasive diagnostic tools in children with severe obesity, with particular focuss on issues of
accuracy, reproducibility, and their potential impact on clinical decision-making.
3. The review could further elaborate on the evidence for bariatric surgery in adolescents with severe
obesity and MAFLD, including indications, long-term outcomes, and risks. The authors note the need
for more research, but a summary of current best practices would be helpful for clinicians.
Response: We thank the Reviewer for this important and constructive comment, we agree that
section concerning bariatric surgery should be more expanded, especially in the article covering
treatment of children with severe obesity. In response, we have expanded the Discussion (lines
307-334) about indications, potential long-term metabolic effects, and risks associate with
bariatric surgery in adolescents, while also highlighting existing gaps in pediatric data.
4. The abstract and introduction are clear, but the abstract could more concisely highlight the main
findings and clinical relevance.
Response: Thank you for pointing this out. We have revised the abstract to more concisely
emphasize the key findings and their clinical importance (lines 19-36).
5. The manuscript's tables and figures are well-presented, but ensuring all abbreviations are defined
upon first use (e.g., ALT, MAFLD, MASLD) will improve readability for a broader audience.
Response: Thank you for this comment. Accordingly, we have revised the text, tables, and figures
to ensure that all abbreviations are clearly defined at their first occurrence in the text. We added
explanation of the abbreviations used in each figure (lines 108, 203-204, 209-213).
6. The discussion section could briefly compare the current findings with similar studies in the field to
contextualize the novelty and significance of the proposed algorithms.
Response: We appreciate this valuable comment. In response, we have revised the Discussion
section to include a brief comparison between our proposed algorithms and existing pediatric
guidelines. We emphasize the additional focus on children with severe obesity as the highest-risk
group and address the practical limitations of non-invasive diagnostic tools in this population. This
paragraph has been added at the end of the Discussion to better contextualize the novelty and
clinical relevance of the proposed algorithms (lines 413-420).
7. The manuscript would benefit from a brief discussion of the potential impact of new noninvasive
biomarkers (e.g., TyG-WC, lipid-derived indices) on future screening and management strategies.
Response: We appreciate this comment. We would like to clarify that the potential impact of
emerging noninvasive biomarkers, including TyG-WC and lipid-derived indices, on future screening
and management strategies is already discussed in detail in the manuscript (Section 3.1.2, Future
Directions). This section summarizes both adult and pediatric evidence supporting their role in risk
stratification and early detection, highlights their practical advantages as simple and cost-effective
tools, and emphasizes the need for further pediatric validation before routine clinical
implementation. To improve clarity, we ensured that this section explicitly links these biomarkers
to future screening strategies and management (lines 233-262).
8. Please mention and discuss the association of sympathetic nervous system overdrive and MASLD /
MAFLD, its potential therapeutic target in adults, and how could this be implemented in adolescence
(please read and refer to https://pubmed.ncbi.nlm.nih.gov/39750025/)
Response: Thank you for this insightful comment. In response, we have expanded the Treatment -
Future Directions (lines 369-383) section to explicitly address the association between sympathetic
nervous system overactivity and MASLD, its emerging role as a therapeutic target in adults, and
the potential for future translation into adolescent care. 

Reviewer 2 Report

Comments and Suggestions for Authors

For the evaluation of this narrative review, I explicitly applied the SANRA scale (Scale for the Assessment of Narrative Review Articles), a validated tool designed to assess the quality of non-systematic reviews (Baethge C, Goldbeck-Wood S, Mertens S. SANRA – a scale for the quality assessment of narrative review articles. Research Integrity and Peer Review. 2019;4:5. https://doi.org/10.1186/s41073-019-0064-8). Based on this framework, the manuscript achieves a good overall quality score and is suitable for publication after minor revisions, as detailed below. The importance of the topic is clearly justified in the Introduction, and the clinical and public health relevance of paediatric MAFLD in the context of severe obesity is convincingly presented. The aims of the review are explicitly stated and remain consistent throughout the manuscript. The scientific reasoning is generally sound, with appropriate integration of current evidence and clinical implications. Regarding the Materials and Methods section (approximately lines 112–122) lists the databases consulted and the main keywords used. However, the description of the literature search is largely narrative. Although a systematic approach is not required for this type of review, I suggest adding a brief clarification on the general inclusion and exclusion criteria (e.g., paediatric age range)and the rationale for prioritising studies published between 2019 and 2025. This minor addition would enhance transparency and methodological clarity, in line with SANRA item 3, without altering the narrative nature of the review. The manuscript appropriately introduces the change in nomenclature from NAFLD/MAFLD to MASLD/MASH (approximately lines 43–52). However, MAFLD and MASLD are used interchangeably in some sections (e.g., lines 311–317). I recommend clearly stating which terminology is adopted throughout the manuscript and maintaining consistency. 

Regarding the formula reported for the TyG index, it differs from the formulation most commonly cited in the literature, which typically includes a natural logarithmic transformation. Please verify the formula, specify the measurement units, and clarify whether this represents a study-specific variant to avoid potential clinical misinterpretation. Similarly, the statement regarding the lack of established paediatric cut-off values for elastography (around lines 164–167) would benefit from a minor grammatical revision (“So far” instead of “As far”) and, if possible, the addition of a reference highlighting the heterogeneity of paediatric cut-offs. Additionally,I have noted a redundant citation of the NASPGHAN guidelines (lines 464–483). If these refer to the same document, I suggest removing the duplication or clarifying whether different versions or sections are cited.  Also, a stylistic repetition (“usually… usually”) is present around lines 126–127 and can be easily corrected. Furthermore, there is an inconsistency in abbreviations between “MRI-PDFF” (around line 156) and “MDI-PDFF” (around lines 389–390), which should be harmonized. In the end, as a constructive suggestion, I encourage the authors to use the SANRA scale as a self-assessment tool when revising the manuscript.

Author Response

Reviewer 2:
For the evaluation of this narrative review, I explicitly applied the SANRA scale (Scale for the
Assessment of Narrative Review Articles), a validated tool designed to assess the quality of nonsystematic reviews (Baethge C, Goldbeck-Wood S, Mertens S. SANRA – a scale for the quality
assessment of narrative review articles. Research Integrity and Peer Review. 2019;4:5.
https://doi.org/10.1186/s41073-019-0064-8). Based on this framework, the manuscript achieves a
good overall quality score and is suitable for publication after minor revisions, as detailed below.
1. The importance of the topic is clearly justified in the Introduction, and the clinical and public
health relevance of paediatric MAFLD in the context of severe obesity is convincingly presented.
2. The aims of the review are explicitly stated and remain consistent throughout the manuscript. The
scientific reasoning is generally sound, with appropriate integration of current evidence and clinical
implications.
Response: We appreciate the reviewer thorough evaluation of our manuscript using the SANRA
scale and thank for the positive overall assessment. In response to the revisions suggested below,
we have carefully revised the manuscript to further improve clarity and alignment with SANRA
criteria.
3. Regarding the Materials and Methods section (approximately lines 112–122) lists the databases
consulted and the main keywords used. However, the description of the literature search is largely
narrative. Although a systematic approach is not required for this type of review, I suggest adding a
brief clarification on the general inclusion and exclusion criteria (e.g., paediatric age range)and the
rationale for prioritising studies published between 2019 and 2025. This minor addition would
enhance transparency and methodological clarity, in line with SANRA item 3, without altering the
narrative nature of the review.
Response: Thank you for this helpful suggestion. We have revised the Methods section to include a
brief clarification of the general inclusion and exclusion criteria, including the pediatric age range,
as well as the rationale for prioritizing studies published between 2019 and 2025 (lines 119-124).
4. The manuscript appropriately introduces the change in nomenclature from NAFLD/MAFLD to
MASLD/MASH (approximately lines 43–52). However, MAFLD and MASLD are used interchangeably
in some sections (e.g., lines 311–317). I recommend clearly stating which terminology is adopted
throughout the manuscript and maintaining consistency.
Response: In accordance with the Editor’s request, the terminology throughout the manuscript has
been updated from MAFLD to MASLD.
5. Regarding the formula reported for the TyG index, it differs from the formulation most commonly
cited in the literature, which typically includes a natural logarithmic transformation. Please verify the
formula, specify the measurement units, and clarify whether this represents a study-specific variant
to avoid potential clinical misinterpretation.
Response: Thank you for identifying this error. The natural logarithm (“ln”) was inadvertently
omitted from the formula during manuscript editing. The correct formula is: TyG = ln(fasting
triglycerides (mg/dL) × fasting glucose (mg/dL))/2, and TyG-WC = TyG × WC. We have corrected
the formula in the manuscript and clarified the measurement units to avoid any potential clinical
misinterpretation (lines 236-237).
6. Similarly, the statement regarding the lack of established paediatric cut-off values for
elastography (around lines 164–167) would benefit from a minor grammatical revision (“So far”
instead of “As far”) and, if possible, the addition of a reference highlighting the heterogeneity of
paediatric cut-offs.
Response: Thank you for this helpful comment. The wording has been corrected to use “So far”
instead of “As far,” and an additional references have been included to emphasize the
heterogeneity of this population (lines 171-174).
7. Additionally,I have noted a redundant citation of the NASPGHAN guidelines (lines 464–483). If
these refer to the same document, I suggest removing the duplication or clarifying whether different
versions or sections are cited.
Response: Thank you for this observation. Indeed, the repeated reference to the NASPGHAN
guidelines referred to the same document, and the redundancy has been removed accordingly.
8. Also, a stylistic repetition (“usually… usually”) is present around lines 126–127 and can be easily
corrected.
Response: Thank you for pointing this out. We have corrected the stylistic repetition in the
indicated section (line 133).
9. Furthermore, there is an inconsistency in abbreviations between “MRI-PDFF” (around line 156)
and “MDI-PDFF” (around lines 389–390), which should be harmonized.
Response: Thank you for noting this inconsistency. We have corrected and harmonized the
abbreviation throughout the manuscript to “MRI-PDFF” (line 468).
10. In the end, as a constructive suggestion, I encourage the authors to use the SANRA scale as a
self-assessment tool when revising the manuscript.
Response: It appears that, after implementing all reviewers’ suggestions, the manuscript now
meets all required SANRA scale criteria. We thank the reviewer for their constructive comments
and guidance, which helped to further improve the quality of the manuscript.
Thank you once again for your valuable contribution to the enhancement of our manuscript. I
believe that your comments have not only improved the clarity of the presentation but have also
contributed significantly to the overall strength of the research. Your guidance has been
instrumental in refining the key aspects of the paper. Please feel free to reach out if further
clarification or information is required.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I have read the revised version and all points have been thoroughly amended.