Review for 10.1186/s12876-025-03712-6 (2025)

Title: Persistence of Anemia in patients with Celiac Disease despite a Gluten Free Diet: A
retrospective study
Version: 4 Date: 05 Nov 2024
Reviewer's report:
Dear Authors,
Thank you very much for submitting your work, and giving me the opportunity to review the
manuscript Persistence of Anemia in Celiac Disease patients despite a Gluten Free Diet: A
retrospective study.
The information provided in the manuscript is interesting and provides information about the
persistence of anemia in adults and children with CD after diagnosis and introduction of gluten
free diet (GFD).
Results of the study show that anemia can still be present in important proportion of adult patients
even after a decade of GFD. This finding is contrasting existing literature that shows consistent
improvement in anemia after the introduction of GFD.
There are some important issues that need to be explained in more detail or need clarification and
need to be addressed by the authors, which could possibly improve the quality of the manuscript.
GENERAL COMMENTS
Manuscript would benefit substantially in clarity with improved English.
Consider using throughout the manuscript (including the title): patients with Celiac Disease
(Anemia), Adults with Celiac Disease (Anemia), Children with Celiac Disease (Anemia) and not
adult celiac patients, pediatric celiac patients… or anemic adults or anemic children or anemic
pediatric patients
SPECIFIC COMMENTS
Comments are listed as they consecutively appeared within the manuscript.
Title
Reflects the nature of the study. Consider using “patients with Celiac Disease”
Abstract
…prevalence of anemia in both adult and pediatric CD patients
Consider using …in both adults and children with CD throughout the text.
Authors should present a clear data on the prevalence of anemia at diagnosis in studied groups.
Perhaps they should also present the data on how many patients had severe anemia if that data
is available.
At T2
Instead of At T2, authors should use At 8-10 years of GFD…
… only a slight reduction
Reduction from 24% to 18% is not slight, however it might not be regarded as highly significant.
It depends on the statistical method.
…anemia persists in 17.8%...
It would be very important to note whether anemia persist in the same patients or has it improved
in some and worsened in the others. Current statement only looks at the general population of
patients with CD.
Introduction
Is genetic testing always included in diagnostic guidelines for CD in adults?
…and histology which usually shows…
Consider using term histopathological changes of intestinal mucosa with … instead of histology
which usually shows…
… and positive anti-endomysial antibodies (EMA),
Authors must make sure to stress that increased EMA should be determined in a second/
confirmatory serum sample.
In the case of no-biopsy approach HLA DQ should have also been performed.
… without endoscopic and histological evaluation
It is not endoscopic evaluation, which is not very specific. Endoscopy is performed to obtain
biopsy specimens for further histopathological examination of intestinal mucosa, where changes
typical of CD are observed: intraepithelial lymphocytosis, crypt hyperplasia and villous atrophy.
CD is a global healthcare disease
CD is a global healthcare problem.
The esteemed prevalence of CD
Please check for English throughout the manuscript.
It is estimated and not the esteemed prevalence of CD.
although CD incidence is increasing in adults [5–7].
although CD incidence is increasing in adults as well [5–7].
Since CD mainly affects the duodenum
Is it true that duodenum is affected the most? Traditionally jejunum was considered to be affected
primarily, and capsule biopsy allowed for jejunal biopsy, however duodenum is easier to reach
with current endoscopes, and as such duodenum was chosen to be the primary site of multiple
biopsies.
in which pro-inflammatory cytokines take iron outside
Improve the English
The main treatment for CD
The only efficient treatment for CD is strict gluten-free diet.
No drug therapy is better than GFD in CD
Please be very careful when stating this. The sentence implies that there are some existing
therapies that are not superior to GFD but are existing on the market and can be of some benefit.
Indeed, there have been several trials on different pharmaceutical therapies, however none has
proven to be clinically relevant yet.
serological signs,
please improve the English.
Please rephrase the term serological signs.
In some patients with CD on a GFD, IDA can be persistent, these cases
Split into two sentences.
intense exercise-induced hemolysis in athletes
As this is hardly an important cause of anemia in CD, authors might consider omitting its
mention.
adult and pediatric CD patients
in adults and children with CD
Methods
including all adult CD patients
Please provide a timeframe in which adult patients with CD were diagnosed. It is very likely
that many that are followed were diagnosed more than two decades ago, some might had been
diagnosed as children.
standard clinical, serologic, endoscopic, and histological criteria as mentioned in the 2014
British guidelines
Are endoscopic features clinically relevant based on the British guidelines?
Considering the British guidelines of 2014 were used, please provide clarification whether
patients diagnosed before 2014 were not included in the study.
were diagnosed with CD according to the 2012 ESPGHAN
Same as above. What about the children diagnosed before 2012.
Especially since the study was approved by University Ethical Board in 2018.
All subjects gave their consent to participate in the current study
Authors should be sure that this is a correct statement. Authors are stating that all patients that
are followed at their adult or pediatric unit were included. It is highly likely that at least some
had not consented with participation.
Did the patients (their parents) give their consent at the time of diagnosis or only at the time
of follow-up?
8-10 years (T2) of GFS
Typo: GFD
The following data were collected
what about ferritin level.
what about histopathology report? Or changes of intestinal mucosa according to Marsh/
Oberhuber classification.
total IgA levels
Total IgA levels are not a part of CD antibodies and should be reported separately, perhaps prior
to CD specific serology.
biopsy assessment was carried out as recommended in the reported guidelines[25,29]
Please also cite Oberhuber (3)
positive tTG IgA class antibodies with titers >10 times the upper limit of normal
Please make sure that confirmatory EMA was done in all children who did not undergo duodenal
biopsy.
Based on the 2012 guidelines all no-biopsy diagnosed children should have also been tested for
HLA DQ2/DQ8.
In the case of a GFD non-adherence, the patients were excluded.
How was a non-adherence assessed in adults and in children?
Exclusion criteria
Would a (perhaps very rare) need for blood transfusion be considered an exclusion.
Outcomes
severity of anemia
How was the severity of anemia determined? Please present this in the methods.
Results
The overall mean HGB levels increased
Were only mean levels of Hb compared between the groups?
It would be very interesting to note how Hb levels had changed longitudinally in individual
patients.
Among the anemic patients
It would be very interesting to know what was the proportion of severely anemic patients in each
group and not merely learn about the mean Hb in anemic group.
Authors should provide at least one measure of dispersity of the data (SD, 95 CI, range),
depending on the normality of distribution.
At T2,
Instead of the T” please use 8-10 years.
slight reduction in the prevalence of anemia was observed
Reduction of anemia from 24% to 18% is not slight. It is a 1/3 change!!! In prevalence.
Baseline characteristics of untreated anemic and non-anemic CD patients
Please rephrase
Baseline characteristics of patients with CD
prevalence of anemia was higher in the female group
Consider providing solid data in the text and indicate whether the differences were not only there
by chance (specify statistical significance).
more commonly had Iron deficiency
Please specify in the methods, how was iron deficiency defined.
anemic patients had Marsh 0 or 1 at T1
Improve English
In majority of patients with anemia (88%) mucosal changes defined as Marsh o (4/23) or Marsh
1 (13/23) were described.
It is very interesting that at baseline Marsh 0 lesions were considered to be compatible with
celiac disease. Can authors clarify this
Discussion
probably due to a more severe clinical presentation at the diagnosis (Table 1).
Younger children more often present with malabsorptive CD (perhaps cite Riznik et al. Clinical
Presentation in Children With Coeliac Disease in Central Europe. J Pediatr Gastroenterol
Nutr. 2021;72(4):546-551. doi: 10.1097/MPG.0000000000003015.), which with their already
reduced iron storage and high iron demand makes them more susceptible for IDA.
…and CD primarily affects this bowel tract.
Improve English for better clarity
about 1/5 of adult celiac patients continue to be anemic despite the healing of duodenal mucosa
Is this statement supported by the data of the study? Were enough of adult patients re-biopsied
to support this?
most of anemic patients at T1 had Marsh 0 or 1
Authors should definitely discuss the high proportion of patients with Marsh Type 0 and Type 1
lesions. They should provide the readers about the other parameters that yielded a final diagnosis
of CD in these patients.
Some anemic patients are refractory to oral iron supplementation
There is no data on the iron supplementation in the results. It only can be assumed that some
patients were prescribed iron supplementation therapy. However, there is no data on the average
duration of such therapy, nor is there any data on the compliance or the need for introduction
of i.v. supplementation.
Our study had a few important limitations
Authors are aware of some of the limitations of the study and are declaring these.
Moreover, during the considered observational period, all the patients followed in our unit were
forced to have an outpatient visit
Can the authors be specific about this enforcing of their patients to visit outpatient clinic?
Tables
Table 1
Some parameters were not described in the methods nor presented in results or discussed in
discussion. These parameters might be omitted.
Table 2
Columns 34-6 should preferably read: T0 vs T1; T0 vs T2; T1 vs T2.
It would be much more interesting to present the data of individual patients as they were followed
longitudinally form diagnosis onward as regards their Hb levels with a cut-off level showing the
threshold of anemia. Such a figure could show trends in Hb.
Currently a reader is only able to see mean Hb level without any knowledge of how many patients
had their anemia improved and how many had it worsened.
Table 3. Marsh degrees in anemic adult Celiac Disease patients
Improve English for better clarity.
Unclear as to what the numbers 44 and 26 refer to in the first row.
Only when reading this table, it becomes clear that only 6 patients at T1 and 1 at T2 had lesions
described as Marsh greater than 1. This is not clearly presented in the main text.
Table 4
This table is perhaps not needed. It is sufficient to present statistics showing that adult age is a
single predictor for anemia in this model.
Figures
Individual patients could be connected to see individual longitudinal trends.