Reviewer ’s report  
 
Title:  Breath test using 13C methacetin does not seem to be useful in the assessment of liver 
function in girls with anorexia nervosa: a case control study  
 
Version: 1 Date: 01 Jan 2018 
 
Reviewer:  Jason  Nagata  
 
Reviewer’s report:  
 
Overall, this is a well -written case control study examining the usefulness of breath test using 
13C methacetin in the assessment of liver funct ion in girls with anorexia nervosa. While the 
overall conclusion based on the title is that the MBT is not useful in the assessment of liver 
function in girls with anorexia nervosa, I think this conclusion should be more clearly explained 
in the results, d iscussion, and conclusions. I also think it is important for the authors to further 
justify the clinical importance of the research question. I have some specific recommendations 
for consideration by the authors.  
 
Abstract: Conclusions: I am not sure that the conclusion "It seems necessary to undertake further 
clinical trials aimed at determining the effect of AN -related exogenous factors on the test result" 
is consistent with the title and negative findings of the study.  
 
Background: Overall, I think the a uthors should further justify the clinical significance and 
relevance of their research question, ie 1) how common is acute liver failure in AN; 2) justify the 
importance of monitoring liver function in AN; and 3) establish the potential value added of the  
MBT. Some of this is in the discussion, but I think it should be moved to the introduction.  
 
p. 3, Line 3 -6. It would be helpful to specify how common/prevalent acute liver failure is in AN - 
my understanding is that it is quite rare.  
 
p. 3, line 11 -16. Ho w common/prevalent are abnormal results of functional liver tests in AN 
(more specific than "relatively often"?  
 
p. 3, line 16: "the organ's function requires constant monitoring" - can you provide further 
references/citations/justification or ideally clin ical guidelines for the constant monitoring of liver 
function. You cite some of these in the discussion  
 
Second paragraph of background: can you add a little more about the value added of breath tests 
compared to other tests compared to the current standard  (ALT, AST). Perhaps cost 
effectiveness. I could understand why the noninvasive nature of breath tests could be a benefit in 
pediatric patients, but most patients with AN are adolescents who will likely have to get a blood 
draw for monitoring of electrolyt es regardless of their liver function.  
 
 
Methods:  
P. 4, line 28. "The control group were age matched -female patients who were hospitalized in 
other pediatric departments" - if these controls were hospitalized patients, I'm not sure I would 
characterize th em as "healthy" controls as they are in the abstract.  
 
What percent of the cases were atypical anorexia nervosa?  
 
Statistical analysis: How did you determine the sample size?  
 
P. 7, line 30 and 35 - "analyzes" should be "analyses"  
 
 
Results:  
 
p. 8, line 56. Was there a difference in liver laboratory parameters (Table 3 labs) and/or MBT 
results between the AN and AAN groups? Prior studies have shown that lower BMI is associated 
with higher ALT in AN.   
 
P 8. Line 61: "abnormally" should be "abnormal"  
 
 
Discussio n: 
 
I would suggest revising the opening/first paragraph of the discussion to reflect the major 
findings and implications of the study. Based on the title, it seems the authors imply that the 
MBT is not useful in the assessment of liver function in girls wi th AN, but the discussion does 
not reflect this. I also think the discussion could be shortened to focus on the discussion points 
that support the authors ultimate conclusions.  
 
I think some of the content in the discussion (prevalence of liver dysfunction in AN, clinical 
guidelines for daily liver enzyme testing) should be moved to the introduction to justify the 
rationale of the study.  
 
P 12. Line 11 -16. I think the authors migh t also discuss other limitations of the MBT versus 
serum laboratory measurement - ie the 120 minute test time during which the patient must 
remain fasting - patients with AN are generally hospitalized for nutritional refeeding and need to 
be refed througho ut the day. The duration of this test could be a barrier to refeeding. Also, for 
patients who may already be struggling to eat given the psychopathology of their illness, having 
to ingest the test dissolved in 200 mL of fluid may be traumatizing for patien ts - was this 
observed among the cases?  
 
p. 15, line 9. Was the rate of liver dysfunction the same in your sample among AN and AAN?  
 
P. 15, line 60. Are the controls really "healthy" children if they were hospitalized? Perhaps this 
should be a limitation.  
 
 
Conclusion:  
 
p. 16, line 25. "the described phenomenon creates a risk of obtaining a higher percentage of false 
negative results" - can you elaborate on this further, perhaps in the discussion?  
 
Are t he 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.  
 
No 
 
Are you able to assess any statistics in the manuscript or would you recommend an 
additional stat istical review?  
If an additional statistical review is recommended, please specify what aspects require further 
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
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 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 o r 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.  
 
I declare that I have no competing interes ts 
 
I agree to the open peer review policy of the journal. I understand that my name will be included 
on my report to the authors and, if the manuscript is accepted for 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 Access 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 include d 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:  Breath test using 13C methacetin does not seem to be useful in the assessment of liver 
function in girls with anorexia nervosa: a case control study  
 
Version: 1 Date: 01 Jan 2018 
 
Reviewer:  Jason  Nagata  
 
Reviewer’s report:  
 
Overall, this is a well -written case control study examining the usefulness of breath test using 
13C methacetin in the assessment of liver funct ion in girls with anorexia nervosa. While the 
overall conclusion based on the title is that the MBT is not useful in the assessment of liver 
function in girls with anorexia nervosa, I think this conclusion should be more clearly explained 
in the results, d iscussion, and conclusions. I also think it is important for the authors to further 
justify the clinical importance of the research question. I have some specific recommendations 
for consideration by the authors.  
 
Abstract: Conclusions: I am not sure that the conclusion "It seems necessary to undertake further 
clinical trials aimed at determining the effect of AN -related exogenous factors on the test result" 
is consistent with the title and negative findings of the study.  
 
Background: Overall, I think the a uthors should further justify the clinical significance and 
relevance of their research question, ie 1) how common is acute liver failure in AN; 2) justify the 
importance of monitoring liver function in AN; and 3) establish the potential value added of the  
MBT. Some of this is in the discussion, but I think it should be moved to the introduction.  
 
p. 3, Line 3 -6. It would be helpful to specify how common/prevalent acute liver failure is in AN - 
my understanding is that it is quite rare.  
 
p. 3, line 11 -16. Ho w common/prevalent are abnormal results of functional liver tests in AN 
(more specific than "relatively often"?  
 
p. 3, line 16: "the organ's function requires constant monitoring" - can you provide further 
references/citations/justification or ideally clin ical guidelines for the constant monitoring of liver 
function. You cite some of these in the discussion  
 
Second paragraph of background: can you add a little more about the value added of breath tests 
compared to other tests compared to the current standard  (ALT, AST). Perhaps cost 
effectiveness. I could understand why the noninvasive nature of breath tests could be a benefit in 
pediatric patients, but most patients with AN are adolescents who will likely have to get a blood 
draw for monitoring of electrolyt es regardless of their liver function.  
 
 
Methods:  
P. 4, line 28. "The control group were age matched -female patients who were hospitalized in 
other pediatric departments" - if these controls were hospitalized patients, I'm not sure I would 
characterize th em as "healthy" controls as they are in the abstract.  
 
What percent of the cases were atypical anorexia nervosa?  
 
Statistical analysis: How did you determine the sample size?  
 
P. 7, line 30 and 35 - "analyzes" should be "analyses"  
 
 
Results:  
 
p. 8, line 56. Was there a difference in liver laboratory parameters (Table 3 labs) and/or MBT 
results between the AN and AAN groups? Prior studies have shown that lower BMI is associated 
with higher ALT in AN.   
 
P 8. Line 61: "abnormally" should be "abnormal"  
 
 
Discussio n: 
 
I would suggest revising the opening/first paragraph of the discussion to reflect the major 
findings and implications of the study. Based on the title, it seems the authors imply that the 
MBT is not useful in the assessment of liver function in girls wi th AN, but the discussion does 
not reflect this. I also think the discussion could be shortened to focus on the discussion points 
that support the authors ultimate conclusions.  
 
I think some of the content in the discussion (prevalence of liver dysfunction in AN, clinical 
guidelines for daily liver enzyme testing) should be moved to the introduction to justify the 
rationale of the study.  
 
P 12. Line 11 -16. I think the authors migh t also discuss other limitations of the MBT versus 
serum laboratory measurement - ie the 120 minute test time during which the patient must 
remain fasting - patients with AN are generally hospitalized for nutritional refeeding and need to 
be refed througho ut the day. The duration of this test could be a barrier to refeeding. Also, for 
patients who may already be struggling to eat given the psychopathology of their illness, having 
to ingest the test dissolved in 200 mL of fluid may be traumatizing for patien ts - was this 
observed among the cases?  
 
p. 15, line 9. Was the rate of liver dysfunction the same in your sample among AN and AAN?  
 
P. 15, line 60. Are the controls really "healthy" children if they were hospitalized? Perhaps this 
should be a limitation.  
 
 
Conclusion:  
 
p. 16, line 25. "the described phenomenon creates a risk of obtaining a higher percentage of false 
negative results" - can you elaborate on this further, perhaps in the discussion?  
 
Are t he 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.  
 
No 
 
Are you able to assess any statistics in the manuscript or would you recommend an 
additional stat istical review?  
If an additional statistical review is recommended, please specify what aspects require further 
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
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 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 o r 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.  
 
I declare that I have no competing interes ts 
 
I agree to the open peer review policy of the journal. I understand that my name will be included 
on my report to the authors and, if the manuscript is accepted for 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 Access 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 include d 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:  Breath test using 13C methacetin does not seem to be useful in the assessment of liver 
function in girls with anorexia nervosa: a case control study  
 
Version: 1 Date: 01 Jan 2018 
 
Reviewer:  Jason  Nagata  
 
Reviewer’s report:  
 
Overall, this is a well -written case control study examining the usefulness of breath test using 
13C methacetin in the assessment of liver funct ion in girls with anorexia nervosa. While the 
overall conclusion based on the title is that the MBT is not useful in the assessment of liver 
function in girls with anorexia nervosa, I think this conclusion should be more clearly explained 
in the results, d iscussion, and conclusions. I also think it is important for the authors to further 
justify the clinical importance of the research question. I have some specific recommendations 
for consideration by the authors.  
 
Abstract: Conclusions: I am not sure that the conclusion "It seems necessary to undertake further 
clinical trials aimed at determining the effect of AN -related exogenous factors on the test result" 
is consistent with the title and negative findings of the study.  
 
Background: Overall, I think the a uthors should further justify the clinical significance and 
relevance of their research question, ie 1) how common is acute liver failure in AN; 2) justify the 
importance of monitoring liver function in AN; and 3) establish the potential value added of the  
MBT. Some of this is in the discussion, but I think it should be moved to the introduction.  
 
p. 3, Line 3 -6. It would be helpful to specify how common/prevalent acute liver failure is in AN - 
my understanding is that it is quite rare.  
 
p. 3, line 11 -16. Ho w common/prevalent are abnormal results of functional liver tests in AN 
(more specific than "relatively often"?  
 
p. 3, line 16: "the organ's function requires constant monitoring" - can you provide further 
references/citations/justification or ideally clin ical guidelines for the constant monitoring of liver 
function. You cite some of these in the discussion  
 
Second paragraph of background: can you add a little more about the value added of breath tests 
compared to other tests compared to the current standard  (ALT, AST). Perhaps cost 
effectiveness. I could understand why the noninvasive nature of breath tests could be a benefit in 
pediatric patients, but most patients with AN are adolescents who will likely have to get a blood 
draw for monitoring of electrolyt es regardless of their liver function.  
 
 
Methods:  
P. 4, line 28. "The control group were age matched -female patients who were hospitalized in 
other pediatric departments" - if these controls were hospitalized patients, I'm not sure I would 
characterize th em as "healthy" controls as they are in the abstract.  
 
What percent of the cases were atypical anorexia nervosa?  
 
Statistical analysis: How did you determine the sample size?  
 
P. 7, line 30 and 35 - "analyzes" should be "analyses"  
 
 
Results:  
 
p. 8, line 56. Was there a difference in liver laboratory parameters (Table 3 labs) and/or MBT 
results between the AN and AAN groups? Prior studies have shown that lower BMI is associated 
with higher ALT in AN.   
 
P 8. Line 61: "abnormally" should be "abnormal"  
 
 
Discussio n: 
 
I would suggest revising the opening/first paragraph of the discussion to reflect the major 
findings and implications of the study. Based on the title, it seems the authors imply that the 
MBT is not useful in the assessment of liver function in girls wi th AN, but the discussion does 
not reflect this. I also think the discussion could be shortened to focus on the discussion points 
that support the authors ultimate conclusions.  
 
I think some of the content in the discussion (prevalence of liver dysfunction in AN, clinical 
guidelines for daily liver enzyme testing) should be moved to the introduction to justify the 
rationale of the study.  
 
P 12. Line 11 -16. I think the authors migh t also discuss other limitations of the MBT versus 
serum laboratory measurement - ie the 120 minute test time during which the patient must 
remain fasting - patients with AN are generally hospitalized for nutritional refeeding and need to 
be refed througho ut the day. The duration of this test could be a barrier to refeeding. Also, for 
patients who may already be struggling to eat given the psychopathology of their illness, having 
to ingest the test dissolved in 200 mL of fluid may be traumatizing for patien ts - was this 
observed among the cases?  
 
p. 15, line 9. Was the rate of liver dysfunction the same in your sample among AN and AAN?  
 
P. 15, line 60. Are the controls really "healthy" children if they were hospitalized? Perhaps this 
should be a limitation.  
 
 
Conclusion:  
 
p. 16, line 25. "the described phenomenon creates a risk of obtaining a higher percentage of false 
negative results" - can you elaborate on this further, perhaps in the discussion?  
 
Are t he 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.  
 
No 
 
Are you able to assess any statistics in the manuscript or would you recommend an 
additional stat istical review?  
If an additional statistical review is recommended, please specify what aspects require further 
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
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 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 o r 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.  
 
I declare that I have no competing interes ts 
 
I agree to the open peer review policy of the journal. I understand that my name will be included 
on my report to the authors and, if the manuscript is accepted for 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 Access 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 include d as confidential comments 
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
assistant