Reviewer ’s report  
 
Title: Frequently abnormal serum gamma -glutamyl transferase a ctivity is associated with future 
development of fatty liver: a retrospective cohort study  
 
Version: 0 Date: 27 Apr 2020  
 
Reviewer: Li-Wei Chen  
 
Reviewer's report:  
 
Hideki Fujii et al submitted a manuscript with a title of frequently abnormal serum gamma -
glutamyl transferase activity is associated with future development of fatty liver: a retrospective 
cohort study. Th ey found the incidence rate of fatty liver change in the abnormal -GGT group 
was higher than that in the Normal -GGT group (10.02/1000 vs. 5.80/1000 person -years; 
10.18/1000 and 3.08/1000 person -years after matching). Consecutive elevated GGT levels 
increase  the risk for fatty liver, and high TG levels in those individuals further independently 
increase the risk. It is an interesting and important issue to discuss the association between serum 
gamma -glutamyl transferase (transpeptidase) (GGT) and fatty liver development. Because GGT 
may be not routinely checked in the clinical practice, this study reminds the possibility of fatty 
liver development in patients with frequently elevated GGT.  
 
 
I have some comments:  
 
1. Because this study uses normal and abnormal of  GGT for analysis. The definition of 
normal (or elevation) GGT value should be clarified. Recently, a different normal range of GGT 
between men and women was found. Did this study use a different normal range of GGT 
between men and women? Why not use the v alue of GGT for analysis? Because use the normal 
and abnormal GGT (dichotomy) will loss some findings, such as the difference of very high 
value and slightly rise value.  
 
2. In this study, abnormal GGT group enrolled individuals had had elevated serum GGT 
levels "more than half of the times" tested during complete annual medical check -ups. This will 
include many conditions, such as persist GGT elevation, two times GGT elevation in three 
follow up, three times GGT elevation in four follow up… I suggest to pe rform a subgroup 
analysis including individuals with persist GGT elevation, comparing to individuals with persist 
normal GGT.  
 
3. The diagnosis of fatty liver in this study was based on results of abdominal 
ultrasonography (US) with liver -kidney contrast an d liver brightness. Because abdominal US 
was operator dependence and liver fatty component less than 20% may be recognized as normal 
by abdominal US, some patients with mild fatty liver may have discrepancy results of fatty liver 
by abdominal US. Was other  method of fatty liver evaluation, such as fatty liver index (FLI) or 
controlled attenuation parameter (CAP) method, used in this study?  
4. A figure of study flow (diagram) should be included, in which how many individuals 
were excluded should be recorded . For example, how many patients with viral hepatitis or under 
operations were excluded out?  
 
5. Could authors explain why individuals were exclude out with high ALP levels and 
ALT levels &gt;1.2 times the normal value at first CMC? Why not ALT level &gt;normal value? 
Do authors mean the follow up ALP or ALT values could be abnormal in these individuals? By 
the way, the abbreviation of ALT was not explained in the manuscript.  
 
6. Could authors explain more detail why factors of BMI, ALT, albumin, and TG 
identified as independent predictors of fatty liver to enter multivariable analysis in the Normal -
GGT group, but factors of FBS or HDL was not identified as independent predictor? Although 
authors claimed high TG levels further independently increase the risk of fatty liver in those with 
normal or abnormal GGT, the HR was very close 1.0 by multivariate analysis in both groups.  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additio nal statistical review is recommended, please speci fy what aspects require further 
assessment in your comments to the editors.  
 
I recommend additional statistical review  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
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 an y way gain or lose financial ly from the 
publication of this manuscript, either now or in the future?  
 
2.  Do you hold any stocks or shares in an organisation t hat 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 re ceived 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.  
 
'I declare that I have no competing interests'  
 
I agree to the open peer review policy of the journal. I understan d that my name will be included 
on my report to the authors and, if the manuscript is accepted f or publication, my named report 
including any attachments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made available under an Open Acc ess Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be in cluded as confidential comments 
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
 
Title: Frequently abnormal serum gamma -glutamyl transferase a ctivity is associated with future 
development of fatty liver: a retrospective cohort study  
 
Version: 0 Date: 27 Apr 2020  
 
Reviewer: Li-Wei Chen  
 
Reviewer's report:  
 
Hideki Fujii et al submitted a manuscript with a title of frequently abnormal serum gamma -
glutamyl transferase activity is associated with future development of fatty liver: a retrospective 
cohort study. Th ey found the incidence rate of fatty liver change in the abnormal -GGT group 
was higher than that in the Normal -GGT group (10.02/1000 vs. 5.80/1000 person -years; 
10.18/1000 and 3.08/1000 person -years after matching). Consecutive elevated GGT levels 
increase  the risk for fatty liver, and high TG levels in those individuals further independently 
increase the risk. It is an interesting and important issue to discuss the association between serum 
gamma -glutamyl transferase (transpeptidase) (GGT) and fatty liver development. Because GGT 
may be not routinely checked in the clinical practice, this study reminds the possibility of fatty 
liver development in patients with frequently elevated GGT.  
 
 
I have some comments:  
 
1. Because this study uses normal and abnormal of  GGT for analysis. The definition of 
normal (or elevation) GGT value should be clarified. Recently, a different normal range of GGT 
between men and women was found. Did this study use a different normal range of GGT 
between men and women? Why not use the v alue of GGT for analysis? Because use the normal 
and abnormal GGT (dichotomy) will loss some findings, such as the difference of very high 
value and slightly rise value.  
 
2. In this study, abnormal GGT group enrolled individuals had had elevated serum GGT 
levels "more than half of the times" tested during complete annual medical check -ups. This will 
include many conditions, such as persist GGT elevation, two times GGT elevation in three 
follow up, three times GGT elevation in four follow up… I suggest to pe rform a subgroup 
analysis including individuals with persist GGT elevation, comparing to individuals with persist 
normal GGT.  
 
3. The diagnosis of fatty liver in this study was based on results of abdominal 
ultrasonography (US) with liver -kidney contrast an d liver brightness. Because abdominal US 
was operator dependence and liver fatty component less than 20% may be recognized as normal 
by abdominal US, some patients with mild fatty liver may have discrepancy results of fatty liver 
by abdominal US. Was other  method of fatty liver evaluation, such as fatty liver index (FLI) or 
controlled attenuation parameter (CAP) method, used in this study?  
4. A figure of study flow (diagram) should be included, in which how many individuals 
were excluded should be recorded . For example, how many patients with viral hepatitis or under 
operations were excluded out?  
 
5. Could authors explain why individuals were exclude out with high ALP levels and 
ALT levels &gt;1.2 times the normal value at first CMC? Why not ALT level &gt;normal value? 
Do authors mean the follow up ALP or ALT values could be abnormal in these individuals? By 
the way, the abbreviation of ALT was not explained in the manuscript.  
 
6. Could authors explain more detail why factors of BMI, ALT, albumin, and TG 
identified as independent predictors of fatty liver to enter multivariable analysis in the Normal -
GGT group, but factors of FBS or HDL was not identified as independent predictor? Although 
authors claimed high TG levels further independently increase the risk of fatty liver in those with 
normal or abnormal GGT, the HR was very close 1.0 by multivariate analysis in both groups.  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additio nal statistical review is recommended, please speci fy what aspects require further 
assessment in your comments to the editors.  
 
I recommend additional statistical review  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
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 an y way gain or lose financial ly from the 
publication of this manuscript, either now or in the future?  
 
2.  Do you hold any stocks or shares in an organisation t hat 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 re ceived 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.  
 
'I declare that I have no competing interests'  
 
I agree to the open peer review policy of the journal. I understan d that my name will be included 
on my report to the authors and, if the manuscript is accepted f or publication, my named report 
including any attachments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made available under an Open Acc ess Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be in cluded as confidential comments 
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title: Frequently abnormal serum gamma -glutamyl transferase a ctivity is associated with future 
development of fatty liver: a retrospective cohort study  
 
Version: 0 Date: 27 Apr 2020  
 
Reviewer: Li-Wei Chen  
 
Reviewer's report:  
 
Hideki Fujii et al submitted a manuscript with a title of frequently abnormal serum gamma -
glutamyl transferase activity is associated with future development of fatty liver: a retrospective 
cohort study. Th ey found the incidence rate of fatty liver change in the abnormal -GGT group 
was higher than that in the Normal -GGT group (10.02/1000 vs. 5.80/1000 person -years; 
10.18/1000 and 3.08/1000 person -years after matching). Consecutive elevated GGT levels 
increase  the risk for fatty liver, and high TG levels in those individuals further independently 
increase the risk. It is an interesting and important issue to discuss the association between serum 
gamma -glutamyl transferase (transpeptidase) (GGT) and fatty liver development. Because GGT 
may be not routinely checked in the clinical practice, this study reminds the possibility of fatty 
liver development in patients with frequently elevated GGT.  
 
 
I have some comments:  
 
1. Because this study uses normal and abnormal of  GGT for analysis. The definition of 
normal (or elevation) GGT value should be clarified. Recently, a different normal range of GGT 
between men and women was found. Did this study use a different normal range of GGT 
between men and women? Why not use the v alue of GGT for analysis? Because use the normal 
and abnormal GGT (dichotomy) will loss some findings, such as the difference of very high 
value and slightly rise value.  
 
2. In this study, abnormal GGT group enrolled individuals had had elevated serum GGT 
levels "more than half of the times" tested during complete annual medical check -ups. This will 
include many conditions, such as persist GGT elevation, two times GGT elevation in three 
follow up, three times GGT elevation in four follow up… I suggest to pe rform a subgroup 
analysis including individuals with persist GGT elevation, comparing to individuals with persist 
normal GGT.  
 
3. The diagnosis of fatty liver in this study was based on results of abdominal 
ultrasonography (US) with liver -kidney contrast an d liver brightness. Because abdominal US 
was operator dependence and liver fatty component less than 20% may be recognized as normal 
by abdominal US, some patients with mild fatty liver may have discrepancy results of fatty liver 
by abdominal US. Was other  method of fatty liver evaluation, such as fatty liver index (FLI) or 
controlled attenuation parameter (CAP) method, used in this study?  
4. A figure of study flow (diagram) should be included, in which how many individuals 
were excluded should be recorded . For example, how many patients with viral hepatitis or under 
operations were excluded out?  
 
5. Could authors explain why individuals were exclude out with high ALP levels and 
ALT levels &gt;1.2 times the normal value at first CMC? Why not ALT level &gt;normal value? 
Do authors mean the follow up ALP or ALT values could be abnormal in these individuals? By 
the way, the abbreviation of ALT was not explained in the manuscript.  
 
6. Could authors explain more detail why factors of BMI, ALT, albumin, and TG 
identified as independent predictors of fatty liver to enter multivariable analysis in the Normal -
GGT group, but factors of FBS or HDL was not identified as independent predictor? Although 
authors claimed high TG levels further independently increase the risk of fatty liver in those with 
normal or abnormal GGT, the HR was very close 1.0 by multivariate analysis in both groups.  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additio nal statistical review is recommended, please speci fy what aspects require further 
assessment in your comments to the editors.  
 
I recommend additional statistical review  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
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 an y way gain or lose financial ly from the 
publication of this manuscript, either now or in the future?  
 
2.  Do you hold any stocks or shares in an organisation t hat 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 re ceived 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.  
 
'I declare that I have no competing interests'  
 
I agree to the open peer review policy of the journal. I understan d that my name will be included 
on my report to the authors and, if the manuscript is accepted f or publication, my named report 
including any attachments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made available under an Open Acc ess Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be in cluded as confidential comments 
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
assistant