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. Downloaded from pediatrics.aappublications.org by guest on August 22, 2014 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: 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. 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 Downloaded from pediatrics.aappublications.org by guest on August 22, 2014 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, Downloaded from pediatrics.aappublications.org by guest on August 22, 2014 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 Downloaded from pediatrics.aappublications.org by guest on August 22, 2014 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 Downloaded from pediatrics.aappublications.org by guest on August 22, 2014 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. Downloaded from pediatrics.aappublications.org by guest on August 22, 2014 e493 REFERENCES 1. Ventura A, Magazzu G, Greco L; SIGEP Study Group for Autoimmune Disorders in Celiac Disease. Duration of exposure to gluten and risk for autoimmune disorders in patients with celiac disease. Gastroenterology. 1999;117(2):297–303 2. Barera G, Bonfanti R, Viscardi M, et al. Occurrence of celiac disease after onset of type 1 diabetes: a 6-year prospective longitudinal study. Pediatrics. 2002;109(5):833– 838 3. Mäki M, Huupponen T, Holm K, Hallstrom O. Seroconversion of reticulin antibodies predicts coeliac disease in insulin dependent diabetes mellitus. Gut. 1995;36(2):239 –242 4. Saukkonen T, Savilahti E, Reijonen H, et al. Coeliac disease: frequent occurrence after clinical onset of insulin dependent childhood diabetes in Finland Study Group. Diabet Med. 1996;13(5): 464 – 470 5. Roldan MB, Barrio R, Roy G, et al. Diagnostic value of serological markers for celiac disease in diabetic children and adolescents. J Pediatr Endocrinol Metab. 1998;11(6):751–756 6. Westman E, Ambler GR, Royle M, et al. Children with coeliac disease and insulin dependent diabetes mellitus— growth, diabetes control and dietary intake. J Pediatr Endocrinol Metab. 1999;12(3):433– 442 7. Cronin CC, Shanahan F. Insulin-dependent diabetes mellitus and coeliac disease. Lancet. 1997; 349(9058):1096 –1097 8. Holmes GK, Prior P, Lane MR, Pope D, Allan RN. Malignancy in coeliac disease: effect of a gluten free diet. Gut. 1989;30(3):333–338 9. Mody RJ, Brown PI, Wechsler DS. Refractory iron deﬁciency anemia as the primary clinical manifestation of celiac disease. J Pediatr Hematol Oncol. 2003;25(2):169 –172 10. Rosenbach Y, Dinari G, Zahavi I, Nitzan M. Short stature as the major manifestation of celiac disease in older children. Clin Pediatr (Phila). 1986;25(1):13–16 11. Mora S, Barera G, Beccio E, et al. A prospective, longitudinal study of the long-term effect of treatment on bone density in children with celiac disease. J Paediatr. 2001;139(4):516 –521 12. Kavak US, Yüce A, Koçak N, et al. Bone mineral density in children with untreated and treated celiac disease. J Pediatr Gastroenterol Nutr. 2003;37(4):434 – 436 13. Abaci A, Esen I, Unuvar T, et al. Two cases presenting with pubertal delay and diagnosed as celiac disease. Clin Pediatr (Phila). 2008;47(6):607– 609 14. Verkasalo MA, Raitakari OT, Viikari J, et al. Undiagnosed silent coeliac disease: a risk for underachievement? Scand J Gastroenterol. 2005;40(12):1407–1412 15. Pynnönen PA, Isometsa ET, Verkasalo MA, et al. Untreated celiac disease and development of mental disorders in children and adolescents. Psychosomatics. 2002;43(4):331–334 16. Pynnönen PA, Isometsa ET, Aronen ET, et al. Mental disorders in adolescents with celiac disease. Psychosomatics. 2004;45(4):325–335 17. Dretzke J, Cummins C, et al. Autoantibody testing in children with newly diagnosed type 1 diabetes mellitus. Health Technol Assess. 2004;8(22):1–183 18. National Institute for Clinical Excellence. Type 1 Diabetes: Diagnosis and Management of Type 1 Diabetes in Children and Young People. London, United Kingdom: National Institute for Clinical Excellence; September 2004 19. Sanchez-Albisua I, Wolf J, Neu A, Geiger H, Wäscher I, Stern M. Coeliac disease in children with type 1 diabetes mellitus: the effect of the gluten-free diet. Diabet Med. 2005;22(8):1079 –1082 20. Rami B, Sumnik Z, Schober E, et al. Screening detected celiac disease in children with type 1 diabetes mellitus: effect on the clinical course (a case control study). J Pediatr Gastroenterol Nutr. 2005;41(3):317–321 21. Amin R, Murphy N, Edge J, et al. A longitudinal study of the effects of a gluten-free diet on glycemic control and weight gain in subjects with type 1 diabetes and celiac disease. Diabet Care. 2002; 25(7):1117–1122 22. Hansen D, Brock-Jacobson B, Lund E, et al. Clinical beneﬁt of a gluten-free diet in type 1 diabetic children with screening-detected celiac disease: a population-based screening study with 2 years’ follow-up. Diabet Care. 2006;29(1):2452–2456 23. Goh C, Banerjee K. Prevalence of coeliac disease in children and adolescents with type 1 diabetes mellitus in a clinic based population. Postgrad Med J. 2007;83(976):132–136 24. Oberhuber G, Grangitsch G, Vogelsang H. The histopathology of coeliac disease: time for a standardized report scheme for pathologists. Eur J Gastroenterol Hepatol. 1999;11(10):1185–1194 25. Tanure MG, Silva IN, Bahia M, Penna J. Prevalence of celiac disease in Brazilian children with type 1 diabetes mellitus. J Pediatr Gastroenterol Nutr. 2006;42(2):155–159 26. Kaspers S, Kordonouri O, Schober E, et al. Anthropometry, metabolic control, and thyroid autoimmunity in type 1 diabetes with celiac disease: a multicentre survey. J Pediatr. 2004;145(6):790 –795 e494 NARULA et al Downloaded from pediatrics.aappublications.org by guest on August 22, 2014 ARTICLES 27. Aktay AN, Lee PC, Kumar V, et al. The prevalence and clinical characteristics of celiac disease in juvenile diabetes in Wisconsin. J Pediatr Gastroenterol Nutr. 2001;33(4):462– 465 28. Saukkonen T, Vaisanen S, Akerblom HK, Savilahti E. Coeliac disease in children and adolescents with type 1 diabetes: a study of growth, glycaemic control, and experiences of families. Acta Paediatr. 2002;91(3):297–302 29. Holmes GKT. Screening for celiac disease in type 1 diabetes. Arch Dis Child. 2002;87(6):495– 498 30. Acerini CL, Ahmed ML, Ross KM, et al. Coeliac disease in children and adolescents with IDDM: clinical characteristics and response to a gluten-free diet. Diabet Med. 1998;15(1):38 – 44 31. Revised criteria for diagnosis of coeliac disease. Report of Working Group of European Society of Paediatric Gastroenterology and Nutrition. Arch Dis Child. 1990;65(8):909 –911 32. Fabiani E, Catassi C, Villari A, et al. Dietary compliance in screening-detected coeliac disease adolescents. Acta Paediatr Suppl. 1996;412:65– 67 33. Mohn A, Cerruto M, Iafusco D, et al. Celiac disease in children and adolescents with type 1 diabetes: importance of hypoglycaemia. J Pediatr Gastroenterol Nutr. 2001;32(1):37– 40 34. Peretti N, Bienvenu F, Bouvet C, et al. The temporal relationship between the onset of type 1 diabetes and celiac disease: a study based on immunoglobulin A antitransglutaminase screening. Pediatrics. 2004;113(5):418 – 422 PEDIATRICS Volume 124, Number 3, September 2009 Downloaded from pediatrics.aappublications.org by guest on August 22, 2014 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 Updated Information & Services including high resolution figures, can be found at: http://pediatrics.aappublications.org/content/124/3/e489.full.h tml References This article cites 33 articles, 10 of which can be accessed free at: http://pediatrics.aappublications.org/content/124/3/e489.full.h tml#ref-list-1 Citations This article has been cited by 2 HighWire-hosted articles: http://pediatrics.aappublications.org/content/124/3/e489.full.h tml#related-urls Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Endocrinology http://pediatrics.aappublications.org/cgi/collection/endocrinol ogy_sub Diabetes Mellitus http://pediatrics.aappublications.org/cgi/collection/diabetes_ mellitus_sub Gastroenterology http://pediatrics.aappublications.org/cgi/collection/gastroenter ology_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pediatrics.aappublications.org/site/misc/Permissions.xht ml Reprints Information about ordering reprints can be found online: http://pediatrics.aappublications.org/site/misc/reprints.xhtml 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. Downloaded from pediatrics.aappublications.org by guest on August 22, 2014