Risk of metabolic syndrome in participants within the normal range of alanine aminotransferase: A population-based nationwide study

Ju-Yeon Cho; Jae Yoon Jeong; Won Sohn

doi:10.1371/journal.pone.0231485

Peer Review History

Original SubmissionDecember 17, 2019
24 Jan 2020 Decision Letter - Ming-Lung Yu, Editor PONE-D-19-34865 Risk of metabolic syndrome in subjects with a normal range of alanine aminotransferase: a population-based nationwide study PLOS ONE Dear Dr Sohn, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. We would appreciate receiving your revised manuscript by Mar 09 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'. 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Thank you for stating the following on the Title page of your manuscript: "This study was supported by research fund from Chosun University, 2016. The fund had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: No ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The community-based study included 43402 adults with ALT<=40 U/L to investigate the associations between serum ALT levels and metabolic syndrome (MS). They found that the prevalence of MS increased with serum ALT levels. In addition, the probability of MS increased with serum ALT levels with dose-response trends. The authors concluded that ALT could be used as a marker to evaluate MS, particularly in a general population with normal ALT levels. The work is clear and straightforward. However, there are still some comments: 1. Although the work is interesting, the clinical utility is limited. There is already clear definitions for MS as the authors indicated in the methods (MS was defined by the updated National Cholesterol Education Program Adult Treatment Panel III standards). Are there any benefits by considering ALT? By including ALT, is it superior to the original definition? 2. It will be interesting to know whether serum ALT levels was correlated to any inflammatory markers or not. 3. It is suggested to calculate fatty liver index and examine the associations between ALT and FLI. Reviewer #2: The authors aimed to investigate the risk of metabolic syndrome (MS) in subjects with normal ALT level in the general population. They concluded that despite within the normal range of ALT, the risk of MS increased as the ALT levels increased. In general, the topic of this work is interesting. However, some issues should be further reconsidered or corrected. 1. The authors should provide the complete data of metabolic syndrome including systolic and diastolic blood pressure. Also, the correlation of each component of metabolic syndrome with serum ALT level should be evaluated. 2. The subjects with elevated ALT levels should not be excluded and could serve as positive controls. 3. The information of medication history including anti-diabetics, statin and anti-hypertensive drugs should be provided. 4. It is noted that the manuscript is filled with some grammatical errors that need to be corrected. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0231485.r001
Revision 1
20 Feb 2020 Author Response Reviewer #1: The community-based study included 43402 adults with ALT<=40 U/L to investigate the associations between serum ALT levels and metabolic syndrome (MS). They found that the prevalence of MS increased with serum ALT levels. In addition, the probability of MS increased with serum ALT levels with dose-response trends. The authors concluded that ALT could be used as a marker to evaluate MS, particularly in a general population with normal ALT levels. The work is clear and straightforward. However, there are still some comments: 1. Although the work is interesting, the clinical utility is limited. There is already clear definitions for MS as the authors indicated in the methods (MS was defined by the updated National Cholesterol Education Program Adult Treatment Panel III standards). Are there any benefits by considering ALT? By including ALT, is it superior to the original definition? : We appreciate your valuable comment. The aim of the study was to investigate the association between serum ALT and MS. The results of our study cannot imply that the addition of ALT in the diagnostic criteria of MS would be superior to the current standards. However, ALT is a basic laboratory test done frequently in the daily clinic and increases in ALT can be a useful marker that implies the presence of MS. 2. It will be interesting to know whether serum ALT levels was correlated to any inflammatory markers or not. : Thank you for your comment. Unfortunately, the present study did not check inflammatory markers such as tumor necrosis factor-alpha (TNF-α), plasminogen activator inhibitor 1 (PAI-1), interleukin-6 (IL-6), leptin or adiponectin. We added this limitation in the discussion section of the revised manuscript (page 14). � Finally, the present study did not clarify the association between serum ALT level and the inflammatory markers such as tumor necrosis factor-alpha (TNF-α), plasminogen activator inhibitor 1 (PAI-1), interleukin-6 (IL-6), leptin and adiponectin. 3. It is suggested to calculate fatty liver index and examine the associations between ALT and FLI. : We appreciate your valuable comment. As you commented, we newly analyzed the relationship between serum ALT and fatty liver. However, we could not calculate the fatty liver index (FLI) because our data did not include γ-glutamyl-transferase. Fatty liver index consists of triglyceride, BMI, γ-glutamyl-transferase and waist circumference. Therefore, we calculated the hepatic steatosis index (HSI) instead of the fatty liver index (FLI). HSI consists of ALT, AST, BMI, diabetes, and sex (Dig Liver Dis 2010;42:503-8.). We analyzed the association between ALT level and HSI. There was a dose-dependent increase of HSI as ALT levels increased in both male and female subjects (Table 2). In male subjects, HSI was 28.0 ± 3.2, 31.9 ± 3.8 and 35.9 ± 4.3 in ALT 0-15 U/L, 15-30 U/L, and 30-40 U/L, respectively (p<0.001). In female subjects, HSI was 28.0 ± 3.0, 31.4 ± 3.8 and 35.7 ± 4.4 in ALT <10 U/L, 10-20 U/L, 20-40 U/L and >40 U/L, respectively (p<0.001). We added these findings in the method section and results section of the revised manuscript (page 7 & 8 and Table 2). � “Hepatic steatosis index (HSI) was calculated to assess the relationship between serum ALT level and fatty liver.” (page 7) � “The mean level of HSI in male and female subjects was 31.6 ± 4.5 and 32.0 ± 4.5, respectively.” (page 8) � There were dose-dependent increases of BMI, waist circumference, SBP, DBP, fasting blood glucose (FBS), total cholesterol, triglyceride, HSI, the prevalence of diabetes mellitus, and the prevalence of MS as ALT level increased in both male and female subjects. Reviewer #2: The authors aimed to investigate the risk of metabolic syndrome (MS) in subjects with normal ALT level in the general population. They concluded that despite within the normal range of ALT, the risk of MS increased as the ALT levels increased. In general, the topic of this work is interesting. However, some issues should be further reconsidered or corrected. 1. The authors should provide the complete data of metabolic syndrome including systolic and diastolic blood pressure. Also, the correlation of each component of metabolic syndrome with serum ALT level should be evaluated. : According to your comments, we added the data for systolic and diastolic blood pressure in the results section and Table 1 & 2 of the revised manuscript (page 8) � “Systolic blood pressure (SBP) of male and female subjects was 121.2 ± 15.9 and 116.4 ± 18.0, respectively. Diastolic blood pressure (DBP) of male and female subjects was 78.1 ± 10.6 and 73.6 ± 10.0, respectively.” Also, we analyzed the correlation of each component of metabolic syndrome with the serum ALT level (Table 4). We added these results in table 4 of the revised manuscript (page 9-10). � “The relationship between serum ALT level and each component of MS in subjects with a normal range of ALT are shown in Table 4. In male subjects, serum ALT level were significantly associated with waist circumference (r=0.321, p<0.001), SBP (r=0.080, p<0.001), DBP (r=0.184, p<0.001), FBS (r=0.094, p<0.001), and triglyceride (r=0.234, p<0.001). In female subjects, serum ALT level were significantly associated with waist circumference (r=0.343, p<0.001), SBP (r=0.227, p<0.001), DBP (r=0.185, p<0.001), FBS (r=0.195, p<0.001), and triglyceride (r=0.269, p<0.001). There was an inverse correlation between HDL cholesterol and ALT activity in both male (r=-0.098, p<0.001) and female (r=-0.140, p<0.001).” 2. The subjects with elevated ALT levels should not be excluded and could serve as positive controls. : According to your comments, we added the data for the subjects with elevated ALT levels in the method section, results section, and supplementary document of the revised manuscript (page 6). � “Finally, 43,402 subjects within the normal range of alanine aminotransferase (ALT ≤40 U/L) were included in the final analysis and we compared these subjects to 3,426 subjects with ALT level >40 U/L (Figure 1).” We also compared the risk of metabolic syndrome the subjects with normal range and abnormal range of ALT (page 11-12). � “Clinical characteristics of the subjects with an abnormal range of ALT (>40 U/L) are presented in Supplementary table 1 and 2. In male subjects, the prevalence of MS was 12.6%, 25.2%, 39.7% and 50.8% in ALT <15 U/L, 15-30 U/L, 30-40 U/L and >40 U/L, respectively. There was a dose-dependent relationship between MS and ALT level in male subjects (p<0.001). In female subjects, the prevalence of MS was 7.2%, 23.3%, 44.7% and 57.8% in ALT <10 U/L, 10-20 U/L, 20-40 U/L and >40 U/L, respectively. There was a dose-dependent relationship between MS and ALT level in female subjects (p<0.001). We compared the risk of MS between the subjects with normal range and abnormal range of ALT (Supplementary table 3). The risk of MS in male subjects is increased when in ALT 15-30 U/L, 30-40 U/L, and >40 U/L compared to ALT<15 U/L, respectively in adjusting age, alcohol consumption, and BMI (aOR 1.57 with 95% CI: 1.40-1.76, aOR 2.54 with 95% CI: 2.21-2.92 and aOR 3.63 with 95% CI: 3.14-4.19, respectively). The risk of MS in female subjects is increased when in ALT 10-20 U/L, 20-40 U/L, and >40 U/L compared to ALT<10 U/L, respectively in adjusting age, alcohol consumption, and BMI (aOR 1.59 with 95% CI: 1.36-1.87, aOR 2.69 with 95% CI: 2.28-3.18 and aOR 4.28 with 95% CI: 3.46-5.31, respectively).” 3. The information of medication history including anti-diabetics, statin and anti-hypertensive drugs should be provided. : As you commented, we added the information regarding the use of anti-diabetic agents, lipid lowering agents, and anti-hypertensive agents. The proportion of the usage of anti-diabetic agents in male and female subjects was 7.7% and 6.0%, respectively. The proportion of the usage of lipid lowering agents in male and female subjects was 4.7% and 5.6%, respectively. The proportion of the usage of anti-hypertensive agents in male and female subjects was 18.8% and 18.8%, respectively. We added these results in Table 1 of the revised manuscript. 4. It is noted that the manuscript is filled with some grammatical errors that need to be corrected. : As you have commented, the manuscript has been edited for grammatical errors. Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0231485.r002
17 Mar 2020 Decision Letter - Ming-Lung Yu, Editor PONE-D-19-34865R1 Risk of metabolic syndrome in subjects within the normal range of alanine aminotransferase: a population-based nationwide study PLOS ONE Dear Dr Sohn, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. ============================== The English should be revised by native English speakers. ============================== We would appreciate receiving your revised manuscript by May 01 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out. We look forward to receiving your revised manuscript. Kind regards, Ming-Lung Yu, MD, PhD Academic Editor PLOS ONE [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: all comments have been addressed adequately. It is suggested that the article could be polished by an English editor before formal publication. Reviewer #2: The authors aimed to investigate the risk of metabolic syndrome (MS) in subjects with normal ALT level in the general population. In general, this is an interesting topic and a clearly written paper. Also, the authors have well responded to the reviewer’s suggestions. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0231485.r003
Revision 2
23 Mar 2020 Author Response Editor’s comment: The English should be revised by native English speakers. : We appreciate your valuable comment. According to your comment, the revised manuscript was examined by an English editing service (www.editage.co.kr). Reviewer #1: all comments have been addressed adequately. It is suggested that the article could be polished by an English editor before formal publication. : We appreciate your valuable comment. According to your comment, the revised manuscript was examined by an English editing service (www.editage.co.kr). Reviewer #2: The authors aimed to investigate the risk of metabolic syndrome (MS) in subjects with normal ALT level in the general population. In general, this is an interesting topic and a clearly written paper. Also, the authors have well responded to the reviewer’s suggestions. : We appreciate your valuable comment. Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0231485.r004
25 Mar 2020 Decision Letter - Ming-Lung Yu, Editor Risk of metabolic syndrome in participants within the normal range of alanine aminotransferase: a population-based nationwide study PONE-D-19-34865R2 Dear Dr. Sohn, We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements. Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication. Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. With kind regards, Ming-Lung Yu, MD, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0231485.r005
Formally Accepted
27 Mar 2020 Acceptance Letter - Ming-Lung Yu, Editor PONE-D-19-34865R2 Risk of metabolic syndrome in participants within the normal range of alanine aminotransferase: a population-based nationwide study Dear Dr. Sohn: I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. For any other questions or concerns, please email plosone@plos.org. Thank you for submitting your work to PLOS ONE. With kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Ming-Lung Yu Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0231485.r006

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