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Gastrointestinal Symptoms in Children With Type 1 Diabetes Screened for Celiac Disease


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Gastrointestinal Symptoms in Children With Type 1

Diabetes Screened for Celiac Disease

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 hadⱖ1 gastrointestinal symptom. Institution of a GFD resolved these symptoms and also had a positive effect on nutritional status in the short-term.


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 biopsy-confirmed 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 chil-dren 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 biopsy-confirmed 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%) hadⱖ1 gastrointestinal symptom. The frequency of gastrointestinal symptoms in negative celiac serology diabetic chil-dren 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 ce-liac serology and are not truly asymptomatic. Institution of a GFD has a positive effect on nutritional status and symptom resolution in the short-term.Pediatrics2009;124:e489–e495


Lesley Porter, AMSPAR,bJosephine Langton, MBChB,a

Veena Rao, MBBS, DCH, MRCPCH,aPaul Davies, PhD, MSc,

BSc,cCarole Cummins, PhD, MSc, BA,c

Jeremy Kirk, MD, FRCP, FRCPCH,bTimothy Barrett, PhD,

MB, BS, MRCP, FRCPCH, DCH,band Susan Protheroe, MD,


Departments ofaGastroenterology,bEndocrinology, and cResearch and Development, Birmingham Children’s Hospital, Birmingham, United Kingdom


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



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: priyanarula28@hotmail.com

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.


increased prevalence of other autoim-mune disorders. CD has a genetic pre-disposition (HLA), a trigger (gluten) in susceptible individuals, and occurs in association with increased antibodies to tissue transglutaminase (TTG).1The

association between CD and type 1 di-abetes 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 gastrointesti-nal malignancy, such as non-Hodgkin lymphoma and cancers of the mouth, pharynx, and esophagus with un-treated CD.8 Undiagnosed CD in

chil-dren may be the underlying cause of refractory iron deficiency anemia,9

short stature,10low bone mineral

den-sity,11,12 and pubertal delay.13

Under-achievement in education and work-ing life has also been observed in adults with silent CD, which may be related to the increased prevalence of depressive and disruptive behav-ioral disorders that have been de-scribed in teenagers with untreated CD.14–16 In addition, the duration of

exposure to gluten in patients with CD may be associated with an in-creased prevalence of other autoim-mune disorders.1 Therefore, early

diagnosis is essential for the preven-tion of serious complicapreven-tions.

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 man-agement of childhood DM recom-mended screening for CD at diagnosis of DM and then every 3 years after.18

diet (GFD) on symptoms and growth in children with DM and CD,19–21although

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 ques-tioned the potential benefits of a GFD and the possible nutritional benefits. Therefore, we wanted to examine the prevalence of symptoms in these chil-dren, the resolution of these symp-toms on a GFD, and to examine the po-tential advantages of the diet.

The aims of this study were to (1) com-pare and audit our practice with the published standards for screening for CD in children with DM (NICE guide-lines, 2004), (2) characterize the chil-dren with DM and biopsy-confirmed CD detected by screening in terms of growth and gastrointestinal symp-toms, 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 gastrointesti-nal symptoms, growth, and insulin re-quirement in children with DM and biopsy-confirmed CD.


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 be-tween 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 dur-ing 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-domysial antibody [EMA] or IgA TTG antibody) measured 6 to 12 months apart if they appeared asymptomatic. The practice from 2002 has been to re-fer all children after 1 positive celiac screening test to the gastroenterology clinic for assessment. TTG antibodies in serum were determined by enzyme-linked immunosorbent assay, and anti-EMAs were measured by indirect im-munofluorescence.

In the pediatric gastroenterology clinic, a gastrointestinal history was taken and a duodenal biopsy recom-mended. Multiple biopsies of the duo-denum were examined in a nonblinded manner by a histopathologist.

CD was diagnosed by using the modi-fied Marsh classification,24with Marsh

type 3 and 4 criteria, which includes total or subtotal villous atrophy with crypt hyperplasia and increased intra-epithelial lymphocytes.

All children with biopsy-confirmed CD were seen by a pediatric dietician and advised to maintain a strict GFD suit-able for children with diabetes and CD.

We recorded the (1) frequency of se-rology 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. Noncompli-ance 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 require-ment at diagnosis of CD and after 1 year of following a GFD if compliant with the diet.


case notes of 50 consecutive children with diabetes and negative celiac se-rology who attended the diabetes clinic for annual review were exam-ined and gastrointestinal symptoms recorded for comparison on the re-vised annual review form.

Fisher’s exact test was used for com-paring the frequency of gastrointesti-nal symptoms between groups. An-thropometry and insulin requirements in children with DM and biopsy-confirmed CD were compared with data a year later (on GFD) by using the pairedttest. Comparisons of an-thropometry and insulin requirement in children with DM with biopsy-confirmed CD and DM with negative ce-liac serology were also performed by using a pairedttest.

Group comparisons of parameters such as median age at diagnosis were made by using Mann-Whitney tests ort

tests when normally distributed.


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 ex-cluded. The median age of diagnosis of DM was 8 years. The median age of di-agnosis of DM in children who subse-quently developed CD was 3.8 years (age range: 1.4 –11 years). Thus, chil-dren who subsequently developed CD were younger at the diagnosis of DM compared with children with DM who did not develop CD (P⫽ .002, Mann-Whitney test). The median age of diag-nosis 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

chil-dren had a normal duodenal biopsy re-sult. These 3 patients are being moni-tored 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 pa-tients, because before 2003 EMA test-ing was performed. All patients apart from 1 were EMA-positive before bi-opsy. Ten (9.8% of children with DM) children were diagnosed with CD be-tween 2003 and June 2006 compared with only 7 (1.6% of children with DM) children before 2003.

Sixteen (94%) children of the 17 chil-dren with DM and CD had celiac serol-ogy 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 serol-ogy 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 addi-tion, 2 families missed appointments. The median time from referral to the gastrointestinal team to biopsy was 3 months (range: 1–16 months), be-cause patients received an appoint-ment for discussion in the gastrointes-tinal clinic before biopsy.

At diagnosis of CD, 13 of the 17 children (76.4%) did haveⱖ1 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 symp-toms 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 retro-spect, after a year on the GFD, they had suffered from gastrointestinal symptoms, which had resolved after treatment with a GFD. Four children re-ported additional benefits retrospec-tively after a year on a GFD.

When these gastrointestinal symp-toms were compared with children with diabetes and negative celiac se-rology, only 3 (6%) of the 50 consecu-tive children who were asked specific gastrointestinal questions at the dia-betes annual review reported symp-toms. 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 af-ter 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 sig-nificant 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 require-ment after 1 year in the GFD compliant


children, although this did not achieve statistical significance.

We also examined change in anthro-pometry and insulin requirement in the 50 consecutive children with DM and negative celiac serology over a pe-riod of 1 year. There was no significant change in weight SDS, height SDS, BMI SDS, or insulin requirement over a pe-riod of 1 year (Table 2). On comparing the change in anthropometry and insu-lin requirements in these 2 groups over a 1-year period, we found a

signif-icant difference in the change in weight SDS (P ⫽ .008) and BMI SDS (P ⫽ .01) between the 2 groups of children.


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 underesti-mate, 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 screening-detected cases of CD in children with DM are reported to be asymptomatic or silent,2,7,27 we have demonstrated

No. Diagnosis of

DM, y

Diagnosis of CD, y

Antibody Titer Follow-up

1 Female 2.4 5.9 Positive NA Yes No Abdominal pain关R兴

2 Male 6.8 11.3 Positive NA Yes Yes None

3 Female 1.4 4.2 Positive NA Yes No Poor weight gain, abdominal distension,

improved mood关R兴

4 Female 2.9 14.1 Positive NA Yes No Loose stools, poor weight gain,

abdominal distension and pain

5 Female 2.8 5.5 Positive ⬎300 Yes Yes Abdominal pain, change in bowel habit

关G兴, improved mood/appetite关R兴

6 Female 3.8 10 Positive ⬎300 Yes No Abdominal pain

7 Male 1.7 5.3 Positive NA Yes No Diarrhea, lost weight before

gastroenterology clinic关G兴, reduced bloating关R兴

8 Male 7.1 9.4 Positive ⬎300 Yes Yes Loose stools, lethargy, improved

behavior, concentration, and energy levels关R兴

9 Male 11.8 13 Positive ⬎300 Yes Yes Appetite increased, less bloated, more

energy, not lethargic, decreased abdominal pain关R兴

10 Male 13 16 Positive ⬎300 Yes Yes Abdominal pain, distension, bloating,


11 Male 6.6 9.5 Positive NA Yes Yes Abdominal pain

12 Male 4 6.1 Positive NA Yes Yes Abdominal pain

13 Female 2.1 9.6 Positive 24.8 Yes Yes Abdominal pain, poor weight gain

14 Female 9.1 12.3 Negative 75.8 Yes No None

15 Male 4 16.6 Positive ⬎300 No None

16 Male 2.1 4.5 Positive ⬎300 No Changed bowel habit

17 Female 1.7 5.5 Positive ⬎300 No None

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 GFD-Compliant Children With DM and CD (N⫽8) Children With DM and Negative Celiac Serology (N⫽50)

Median Value at Diagnosis (Range)

Median Value After 1-y Follow-up on

GFD (Range)

P Median Value (Range) Median Value After

1 y (Range)


Weight SDS ⫺0.085 (⫺0.56 to 1.24) 0.285 (⫺0.48 to 1.32) .008 0.572 (⫺2.72 to 5.45) 0.655 (⫺2.56 to 4.57) .80

Height SDS 0.278 (⫺0.71 to 0.49) 0.175 (⫺0.89 to 0.84) .53 ⫺0.149 (⫺3.09 to 2.3) ⫺0.190 (⫺2.97 to 2.62) .49

BMI SDS 0.185 (⫺0.84 to 1.32) 0.910 (⫺0.68 to 1.46) .02 0.894 (⫺1.89 to 2.90) 0.890 (⫺2.18 to 2.68) .21


that many children do have subtle gas-trointestinal complaints that may indi-cate CD. Directing specific questions may help increase the yield of gastro-intestinal symptoms in these children as demonstrated in this study. Symp-tom reporting may be higher in a gas-troenterology clinic compared with a diabetic clinic, because questions may be more specifically directed, which may result in some bias. However, questions about gastrointestinal symp-toms were incorporated in the annual diabetes review in an attempt to re-duce this bias.

Symptoms may only be apparent after direct questioning or recognized in retrospect after institution of a GFD.7,22,28,29We found that the majority

of children (76.4%) hadⱖ1 gastroin-testinal symptom compared with a smaller number (33%–50%) in previ-ous studies.19,30 A retrospective

ques-tionnaire study found that 75% of these children reported some gastro-intestinal 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 ab-normality on biopsy, followed by clini-cal remission on a GFD. We observed that all children did have a positive clinical response to a GFD, as observed in a previous study.22An additional

bi-opsy is recommended to verify the ef-fect 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 symp-toms. The significant difference ob-served in gastrointestinal symptoms in this study, when compared with chil-dren with DM and negative celiac

se-rology, is additional supportive evi-dence. Children in this study also reported improved physical and psy-chological wellbeing once they fol-lowed a GFD, demonstrating that diag-nosis and institution of a GFD is beneficial.

Poor weight gain after institution of a GFD has been shown in a group of chil-dren with DM,20suggesting that they

struggled to eat a GFD suitable for chil-dren with diabetes. We found that com-pliance with such a restricted diet was not easy in all children. However, im-portantly, we observed a significant improvement in weight and BMI SDS in those children who were compliant with the diet, but not in those who con-tinued to eat gluten. In addition, when we compared the change over 1 year in weight SDS and BMI SDS in these chil-dren with the chilchil-dren who had DM and negative celiac serology, a significant difference was observed. Thus, the sig-nificant improvement in weight SDS and BMI SDS in the compliant children was likely to be secondary to the GFD. This may demonstrate an improved ap-petite and food intake along with in-creased absorption because of muco-sal healing after a GFD in children with DM and CD.

This significant improvement in nutri-tional status provides a strong argu-ment to treat children with screening-detected CD with a GFD and is useful information when counseling families on the potential benefits of a GFD. Our dietary compliance rate (57%) is simi-lar 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,33this is not universal.

Peretti et al34 reported no effect of

treatment with a GFD on diabetic con-trol, and another group observed dete-rioration in metabolic control in some patients.28We 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 re-quirement may not be related to man-agement of CD, however, it is possible that improved appetite and increased food intake, or even improved absorp-tion of food after the reversal of the mucosal damage on a GFD, may result in the need to increase the insulin dose.


Children with DM and screening-detected 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 con-dition and the strict dietary regimen that it imposes.

Targeting specific questions on gastro-intestinal symptoms at the annual re-view for DM may identify candidates with CD before the third yearly screen-ing. Extended follow-up studies are re-quired to document the long-term clin-ical benefit of CD screening and treatment in children with screening-detected CD.


Duration of exposure to gluten and risk for autoimmune disorders in patients with celiac disease.


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DOI: 10.1542/peds.2008-2434 originally published online August 10, 2009;



Cummins, Jeremy Kirk, Timothy Barrett and Susan Protheroe

Priya Narula, Lesley Porter, Josephine Langton, Veena Rao, Paul Davies, Carole


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DOI: 10.1542/peds.2008-2434 originally published online August 10, 2009;



Cummins, Jeremy Kirk, Timothy Barrett and Susan Protheroe

Priya Narula, Lesley Porter, Josephine Langton, Veena Rao, Paul Davies, Carole

Celiac Disease

Gastrointestinal Symptoms in Children With Type 1 Diabetes Screened for


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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 DMand Negative Celiac Serology


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