Medical Journal of The Islamic Republic of Iran National Research Centre of Medical Sciences of I.R. IRAN ISSN: 1016-1430 Vol. 18, Num. 1, 2004, pp. 39-43

Medical Journal of the Islamic Republic of Iran , Vol. 18, No. 1, May, 2004, pp. 39-43

PREVALENCE OF CELIAC DISEASE IN CHILDREN AND ADOLESCENTS WITH TYPE I DIABETES MELLITUS

From the Pediatrics Department, Imam Khomeini Hospital, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Correspondence: H.Moayeri, Department of Pediatric Endocrinology, Imam Khomeini Hospital, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Tel: + 98218004446, Fax: + 98218270902, E. Mail: H. Moayeri @ radsa net.

Code Number: mr04007

The association of celiac disease and type I diabetes mellitus has been known for some time. This study was undertaken to investigate the prevalence of celiac disease (CD) in diabetic children and adolescents. Eighty-seven patients (44 females, 43 males) aged 2- 18 years, with type I diabetes participated in this study. A group of 87 healthy unrelated girls and boys matched for age and gender served as controls. They were screened for the presence of celiac disease related marker [IgA - endomysial antibody (EMA)] and patients who were EMA positive further investigated with intestinal biopsy. Among diabetic patients a 3.4% prevalence of celiac disease was observed, a value significantly higher than that found among healthy controls. Girls were more frequently EMA positive than boys. Intestinal biopsies of all 3 patients with positive EMA showed a histologic picture confirming the diagnosis of CD. Diabetics with CD were significantly younger, had an earlier onset of diabetes, had a lower height and weight standard deviation score and poorer glycemic control compared with diabetics without CD (p<0.05). We failed to show any significant correlation between EMA- positivity and duration of diabetes. The results suggest EMA - positivity to be a good immunological marker for use in screening for celiac disease and such screening to be justified in our patients with type I diabetes mellitus, regardless of diabetes duration.

Keywords: Adolescents, Children, Celiac disease (CD), IgA - endomysial antibody (EMA), Type I diabetes mellitus.

INTRODUCTION

Type I or insulin dependent diabetes mellitus (IDDM) is an organ–specific autoimmune disease in which T-cell mediated destruction of pancreatic beta cells take place. Gluten-sensitive enteropathy or celiac disease (CD) is a heterogeneous disorder involving abnormalities in the small intestinal mucosa (villous atrophy and crypt hyperplasia), which ranges from silent asymptomatic forms to active malabsorption syndromes.^1,2 Although the pathogenesis of the disease remains unclear, it involves genetic determinants and environmental factors together. Gluten has been identified as the trigger molecule in CD development. The presence of different antibodies (antigliadin, antiendomysial, antireticulin and others) are indicative of possible CD, but diagnostic confirmation is based on histologic examination of specimens obtained in intestinal biopsy. The association of type I diabetes mellitus and CD has been known for some years^3-10 and in initial studies based on clinical data, a prevalence of approximately 1% to 1.5% has been calculated among patients with diabetes. However, within the past few years several studies have shown the prevalence of CD in diabetes to be even higher than considered previously. The use of CD–specific immunologic markers in

MATERIAL AND METHODS

Subjects

Eighty - seven patients (44F, 43M) with type I diabetes mellitus (median diabetes duration 4.1 years, range 1-12 years) were studied at the Pediatrics Department of Tehran University of Medical Sciences. The age range of the study participants was 2-18 years with a mean age of 11.7 ± 4.5 years. They were diagnosed as having diabetes type I on the basis of World Health Organization (WHO) criteria.27 The patients initially showed typical symptoms of hyperglycemia and 48.9% of them presented with ketoacidosis or impaired consciousness as the first manifestation of the disease. All of the patients required insulin replacement therapy for survival or to achieve adequate metabolic control from the time of diagnosis.

Control subjects included 87 age and gender matched normal children (43F, 45M) with a median age of 11.1±3.9 years, range 3-18.5 years. None of the control subjects disclosed any symptoms compatible with CD and none were growth retarded. None of them had a family history of type I diabetes or CD. Age, sex, age at onset of diabetes, daily dose of insulin injection, weight and height were recorded in a questionnaire. Each patient and control were requested to fill a questionnaire by answering yes or no to a set of questions regarding symptoms of CD.

After ruling out IgA deficiency in all subjects IgA class endomysial antibody (EMA) was measured by an immunofluorescence technique as an initial screening test for CD. In diabetic patients, serum glucose concentration and glycohemoglobin (HbA1c) were measured.

Subjects with EMA were offered intestinal biopsy. Endoscopic duodenal biopsies were taken and examined histologically by an expert pathologist.

CD was diagnosed when the intestinal mucosa showed partial or total atrophy, crypt hyperplasia and intraepithelial lymphocytic infiltration according to the latest criteria of the European Society for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN).28

All results are presented as the mean±SD. Comparison between groups was performed using Student's t-test. A p value of 5% or less was considered statistically significant.

Among the 87 patients with type I diabetes, 3 (3.4%) were positive for EMA. In the control group none had EMA. None of the subjects and controls were IgA deficient. Three EMA positive patients exhibited histologic findings in their intestinal biopsy specimens supporting the diagnosis of CD. The diabetics with CD did not report any symptoms indicating CD at the first interview. At the time of biopsy, about 6 months later two patients showed symptoms compatible with CD (loose stools, abdominal discomfort). Clinical characteristics and biochemical measurements in diabetics with CD and without CD are compared in Table I. The diabetic patients with CD had a median age of 7.2 ± 2.1 yr at the time of screening and a median duration of diabetes of 3.5 ± 1.8 yr compared with 12.2 ± 3.2 yr and 4.1 ± 1.7 yr respectively in diabetics without CD. The diabetic subjects with CD were significantly younger than the group of diabetics without CD. They also had an earlier onset of diabetes, mean age 3.1±1.6 yr compared with 7.8 ± 3.4 yr in patients without CD (p<0.05). In diabetic patients with CD the mean height standard deviation score (SDS) was -3.4 ± 1.24 cm compared with -2.1 ± 1.1 cm in patients without CD. In patients with CD, the mean weight SDS was - 2.6 ± 0.96 kg compared with -1.2 ± 0.82 kg in patients without CD. So in patients with CD the mean height and weight SDS were significantly lower compared with diabetes without CD. There were significant differences between the two groups with regard to the glycemic control (the mean glucose concentration was 267 ± 34 mg/ dL vs 185 ± 41mg/dL; HbA_Ic : 11.25 ± 0.75 vs 8.9 ± 1.4 percent in patients with CD and without CD respectively).

The prevalence of CD among diabetic patients ranges from 0.61% to 7.8% in various reports^3-10 but recent studies based on screening results with the sensitive EMA method show the highest prevalence of CD to be between 2.8% and 16.4%.^11-17

In the present study, out of 87 children with type I diabetes, 3 patients met the revised ESPGHAN criteria for celiac disease,²⁸ resulting in a prevalence of 3.4% of CD among diabetic patients in our study group.

The differences among results in various studies may be because of the difficulty of accurately evaluating the frequency when estimated from clinical findings and many initial studies were based on this method. Patients in risk groups such as diabetics represent a special case, as they may be symptom-free. So the existence of subclinical forms of the disease (silent or latent CD) that may not be accounted for, and the different antibody detection methods [antigliadin antibody (AGA)] as initial screening tests29-31 could explain this discrepancy. Because as previously reported^{21, 26, 32-34} AGA was not reliable, only a small proportion of isolated AGA positive patients exhibit pathologic mucosa. Finally, the wide range of prevalences in various reports may also be due to differences in ethnic groups, geographic area and population size in each report. In the present study, CD was more frequent in female patients, and diabetics with CD had a significantly earlier onset of diabetes, had a lower height and weight SDS and poorer glycemic control compared with diabetics without CD (p<0.05). Diabetic patients with CD were significantly younger than the group of diabetics without CD, possibly indicating that patients have a more aggressive autoimmune disease response.

We failed to show any significant correlation between CD and diabetes duration, similar to the majority of previous reports.^11,14,15,16 In the present survey and other studies^14-17 all EMA positive patients who underwent intestinal biopsy had CD, thus showing the predictive value of EMA positivity to be as high among patients with type I diabetes as the general population.

In summary, EMA analysis is considered to be the most powerful tool currently available for serologic screening of CD at least in children above 2 years of age.^35-36 Some authors suggest regular screening with CD related antibodies in children with type I diabetes.^13,37 In Iran routine screening for CD disease related antibodies in diabetics is not common practice. Thus, from a clinical point of view, EMA screening should be a part of health assessment in patients with type I diabetes, because diabetic patients with CD diagnosed by screening often have no or only mild symptoms of the disease.

However, a gluten-free diet in asymptomatic patients may not only increase the general well - being of the patients and improve glycemic control but also prevent the well - known complications of CD, such as malnutrition, growth failure, pubertal delay, osteoporosis, infertility and intestinal malignancies.^38-40

REFERENCES

1. Trier JS: Celiac sprue. N Engl J Med 325: 1709-19, 1991.
2. Tighe MR, Ciclitira PJ: The implications of recent advancesin celiac disease. Acta Pediatr 82: 805-10, 1993.
3. Lorini R, Scaramuzza A, Vitali L, et al: Clinical aspects of celiac disease in children with insulin dependent diabetes mellitus. J Pediatr Endocrinol Metab 9: 101-11, 1996.
4. Schober E, Granditsch G: IDDM and celiac disease. Diabe-tes Care 17: 1549-50, 1994.
5. Saukkonen T, Savilahti E, Tumilehtowolf E, Reijonen H, Ilonen J, Akerblom HK: Childhood Diabetes in Finland Study Group. Celiac disease is often provoked after clini- cal onset of insulin dependent diabetes mellitus. Eur J Endocrinol 132 (suppl I) : 24, 1995.
6. Controneo P, Devitis I, Addesa S,Ghirlanda G: Celiac disease and insulin dependent diabetes mellitus: A multicentric study. Diabetologica 39 (suppl l) : A27, 1996.
7. Sigurs N, Johansson C, Elfstrand PO, Viander M, Lanner A: Prevalence of celiac disease in diabetic children and adoles- cents in Sweden. Acta Pediatr 82: 748-51, 1993.
8. Rossi TM, Albini CH, Kumar V: Incidence of celiac disease identified by the presence of serum endomysial antibodies in children with chronic diarrhea, short stature, or insulin dependent diabetes mellitus. J Pediatr 123: 262-4, 1993.
9. Pocecco M, Ventura A: Celiac disease and insulin dependent diabetes mellitus. A casual association? Acta Pediatr84: 1432-3, 1995.
10. Savilahti E, Simell O, Koskimies S, Rilva A, Akerblom HK: Celiac disease in insulin dependent diabetes mellitus. J Pediatr 108: 690-3, 1986.
11. Cronin CC, Shanahan F: Insulin dependent diabetes melli-tus and celiac disease. Lancet 349: 1096-7, 1997.
12. Koletzko S, Burgin WA, Koletzko B, Knapp M, Burger W, Gruneklee D, et al: Prevalence of celiac disease in dia- betic children and adolescents. A multicenter study. Eur J Pediatr 148: 113-7, 1998.
13. Saukkonen T, Savilahti E, Reijonen H, Honen J, Tuomilehto WE, Akerblom, HK: Celiac disease; frequent occurrence after clinical onset of insulin dependent diabetes mellitus. Chilhood Diabetes in Finland Study Group. Diab Med 13: 469-70, 1996.
14. Boudraa G, Hachelaf W, Benbouabdellah M, Belkadi M, Benmansour FZ , Touhami M: Prevalence of celiac disease in diabetic children and first degree relatives in West Alge- ria: screening with serologic markers. Acta Pediatr Supp1 412: 58-60, 1996.
15. Iscarlsson AK, Axelsson IE, Borulf SK, Bredberg AC, Lindberg BA, Sjoberg KG, et al: Prevalence of IgA- antiendomysium and IgA antigliadin autoantibodies at di- agnosis of insulin dependent diabetes mellitus in Swedish children and adolescents. Pediatrics 103: 1248-52, 1999.
16. Hansen D, Bennedbaek FN, Hansen LK, Madsen H,Hegedus L, Jacobsen BB, Hsuby S: High prevalence of celiac disease in Danish children with type I diabetes mellitus. Acta Pediatr 90: 1238-48, 2001.
17. Juan C, Castano L, Itxaso R, Bilbao J, Arrieta A, Masdevall G, Maria D: Association of insulin dependent diabetes mellitus and celiac disease. A study based on serologic markers. J Pediatr Gastroent Nutr (JPGN) 27: 47-52, 1998.
18. Catassi C, Fabiani E, Ratsch 1M, Coppa GV, Giorgi PL, Pierdomenico R, et al: The celiac iceberg in Italy. A multicenter anti-gliadin antibodies screening for celiac disease in school age subjects. Acta Pediatr Suppl 412: 29-35, 1996.
19. Kolho KL, Farkkila MA, Savilhati E: Undiagnosed ce-liac disease is common in Finnish adults. Scand J Gastroenterol 33: 1280-3, 1998.
20. Sjoberg K, Eriksson S: Regional differences in celiac dis-ease prevalence in Scandinavia? Scand J Gastroenterol 34: 41-5, 1999.
21. Vogelsang H, Genser D, Wyatt J, Lochs H, Ferenci P, Granditsch G, et al: Screening for celiac disease: a pro- spective study on the value of non-invasive tests. Am J Gastroenterol 90: 394-8, 1995.
22. Dieterich W, Ehnis T, Bauer M, Donner P, Volta V, Riecken EO, et al: Identification of tissue transglutaminase as predictors of celiac disease. Nat Med 3: 797-801, 1997.
23. Dieterich W, laag E, Schopper H, Volta U, Ferguson A, Gillett H, et al: Autoantibodies to tissue transglutaminase as predictors of celiac disease. Gastroenterology 115: 1317-21, 1998.
24. Bazzigaluppi E, lampasona V, Barera G. Chiumello G, et al: Comparison of tissue transglutaminase specific anti- body assays with established antibody measurements for celiac disease. J Autoimmun 12: 51-6, 1999.
25. Troncone R, Maurano F, Rossi M, Micillio M, Greco L, Auriccho R, et al: IgA antibodies to tissue transglutaminase: an effective diagnostic test for celiac disease. J Pediatr 134: 166-71, 1999.
26. Sulkanen S, Halttunen T, Laurila K, Kohlo KL, Korponay SI, Samesto A, et al: Tissue transglutaminase autoanti- body enzyme linked immunosorbent assay in detecting celiac disease. Gastroenterology 115: 1322-8, 1998.
27. Alberti K GM, Zimmet Z: Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1. Diagnosis and classification of diabetes mellitus. Pro-visional report of a WHO Consultation. Diabet Med 15: 539-53, 1998.
28. Report of Working Group of European Society of Pediatrics Gastroenterology and Nutrition: Revised criteria for diagnosis of celiac disease. Arch Dis 65:909-11, 1990.
29. Collin P, Helin H, Maki M, Hallstrom O, Karvonen AL: Follow up of patients positive in reticulin and gliadin H. Moayeri and S.H. Bahremand antibody tests with normal small bowel biopsy findings. Scand Gastroenterol 28: 595-8, 1993.
30. Maki M, Hupponen T, Holm K, Hallstrom O: Seroconversion of reticulin autoantibodies predict celiac disease in insulin dependent diabetes mellitus. Scand Gastroenterol 36: 239-42, 1995.
31. Catassi C, Natalini G, Ratsch 1M, Gabrielli O, Coppa GV, Giorgi PL: Documented latent celiac disease in a child with insulin dependent diabetes mellitus. Eur J Pediatr 150: 832- 4, 1991.
32. Vitoria JC, Arrieta A, Astigarraga I, Garcia - Masdevall D, Rodriguez - Soriano J: Use of serologic markers as a screen- ing test in family members with celiac disease. J Pediatr Gastroenterol Nutr 19: 304-9, 1994
33. Schober E, Granditsch G. IDDM and celiac disease. Dia- betes Care 17: 1594-50, 1994
34. Bazzigaluppi E, Lampasona V, Barera G, Venerando A, Bianchi C, Chiumello G, et al: Comparison of tissue trans-glutaminase- specific antibody assays with estabished antibody measurements for celiac disease. J Autoimmun 12:51-6, 1999.
35. Sategna - Guidetti C, Grosso S, Bruno M, Bruna- Grooso S: Comparison of serum anti - gliadin, antiendomysiumand anti-jejunum antibodies in adult celiac sprue. J Clin Gastroenterol 20: 17-21, 1995.
36. Corrao G, Corazza GR, Andreani MI, Torchio P, Valentini RA, Galatola G., et al: The reliability of noninvasive testes for celiac disease. Gastroenterology 108: 608-14, 1995.
37. Fraser - Reynolds KA, Butzner JD, Stephure DK, TrussellAR, Scott RB: Use of immunoglobulin A- antiendomysial antibody to screen for celiac disease in North American children with type I diabetes. Diabetes Care 21: 1985-9, 1998.
38. Acerini CL, Ahmed ML, Ross KM, Sullivan PB, Bird G, Dunger DB: Celiac disease in children and adolescents with IDDM: clinical characteristics and response to gluten - free diet. Diab Med 15: 38-44, 1998.
39. Ferguson A, Kingstone K: Celiac disease and malignan- cies. Acta Paediatr Suppl 412: 78-81, 1996.
40. Holmes GK: Non - malignant complications of celiac dis-ease. Acta Paediatr Suppl 412: 68-75, 1996.

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