https://doi.org/10.5812/ijp.97306

Prevalence of Celiac Disease in Children with Type 1 Diabetes Mellitus in the South of Turkey

authors:

avatar Yasin Sahin ORCID 1 , * , avatar Meltem Didem Cakir ORCID 2 , avatar Mehmet Isakoca ORCID 2 , avatar Derya Aydin Sahin ORCID 3

Clinics of Pediatric Gastroenterology, Mersin City Training and Research Hospital, Mersin, Turkey
Clinics of Pediatric Endocrinology, Mersin City Training and Research Hospital, Mersin, Turkey
Clinics of Pediatrics, Mersin City Training and Research Hospital, Mersin, Turkey
Iranian Journal of Pediatrics: Vol.30, issue 1; e97306
published online: December 9, 2019
article type: Research Article
received: August 18, 2019
revised: October 10, 2019
accepted: October 23, 2019

How To Cite Sahin Y, Cakir M D, Isakoca M, Aydin Sahin D. Prevalence of Celiac Disease in Children with Type 1 Diabetes Mellitus in the South of Turkey. Iran J Pediatr. 2020;30(1):e97306. https://doi.org/10.5812/ijp.97306.

Abstract

Background:

Type 1 Diabetes Mellitus (DM), autoimmune disorders, relatives of celiac patients have higher risk of developing celiac disease (CD) because they share the same HLA type. Celiac disease and type 1 DM are autoimmune and common in children. According to international guidelines, serological screening for CD in children and adults with type 1 DM is recommended but there is no consensus on how often it will be performed.

Objectives:

We aimed to investigate the prevalence of CD in children with type 1 diabetes mellitus (DM).

Methods:

This current study was carried out between 01 March 2017 and 15 December 2018. 273 children with type 1 DM were included in the study. Tissue transglutaminase antibody IgA (tTG IgA) and total IgA levels were measured in all patients. The patients with tTG IgA positivity underwent gastroduodenoscopy.

Results:

Of the 273 patients (139 girls), the mean age was 11.61 ± 3.73 years. tTG IgA was positive in 23 patients, and 2 of them refused the process of endoscopy. Gastroduodenoscopy was performed on other patients. 11 patients with Marsh 3, 2 patients with Marsh 2, 4 patients with Marsh 1, and 4 patients with Marsh 0 were detected in the present study. In other words, 12 patients were diagnosed with CD. Nine of 12 patients diagnosed with CD were diagnosed within the first 5 years after the diagnosis of type 1 DM.

Conclusions:

We found that the prevalence of biopsy-proven CD in children with type 1 DM was 4.4%, which was approximately 9 times higher than the prevalence of CD in the general population. In the current study, 9 of 12 patients diagnosed with CD were diagnosed within the first 5 years after DM. According to our results, we recommend that screening tests for CD should be performed at least once a year for 5 years in children with Type 1 DM, even if the patients are asymptomatic.

1. Background

Celiac disease (CD) is an immune-mediated systemic disease triggered by gluten intake in genetically susceptible individuals and affects approximately 1% of the general population. The clinical findings of celiac disease change over time. Instead of classical symptoms, atypical symptoms such as diarrhea, growth retardation, abdominal distention and chronic constipation may be the only sign of celiac disease, and also no symptoms may be seen (1).

Type 1 diabetes mellitus (DM) is an autoimmune disease characterized by insulin deficiency as a result of autoimmune destruction of beta cells (2).

Type 1 DM, autoimmune disorders, relatives of celiac patients have higher risk of developing CD because they share the same HLA type (3). Celiac disease and type 1 DM are autoimmune and common in children. Both diseases have a common genetic locus on the short arm of chromosome 6. Because they have a common genetic background, both diseases frequently occur (4). Also, different non-HLA locations associated with CD and type 1 DM has been reported (5).

The relationship between type 1 DM and CD is well known, and the prevalence of biopsy-proven CD has been reported to be 1.6% - 16.4% (6-10).

Timely diagnosis of celiac patients is important in preventing long-term complications such as osteopenia, growth retardation, infertility and malignancies associated with untreated disease (11, 12).

Early diagnosis of CD in patients with type 1 DM has been reported to improve patients’ clinical parameters such as weight and serum ferritin levels, and have positive impact on quality of life (13, 14).

2. Objectives

According to international guidelines, serological screening for CD in children and adults with type 1 DM is recommended but there is no consensus on how often it will be performed.

In the present study, we aimed to investigate the prevalence of CD in children with type 1 DM.

3. Methods

This present study was carried out between 01 March 2017 and 15 December 2018 in the Clinics of Pediatric Gastroenterology and Endocrinology. 273 children with type 1 DM were included in the study. Patients with concomitant autoimmune diseases and patients who refused to participate were excluded from the study.

One patient diagnosed with CD before the diagnosis of type 1 DM was excluded from the study. Written informed consent was not obtained as the study is retrospective. But The Local Ethics Committee approved the current study (10 January 2019-2019/08).

We used the ESPGHAN guideline of celiac disease “Asymptomatic Child or Adolescent With CD-associated Conditions”. If HLA testing is available, it should be offered as the first line test. If HLA testing is not done, then an anti-TG2 IgA test and total IgA determination as first line tests should be performed. If antibodies are negative, then repeated testing for CD-specific antibodies is recommended. To avoid unnecessary biopsies in individuals with low-CD specific antibody levels (i.e. < 3 times ULN), it is recommended that the more specific test for anti-endomysial antibody (EMA) be performed. If the EMA test is positive, then the child should be referred for duodenal biopsies. If the EMA test is negative, then repeated serological testing on a normal gluten-containing in diet 3 to 6 monthly intervals is recommended (1).

Patients were evaluated in terms of clinical and laboratory findings of CD. Tissue transglutaminase antibody IgA (tTG IgA) and total IgA levels were measured in all patients (1). The normal range of tTG IgA and EMA IgA is below 20 U/L. The cutt-off value of IgA level is 5 mg/dL. Tissue transglutaminase antibody IgG was analysed in patients with IgA deficiency (15).

The patients with tTG IgA positivity underwent gastroduodenoscopy. At least four biopsies from duodenum and one biopsies from bulb were obtained. All biopsies were evaluated according to the Marsh classification criteria (16). Marsh stage 0: normal mucosa, Marsh stage 1: increased intraepithelial lymphocytosis (> 40 lymphocytes per 100 epithelial cells), Marsh stage 2: increased intraepithelial lymphocytosis with crypt hyperplasia, Marsh stage 3a: increased intraepithelial lymphocytosis with crypt hyperplasia and partial villous atrophy, Marsh stage 3b: increased intraepithelial lymphocytosis with crypt hyperplasia and subtotal villous atrophy, and Marsh stage 3c: increased intraepithelial lymphocytosis with crypt hyperplasia and total villous atrophy.

Statistical analysis was performed using SPSS software version 13.0 (SPAA Inc, Chicago IL, USA). Categorical data were reported as percentages and continuous data as mean standard deviation (SD) or median (interquartile range). Independent-Samples t-test was used for nominal data with normal distribution. Mann Whitney U test was used for the parameters which did not show a normal distribution.

4. Results

Of the 273 patients (139 girls), the mean age was 11.61 ± 3.73 years and the mean age of patients at the diagnosis of type 1 DM was 8.21 ± 3.62 years (Table 1). Tissue transglutaminase antibody IgG was analysed in three of patients who have IgA deficiency, and no positivity was found.

In our study, tTG IgA was positive in 23 patients, and 2 of them who have no symptoms of CD refused the process of endoscopy. 6 patients had low tTG levels (< 3 times ULN), EMA test is analysed in those patients to avoid unnecessary biopsies. All of them had EMA positivity. Thus, gastroduodenoscopy was performed on other 21 patients. 11 patients with Marsh stage 3, 2 patients with Marsh stage 2, 4 patients with Marsh stage 1, and 4 patients with Marsh stage 0 were detected in the present study. In other words, 12 patients were diagnosed with CD, 5 patients were diagnosed with potential CD (Table 2). Those patients were followed-up. One of the patients with Marsh stage 2 was found to have helicobacter positivity. After the eradication treatment of Helicobacter pylori, endoscopy was performed, and multipl biopsies were obtained from the duodenum and bulb. The result of pathology was consistent with Marsh stage 0.

Table 1.

Demographic and Laboratory Characteristics of Patientsa

VariablesPatients (N = 273)
Age, y11.61 ± 3.73
Sex, female/male139/134
Height, cm144.89 ± 19.49
Weight, kg41.32 ± 15.64
Age at diagnosis, y8.21 ± 3.62
tTG IgA, U/mL5.70 (IQR 5.00)
Total IgA, mg/dL159.00 (IQR 98.50)

Abbreviations: IQR, interquartile range; tTG, tissue transglutaminase

aValues are expressed as mean ± SD or median (interquartile range).

Table 2.

The Laboratory Data of Patients with tTG IgA Positivity

Patient No.Age, y/SexAge at Diagnosis of DM, ytTG IgA, U/mLPathology
18.8/fa5.0126.0Marsh 3a
28.8/fa3.5195.0Marsh 3b
313.2/ma3.0181.0Marsh 3a
411.3/fa9.7142.0Marsh 3a
54.0/ma1.7124.4Marsh 3a
610.0/fa5.8186.2Marsh 3a
76.5/ma1.5135.0Marsh 3c
813.5/fa12.5142.0Marsh 3a
913.5/ma5.0172.0Marsh 3a
105.5/ma5.025.4Marsh 3a
1112.1/fa11.8142.0Marsh 3a
129.0/fa5.949.8Marsh 2
137.6/f4.169.8Marsh 2
146.8/f6.635.2Marsh 1
159.3/m2.034.1Marsh 1
1617.0/f4.099.6Marsh 1
176.5/m3.0168.3Marsh 1
1810.0/m5.040.7Marsh 0
199.1/f8.5166.0Marsh 0
2010.5/m9.0185.9Marsh 0
219.7/m9.542.5Marsh 0

Abbreviation: DM, diabetes mellitus

aAge at diagnosis of celiac disease

Seven of 12 celiac patients was asymptomatic. Three of the symptomatic patients had failure to thrive, one patient had chronic constipation, and one had anemia. The seroprevalence of CD and biopsy-proven prevalence of CD were 8.4 and 4.4%, respectively.

In our study, 9 of 12 patients diagnosed with CD were diagnosed within the first 5 years after the diagnosis of type 1 DM, four of them were diagnosed within 2 years.

5. Discussion

The prevalence of CD has increased dramatically in the last two decades due to the use of sensitive and specific serological tests and a better understanding of the disease by physicians (17). Although serological tests for CD are recommended in high-risk groups, the majority of asymptomatic patients are still undiagnosed (18).

In a systematic review and meta-analysis, the prevalence of biopsy-proven CD was reported to be 0.7% in the general population worldwide (19).

The prevalence of biopsy-proven CD in type 1 DM has been reported to be 1.6% - 16.4% (6-10). As consistent with the literature, the biopsy-proven prevalence of CD in children with type 1 DM was 4.4%.

ESPGHAN and BSGHAN recommend HLA DQ analysis in addition to tTG IgA test as the first-choice screening test in high-risk groups such as type 1 DM. It was suggested that no further examination is necessary for CD in patients with negative findings (1, 20).

In addition to that, it has been reported that HLA typing was not cost-effective in patients with type 1 DM, as HLA-DQ2 / 8 positivity was detected in approximately 90% of patients (21, 22). Due to the high cost, HLA typing is often not possible. In our study, we could not perform HLA typing because of the high cost.

It has been reported that approximately 85% of type 1 DM patients diagnosed with CD were asymptomatic in a systematic review and meta-analysis (23). As compatible with literature, 7 of 12 patients (58.3%) diagnosed with CD are asymtomatic.

In a systematic review, it has been recommended that screening tests for CD should be performed within the first 2 years and 5 years after the diagnosis of type 1 DM, since CD is usually diagnosed within 5 years in type 1 DM patients (23). As consistent with the literature, 9 of 12 patients diagnosed with CD were diagnosed within the first 5 years after the diagnosis of type 1 DM in our study. Also, four of those patients were diagnosed with CD within 2 years after the diagnosis of DM.

The risk of developing CD is higher in female gender and younger patients diagnosed with DM (6, 24, 25). As consistent with those studies, 7 of our patients diagnosed with CD were 5 years or younger, but there was male dominance. The reason for this gender difference may be a cross-sectional study.

In a multicenter study including healthy school age children, the prevalence of CD was found to be 0.47% in our country (26). In the curent study, the prevalence of biopsy-proven CD in children with type 1 DM was found to be 4.4%, which is approximately 9 times higher than in the general population.

It has been reported that patients with undiagnosed CD and DM had worse glycemic control and a higher prevalence of retinopathy and nephropathy (27, 28). In those patients, 1-year gluten-free diet was found to be safe and had no negative effect on quality of life.

5.1. Limitations

First, two of our patients refused the process of endoscopy because having no symptoms associated with CD. If he had accepted the gastroduodenoscopy, the biopsy-proven prevalence of CD would be higher. Second, HLA-DQ analysis could not be performed to patients due to the high costs of HLA analysis. Third, because CD can be diagnosed at all stages in life, the follow-up period may be short. Therefore, we may have detected a less prevalence of CD than expected.

5.2. Conclusions

We found that the prevalence of biopsy-proven CD in children with type 1 DM was 4.4%, which was approximately 9 times higher than the prevalence of CD in the general population. In the current study, 9 of 12 patients diagnosed with CD were diagnosed within the first 5 years after DM. In addition, 58.3% of our patients with CD were asymptomatic. According to our results, we recommend that screening tests for CD should be performed at least once a year for 5 years in children with Type 1 DM, even if the patients are asymptomatic.

References

  • 1.

    Husby S, Koletzko S, Korponay-Szabo IR, Mearin ML, Phillips A, Shamir R, et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. 2012;54(1):136-60. [PubMed ID: 22197856]. https://doi.org/10.1097/MPG.0b013e31821a23d0.

  • 2.

    Larizza D, Calcaterra V, Klersy C, Badulli C, Caramagna C, Ricci A, et al. Common immunogenetic profile in children with multiple autoimmune diseases: The signature of HLA-DQ pleiotropic genes. Autoimmunity. 2012;45(6):470-5. [PubMed ID: 22686660]. https://doi.org/10.3109/08916934.2012.697594.

  • 3.

    Gujral N, Freeman HJ, Thomson AB. Celiac disease: prevalence, diagnosis, pathogenesis and treatment. World J Gastroenterol. 2012;18(42):6036-59. [PubMed ID: 23155333]. [PubMed Central ID: PMC3496881]. https://doi.org/10.3748/wjg.v18.i42.6036.

  • 4.

    Salardi S, Volta U, Zucchini S, Fiorini E, Maltoni G, Vaira B, et al. Prevalence of celiac disease in children with type 1 diabetes mellitus increased in the mid-1990 s: An 18-year longitudinal study based on anti-endomysial antibodies. J Pediatr Gastroenterol Nutr. 2008;46(5):612-4. [PubMed ID: 18493223]. https://doi.org/10.1097/MPG.0b013e31815d697e.

  • 5.

    Smyth DJ, Plagnol V, Walker NM, Cooper JD, Downes K, Yang JH, et al. Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med. 2008;359(26):2767-77. [PubMed ID: 19073967]. [PubMed Central ID: PMC2840835]. https://doi.org/10.1056/NEJMoa0807917.

  • 6.

    Poulain C, Johanet C, Delcroix C, Levy-Marchal C, Tubiana-Rufi N. Prevalence and clinical features of celiac disease in 950 children with type 1 diabetes in France. Diabetes Metab. 2007;33(6):453-8. [PubMed ID: 17964843]. https://doi.org/10.1016/j.diabet.2007.06.004.

  • 7.

    Al-Hussaini A, Sulaiman N, Al-Zahrani M, Alenizi A, El Haj I. High prevalence of celiac disease among Saudi children with type 1 diabetes: A prospective cross-sectional study. BMC Gastroenterol. 2012;12:180. [PubMed ID: 23259699]. [PubMed Central ID: PMC3543703]. https://doi.org/10.1186/1471-230X-12-180.

  • 8.

    Baptista ML, Koda YK, Mitsunori R, Ioshii SO; Nisihara. Prevalence of celiac disease in Brazilian children and adolescents with type 1 diabetes mellitus. J Pediatr Gastroenterol Nutr. 2005;41(5):621-4. [PubMed ID: 16254520]. https://doi.org/10.1097/01.mpg.0000181400.57884.c3.

  • 9.

    Djuric Z, Stamenkovic H, Stankovic T, Milicevic R, Brankovic L, Ciric V, et al. Celiac disease prevalence in children and adolescents with type 1 diabetes from Serbia. Pediatr Int. 2010;52(4):579-83. [PubMed ID: 20113423]. https://doi.org/10.1111/j.1442-200X.2010.03085.x.

  • 10.

    Boudraa G, Hachelaf W, Benbouabdellah M, Belkadi M, Benmansour FZ, Touhami M. Prevalence of coeliac disease in diabetic children and their first- degree relatives in west Algeria: Screening with serological markers. Acta Paediatr Suppl. 1996;412:58-60. [PubMed ID: 8783762]. https://doi.org/10.1111/j.1651-2227.1996.tb14254.x.

  • 11.

    Bjorck S, Brundin C, Karlsson M, Agardh D. Reduced bone mineral density in children with screening-detected celiac disease. J Pediatr Gastroenterol Nutr. 2017;65(5):526-32. [PubMed ID: 28319607]. https://doi.org/10.1097/MPG.0000000000001568.

  • 12.

    van der Pals M, Myleus A, Norstrom F, Hammarroth S, Hogberg L, Rosen A, et al. Body mass index is not a reliable tool in predicting celiac disease in children. BMC Pediatr. 2014;14:165. [PubMed ID: 24981433]. [PubMed Central ID: PMC4094403]. https://doi.org/10.1186/1471-2431-14-165.

  • 13.

    Hansen D, Brock-Jacobsen B, Lund E, Bjorn C, Hansen LP, Nielsen C, 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. Diabetes Care. 2006;29(11):2452-6. [PubMed ID: 17065683]. https://doi.org/10.2337/dc06-0990.

  • 14.

    Nachman F, Maurino E, Vazquez H, Sfoggia C, Gonzalez A, Gonzalez V, et al. Quality of life in celiac disease patients: Prospective analysis on the importance of clinical severity at diagnosis and the impact of treatment. Dig Liver Dis. 2009;41(1):15-25. [PubMed ID: 18602354]. https://doi.org/10.1016/j.dld.2008.05.011.

  • 15.

    Barak M, Rozenberg O, Froom P, Grinberg M, Reginashvili D, Henig C, et al. Challenging our serological algorithm for celiac disease (CD) diagnosis by the ESPGHAN guidelines. Clin Chem Lab Med. 2013;51(11):e257-9. [PubMed ID: 23839814]. https://doi.org/10.1515/cclm-2013-0267.

  • 16.

    Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity ('celiac sprue'). Gastroenterology. 1992;102(1):330-54. [PubMed ID: 1727768].

  • 17.

    White LE, Merrick VM, Bannerman E, Russell RK, Basude D, Henderson P, et al. The rising incidence of celiac disease in Scotland. Pediatrics. 2013;132(4):e924-31. [PubMed ID: 24019416]. https://doi.org/10.1542/peds.2013-0932.

  • 18.

    Garnier-Lengline H, Cerf-Bensussan N, Ruemmele FM. Celiac disease in children. Clin Res Hepatol Gastroenterol. 2015;39(5):544-51. [PubMed ID: 26186878]. https://doi.org/10.1016/j.clinre.2015.05.024.

  • 19.

    Singh P, Arora A, Strand TA, Leffler DA, Catassi C, Green PH, et al. Global prevalence of celiac disease: Systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2018;16(6):823-836 e2. [PubMed ID: 29551598]. https://doi.org/10.1016/j.cgh.2017.06.037.

  • 20.

    Murch S, Jenkins H, Auth M, Bremner R, Butt A, France S, et al. Joint BSPGHAN and Coeliac UK guidelines for the diagnosis and management of coeliac disease in children. Arch Dis Child. 2013;98(10):806-11. [PubMed ID: 23986560]. https://doi.org/10.1136/archdischild-2013-303996.

  • 21.

    Mitchell RT, Sun A, Mayo A, Forgan M, Comrie A, Gillett PM. Coeliac screening in a Scottish cohort of children with type 1 diabetes mellitus: Is DQ typing the way forward? Arch Dis Child. 2016;101(3):230-3. [PubMed ID: 26718815]. [PubMed Central ID: PMC4789707]. https://doi.org/10.1136/archdischild-2015-309754.

  • 22.

    Elias J, Hoorweg-Nijman JJ, Balemans WA. Clinical relevance and cost-effectiveness of HLA genotyping in children with Type 1 diabetes mellitus in screening for coeliac disease in the Netherlands. Diabet Med. 2015;32(6):834-8. [PubMed ID: 25546232]. https://doi.org/10.1111/dme.12658.

  • 23.

    Pham-Short A, Donaghue KC, Ambler G, Phelan H, Twigg S, Craig ME. Screening for celiac disease in type 1 diabetes: A systematic review. Pediatrics. 2015;136(1):e170-6. [PubMed ID: 26077482]. https://doi.org/10.1542/peds.2014-2883.

  • 24.

    Cerutti F, Bruno G, Chiarelli F, Lorini R, Meschi F, Sacchetti C, et al. Younger age at onset and sex predict celiac disease in children and adolescents with type 1 diabetes: An Italian multicenter study. Diabetes Care. 2004;27(6):1294-8. [PubMed ID: 15161778]. https://doi.org/10.2337/diacare.27.6.1294.

  • 25.

    Pham-Short A, Donaghue KC, Ambler G, Chan AK, Craig ME. Coeliac disease in Type 1 diabetes from 1990 to 2009: Higher incidence in young children after longer diabetes duration. Diabet Med. 2012;29(9):e286-9. [PubMed ID: 22672045]. https://doi.org/10.1111/j.1464-5491.2012.03720.x.

  • 26.

    Dalgic B, Sari S, Basturk B, Ensari A, Egritas O, Bukulmez A, et al. Prevalence of celiac disease in healthy Turkish school children. Am J Gastroenterol. 2011;106(8):1512-7. [PubMed ID: 21691340]. https://doi.org/10.1038/ajg.2011.183.

  • 27.

    Leeds JS, Hopper AD, Hadjivassiliou M, Tesfaye S, Sanders DS. High prevalence of microvascular complications in adults with type 1 diabetes and newly diagnosed celiac disease. Diabetes Care. 2011;34(10):2158-63. [PubMed ID: 21911773]. [PubMed Central ID: PMC3177718]. https://doi.org/10.2337/dc11-0149.

  • 28.

    Mohn A, Cerruto M, Iafusco D, Prisco F, Tumini S, Stoppoloni O, et al. Celiac disease in children and adolescents with type I diabetes: Importance of hypoglycemia. J Pediatr Gastroenterol Nutr. 2001;32(1):37-40. [PubMed ID: 11176322]. https://doi.org/10.1097/00005176-200101000-00012.