Reviewer’s report
Title: 
Normalization of 
γ
-glutamyl transferase levels is associated with better metabolic control in
individuals with nonalcoholic fatty liver disease
Version: 
1 
Date: 
16 Mar 2021
Reviewer's report:
Although the authors many issues clarified, there are still unclearness. The authors find my further
comments below.
Abstract
1. "We conducted a retrospective analysis of patients with NAFLD who were receiving therapy from
January 2011 to December 2019." Please consider explaining shortly what kind of therapy the patients
received. 
2. "Weight loss (OR = 1.21, 95%CI: 1.11~1.32, P <0.001), ALT normalization 1 (OR = 2.75, 95%CI:
1.41~5.36, P = 0.01), TG and HOMAIR decreased to normal levels (OR = 2.03, 95%CI: 1.11~3.71, P =
0.02; OR = 2.04,3 95%CI: 1.07~3.89, P = 0.03) were independent protective factors for GGT
normalization. Elevated baseline GGT (OR = 0.99, 95%CI: 0.98~0.99, P = 0.01) was a risk factor.". 
Here
instead of "TG and HOMAIR decreased to normal levels", 
I recommend "lower TG and HOMA-IR
values". 
Methods
1. "All the subjects were examined using abdominal ultrasonography, and the ultrasound technicians did
not know the aim of this study.". Were the ultrasonographic examinations conducted by physicians? If so I
recommend radiologist, internist, gastroenterologist etc. rather than ultrasound technician. Instead of "not
knowing the aim of the study", "blinded to the study" would be a better expression.
2. It is still not clear how the study was conducted. The authors stated that the study was retrospective. If
so how many patients were initially present and how many of them were excluded following the excluding
criteria. I recommend adding a chart explaining the patient exclusion. How was informed consent provided
from the each patient? Were also patients present who did not give informed consent? Also a consecutive
recruiting of patients sounds like a prospectively conducted study. 
3. A limited alcohol consumption is 20 g/day in females and 30 g/day in males (J. Hepatol.
2016;64:1388-1402., Hepatology. 2018;67:328-357.). I recommend defining significant alcohol
consumption as I stated here which I believe do not change the patient recruitment to their study. 
4. "Patients in this study were recruited from 1 January 2011 to 31 December 2019, whereas MRI-PDFF
was available in our NAFLD center until January 2015. Among 1048 NAFLD patients diagnosed by
ultrasound, 630 patients (60%) underwent MRI-PDFF examination at baseline and 221 patients received
repeated MRI-PDFF measurements in the sixth month .". Please add this information also to the
manuscript and also discuss as a limitation. Normally MRIPDFF is a very sensitive method for diagnosis
of hepatic steatosis. However, the patients were diagnosed by ultrasonography which may cause that
patients with a lower hepatic steatosis were missed. 
Results
1. The authors analysed the relationship between GGT and hepatic steatosis defined and followed-up by
MRI-PDFF and they found a weak correlation. As known simple hepatic steatosis is usually benign and is
not usually associated with increased liver enzymes. The main prognostic factor is the presence of hepatic
fibrosis. For the estimation of hepatic fibrosis FIB-4 and NFS are reliable scoring systems also
recommended in major guidelines (J Hepatol. 2016 Jun;64(6):1388-402.; Hepatol Int. 2020
Dec;14(6):889-919.; Hepatology. 2018 Jan;67(1):328-357.). Moreover, they have been shown to perform
accurately in patients both with normal and abnormal transaminase levels (Hepatology Forum 2020; 1(1):
8-13). However, their diagnostic ability lies on accurate exclusion of advanced fibrosis rather than
detection of it (Gut Liver. 2020 Jul 15;14(4):486-491.). I recommend calculating at least FIB-4 for the
sake of showing the relationship between GGT and ALT normalization and hepatic fibrosis and discussing
this issue in limitations section in the light of these references. 
Publons Reviewer Recognition
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published on its webservice if you have registered for such service or help editors to identify candidate
reviewers. Please find the details of processing in Publons’ privacy policy
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Yes
Declaration of competing interests
Please complete a declaration of competing interests, considering the
following questions:
1
. 
Have you in the past five years received reimbursements, fees, funding, or salary from an
organisation that may in any way gain or lose financially from the publication of this manuscript,
either now or in the future?
2
. 
Do you hold any stocks or shares in an organisation that may in any way gain or lose financially
from the publication of this manuscript, either now or in the future?
3
. 
Do you hold or are you currently applying for any patents relating to the content of the manuscript?
4
. 
Have you received reimbursements, fees, funding, or salary from an organization that holds or has
applied for patents relating to the content of the manuscript?
5
. 
Do you have any other financial competing interests?
6
. 
Do you have any non-financial competing interests in relation to this paper?
If you can answer no to all of the above, write 'I declare that I have no competing interests' below. If your
reply is yes to any, please give details below.
There is no conflict of interest.
Reviewer Publication Consent.
 I agree for my report to be made available under an Open Access
Creative Commons CC-BY License (
 http://creativecommons.org/licenses/by/4.0
) if this manuscript is
accepted for publication. Any comments that I do not wish to be included in the published report have
been included as confidential comments to the editor, which will not be published.
If you are not happy
for us to publish this report, please contact the editorial office before completing the review.
If you
wish, you can include your name in your published report. Please note you must decide whether to
include your name at the start of the process and confirm this decision whenever prompted. If you
change your decision later, we will not be able to publish your name.
I agree to the terms of the CC-BY 4.0 license; please 
do not
 publish my name with my report. (default)
Is the study design appropriate to answer the research question (including the use of appropriate controls),
and are the conclusions supported by the evidence presented?
No
Are the methods sufficiently described to allow the study to be repeated?
No
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
No
Are the images in this manuscript (including electrophoretic gels and blots) free from apparent
manipulation?
Yes
Reviewer’s report
Title: 
Normalization of 
γ
-glutamyl transferase levels is associated with better metabolic control in
individuals with nonalcoholic fatty liver disease
Version: 
1 
Date: 
16 Mar 2021
Reviewer's report:
Although the authors many issues clarified, there are still unclearness. The authors find my further
comments below.
Abstract
1. "We conducted a retrospective analysis of patients with NAFLD who were receiving therapy from
January 2011 to December 2019." Please consider explaining shortly what kind of therapy the patients
received. 
2. "Weight loss (OR = 1.21, 95%CI: 1.11~1.32, P <0.001), ALT normalization 1 (OR = 2.75, 95%CI:
1.41~5.36, P = 0.01), TG and HOMAIR decreased to normal levels (OR = 2.03, 95%CI: 1.11~3.71, P =
0.02; OR = 2.04,3 95%CI: 1.07~3.89, P = 0.03) were independent protective factors for GGT
normalization. Elevated baseline GGT (OR = 0.99, 95%CI: 0.98~0.99, P = 0.01) was a risk factor.". 
Here
instead of "TG and HOMAIR decreased to normal levels", 
I recommend "lower TG and HOMA-IR
values". 
Methods
1. "All the subjects were examined using abdominal ultrasonography, and the ultrasound technicians did
not know the aim of this study.". Were the ultrasonographic examinations conducted by physicians? If so I
recommend radiologist, internist, gastroenterologist etc. rather than ultrasound technician. Instead of "not
knowing the aim of the study", "blinded to the study" would be a better expression.
2. It is still not clear how the study was conducted. The authors stated that the study was retrospective. If
so how many patients were initially present and how many of them were excluded following the excluding
criteria. I recommend adding a chart explaining the patient exclusion. How was informed consent provided
from the each patient? Were also patients present who did not give informed consent? Also a consecutive
recruiting of patients sounds like a prospectively conducted study. 
3. A limited alcohol consumption is 20 g/day in females and 30 g/day in males (J. Hepatol.
2016;64:1388-1402., Hepatology. 2018;67:328-357.). I recommend defining significant alcohol
consumption as I stated here which I believe do not change the patient recruitment to their study. 
4. "Patients in this study were recruited from 1 January 2011 to 31 December 2019, whereas MRI-PDFF
was available in our NAFLD center until January 2015. Among 1048 NAFLD patients diagnosed by
ultrasound, 630 patients (60%) underwent MRI-PDFF examination at baseline and 221 patients received
repeated MRI-PDFF measurements in the sixth month .". Please add this information also to the
manuscript and also discuss as a limitation. Normally MRIPDFF is a very sensitive method for diagnosis
of hepatic steatosis. However, the patients were diagnosed by ultrasonography which may cause that
patients with a lower hepatic steatosis were missed. 
Results
1. The authors analysed the relationship between GGT and hepatic steatosis defined and followed-up by
MRI-PDFF and they found a weak correlation. As known simple hepatic steatosis is usually benign and is
not usually associated with increased liver enzymes. The main prognostic factor is the presence of hepatic
fibrosis. For the estimation of hepatic fibrosis FIB-4 and NFS are reliable scoring systems also
recommended in major guidelines (J Hepatol. 2016 Jun;64(6):1388-402.; Hepatol Int. 2020
Dec;14(6):889-919.; Hepatology. 2018 Jan;67(1):328-357.). Moreover, they have been shown to perform
accurately in patients both with normal and abnormal transaminase levels (Hepatology Forum 2020; 1(1):
8-13). However, their diagnostic ability lies on accurate exclusion of advanced fibrosis rather than
detection of it (Gut Liver. 2020 Jul 15;14(4):486-491.). I recommend calculating at least FIB-4 for the
sake of showing the relationship between GGT and ALT normalization and hepatic fibrosis and discussing
this issue in limitations section in the light of these references. 
Publons Reviewer Recognition
. Springer Nature can send verification of this review directly to Publons
(a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on
the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal,
and date of your review submission (the “Review Data”) will then be transmitted to Publons after the final
decision on the manuscript has been made. If you have already registered at Publons, they will notify you
of the receipt of this review and update your profile 
as per your settings and their policy. If you are not
registered with Publons, you will receive an email from them asking you to register in order for them to
be able to recognize your review on your new profile page. Publons may use the Review Data to generate
derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity
of such information. For example, Publons may verify your record as a reviewer by updating your profile
published on its webservice if you have registered for such service or help editors to identify candidate
reviewers. Please find the details of processing in Publons’ privacy policy
https://publons.com/about/terms
Yes
Declaration of competing interests
Please complete a declaration of competing interests, considering the
following questions:
1
. 
Have you in the past five years received reimbursements, fees, funding, or salary from an
organisation that may in any way gain or lose financially from the publication of this manuscript,
either now or in the future?
2
. 
Do you hold any stocks or shares in an organisation that may in any way gain or lose financially
from the publication of this manuscript, either now or in the future?
3
. 
Do you hold or are you currently applying for any patents relating to the content of the manuscript?
4
. 
Have you received reimbursements, fees, funding, or salary from an organization that holds or has
applied for patents relating to the content of the manuscript?
5
. 
Do you have any other financial competing interests?
6
. 
Do you have any non-financial competing interests in relation to this paper?
If you can answer no to all of the above, write 'I declare that I have no competing interests' below. If your
reply is yes to any, please give details below.
There is no conflict of interest.
Reviewer Publication Consent.
 I agree for my report to be made available under an Open Access
Creative Commons CC-BY License (
 http://creativecommons.org/licenses/by/4.0
) if this manuscript is
accepted for publication. Any comments that I do not wish to be included in the published report have
been included as confidential comments to the editor, which will not be published.
If you are not happy
for us to publish this report, please contact the editorial office before completing the review.
If you
wish, you can include your name in your published report. Please note you must decide whether to
include your name at the start of the process and confirm this decision whenever prompted. If you
change your decision later, we will not be able to publish your name.
I agree to the terms of the CC-BY 4.0 license; please 
do not
 publish my name with my report. (default)
Is the study design appropriate to answer the research question (including the use of appropriate controls),
and are the conclusions supported by the evidence presented?
No
Are the methods sufficiently described to allow the study to be repeated?
No
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
No
Are the images in this manuscript (including electrophoretic gels and blots) free from apparent
manipulation?
Yes
Please review this paper.
user
Reviewer’s report
Title: 
Normalization of 
γ
-glutamyl transferase levels is associated with better metabolic control in
individuals with nonalcoholic fatty liver disease
Version: 
1 
Date: 
16 Mar 2021
Reviewer's report:
Although the authors many issues clarified, there are still unclearness. The authors find my further
comments below.
Abstract
1. "We conducted a retrospective analysis of patients with NAFLD who were receiving therapy from
January 2011 to December 2019." Please consider explaining shortly what kind of therapy the patients
received. 
2. "Weight loss (OR = 1.21, 95%CI: 1.11~1.32, P <0.001), ALT normalization 1 (OR = 2.75, 95%CI:
1.41~5.36, P = 0.01), TG and HOMAIR decreased to normal levels (OR = 2.03, 95%CI: 1.11~3.71, P =
0.02; OR = 2.04,3 95%CI: 1.07~3.89, P = 0.03) were independent protective factors for GGT
normalization. Elevated baseline GGT (OR = 0.99, 95%CI: 0.98~0.99, P = 0.01) was a risk factor.". 
Here
instead of "TG and HOMAIR decreased to normal levels", 
I recommend "lower TG and HOMA-IR
values". 
Methods
1. "All the subjects were examined using abdominal ultrasonography, and the ultrasound technicians did
not know the aim of this study.". Were the ultrasonographic examinations conducted by physicians? If so I
recommend radiologist, internist, gastroenterologist etc. rather than ultrasound technician. Instead of "not
knowing the aim of the study", "blinded to the study" would be a better expression.
2. It is still not clear how the study was conducted. The authors stated that the study was retrospective. If
so how many patients were initially present and how many of them were excluded following the excluding
criteria. I recommend adding a chart explaining the patient exclusion. How was informed consent provided
from the each patient? Were also patients present who did not give informed consent? Also a consecutive
recruiting of patients sounds like a prospectively conducted study. 
3. A limited alcohol consumption is 20 g/day in females and 30 g/day in males (J. Hepatol.
2016;64:1388-1402., Hepatology. 2018;67:328-357.). I recommend defining significant alcohol
consumption as I stated here which I believe do not change the patient recruitment to their study. 
4. "Patients in this study were recruited from 1 January 2011 to 31 December 2019, whereas MRI-PDFF
was available in our NAFLD center until January 2015. Among 1048 NAFLD patients diagnosed by
ultrasound, 630 patients (60%) underwent MRI-PDFF examination at baseline and 221 patients received
repeated MRI-PDFF measurements in the sixth month .". Please add this information also to the
manuscript and also discuss as a limitation. Normally MRIPDFF is a very sensitive method for diagnosis
of hepatic steatosis. However, the patients were diagnosed by ultrasonography which may cause that
patients with a lower hepatic steatosis were missed. 
Results
1. The authors analysed the relationship between GGT and hepatic steatosis defined and followed-up by
MRI-PDFF and they found a weak correlation. As known simple hepatic steatosis is usually benign and is
not usually associated with increased liver enzymes. The main prognostic factor is the presence of hepatic
fibrosis. For the estimation of hepatic fibrosis FIB-4 and NFS are reliable scoring systems also
recommended in major guidelines (J Hepatol. 2016 Jun;64(6):1388-402.; Hepatol Int. 2020
Dec;14(6):889-919.; Hepatology. 2018 Jan;67(1):328-357.). Moreover, they have been shown to perform
accurately in patients both with normal and abnormal transaminase levels (Hepatology Forum 2020; 1(1):
8-13). However, their diagnostic ability lies on accurate exclusion of advanced fibrosis rather than
detection of it (Gut Liver. 2020 Jul 15;14(4):486-491.). I recommend calculating at least FIB-4 for the
sake of showing the relationship between GGT and ALT normalization and hepatic fibrosis and discussing
this issue in limitations section in the light of these references. 
Publons Reviewer Recognition
. Springer Nature can send verification of this review directly to Publons
(a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on
the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal,
and date of your review submission (the “Review Data”) will then be transmitted to Publons after the final
decision on the manuscript has been made. If you have already registered at Publons, they will notify you
of the receipt of this review and update your profile 
as per your settings and their policy. If you are not
registered with Publons, you will receive an email from them asking you to register in order for them to
be able to recognize your review on your new profile page. Publons may use the Review Data to generate
derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity
of such information. For example, Publons may verify your record as a reviewer by updating your profile
published on its webservice if you have registered for such service or help editors to identify candidate
reviewers. Please find the details of processing in Publons’ privacy policy
https://publons.com/about/terms
Yes
Declaration of competing interests
Please complete a declaration of competing interests, considering the
following questions:
1
. 
Have you in the past five years received reimbursements, fees, funding, or salary from an
organisation that may in any way gain or lose financially from the publication of this manuscript,
either now or in the future?
2
. 
Do you hold any stocks or shares in an organisation that may in any way gain or lose financially
from the publication of this manuscript, either now or in the future?
3
. 
Do you hold or are you currently applying for any patents relating to the content of the manuscript?
4
. 
Have you received reimbursements, fees, funding, or salary from an organization that holds or has
applied for patents relating to the content of the manuscript?
5
. 
Do you have any other financial competing interests?
6
. 
Do you have any non-financial competing interests in relation to this paper?
If you can answer no to all of the above, write 'I declare that I have no competing interests' below. If your
reply is yes to any, please give details below.
There is no conflict of interest.
Reviewer Publication Consent.
 I agree for my report to be made available under an Open Access
Creative Commons CC-BY License (
 http://creativecommons.org/licenses/by/4.0
) if this manuscript is
accepted for publication. Any comments that I do not wish to be included in the published report have
been included as confidential comments to the editor, which will not be published.
If you are not happy
for us to publish this report, please contact the editorial office before completing the review.
If you
wish, you can include your name in your published report. Please note you must decide whether to
include your name at the start of the process and confirm this decision whenever prompted. If you
change your decision later, we will not be able to publish your name.
I agree to the terms of the CC-BY 4.0 license; please 
do not
 publish my name with my report. (default)
Is the study design appropriate to answer the research question (including the use of appropriate controls),
and are the conclusions supported by the evidence presented?
No
Are the methods sufficiently described to allow the study to be repeated?
No
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
No
Are the images in this manuscript (including electrophoretic gels and blots) free from apparent
manipulation?
Yes
assistant