Title: Celiac disease autoimmunity among Nigerian children and adolescents with type 1
diabetes mellitus
Version: 4 Date: 27 Jun 2024
Reviewer's report:
Dear Authors,
Thank you very much for submitting your work, and giving me the opportunity to review
the manuscript Celiac disease among Nigerian children and adolescents with type 1 diabetes
mellitus.
The information provided in the manuscript provides the information about the occurrence of
celiac disease in population of children with type 1 DM in Nigeria.
Results of the study show that about 5% of children with T1DM in Nigeria is seropositive for
celiac disease specific antibodies, which indicates that the prevalence of celiac disease in Nigeria
is severely underestimated.
Authors call for better screening strategies for celiac disease in Nigeria.
There are some very important issues that need to be explained in more detail or need further
clarification and need to be addressed by the authors, which could possibly improve the quality
of the work.
GENERAL COMMENTS
The study is focusing on children with type 1 DM (T1DM), where authors were actively
searching for celiac disease (CD).
As the six cases which were found in the study were not diagnosed based on the current
guidelines by any of pediatric GI societies (ESPGHAN or NASPGHAN), it is strongly suggested
that the term patients (children) with celiac autoimmunity is used instead of patients (children)
with celiac disease.
The manuscript could benefit from review of English language.
SPECIFIC COMMENTS
Title
Reflects the nature of the study.
Abstract
Should be modified according to the changes in the main text when necessary.
Keywords
Appropriate
Introduction/Background
Consider adding abdominal pain as an important symptom of celiac disease in children.
Iron deficiency anemia is not an atypical presentation. It is a part of malabsorption syndrome,
which is typical of celiac disease.
Please disclose other risk groups as well (e.g. Autoimmune thyroiditis, Selective IgA
deficiency). Perhaps add first degree relatives.
In a paragraph focusing on the prevalence of CD in different African regions make sure to
separate the studies of prevalence in general population form the studies where the prevalence
in T1DM children was described.
Methods
Study location
It would be interesting to disclose basic demographic data for Nigeria, such as the total
population, number of children, number of people with T1DM and the number of tertiary
pediatric hospitals.
Why was a selection of seven tertiary health facilities made. Would it not be better to include
institutions randomly or to include all of them.
Estimation of celiac disease and diagnosis of celiac disease
Did the seven different hospitals used the same test kits for anti-tTG? Did they used the same
EMA test kit.
Why was a decision made to test for EMA in IgA deficient patients. EMA test is mostly IgA
based, so this approach could increase the risk of false negative results.
It is suggested by the authors that EMA results were presented as U/l where more than 20U/
l would be considered positive. EMA is mostly qualitative (indirect immunofluorescence) test,
where only a positive/negative results are presented. Rarely there are dilutions presented. In such
case dilutions above a certain level that are still giving the positive result are considered to be
positive. How does the 20U/l relate to this?
Total IgA levels in celiac disease plays a role only if deficient. Consider presenting the lower
levels of normality for different age groups, since it is known that these differ by age.
Were all the positive patients sent to a single center where the biopsy was performed? Or were
biopsies performed in all tertiary centers?
The sedation technique used for intestinal biopsy as well as the entire endoscopy procedure is
very extensive and does not add to the content of the study, which should be focusing on celiac
disease in T1DM. Consider substantial shortening.
Why was a decision made to take only 4 samples from descending duodenum and none was
taken from the bulb, as it is recommended?
Please clarify whether the Marsh I would be considered to be diagnostic of celiac disease in
children included in the study.
Data analysis
Some of the parameters might not be normally distributed. In these cases, median (IQR) should
be used.
Results
Prevalence of celiac disease in children with T1DM
How was a final prevalence calculated?
Which patients were considered to have celiac disease? All seropositive? All seropositive with
very high titers of tTG and with secondary sample tested for EMA at different time (as suggested
by ESPGHAN guidelines).
When a low serum IgA was found in T1DM, were they tested for any of the available IgG tests
(tTG IgG, DGP IgG). It is not clear whether the EMA used in the study was of an IgG class,
which is very unlikely as it is very rarely used.
It is a pity that only one patient underwent intestinal biopsy. Could the authors provide the reason
for such a low figure?
The image of the intestinal mucosa presented, has some problems.
Despite the villi being present the orientation is questionable, since there are too many crypts
seen in a single section. In such cases a reorientation of a sample is indicated. It is very likely
that if aligned properly there would indeed be changes suggestive of celiac disease.
Discussion
It should be made clear that the diagnosis of celiac disease was not confirmed in practically any
of the included children.
Patients with abnormal titers can be described as patients with celiac autoimmunity, but perhaps
the term celiac disease should be carefully used in these circumstances.
Due to the very low number of seropositive T1DM patients (six) it is very hard to draw any firm
conclusions regarding the differences between the groups.
“However, the mean age of the participants with elevated anti-tTG IgA”
It is not clear whether this is a mean age at diagnosis of T1DM or is this the mean age of celiac
seropositivity.
The term female bias is not recommended. Please find a better term.
Important limitation of the study is also a low number of seropositive patients, which does not
allow to draw any firm conclusions.
It should be strongly stressed that the data form this study shows that the number of children
with celiac disease is very likely to be high in general population of Nigeria and that programs
for active screening of risk populations as well as active searching for the disease in clinical
settings should be supported in the country.
Tables
Table 1.
There is no need to describe the level of education of children in a table. It can be largely affected
by the age of children of which more than 60% are younger than 14y. This information does
not add anything to the study.
Not clear whether the data on gluten consumption adds much to the study. It is surprising that
a substantial proportion of participants eat gluten less than once a month. And many do not eat
it daily.
Table 2.
As it can be seen, all the patients have normal total IgA.
Three patients have rather low titers of tTG, one has a moderate elevation and two are the ones
who could be eligible for a no biopsy diagnosis. Unfortunately, one had negative EMA.
It is not clear if the EMA was done in the same sample or in a separate sample (as it should be).
These findings are in accordance with the data of several other studies where a low titer of
tTG can be found in T1DM children. If these children are observed longitudinally in many a
spontaneous normalization of titers can be found.
Authors should be very careful when calling these patients celiac disease patients. It is strongly
suggested to use a term “patient with celiac autoimmunity”, to prevent false conclusions, and
unnecessary overestimation.
Table 4.
Based on the results in the table two patients with celiac autoimmunity did not present with
any GI symptoms. In the text it does say that only one was asymptomatic. Please make sure to
clarify which is correct.
Figures
Images 1 and 4 are the same. Different magnification is used and image is flipped by 180°.
No need to present the data about Hp.
As regards the orientation; the number of crypts in the section indicate the cross sectional
cut, which can be a cause of misinterpretation. It is clear, that lamina propria is infiltrated by
lymphocytes, but it is hard to see if there is also an increase in intraepithelial lymphocytes.
Title: Celiac disease autoimmunity among Nigerian children and adolescents with type 1
diabetes mellitus
Version: 4 Date: 27 Jun 2024
Reviewer's report:
Dear Authors,
Thank you very much for submitting your work, and giving me the opportunity to review
the manuscript Celiac disease among Nigerian children and adolescents with type 1 diabetes
mellitus.
The information provided in the manuscript provides the information about the occurrence of
celiac disease in population of children with type 1 DM in Nigeria.
Results of the study show that about 5% of children with T1DM in Nigeria is seropositive for
celiac disease specific antibodies, which indicates that the prevalence of celiac disease in Nigeria
is severely underestimated.
Authors call for better screening strategies for celiac disease in Nigeria.
There are some very important issues that need to be explained in more detail or need further
clarification and need to be addressed by the authors, which could possibly improve the quality
of the work.
GENERAL COMMENTS
The study is focusing on children with type 1 DM (T1DM), where authors were actively
searching for celiac disease (CD).
As the six cases which were found in the study were not diagnosed based on the current
guidelines by any of pediatric GI societies (ESPGHAN or NASPGHAN), it is strongly suggested
that the term patients (children) with celiac autoimmunity is used instead of patients (children)
with celiac disease.
The manuscript could benefit from review of English language.
SPECIFIC COMMENTS
Title
Reflects the nature of the study.
Abstract
Should be modified according to the changes in the main text when necessary.
Keywords
Appropriate
Introduction/Background
Consider adding abdominal pain as an important symptom of celiac disease in children.
Iron deficiency anemia is not an atypical presentation. It is a part of malabsorption syndrome,
which is typical of celiac disease.
Please disclose other risk groups as well (e.g. Autoimmune thyroiditis, Selective IgA
deficiency). Perhaps add first degree relatives.
In a paragraph focusing on the prevalence of CD in different African regions make sure to
separate the studies of prevalence in general population form the studies where the prevalence
in T1DM children was described.
Methods
Study location
It would be interesting to disclose basic demographic data for Nigeria, such as the total
population, number of children, number of people with T1DM and the number of tertiary
pediatric hospitals.
Why was a selection of seven tertiary health facilities made. Would it not be better to include
institutions randomly or to include all of them.
Estimation of celiac disease and diagnosis of celiac disease
Did the seven different hospitals used the same test kits for anti-tTG? Did they used the same
EMA test kit.
Why was a decision made to test for EMA in IgA deficient patients. EMA test is mostly IgA
based, so this approach could increase the risk of false negative results.
It is suggested by the authors that EMA results were presented as U/l where more than 20U/
l would be considered positive. EMA is mostly qualitative (indirect immunofluorescence) test,
where only a positive/negative results are presented. Rarely there are dilutions presented. In such
case dilutions above a certain level that are still giving the positive result are considered to be
positive. How does the 20U/l relate to this?
Total IgA levels in celiac disease plays a role only if deficient. Consider presenting the lower
levels of normality for different age groups, since it is known that these differ by age.
Were all the positive patients sent to a single center where the biopsy was performed? Or were
biopsies performed in all tertiary centers?
The sedation technique used for intestinal biopsy as well as the entire endoscopy procedure is
very extensive and does not add to the content of the study, which should be focusing on celiac
disease in T1DM. Consider substantial shortening.
Why was a decision made to take only 4 samples from descending duodenum and none was
taken from the bulb, as it is recommended?
Please clarify whether the Marsh I would be considered to be diagnostic of celiac disease in
children included in the study.
Data analysis
Some of the parameters might not be normally distributed. In these cases, median (IQR) should
be used.
Results
Prevalence of celiac disease in children with T1DM
How was a final prevalence calculated?
Which patients were considered to have celiac disease? All seropositive? All seropositive with
very high titers of tTG and with secondary sample tested for EMA at different time (as suggested
by ESPGHAN guidelines).
When a low serum IgA was found in T1DM, were they tested for any of the available IgG tests
(tTG IgG, DGP IgG). It is not clear whether the EMA used in the study was of an IgG class,
which is very unlikely as it is very rarely used.
It is a pity that only one patient underwent intestinal biopsy. Could the authors provide the reason
for such a low figure?
The image of the intestinal mucosa presented, has some problems.
Despite the villi being present the orientation is questionable, since there are too many crypts
seen in a single section. In such cases a reorientation of a sample is indicated. It is very likely
that if aligned properly there would indeed be changes suggestive of celiac disease.
Discussion
It should be made clear that the diagnosis of celiac disease was not confirmed in practically any
of the included children.
Patients with abnormal titers can be described as patients with celiac autoimmunity, but perhaps
the term celiac disease should be carefully used in these circumstances.
Due to the very low number of seropositive T1DM patients (six) it is very hard to draw any firm
conclusions regarding the differences between the groups.
“However, the mean age of the participants with elevated anti-tTG IgA”
It is not clear whether this is a mean age at diagnosis of T1DM or is this the mean age of celiac
seropositivity.
The term female bias is not recommended. Please find a better term.
Important limitation of the study is also a low number of seropositive patients, which does not
allow to draw any firm conclusions.
It should be strongly stressed that the data form this study shows that the number of children
with celiac disease is very likely to be high in general population of Nigeria and that programs
for active screening of risk populations as well as active searching for the disease in clinical
settings should be supported in the country.
Tables
Table 1.
There is no need to describe the level of education of children in a table. It can be largely affected
by the age of children of which more than 60% are younger than 14y. This information does
not add anything to the study.
Not clear whether the data on gluten consumption adds much to the study. It is surprising that
a substantial proportion of participants eat gluten less than once a month. And many do not eat
it daily.
Table 2.
As it can be seen, all the patients have normal total IgA.
Three patients have rather low titers of tTG, one has a moderate elevation and two are the ones
who could be eligible for a no biopsy diagnosis. Unfortunately, one had negative EMA.
It is not clear if the EMA was done in the same sample or in a separate sample (as it should be).
These findings are in accordance with the data of several other studies where a low titer of
tTG can be found in T1DM children. If these children are observed longitudinally in many a
spontaneous normalization of titers can be found.
Authors should be very careful when calling these patients celiac disease patients. It is strongly
suggested to use a term “patient with celiac autoimmunity”, to prevent false conclusions, and
unnecessary overestimation.
Table 4.
Based on the results in the table two patients with celiac autoimmunity did not present with
any GI symptoms. In the text it does say that only one was asymptomatic. Please make sure to
clarify which is correct.
Figures
Images 1 and 4 are the same. Different magnification is used and image is flipped by 180°.
No need to present the data about Hp.
As regards the orientation; the number of crypts in the section indicate the cross sectional
cut, which can be a cause of misinterpretation. It is clear, that lamina propria is infiltrated by
lymphocytes, but it is hard to see if there is also an increase in intraepithelial lymphocytes.
Please review this paper.
user
Title: Celiac disease autoimmunity among Nigerian children and adolescents with type 1
diabetes mellitus
Version: 4 Date: 27 Jun 2024
Reviewer's report:
Dear Authors,
Thank you very much for submitting your work, and giving me the opportunity to review
the manuscript Celiac disease among Nigerian children and adolescents with type 1 diabetes
mellitus.
The information provided in the manuscript provides the information about the occurrence of
celiac disease in population of children with type 1 DM in Nigeria.
Results of the study show that about 5% of children with T1DM in Nigeria is seropositive for
celiac disease specific antibodies, which indicates that the prevalence of celiac disease in Nigeria
is severely underestimated.
Authors call for better screening strategies for celiac disease in Nigeria.
There are some very important issues that need to be explained in more detail or need further
clarification and need to be addressed by the authors, which could possibly improve the quality
of the work.
GENERAL COMMENTS
The study is focusing on children with type 1 DM (T1DM), where authors were actively
searching for celiac disease (CD).
As the six cases which were found in the study were not diagnosed based on the current
guidelines by any of pediatric GI societies (ESPGHAN or NASPGHAN), it is strongly suggested
that the term patients (children) with celiac autoimmunity is used instead of patients (children)
with celiac disease.
The manuscript could benefit from review of English language.
SPECIFIC COMMENTS
Title
Reflects the nature of the study.
Abstract
Should be modified according to the changes in the main text when necessary.
Keywords
Appropriate
Introduction/Background
Consider adding abdominal pain as an important symptom of celiac disease in children.
Iron deficiency anemia is not an atypical presentation. It is a part of malabsorption syndrome,
which is typical of celiac disease.
Please disclose other risk groups as well (e.g. Autoimmune thyroiditis, Selective IgA
deficiency). Perhaps add first degree relatives.
In a paragraph focusing on the prevalence of CD in different African regions make sure to
separate the studies of prevalence in general population form the studies where the prevalence
in T1DM children was described.
Methods
Study location
It would be interesting to disclose basic demographic data for Nigeria, such as the total
population, number of children, number of people with T1DM and the number of tertiary
pediatric hospitals.
Why was a selection of seven tertiary health facilities made. Would it not be better to include
institutions randomly or to include all of them.
Estimation of celiac disease and diagnosis of celiac disease
Did the seven different hospitals used the same test kits for anti-tTG? Did they used the same
EMA test kit.
Why was a decision made to test for EMA in IgA deficient patients. EMA test is mostly IgA
based, so this approach could increase the risk of false negative results.
It is suggested by the authors that EMA results were presented as U/l where more than 20U/
l would be considered positive. EMA is mostly qualitative (indirect immunofluorescence) test,
where only a positive/negative results are presented. Rarely there are dilutions presented. In such
case dilutions above a certain level that are still giving the positive result are considered to be
positive. How does the 20U/l relate to this?
Total IgA levels in celiac disease plays a role only if deficient. Consider presenting the lower
levels of normality for different age groups, since it is known that these differ by age.
Were all the positive patients sent to a single center where the biopsy was performed? Or were
biopsies performed in all tertiary centers?
The sedation technique used for intestinal biopsy as well as the entire endoscopy procedure is
very extensive and does not add to the content of the study, which should be focusing on celiac
disease in T1DM. Consider substantial shortening.
Why was a decision made to take only 4 samples from descending duodenum and none was
taken from the bulb, as it is recommended?
Please clarify whether the Marsh I would be considered to be diagnostic of celiac disease in
children included in the study.
Data analysis
Some of the parameters might not be normally distributed. In these cases, median (IQR) should
be used.
Results
Prevalence of celiac disease in children with T1DM
How was a final prevalence calculated?
Which patients were considered to have celiac disease? All seropositive? All seropositive with
very high titers of tTG and with secondary sample tested for EMA at different time (as suggested
by ESPGHAN guidelines).
When a low serum IgA was found in T1DM, were they tested for any of the available IgG tests
(tTG IgG, DGP IgG). It is not clear whether the EMA used in the study was of an IgG class,
which is very unlikely as it is very rarely used.
It is a pity that only one patient underwent intestinal biopsy. Could the authors provide the reason
for such a low figure?
The image of the intestinal mucosa presented, has some problems.
Despite the villi being present the orientation is questionable, since there are too many crypts
seen in a single section. In such cases a reorientation of a sample is indicated. It is very likely
that if aligned properly there would indeed be changes suggestive of celiac disease.
Discussion
It should be made clear that the diagnosis of celiac disease was not confirmed in practically any
of the included children.
Patients with abnormal titers can be described as patients with celiac autoimmunity, but perhaps
the term celiac disease should be carefully used in these circumstances.
Due to the very low number of seropositive T1DM patients (six) it is very hard to draw any firm
conclusions regarding the differences between the groups.
“However, the mean age of the participants with elevated anti-tTG IgA”
It is not clear whether this is a mean age at diagnosis of T1DM or is this the mean age of celiac
seropositivity.
The term female bias is not recommended. Please find a better term.
Important limitation of the study is also a low number of seropositive patients, which does not
allow to draw any firm conclusions.
It should be strongly stressed that the data form this study shows that the number of children
with celiac disease is very likely to be high in general population of Nigeria and that programs
for active screening of risk populations as well as active searching for the disease in clinical
settings should be supported in the country.
Tables
Table 1.
There is no need to describe the level of education of children in a table. It can be largely affected
by the age of children of which more than 60% are younger than 14y. This information does
not add anything to the study.
Not clear whether the data on gluten consumption adds much to the study. It is surprising that
a substantial proportion of participants eat gluten less than once a month. And many do not eat
it daily.
Table 2.
As it can be seen, all the patients have normal total IgA.
Three patients have rather low titers of tTG, one has a moderate elevation and two are the ones
who could be eligible for a no biopsy diagnosis. Unfortunately, one had negative EMA.
It is not clear if the EMA was done in the same sample or in a separate sample (as it should be).
These findings are in accordance with the data of several other studies where a low titer of
tTG can be found in T1DM children. If these children are observed longitudinally in many a
spontaneous normalization of titers can be found.
Authors should be very careful when calling these patients celiac disease patients. It is strongly
suggested to use a term “patient with celiac autoimmunity”, to prevent false conclusions, and
unnecessary overestimation.
Table 4.
Based on the results in the table two patients with celiac autoimmunity did not present with
any GI symptoms. In the text it does say that only one was asymptomatic. Please make sure to
clarify which is correct.
Figures
Images 1 and 4 are the same. Different magnification is used and image is flipped by 180°.
No need to present the data about Hp.
As regards the orientation; the number of crypts in the section indicate the cross sectional
cut, which can be a cause of misinterpretation. It is clear, that lamina propria is infiltrated by
lymphocytes, but it is hard to see if there is also an increase in intraepithelial lymphocytes.
assistant