Metabolic Dysfunction-Associated Steatotic Liver Disease and the Risk of Chronic Periodontitis: A Nationwide Cohort Study
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis is a retrospective population-based cohort study based on data from a national health insurance service with 101,981 participants diagnosed with periodontitis. The association between metabolic dysfunction-associated steatotic liver disease and the risk of chronic periodontitis was evaluated.
The nature of retrospective analysis is however biased by the reliable data availability. This study is based on indirectly diagnosis of periodontitis. The diagnosis in not clinical, set by experienced periodontology specialists, but on potential procedures which could suggest the periodontal disease. However, some of the procedures used as classifiers of chronic periodontitis are not the disease specific, and are widely used in other indications and cannot be classified as “periodontal treatment”(e.g. tooth extraction, bone grafting for alveolar bone defects). Such a method of diagnosing chronic periodontitis lead to overestimation.
Likewise, using FLI as MASLD diagnostic tool produces bias of diagnosis. Having cut off 30, the FLI is estimated to be: sensitivity 67-87% and specificity of only 64-70%; with the cut off value the specificity is more than 80% (and you demonstrated that with FLI>60 participants had significantly higher risks for both chronic and severe chronic periodontitis; so the stringent entry criteria are important for reliable conclusions). In clinical practice the FLI result is than validated.
May by as a linking observation between MASLD and periodontitis you can mention the observations like: Kuraji R, Ye C, Zhao C, Gao L, Martinez A, Miyashita Y, Radaic A, Kamarajan P, Le C, Zhan L, Range H, Sunohara M, Numabe Y, Kapila YL. Nisin lantibiotic prevents NAFLD liver steatosis and mitochondrial oxidative stress following periodontal disease by abrogating oral, gut and liver dysbiosis. NPJ Biofilms Microbiomes. 2024 Jan 17;10(1):3. doi: 10.1038/s41522-024-00476-x.
Author Response
Response to Reviewer Comments
Manuscript ID: Nutrients_3378051
Manuscript title: Metabolic Dysfunction-associated Steatotic Liver Disease and the Risk of Chronic Periodontitis: A Nationwide Cohort Study
Thank you for providing us with the opportunity to revise our manuscript (ID: Nutrients-3378051) submitted to Nutrients.
We are grateful for the valuable and constructive comments from the reviewer, which have been instrumental in improving the quality of our work. In response to the reviewer’ suggestions, we have carefully revised the manuscript and provided detailed responses to each comment. The revised content is highlighted in blue in the updated manuscript for your convenience.
We appreciate your time and effort in overseeing the review process and look forward to your further evaluation of our work. Please feel free to let us know if additional revisions or clarifications are needed.
Thank you once again for this opportunity.
Reviewer 1 Comments
This is a retrospective population-based cohort study based on data from a national health insurance service with 101,981 participants diagnosed with periodontitis. The association between metabolic dysfunction-associated steatotic liver disease and the risk of chronic periodontitis was evaluated.
The nature of retrospective analysis is however biased by the reliable data availability. This study is based on indirectly diagnosis of periodontitis. The diagnosis in not clinical, set by experienced periodontology specialists, but on potential procedures which could suggest the periodontal disease. However, some of the procedures used as classifiers of chronic periodontitis are not the disease specific, and are widely used in other indications and cannot be classified as “periodontal treatment”(e.g. tooth extraction, bone grafting for alveolar bone defects). Such a method of diagnosing chronic periodontitis lead to overestimation.
Response : Thank you for your precise comments. As you mentioned, if we define chronic periodontitis only by ICD-10 codes, there is a lot of overdiagnosis. In particular, according to the previous study (J Clin Periodontol. 2024 Sep;51(9):1188-1198. doi: 10.1111/jcpe.14031.), there is a large amount of overdiagnosis after the scaling reimbursement policy, in July 2013. Accordingly, we defined the outcome as cases of chronic periodontitis (ICD-10 code, K05) with moderate to severe procedures, used in previous studies (J Periodontol. 2024 Jul 7. doi: 10.1002/JPER.24-0171. / BMC Pulm Med. 2019 Dec 30;19(1):268. doi: 10.1186/s12890-019-1017-1. / Oral Dis. 2024 Jul;30(5):3440-3451. doi: 10.1111/odi.14784.). For a more robust analysis, we conducted additional analysis with the outcome as cases of chronic periodontitis with severe procedures.
Likewise, using FLI as MASLD diagnostic tool produces bias of diagnosis. Having cut off 30, the FLI is estimated to be: sensitivity 67-87% and specificity of only 64-70%; with the cut off value the specificity is more than 80% (and you demonstrated that with FLI>60 participants had significantly higher risks for both chronic and severe chronic periodontitis; so the stringent entry criteria are important for reliable conclusions). In clinical practice the FLI result is than validated.
Response : Thank you for your insightful comment regarding the use of the Fatty Liver Index (FLI) in our study and the potential biases associated with its cut-off values. As noted, we used FLI ≥ 30 as the diagnostic threshold for metabolic dysfunction-associated steatotic liver disease (MASLD), consistent with prior research conducted in Asian populations, particularly Korean adults (Lee, Hyeok-Hee, et al. "Metabolic dysfunction-associated steatotic liver disease and risk of cardiovascular disease." Gut 73.3 (2024): 533-540).
The rationale for selecting this threshold is based on its validated sensitivity and specificity, which have been extensively discussed in prior studies. In particular:
Validated Diagnostic Tool for Hepatic Steatosis:
The cut-off of FLI ≥ 30 is widely recognized as a diagnostic marker for hepatic steatosis in epidemiological research. This threshold has been validated in Asian populations, with an AUROC of 0.87, providing a balance between sensitivity (67–87%) and specificity (64–70%) (Rinella, Mary E., et al. "AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease." Hepatology 77.5 (2023): 1797-1835).
Recognition of Higher Specificity with FLI > 60:
While FLI > 60 demonstrates higher specificity (>80%), this stricter cut-off may exclude individuals with mild or early-stage hepatic steatosis. However, we acknowledge the clinical importance of stringent entry criteria, as demonstrated in other studies that report stronger associations between FLI > 60 and adverse outcomes, such as periodontitis and cardiovascular disease
FLI ≥ 30 was chosen to ensure broader inclusion criteria for identifying individuals at risk for MASLD, consistent with epidemiological studies.
The potential benefits of using a higher cut-off, such as FLI > 60, to improve specificity and enhance the association with more severe disease states, have been recognized as an important consideration in clinical contexts.
We hope this adequately addresses your concerns, and we remain open to further suggestions.
May by as a linking observation between MASLD and periodontitis you can mention the observations like: Kuraji R, Ye C, Zhao C, Gao L, Martinez A, Miyashita Y, Radaic A, Kamarajan P, Le C, Zhan L, Range H, Sunohara M, Numabe Y, Kapila YL. Nisin lantibiotic prevents NAFLD liver steatosis and mitochondrial oxidative stress following periodontal disease by abrogating oral, gut and liver dysbiosis. NPJ Biofilms Microbiomes. 2024 Jan 17;10(1):3. doi: 10.1038/s41522-024-00476-x.
Response : Thank you for introducing this insightful study highlighting the potential link between MASLD and periodontitis through the modulation of oral, gut, and liver dysbiosis. The findings presented in the work by Kuraji et al. (NPJ Biofilms Microbiomes. 2024;10(1):3. doi:10.1038/s41522-024-00476-x) provide a compelling perspective on the mechanisms connecting periodontal disease, liver steatosis, and oxidative stress, which are of significant relevance to our current study.
In response to your valuable suggestion, we have revised the Discussion section to incorporate this reference and its relevance to our findings. Specifically, we have added the following content:
Revised Content (Lines 275–281):
The incorporation of this study strengthens the argument that addressing periodontal dysbiosis can play a role in mitigating metabolic dysfunction and liver disease progression.
We appreciate your recommendation to include this valuable study, as it enhances the depth, relevance, and clinical implications of our findings.
Author Response File: 
Author Response.docx
Reviewer 2 Report
Comments and Suggestions for AuthorsThis manuscript used a retrospective population-based cohort study to investigate the association between steatotic liver disease (SLD) subtypes and the incidence of chronic periodontitis (CP) in a nationwide cohort. The authors found that individuals with MASLD and MetALD are at an elevated risk of developing CP and indicated the importance of periodontal health management in reducing the risk of CP among SLD populations. The topic is interesting to the audience and may have some good impacts on health care management. Some comments I have for this manuscript are as following:
1. The introduction section could be more informative. The authors could introduce more about CP and its risk factors. In addition, what other diseases are currently associated with or the risk factor of CP?
2. The exclusive criteria are also not clear to me. The authors excluded cancer patients, how about some other chronic inflammatory diseases/metabolic diseases such as colitis and gastritis?
3. It is not clear to me how the authors classify the subjects with/without risk factors. What are the risk factors? Why do the authors select these as risk factors?
4. It is not clear whether the authors considered which took first for the subjects, (SLD or CP?) for the SLD groups.
5. The discussion section should focus more on the results. The association between obesity and CP can be simplified. In addition, the authors could propose some potential impacts for health care management with the correlation between SLD and CP.
Author Response
Response to Reviewer Comments
Manuscript ID: Nutrients_3378051
Manuscript title: Metabolic Dysfunction-associated Steatotic Liver Disease and the Risk of Chronic Periodontitis: A Nationwide Cohort Study
Thank you for providing us with the opportunity to revise our manuscript (ID: Nutrients-3378051) submitted to Nutrients.
We are grateful for the valuable and constructive comments from the reviewer, which have been instrumental in improving the quality of our work. In response to the reviewer’ suggestions, we have carefully revised the manuscript and provided detailed responses to each comment. The revised content is highlighted in blue in the updated manuscript for your convenience.
We appreciate your time and effort in overseeing the review process and look forward to your further evaluation of our work. Please feel free to let us know if additional revisions or clarifications are needed.
Thank you once again for this opportunity.
Reviewer 2 Comments
This manuscript used a retrospective population-based cohort study to investigate the association between steatotic liver disease (SLD) subtypes and the incidence of chronic periodontitis (CP) in a nationwide cohort. The authors found that individuals with MASLD and MetALD are at an elevated risk of developing CP and indicated the importance of periodontal health management in reducing the risk of CP among SLD populations. The topic is interesting to the audience and may have some good impacts on health care management. Some comments I have for this manuscript are as following
- The introduction section could be more informative. The authors could introduce more about CP and its risk factors. In addition, what other diseases are currently associated with or the risk factor of CP?
Response : Thank you for your valuable suggestion. In response, we have revised the Introduction section to provide additional information regarding chronic periodontitis (CP) and its associated systemic conditions. Specifically, we have incorporated a sentence highlighting diseases linked to CP, such as cardiovascular disease, diabetes, obesity, and dyslipidemia.
The changes can be found on lines 61–62 of the revised manuscript:
This addition ensures that the Introduction is more informative and provides a broader context regarding the risk factors and systemic associations of CP.
We hope this revision meets your expectations, and we remain open to further suggestions for improvement.
- The exclusive criteria are also not clear to me. The authors excluded cancer patients, how about some other chronic inflammatory diseases/metabolic diseases such as colitis and gastritis?
Response : Thank you for pointing this out and allowing us to clarify the exclusion criteria used in our study.
In this study, we applied strict and comprehensive exclusion criteria to ensure a robust classification of participants into Normal, MASLD, and MetALD groups. Specifically, we excluded conditions that could independently cause or significantly influence the development of hepatic steatosis. These included:
Liver Diseases:
Viral hepatitis (e.g., hepatitis B or C infection),
Autoimmune hepatitis,
Alcoholic hepatitis,
Wilson's disease.
These conditions are known to directly contribute to hepatic steatosis, and their inclusion could have confounded the results.
Cancer and Liver Cirrhosis:
Patients with any form of cancer or liver cirrhosis were excluded, as treatment interventions (e.g., chemotherapy, radiation therapy, or advanced cirrhosis management) could introduce significant bias in the analysis.
Extreme Laboratory Values:
We excluded participants with extreme values in laboratory tests at both ends of the spectrum to avoid distortion of the results due to outliers.
By implementing these rigorous criteria, we ensured that the study population represented a well-defined cohort for assessing the association between steatotic liver disease subtypes (MASLD and MetALD) and chronic periodontitis.
We have provided additional clarification on the exclusion criteria in the Methods section of the revised manuscript for greater transparency.
We hope this explanation addresses your concern, and we appreciate the opportunity to clarify this aspect of our study.
- It is not clear to me how the authors classify the subjects with/without risk factors. What are the risk factors? Why do the authors select these as risk factors?
Response : Thank you for your thoughtful question regarding the classification of subjects with or without risk factors in our study. The cardiometabolic risk factors (CMRFs) referred to in our study align with those defined in the Delphi consensus paper on metabolic dysfunction-associated steatotic liver disease (MASLD) (Rinella, Mary E., et al. "A multisociety Delphi consensus statement on new fatty liver disease nomenclature." Hepatology 78.6 (2023): 1966-1986). These risk factors were identified and refined through a robust Delphi process led by international experts, incorporating both scientific evidence and consensus among stakeholders.
The five primary CMRFs include:
1) Type 2 Diabetes Mellitus (T2DM): A well-established predictor of insulin resistance and hepatic steatosis.
2) Obesity (Body Mass Index ≥30 kg/m² or increased waist circumference): Closely associated with metabolic dysfunction and liver fat accumulation.
3) Dyslipidemia (Elevated triglycerides or reduced HDL-C): Reflecting disturbances in lipid metabolism linked to metabolic syndrome.
4) Hypertension: Representing cardiovascular risk associated with hepatic steatosis.
5) Impaired Glucose Tolerance or Prediabetes: Indicating early metabolic dysfunction relevant to hepatic fat deposition.
These risk factors were selected for their strong epidemiological and pathophysiological links to insulin resistance, which is central to MASLD pathogenesis. Additionally, their simplicity and feasibility in clinical application make them practical for identifying at-risk individuals across diverse healthcare settings globally.
The inclusion of these specific CMRFs in the MASLD diagnostic criteria reflects their established role in identifying patients with metabolic dysfunction and liver disease. Importantly, the intent was to provide an affirmative diagnostic framework based on measurable and validated criteria, rather than relying on exclusionary definitions, which often lack precision.
We hope this explanation provides clarity regarding the rationale for selecting these CMRFs and their importance in the study. Please do not hesitate to let us know if additional information is required.
- It is not clear whether the authors considered which took first for the subjects, (SLD or CP?) for the SLD groups.
Response : Thank you for your insightful question regarding the classification of SLD and CP in the study population. In our study, fatty liver was defined using the Fatty Liver Index (FLI), a validated and non-invasive tool for detecting hepatic steatosis. Participants with an FLI of ≥30 were classified as having steatotic liver disease (SLD). Those with an FLI below 30 were categorized as “normal” and subdivided based on the presence or absence of cardiometabolic risk factors (CMRFs).
To address the definition of MASLD, this condition was classified as hepatic steatosis combined with at least one of the following five CMRFs:
1) Type 2 Diabetes Mellitus (T2DM): A well-established predictor of insulin resistance and hepatic steatosis.
2) Obesity (Body Mass Index ≥30 kg/m² or increased waist circumference): Closely associated with metabolic dysfunction and liver fat accumulation.
3) Dyslipidemia (Elevated triglycerides or reduced HDL-C): Reflecting disturbances in lipid metabolism linked to metabolic syndrome.
4) Hypertension: Representing cardiovascular risk associated with hepatic steatosis.
5) Impaired Glucose Tolerance or Prediabetes: Indicating early metabolic dysfunction relevant to hepatic fat deposition.
Additionally, MASLD was distinguished from metabolic alcohol-associated liver disease (MetALD) based on alcohol consumption thresholds: MASLD included individuals with low alcohol consumption (<30 g/day for men and <20 g/day for women), while MetALD involved moderate alcohol consumption combined with CMRFs.
This framework was developed following the revised terminology and diagnostic criteria proposed by the Delphi consensus on SLD (Rinella, Mary E., et al. Hepatology, 2023). By incorporating these definitions, our study aimed to provide a comprehensive understanding of how hepatic steatosis and metabolic dysfunction interact with chronic periodontitis.
We hope this clarification addresses your concerns. Please do not hesitate to let us know if further elaboration is required.
- The discussion section should focus more on the results. The association between obesity and CP can be simplified. In addition, the authors could propose some potential impacts for health care management with the correlation between SLD and CP.
Response : We appreciate the reviewer’s valuable feedback and have revised the discussion section to address the concerns raised. The following changes were made:
- Focus on Results:
We streamlined the discussion to emphasize the study results, specifically highlighting the association between SLD subtypes and chronic periodontitis (CP) while discussing alcohol consumption as a significant factor.
Revised Content (Lines 264–266):
- Simplification of Obesity and CP Relationship:
We simplified the description of the obesity-CP relationship by removing redundant details and focusing on key inflammatory mechanisms.
Revised Content (Lines 305–307):
- Health Care Management Implications:
To propose the potential clinical impact of the correlation between SLD and CP, we added a practical suggestion for bidirectional screening to improve early detection and integrated management strategies.
Newly Added Content (Lines 355–362):
We thank the reviewer for their constructive feedback, which has improved the clarity and impact of the discussion section.
Author Response File: Author Response.docx
Reviewer 3 Report
Comments and Suggestions for AuthorsThe report features a well-organised and informed structure and an accurate scientific tone. My only comment relates to a minor pro forma matter: the authors should also discuss the study’s strengths besides its limitations.
Author Response
Response to Reviewer Comments
Manuscript ID: Nutrients_3378051
Manuscript title: Metabolic Dysfunction-associated Steatotic Liver Disease and the Risk of Chronic Periodontitis: A Nationwide Cohort Study
Thank you for providing us with the opportunity to revise our manuscript (ID: Nutrients-3378051) submitted to Nutrients.
We are grateful for the valuable and constructive comments from the reviewer, which have been instrumental in improving the quality of our work. In response to the reviewer’ suggestions, we have carefully revised the manuscript and provided detailed responses to each comment. The revised content is highlighted in blue in the updated manuscript for your convenience.
We appreciate your time and effort in overseeing the review process and look forward to your further evaluation of our work. Please feel free to let us know if additional revisions or clarifications are needed.
Thank you once again for this opportunity.
Reviewer 3 Comments
The report features a well-organised and informed structure and an accurate scientific tone. My only comment relates to a minor pro forma matter: the authors should also discuss the study’s strengths besides its limitations.
Response : We greatly appreciate the reviewer’s thoughtful and constructive comment regarding the need to discuss the study’s strengths in addition to its limitations. In response to this valuable suggestion, we have revised the discussion section to include a clear outline of the study’s strengths. These revisions emphasize the robust methodological design and clinical implications of our findings, providing a more balanced perspective.
Revised Content (Lines 348–364):
These additions highlight the strengths of our study, including its large sample size, long-term follow-up, and rigorous analytical methods, while underscoring its clinical relevance and practical implications for healthcare management.
We thank the reviewer once again for this insightful recommendation, which has improved the completeness and balance of our discussion section.
Author Response File: Author Response.docx
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsI see that the auuthors can not go further, and the study limitations are still present, but may be it is hard to overcome. Someow the arguments presented in response can be accepted.
I you have enough space, you can accept the paper in the current form.
Reviewer 2 Report
Comments and Suggestions for AuthorsThe revision looks good to me.
