Reviewer’s report
Title: 
No association of serum ferritin levels with advanced liver fibrosis in
untreated German patients with autoimmune hepatitis
Version: 
0 
Date: 
07 Jul 2022
Reviewer's report:
In their letter, Engel et al. reported that they could not validate the findings of
Chen et al. that was published in the January 2022 issue of BMC
Gastroenterology. The letter includes some important points that could be of
value for the scientific conversation, however a few modifications might be
advisable.
It is absolutely a fair point that an odd ratio of 1.002 has a questionable practical
relevance. However, it can still have value from a scientific point of view.
Importantly, small effects like this are hard to validate (and probably would
require bigger cohorts). But the main concern is that the authors did not repeat
the analysis as it was performed in the paper from Chen et al. If the aim of a
paper is to validate (or disprove) a previous finding, then the authors should try
to reproduce the original analysis as much as possible as a first step. Only after
that should they do any corrections if they have concerns about the used
methods, and report both results. 
However, Engel et al. did not evaluate absolute ferritin levels as Chen et al. but
they normalized ferritin concentrations to the ULN "to avoid bias by different
reference values for different age groups and gender". Patients' age and sex can
indeed influence their ferritin levels (but so can inflammation and bleeding),
however normalization is not necessarily the best way to deal with this effect. In
fact, these factors were considered in the uni and multivariate regression analysis
of the original paper: sex was not associated with fibrosis, and age lost
significance in the multivariate model against other factors including ferritin
level. On the other hand, normalization can cover the possible subtle effect of
ferritin level. Furthermore, it is possible that ferritin above a certain level induces
fibrotic pathways in a particular cell type (for example stellate cells) regardless
of the accepted ULN of the age and sex category where the investigated patients
belong to. In fact, iron independent fibrosis facilitating effect of the ferritin
molecule has been reported in rats (Ruddell RG, et al. Ferritin functions as a
proinflammatory cytokine via iron-independent protein kinase C zeta/nuclear
factor kappaB-regulated signaling in rat hepatic stellate cells. Hepatology. 2009).
Therefore, it is hard to decide which is the right way to analyze and both
approaches have their pros and cons. Consequently, the authors should present
the results of both.
Additionally, after logarithmic transformation of the ferritin levels, the
regression analysis might result in higher odds ratio.
Finally, the suggestion for Chen et al. to validate the treatment response score of
Taubert et al. is reasonable and potentially beneficial for the medical community.
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No
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.
I declare that I have no competing interests.
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?
Yes
Are the methods sufficiently described to allow the study to be repeated?
Yes
Is the use of statistics and treatment of uncertainties appropriate?
No
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
Reviewer’s report
Title: 
No association of serum ferritin levels with advanced liver fibrosis in
untreated German patients with autoimmune hepatitis
Version: 
0 
Date: 
07 Jul 2022
Reviewer's report:
In their letter, Engel et al. reported that they could not validate the findings of
Chen et al. that was published in the January 2022 issue of BMC
Gastroenterology. The letter includes some important points that could be of
value for the scientific conversation, however a few modifications might be
advisable.
It is absolutely a fair point that an odd ratio of 1.002 has a questionable practical
relevance. However, it can still have value from a scientific point of view.
Importantly, small effects like this are hard to validate (and probably would
require bigger cohorts). But the main concern is that the authors did not repeat
the analysis as it was performed in the paper from Chen et al. If the aim of a
paper is to validate (or disprove) a previous finding, then the authors should try
to reproduce the original analysis as much as possible as a first step. Only after
that should they do any corrections if they have concerns about the used
methods, and report both results. 
However, Engel et al. did not evaluate absolute ferritin levels as Chen et al. but
they normalized ferritin concentrations to the ULN "to avoid bias by different
reference values for different age groups and gender". Patients' age and sex can
indeed influence their ferritin levels (but so can inflammation and bleeding),
however normalization is not necessarily the best way to deal with this effect. In
fact, these factors were considered in the uni and multivariate regression analysis
of the original paper: sex was not associated with fibrosis, and age lost
significance in the multivariate model against other factors including ferritin
level. On the other hand, normalization can cover the possible subtle effect of
ferritin level. Furthermore, it is possible that ferritin above a certain level induces
fibrotic pathways in a particular cell type (for example stellate cells) regardless
of the accepted ULN of the age and sex category where the investigated patients
belong to. In fact, iron independent fibrosis facilitating effect of the ferritin
molecule has been reported in rats (Ruddell RG, et al. Ferritin functions as a
proinflammatory cytokine via iron-independent protein kinase C zeta/nuclear
factor kappaB-regulated signaling in rat hepatic stellate cells. Hepatology. 2009).
Therefore, it is hard to decide which is the right way to analyze and both
approaches have their pros and cons. Consequently, the authors should present
the results of both.
Additionally, after logarithmic transformation of the ferritin levels, the
regression analysis might result in higher odds ratio.
Finally, the suggestion for Chen et al. to validate the treatment response score of
Taubert et al. is reasonable and potentially beneficial for the medical community.
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
No
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.
I declare that I have no competing interests.
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?
Yes
Are the methods sufficiently described to allow the study to be repeated?
Yes
Is the use of statistics and treatment of uncertainties appropriate?
No
Is the presentation of the work clear?
Yes
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: 
No association of serum ferritin levels with advanced liver fibrosis in
untreated German patients with autoimmune hepatitis
Version: 
0 
Date: 
07 Jul 2022
Reviewer's report:
In their letter, Engel et al. reported that they could not validate the findings of
Chen et al. that was published in the January 2022 issue of BMC
Gastroenterology. The letter includes some important points that could be of
value for the scientific conversation, however a few modifications might be
advisable.
It is absolutely a fair point that an odd ratio of 1.002 has a questionable practical
relevance. However, it can still have value from a scientific point of view.
Importantly, small effects like this are hard to validate (and probably would
require bigger cohorts). But the main concern is that the authors did not repeat
the analysis as it was performed in the paper from Chen et al. If the aim of a
paper is to validate (or disprove) a previous finding, then the authors should try
to reproduce the original analysis as much as possible as a first step. Only after
that should they do any corrections if they have concerns about the used
methods, and report both results. 
However, Engel et al. did not evaluate absolute ferritin levels as Chen et al. but
they normalized ferritin concentrations to the ULN "to avoid bias by different
reference values for different age groups and gender". Patients' age and sex can
indeed influence their ferritin levels (but so can inflammation and bleeding),
however normalization is not necessarily the best way to deal with this effect. In
fact, these factors were considered in the uni and multivariate regression analysis
of the original paper: sex was not associated with fibrosis, and age lost
significance in the multivariate model against other factors including ferritin
level. On the other hand, normalization can cover the possible subtle effect of
ferritin level. Furthermore, it is possible that ferritin above a certain level induces
fibrotic pathways in a particular cell type (for example stellate cells) regardless
of the accepted ULN of the age and sex category where the investigated patients
belong to. In fact, iron independent fibrosis facilitating effect of the ferritin
molecule has been reported in rats (Ruddell RG, et al. Ferritin functions as a
proinflammatory cytokine via iron-independent protein kinase C zeta/nuclear
factor kappaB-regulated signaling in rat hepatic stellate cells. Hepatology. 2009).
Therefore, it is hard to decide which is the right way to analyze and both
approaches have their pros and cons. Consequently, the authors should present
the results of both.
Additionally, after logarithmic transformation of the ferritin levels, the
regression analysis might result in higher odds ratio.
Finally, the suggestion for Chen et al. to validate the treatment response score of
Taubert et al. is reasonable and potentially beneficial for the medical community.
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
No
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.
I declare that I have no competing interests.
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?
Yes
Are the methods sufficiently described to allow the study to be repeated?
Yes
Is the use of statistics and treatment of uncertainties appropriate?
No
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
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