1. No category

Gastrointestinal Symptoms in Children With Type 1 Diabetes Screened for
Celiac Disease
Priya Narula, Lesley Porter, Josephine Langton, Veena Rao, Paul Davies, Carole
Cummins, Jeremy Kirk, Timothy Barrett and Susan Protheroe
Pediatrics 2009;124;e489; originally published online August 10, 2009;
DOI: 10.1542/peds.2008-2434
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/124/3/e489.full.html
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2009 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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ARTICLES
Gastrointestinal Symptoms in Children With Type 1
Diabetes Screened for Celiac Disease
CONTRIBUTORS: Priya Narula, MD, MBBS, DNB, MRCPCH,a
Lesley Porter, AMSPAR,b Josephine Langton, MBChB,a
Veena Rao, MBBS, DCH, MRCPCH,a Paul Davies, PhD, MSc,
BSc,c Carole Cummins, PhD, MSc, BA,c
Jeremy Kirk, MD, FRCP, FRCPCH,b Timothy Barrett, PhD,
MB, BS, MRCP, FRCPCH, DCH,b and Susan Protheroe, MD,
MBChB, FRCPCHa
Departments of aGastroenterology, bEndocrinology, and
cResearch and Development, Birmingham Children’s Hospital,
Birmingham, United Kingdom
WHAT’S KNOWN ON THIS SUBJECT: The association between CD
and DM is well described. Children with DM who are diagnosed
with CD by serological screening are often reported to be
asymptomatic.
WHAT THIS STUDY ADDS: In our study, the majority of children
had ⱖ1 gastrointestinal symptom. Institution of a GFD resolved
these symptoms and also had a positive effect on nutritional
status in the short-term.
KEY WORDS
type 1 diabetes, celiac disease, gastrointestinal symptoms
ABBREVIATIONS
CD— celiac disease
DM—type 1 diabetes mellitus
GFD— gluten-free diet
SDS—SD score
TTG—tissue transglutaminase
NICE—National Institute of Clinical Excellence
EMA— endomysial antibody
www.pediatrics.org/cgi/doi/10.1542/peds.2008-2434
doi:10.1542/peds.2008-2434
Accepted for publication Apr 10, 2009
Address correspondence to Priya Narula, MD, MBBS, DNB,
MRCPCH, 393 Redmires Rd, Lodgemoor, Sheffield S104LE, United
Kingdom. E-mail: [email protected]
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2009 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have
no financial relationships relevant to this article to disclose.
abstract
BACKGROUND: The association between celiac disease (CD) and type 1
diabetes mellitus (DM) is recognized. Most cases of CD in patients with
DM are reported to be asymptomatic.
OBJECTIVES: The objectives of this study were to (1) compare and
audit our practice with the published standards for screening for CD in
children with DM, (2) characterize the children with DM and biopsyconfirmed CD, in terms of growth and gastrointestinal symptoms, and
compare them with children with DM and negative celiac serology, and
(3) document the effects of a gluten-free diet (GFD) after 1 year of
gastrointestinal symptoms, growth, and insulin requirement.
METHOD: We performed a retrospective case-note review of 22 children with DM, positive celiac serology ⫾ biopsy-confirmed CD, and 50
children with DM and negative celiac serology.
RESULTS: Twenty-two children (3.9% of the total diabetic population)
had positive celiac serology on screening, with 17 (3%) having biopsyconfirmed CD. Ninety-four percent of the children had standardized
celiac serology testing. At diagnosis of CD, 13 of the 17 biopsy-positive
children (76.4%) had ⱖ1 gastrointestinal symptom. The frequency of
gastrointestinal symptoms in negative celiac serology diabetic children was 6% (3 of 50) (P ⬍ .0005). Symptoms resolved in all children
after introduction of a GFD. A significant improvement in weight SD
score (P ⫽ .008) and BMI SD score (P ⫽ .02) was noted in those
compliant with a GFD after 1 year.
CONCLUSIONS: Children with DM and CD have a higher frequency of
gastrointestinal symptoms than their diabetic peers with negative celiac serology and are not truly asymptomatic. Institution of a GFD has a
positive effect on nutritional status and symptom resolution in the
short-term. Pediatrics 2009;124:e489–e495
PEDIATRICS Volume 124, Number 3, September 2009
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e489
Celiac disease (CD) is an autoimmune
enteropathy that is associated with an
increased prevalence of other autoimmune disorders. CD has a genetic predisposition (HLA), a trigger (gluten) in
susceptible individuals, and occurs in
association with increased antibodies
to tissue transglutaminase (TTG).1 The
association between CD and type 1 diabetes mellitus (DM) is well known.2
The prevalence of biopsy-proven CD in
children with DM has been reported to
be 2.4% to 6.7% with varying duration
of DM.2–6
Most cases of CD with DM are reported
to be asymptomatic or silent and are
detected by serologic screening.7
Screening and treating asymptomatic
CD is motivated by the demonstration
of an increased risk for gastrointestinal malignancy, such as non-Hodgkin
lymphoma and cancers of the mouth,
pharynx, and esophagus with untreated CD.8 Undiagnosed CD in children may be the underlying cause of
refractory iron deficiency anemia,9
short stature,10 low bone mineral density,11,12 and pubertal delay.13 Underachievement in education and working life has also been observed in
adults with silent CD, which may be
related to the increased prevalence
of depressive and disruptive behavioral disorders that have been described in teenagers with untreated
CD.14–16 In addition, the duration of
exposure to gluten in patients with
CD may be associated with an increased prevalence of other autoimmune disorders.1 Therefore, early
diagnosis is essential for the prevention of serious complications.
A national survey of current screening
practices revealed a wide variation in
the United Kingdom.17 Subsequently,
guidance from the National Institute of
Clinical Excellence (NICE) on the management of childhood DM recommended screening for CD at diagnosis
of DM and then every 3 years after.18
e490
NARULA et al
Inconsistent results have been observed on the effect of a gluten-free
diet (GFD) on symptoms and growth in
children with DM and CD,19–21 although
some studies suggest clinical benefit.22
Reports on the effect of CD on growth
have been conflicting.21,23 In addition,
many families seen in our clinic questioned the potential benefits of a GFD
and the possible nutritional benefits.
Therefore, we wanted to examine the
prevalence of symptoms in these children, the resolution of these symptoms on a GFD, and to examine the potential advantages of the diet.
The aims of this study were to (1) compare and audit our practice with the
published standards for screening for
CD in children with DM (NICE guidelines, 2004), (2) characterize the children with DM and biopsy-confirmed CD
detected by screening in terms of
growth and gastrointestinal symptoms, and compare them with children
with DM and negative celiac serology,
and (3) document the effects of a GFD
after 1 year in terms of gastrointestinal symptoms, growth, and insulin requirement in children with DM and
biopsy-confirmed CD.
METHODS
We performed a retrospective case-note
audit of children with DM and positive
celiac serology who were under the care
of Birmingham Children’s Hospital between 1998 and June 2006. Children
were identified from the diabetes unit
database. Ethical approval was not
sought, because data were anonymous
within the audit. Inclusion criteria were
(1) DM as demonstrated by an absolute
insulin requirement from diagnosis and
the tendency to produce ketonuria during episodes of hyperglycemia, and (2)
biopsy-confirmed CD. Children who were
diagnosed with CD before the onset of
diabetes were excluded.
The practice from 1998 to 2002 was to
refer children to the pediatric gastro-
enterology clinic once they had 2 positive serology results (positive antiendomysial antibody [EMA] or IgA TTG
antibody) measured 6 to 12 months
apart if they appeared asymptomatic.
The practice from 2002 has been to refer all children after 1 positive celiac
screening test to the gastroenterology
clinic for assessment. TTG antibodies
in serum were determined by enzymelinked immunosorbent assay, and antiEMAs were measured by indirect immunofluorescence.
In the pediatric gastroenterology
clinic, a gastrointestinal history was
taken and a duodenal biopsy recommended. Multiple biopsies of the duodenum were examined in a nonblinded
manner by a histopathologist.
CD was diagnosed by using the modified Marsh classification,24 with Marsh
type 3 and 4 criteria, which includes
total or subtotal villous atrophy with
crypt hyperplasia and increased intraepithelial lymphocytes.
All children with biopsy-confirmed CD
were seen by a pediatric dietician and
advised to maintain a strict GFD suitable for children with diabetes and CD.
We recorded the (1) frequency of serology screening for CD, (2) time from
diagnosis of diabetes to diagnosis of
CD, (3) presence of gastrointestinal
symptoms at serology screening and
during consultation in the pediatric
gastroenterology clinic before biopsy,
(4) compliance with a GFD. Noncompliance with a GFD was recorded in the
presence of positive celiac serology at
1 year and/or the child admitting to
noncompliance at follow-up, and (5)
anthropometry and insulin requirement at diagnosis of CD and after 1
year of following a GFD if compliant
with the diet.
Direct questions about the presence of
gastrointestinal symptoms were incorporated in the annual diabetes review from May 2005. Subsequently,
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ARTICLES
case notes of 50 consecutive children
with diabetes and negative celiac serology who attended the diabetes
clinic for annual review were examined and gastrointestinal symptoms
recorded for comparison on the revised annual review form.
Fisher’s exact test was used for comparing the frequency of gastrointestinal symptoms between groups. Anthropometry and insulin requirements
in children with DM and biopsyconfirmed CD were compared with
data a year later (on GFD) by using
the paired t test. Comparisons of anthropometry and insulin requirement
in children with DM with biopsyconfirmed CD and DM with negative celiac serology were also performed by
using a paired t test.
Group comparisons of parameters
such as median age at diagnosis were
made by using Mann-Whitney tests or t
tests when normally distributed.
RESULTS
There were 556 children with DM on
the database registered until June
2006. In 1 child, CD predated the onset
of diabetes and this child was excluded. The median age of diagnosis of
DM was 8 years. The median age of diagnosis of DM in children who subsequently developed CD was 3.8 years
(age range: 1.4 –11 years). Thus, children who subsequently developed CD
were younger at the diagnosis of DM
compared with children with DM who
did not develop CD (P ⫽ .002, MannWhitney test). The median age of diagnosis of screening-detected CD was 9.5
years (age range: 4.2–16.6 years).
There were 22 children with positive
celiac serology (3.9% of total) on
screening and 17 (3% of total) with
biopsy-confirmed CD. There were 5
children with positive serology who
did not have biopsy-confirmed CD; all 5
were positive for TTG antibodies but
only 2 had positive anti-EMA. Three chilPEDIATRICS Volume 124, Number 3, September 2009
dren had a normal duodenal biopsy result. These 3 patients are being monitored with plans to repeat the biopsy at
an interval of 1 year. One adolescent
was transferred to adult services for a
biopsy and 1 patient (age 16) declined
a biopsy and is now also under adult
services.
The positive predictive value of celiac
serology was therefore 77.2% (95%
confidence interval: 54.6%–92.2%). The
median TTG level before biopsy was
⬎300 U/mL (range: 24.8 to ⬎300). This
level was available for 10 of 17 patients, because before 2003 EMA testing was performed. All patients apart
from 1 were EMA-positive before biopsy. Ten (9.8% of children with DM)
children were diagnosed with CD between 2003 and June 2006 compared
with only 7 (1.6% of children with DM)
children before 2003.
Sixteen (94%) children of the 17 children with DM and CD had celiac serology testing as recommended by the
NICE guidelines, which is at least once
3 yearly, although only 1 (5.8%) had
screening performed at diagnosis of
diabetes.
The median time from a positive serology test to biopsy and diagnosis was
0.6 years (range: 0.2– 4.3 years). The
long interval resulted largely from
the practice before 2003 of repeating
the celiac serology (after 6 –12 months)
if a child seemed well before referral
to the gastrointestinal clinic. In addition, 2 families missed appointments.
The median time from referral to the
gastrointestinal team to biopsy was 3
months (range: 1–16 months), because patients received an appointment for discussion in the gastrointestinal clinic before biopsy.
At diagnosis of CD, 13 of the 17 children
(76.4%) did have ⱖ1 gastrointestinal
symptom on direct questioning (Table
1). On referral to the gastrointestinal
clinic, 8 of the 17 children had reported
symptoms in the diabetic clinic. When
seen in the gastrointestinal clinic, 3
more children reported subtle symptoms that they had not discussed at
the diabetic clinic such as abdominal
pain, change in bowel habit, diarrhea,
and bloating. In addition, 2 children
who did not report any symptoms at
this stage remarked that, in retrospect, after a year on the GFD, they
had suffered from gastrointestinal
symptoms, which had resolved after
treatment with a GFD. Four children reported additional benefits retrospectively after a year on a GFD.
When these gastrointestinal symptoms were compared with children
with diabetes and negative celiac serology, only 3 (6%) of the 50 consecutive children who were asked specific
gastrointestinal questions at the diabetes annual review reported symptoms. This difference was significant
(P ⬍ .0005, Fisher’s exact test). The
median age of this group of children
was 11.5 years (age range: 5.7–16.6
years).
Symptoms resolved in all children after institution of a GFD. Two children
reported improved energy levels and
improved mood and 1 child improved
concentration. All had complete
blood count checked and none had
anemia.
Of the 17 children with DM and CD, 14
have completed follow-up for 1 year.
We found that only 8 (57.1%) were
fully compliant with the GFD. The 6
children who were not compliant
with a strict GFD either had positive
serology at 1 year and/or admitted to
noncompliance.
After institution of GFD, there was a significant improvement in BMI SD score
(SDS) in the GFD-compliant children
(P ⫽ .02) (Table 2). There was also a
significant improvement in weight SDS
after 1 year (P ⫽ .008) (Table 2). There
was an increase in the insulin requirement after 1 year in the GFD compliant
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e491
TABLE 1 Clinical Characteristics of Children With Type 1 Diabetes and Biopsy-Confirmed Celiac Disease
Patient
No.
Gender
Age at
Diagnosis of
DM, y
Age at
Diagnosis of
CD, y
Antiendomysial
Antibody
TTG
Titer
Completed 1-y
Follow-up
Compliance
Symptoms
1
2
3
Female
Male
Female
2.4
6.8
1.4
5.9
11.3
4.2
Positive
Positive
Positive
NA
NA
NA
Yes
Yes
Yes
No
Yes
No
4
Female
2.9
14.1
Positive
NA
Yes
No
5
Female
2.8
5.5
Positive
⬎300
Yes
Yes
6
7
Female
Male
3.8
1.7
10
5.3
Positive
Positive
⬎300
NA
Yes
Yes
No
No
8
Male
7.1
9.4
Positive
⬎300
Yes
Yes
9
Male
11.8
13
Positive
⬎300
Yes
Yes
10
Male
13
16
Positive
⬎300
Yes
Yes
11
12
13
14
15
16
17
Male
Male
Female
Female
Male
Male
Female
9.5
6.1
9.6
12.3
16.6
4.5
5.5
Positive
Positive
Positive
Negative
Positive
Positive
Positive
NA
NA
24.8
75.8
⬎300
⬎300
⬎300
Yes
Yes
Yes
Yes
No
No
No
Yes
Yes
Yes
No
Abdominal pain 关R兴
None
Poor weight gain, abdominal distension,
improved mood 关R兴
Loose stools, poor weight gain,
abdominal distension and pain
Abdominal pain, change in bowel habit
关G兴, improved mood/appetite 关R兴
Abdominal pain
Diarrhea, lost weight before
gastroenterology clinic 关G兴, reduced
bloating 关R兴
Loose stools, lethargy, improved
behavior, concentration, and energy
levels 关R兴
Appetite increased, less bloated, more
energy, not lethargic, decreased
abdominal pain 关R兴
Abdominal pain, distension, bloating,
diarrhea 关G兴
Abdominal pain
Abdominal pain
Abdominal pain, poor weight gain
None
None
Changed bowel habit
None
6.6
4
2.1
9.1
4
2.1
1.7
NA indicates not available; R, in retrospect; G, in pediatric gastroenterology clinic.
TABLE 2 Change in Anthropometry and Insulin Requirement Over a 1-Year Period in GFD-Compliant Children With DM and CD and in Children With DM
and Negative Celiac Serology
Parameters
Weight SDS
Height SDS
BMI SDS
Insulin requirement, U/kg per d
GFD-Compliant Children With DM and CD (N ⫽ 8)
Median Value After
1-y Follow-up on
GFD (Range)
P
Median Value (Range)
Median Value After
1 y (Range)
P
⫺0.085 (⫺0.56 to 1.24)
0.278 (⫺0.71 to 0.49)
0.185 (⫺0.84 to 1.32)
0.79 (0.62 to 1.41)
0.285 (⫺0.48 to 1.32)
0.175 (⫺0.89 to 0.84)
0.910 (⫺0.68 to 1.46)
0.93 (0.61 to 1.39)
.008
.53
.02
.11
0.572 (⫺2.72 to 5.45)
⫺0.149 (⫺3.09 to 2.3)
0.894 (⫺1.89 to 2.90)
0.995 (0.5 to 1.89)
0.655 (⫺2.56 to 4.57)
⫺0.190 (⫺2.97 to 2.62)
0.890 (⫺2.18 to 2.68)
1.055 (0.66 to 1.93)
.80
.49
.21
.49
children, although this did not achieve
statistical significance.
We also examined change in anthropometry and insulin requirement in
the 50 consecutive children with DM
and negative celiac serology over a period of 1 year. There was no significant
change in weight SDS, height SDS, BMI
SDS, or insulin requirement over a period of 1 year (Table 2). On comparing
the change in anthropometry and insulin requirements in these 2 groups
over a 1-year period, we found a signife492
NARULA et al
Children With DM and Negative Celiac Serology (N ⫽ 50)
Median Value at
Diagnosis (Range)
icant difference in the change in
weight SDS (P ⫽ .008) and BMI SDS
(P ⫽ .01) between the 2 groups of
children.
DISCUSSION
Biopsy confirmed CD had a prevalence
of 3% in this group of children with DM,
in keeping with previous reports. This
figure may be a lifetime underestimate, because serial screening over a
period of years may identify additional
cases. Two likely cases have not been
documented, because 1 adolescent
was transferred to adult services and
1 declined a biopsy. We confirmed the
observation that children with DM who
went on to develop CD were younger at
diagnosis of DM than other children
with DM.5,22,25,26 This may suggest a
more aggressive autoimmune process
in children with DM and CD.
Although a majority of screeningdetected cases of CD in children with
DM are reported to be asymptomatic
or silent,2,7,27 we have demonstrated
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ARTICLES
that many children do have subtle gastrointestinal complaints that may indicate CD. Directing specific questions
may help increase the yield of gastrointestinal symptoms in these children
as demonstrated in this study. Symptom reporting may be higher in a gastroenterology clinic compared with a
diabetic clinic, because questions may
be more specifically directed, which
may result in some bias. However,
questions about gastrointestinal symptoms were incorporated in the annual
diabetes review in an attempt to reduce this bias.
Symptoms may only be apparent after
direct questioning or recognized in
retrospect after institution of a
GFD.7,22,28,29 We found that the majority
of children (76.4%) had ⱖ1 gastrointestinal symptom compared with a
smaller number (33%–50%) in previous studies.19,30 A retrospective questionnaire study found that 75% of
these children reported some gastrointestinal complaint, most commonly
flatulence.28
Current guidelines for diagnosis of
CD31 require that the children have
symptoms characteristic of CD with
the typical small intestinal mucosal abnormality on biopsy, followed by clinical remission on a GFD. We observed
that all children did have a positive
clinical response to a GFD, as observed
in a previous study.22 An additional biopsy is recommended to verify the effect of a GFD if the clinical response is
equivocal.31
Resolution of symptoms observed with
a GFD in this study would suggest that
CD was causally related to these symptoms. The significant difference observed in gastrointestinal symptoms
in this study, when compared with children with DM and negative celiac se-
PEDIATRICS Volume 124, Number 3, September 2009
rology, is additional supportive evidence. Children in this study also
reported improved physical and psychological wellbeing once they followed a GFD, demonstrating that diagnosis and institution of a GFD is
beneficial.
Poor weight gain after institution of a
GFD has been shown in a group of children with DM,20 suggesting that they
struggled to eat a GFD suitable for children with diabetes. We found that compliance with such a restricted diet was
not easy in all children. However, importantly, we observed a significant
improvement in weight and BMI SDS in
those children who were compliant
with the diet, but not in those who continued to eat gluten. In addition, when
we compared the change over 1 year in
weight SDS and BMI SDS in these children with the children who had DM and
negative celiac serology, a significant
difference was observed. Thus, the significant improvement in weight SDS
and BMI SDS in the compliant children
was likely to be secondary to the GFD.
This may demonstrate an improved appetite and food intake along with increased absorption because of mucosal healing after a GFD in children with
DM and CD.
This significant improvement in nutritional status provides a strong argument to treat children with screeningdetected CD with a GFD and is useful
information when counseling families
on the potential benefits of a GFD. Our
dietary compliance rate (57%) is similar to previous published (30%–52%)
compliance rates in these children.6,32
A joint gastrointestinal/DM clinic has
also been set up to provide additional
counseling and support in an attempt
to improve compliance above the rate
of 57% that we achieved.
Although an improvement in metabolic
control has been observed in children
with CD and DM after institution of a
GFD in 1 study,33 this is not universal.
Peretti et al34 reported no effect of
treatment with a GFD on diabetic control, and another group observed deterioration in metabolic control in some
patients.28 We observed an increase in
insulin requirement in a majority of
children compliant with a GFD after 1
year on a GFD. This finding is likely to be
multifactorial and reasons may vary
within the group. Increased insulin requirement may not be related to management of CD, however, it is possible
that improved appetite and increased
food intake, or even improved absorption of food after the reversal of the
mucosal damage on a GFD, may result
in the need to increase the insulin
dose.
CONCLUSIONS
Children with DM and screeningdetected CD have a considerably
higher frequency of gastrointestinal
symptoms than their CD serology–
negative peers and are not truly
asymptomatic. Our findings suggest
that institution of a GFD has a positive
effect on nutritional status in the
short-term. This is helpful information
when counseling children and families
who might find it difficult to adjust to
the prospect of a second medical condition and the strict dietary regimen
that it imposes.
Targeting specific questions on gastrointestinal symptoms at the annual review for DM may identify candidates
with CD before the third yearly screening. Extended follow-up studies are required to document the long-term clinical benefit of CD screening and
treatment in children with screeningdetected CD.
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e493
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PEDIATRICS Volume 124, Number 3, September 2009
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e495
Gastrointestinal Symptoms in Children With Type 1 Diabetes Screened for
Celiac Disease
Priya Narula, Lesley Porter, Josephine Langton, Veena Rao, Paul Davies, Carole
Cummins, Jeremy Kirk, Timothy Barrett and Susan Protheroe
Pediatrics 2009;124;e489; originally published online August 10, 2009;
DOI: 10.1542/peds.2008-2434
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