Disease activity and iron status in children with inflammatory bowel disease

Children with inflammatory bowel disease (IBD) have an increased risk of
developing iron deficiency (ID). Studies in children with IBD report prevalence
rates of ID between 20% and 88%. However, studies reporting on ID in children
are difficult to compare since different definitions, iron indices and cut-off
values are used. ID in children with IBD can be an absolute or a functional
deficiency, or both. Both types of ID represent two different forms of impaired
iron homeostasis. Absolute ID refers to depleted iron stores due to
insufficient dietary intake, iron malabsorption and/or (chronic) blood loss
from the gastrointestinal tract due to (chronic) inflammation of the intestinal
epithelium. Iron deficiency anemia (IDA) occurs when iron stores are exhausted
and iron availability to the erythropoiesis is compromised. In functional ID
pro-inflammatory cytokines, especially interleukin-6 (IL-6), induce changes in
iron homeostasis by upregulating hepcidin expression. Hepcidin is a
25-amino-acid peptide hormone, primarily synthesized in the liver, that reduces
iron efflux from enterocytes and macrophages, and hereby causing an increased
uptake and retention of iron in strorage sites of the reticuloendothelial
system. This leads to a limitation of the availability of iron for erythroid
progenitor cells (iron-restricted erythropoiesis). Ultimately, this can lead to
the so-called anemia of chronic disease (ACD). Regarding the pathophysiology of
ID in children with IBD, we hypothesize that increased disease activity (i.e.
more inflammation) is associated with an increased risk of developing ID.
Furthermore, patients with IBD are at increased risk of vitamin D deficiency
(VDD) compared to the general population, because of decreased nutrient intake
or absorption and/or increased losses in stool. Studies in children and
adolescents with IBD report prevalence rates of VDD between 6% and 62%. The
co-existence of VDD and ID has been described in several populations other than
children with IBD. Several possible mechanisms have been proposed in order to
explain this co-existence. However, data regarding the relation between vitamin
D status and iron status in children with IBD are practically non-existent.

Primary Objective:
To investigate the relationship between disease activity and iron deficiency
(i.e. absolute and functional ID combined) in children with IBD.

Secondary Objectives:
1.To establish the prevalence of iron deficiency (both absolute and functional)
and anemia (IDA and ACD) in children with IBD.

2.To assess whether the following factors contribute to iron deficiency (both
absolute and functional) and anemia (IDA and ACD) in children with IBD:
• Sex
• Ethnicity
• Parental educational level
• Socioeconomic status (SES)
• Dietary iron intake
• Menstrual cycle
• Disease related factors: use and type of medication, duration of disease, IBD
related surgery

3.To investigate the relationship between FC-levels and different iron
parameters reflecting different aspects of iron homeostasis in children with
IBD.

4. To investigate whether change in disease activity over time effects iron
status in children with IBD. In order to do so, we will measure various
parameters (i.e. SF, RDW, ZnPP/H and hepcidin) at inclusion (t=0) and after six
months (t=after 6 months).

5.To establish the prevalence of vitamin D deficiency in children with IBD, and
to investigate the relation between vitamin D status and iron status in
children with IBD.

We will conduct a multi-center prospective observational study.

Benefits: no benefits are to be expected when participating in this prospective
observational study (i.e. non-therapeutic research).

Risks and burden:
- At inclusion, all (parents of) eligible children with IBD will also be asked
to fill out a questionnaire (Q1). This questionnaire will include questions
related to factors known or suspected to influence iron status, vitamin D
status and the presence of anemia, such as parental marital status, parental
educational level and ethnicity. This may cause some inconvenience, but is
considered a minimal burden. This questionnaire will only be obtained once, at
time of inclusion.
- At inclusion and after 6 months, all (parents of) eligible children with IBD
will be asked to fill out a questionnaire (Q2). This questionnaire will include
questions related to factors known or suspected to influence iron status,
vitamin D status and the presence of anemia, such as use of
medication/supplements. This may cause some inconvenience, but is considered a
minimal burden.
- At inclusion and after 6 months, 3 ml extra blood will be drawn for
determining hepcidin, 25[OH] vitamin D, vitamin B12 and folic acid. Since the
extra blood needed for this study will be drawn from the same blood sample that
is being taken as part of regular check-ups, there is no extra invasive moment
(i.e. no extra risk) for the participating subject.
- After informed consent is obtained, all (parents of) eligible children
with IBD will be asked to record the dietary intake for three days after the
scheduled blood draw (at inclusion and after 6 months) to obtain information
regarding the dietary intake. The recording of the dietary intake will take
about 10-15 minutes per day. This may cause some inconvenience, but is
considered a minimal burden.

Group relatedness: this study could not be conducted without the participation
of subjects belonging to the group in question (i.e. children with IBD).