Coeliac Disease in Children and Adolescents with Type 1 Diabetes Mellitus

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1 Clin Pediatr Endocrinol 1998; 7(2), Copyright 1998 by The Japanese Society for Pediatric Endocrinology Coeliac Disease in Children and Adolescents with Type 1 Diabetes Mellitus Francesco Chiarelli, Mariangela Catino, Andrea Mezzetti and Stefano Tumini Department of Medicine, Division of Pediatrics, University of Chieti, Italy Abstract The aim of this study was to determine the prevalence of coeliac disease in 189 children and adolescents with type 1 diabetes mellitus (age range 10 months to 28.2 years). All patients were tested for gliadin IgA antibodies and endomysium antibodies. Twenty-three patients had high gliadin IgA levels and 14 had endomysium antibodies. Antibody positive subjects were selected for a small bowel biopsy. Biopsy was performed in 11 subjects: 1 refused, 1 was normal and 9 had subtotal or total villous atrophy suggestive of coeliac disease. The prevalence of coeliac disease in this large group of diabetic children, adolescents, and young adults was 4.8%, confirming that the risk of developing coeliac disease is substantially increased in diabetic children. Key words: coeliac disease, insulin-dependent diabetes mellitus, children, adolescents, prevalence Introduction Received: July 29, 1998 Accepted: September 18, 1998 Correspondence: Prof. F. Chiarelli, Department of Pediatrics, University of Chieti, Ospedale Policlinico, Via dei Vestini 5, Chieti, Italy Coeliac disease is generally defined as gluten-dependent severe enteropathy of the small intestine, and is characterized by villous atrophy, crypt cell hyperplasia, and lymphocyte infiltration (γ/δ T-lymphocytes) into the epithelium and lamina propria. Many diseases have been found to be associated with coeliac disease, and type 1 diabetes is one of the organ specific autoimmune disorders which has been described as associated to coeliac disease (1). Recent studies have reported an increased prevalence of coeliac disease in patients with insulin-dependent diabetes mellitus ( %) (2 20). The high prevalence justifies routine screening for gliadin and endomisium antibodies. Anti-gliadin (AGA) and anti-endomysial (EMA) antibodies are considered sensible markers for coeliac disease, although there is disagreement about their specificity (21). The aim of the present study is to evaluate the prevalence of coeliac disease in a large group of children with insulin-dependent diabetes mellitus by screening with the anti-gliadin and anti-endomysial tests, and to describe the clinical characteristics of patients with coeliac disease and insulin-dependent diabetes mellitus. Patients and Methods One hundred and eighty-nine patients with insulin-dependent (type 1) diabetes mellitus (98 males and 91 females; age range from 10 months to 28.2 yrs) attending the Diabetes Unit at the Department of Pediatrics in Chieti, Italy, were screened for coeliac disease with the IgA antigliadin (AGA) test and IgA anti-endomysial

2 126 Chiarelli et al. Vol.7 / No.2 (EMA) test, or the IgG anti-gliadin test, in patients with IgA deficit. All patients were receiving human insulin. Patients with positive antibody test results had endoscopy with small bowel biopsy to look for histologic evidence of coeliac disease. AGAs of both IgA and IgG, were measured by enzyme-linked immunosorbent assay (ELISA). EMA was determined by immunofluorescence (IF) on unfixed cryostat sections of distal monkey oesophagus as antigen with fluorescein-conjugated antibody to human IgA. These blood tests were performed on a serum sample from every patient. IgA-AGA normal values were defined as IgA<0.25 mg/l or <10 AU. Clinical features, HbA1C, mean red cell volume, and ferritin were evaluated at diagnosis and 6 months later. Coeliac disease was diagnosed by internationally accepted criteria 1) positive antibody test results, and 2) histologic evidence of gluten-sensitive enteropathy (loss of villous architecture, crypt hyperplasia, and proliferation of intraepithelial lymphocytes) (22). Results A total of 152 subjects (80.4%) were antibody negative. IgA-AGA were positive in 23 of 189 patients (12.1%), and nobody had IgA deficit. EMA were present in 14 of 189 patients (7.4%). Intestinal biopsy was performed in 11/14 subjects with persistent IgA-AGA and EMA: diagnosis of coeliac disease was confirmed in 9/11 subjects; one asymptomatic girl, with short stature as the only atypical sign, refused. The total prevalence of coeliac disease in our diabetic patients was 9/189 (4.8%; 5 males; age range at coeliac disease diagnosis from 6 to 25 yrs). Coeliac disease had not been diagnosed in any patient before the onset of IDDM. Despite typical morphologic findings of coeliac disease, six patients (4 males and 2 females), with coeliac disease diagnosed after 1.3 to 19 years of IDDM, did not report intestinal symptoms, and growth and pubertal development were normal. The other three patients were two girls and a boy. Patient #4 (Table 1) was a girl in whom markers of coeliac disease became positive after 5 years of IDDM diagnosis. She complained of arthralgia and iron deficiency, suggestive for coeliac disease. Moreover, she had bilateral glaucoma, disfagia, dyspnea and asthenia as concomitant symptoms. After adopting a gluten-free diet (GFD) arthralgia disappeared and the antibody became negative. Patient #6 was a boy with polyglandular autoimmune syndrome (Addison s disease, Hashimoto thyroiditis, and IDDM) in whom the specific markers for coeliac disease became positive after 5.1 years of IDDM. He was the only one who complained of malabsorption as a specific symptom of coeliac disease. Patient #9 was a child with normal growth who only complained of recurrent abdominal pain. The insulin dosage and HbA1C values were the same in patients with coeliac disease and IDDM and in those with IDDM only. Anemia was not evident in any of the patients tested. None of our patients had skin rashes consistent with dermatitis herpetiformis. After starting a gluten-free diet (GFD), AGA levels normalized and EMA became negative in all the patients. Discussion The high prevalence of coeliac disease among patients with IDDM justifies routine screening for anti-gliadin (AGA) and anti-endomysial (EMA) antibodies. In our study we identified 9 of 189 patients with insulin-dependent diabetes mellitus who had serologic and histologic evidence of coeliac disease. The prevalence of coeliac disease observed in our type 1 diabetic patients (4.8%) is similar

3 December 1998 Coeliac Disease and IDDM in Children 127 Table 1 Clinical characteristics and laboratory findings in patients with IDDM and coeliac disease Case # Sex Age at diagnosis Signs and symptoms Serology Biopsy (years) suggestive of CD or IDDM CD concomitant disease AGA-IgA EMA 1 F None + + Subtotal villous atrophy 2 M None + + Partial villous atrophy 3 M None + + Subtotal villous atrophy and intraepithelial lymphocytes 4 F Arthralgia, Iron deficency, Asthenia, + Subtotal/partial villous Bilateral glaucoma, Disfagia, Dyspnea atrophy 5 M None + + Subtotal villous atrophy 6 M Polyendocrine autoimmune syndrome + + Subtotal villous atrophy (IDDM, Addison s disease, Hashimoto and intraepithelial thyroiditis) lymphocytes 7 M 6 25 None + + Partial villous atrophy 8 F None + + Subtotal villous atrophy 9 F Recurrent abdominal pain + + Subtotal villous atrophy to that reported by Acerini and colleagues (20) who found that just 4.8% of their patients with IDDM had coexistent coeliac disease. The anti-endomysial antibody (EMA) test used to screen for coeliac disease in our study is more sensitive than the anti-gliadin (AGA) test. In fact, at diagnosis and during follow-up, we found high IgA-AGA levels in 23 of 189 patients (12.1%); EMA antibodies were present in 14 of 189 (7.4%), and intestinal biopsy confirmed coeliac disease in nine patients. These results, as previously reported by others (3, 23), suggest that high AGA levels at onset of diabetes are a transient abnormal immunological response and do not predict the occurrence of coeliac disease. Moreover, a non specific increase in IgA-AGA levels has been reported in patients with another disease of autoimmune origin, juvenile chronic arthritis, who were biopsy negative for coeliac disease (24, 25). This suggests that, to exclude coeliac disease, a jejunal biopsy should be performed on all diabetic children with double-positivity of IgA gliadin and anti-endomysial antibodies. Coeliac disease in diabetic patients is frequently asymptomatic and is detected only through antibody screening. In our study, clinical history and routine biochemical testing did not help to predict which diabetic patients had coeliac disease. In fact, only one of our coeliac patients had malabsorption as a sign of coeliac disease. He also had signs and symptoms of Hashimoto thyroiditis and Addison s disease. This may be explained through the frequent association between coeliac disease, IDDM and other autoimmune diseases. This association might be due to the deposition of immune complexes in target organs. The antigens involved could either be derived from the damaged mucosa or from gluten. Only occasionally coeliac disease precedes the onset of IDDM, but in the majority of patients (as in our study) coeliac disease is diagnosed only after the onset of IDDM (8). Therefore, screening and biopsy of IDDM patients only once is not sufficient to exclude coeliac dis-

4 128 Chiarelli et al. Vol.7 / No.2 ease later in life on the criteria of normal mucosa. Repeated serological screening with antibody tests (with high sensitivity and specificity) is necessary, and another biopsy should be performed, if required. Coeliac disease may therefore be treated at an early stage, and the majority of its complications, especially malignant lymphoma, can be prevented. In conclusion, our study confirms the high prevalence of coeliac disease among diabetic children and adolescents, and suggests that gastrointestinal damage may be present in patients with diabetes in the absence of symptoms and signs of coeliac disease. Nonetheless, the presence of coeliac disease does not influence glycaemic and metabolic control in these patients. References 1. Di Mario U, Anastasi E, Mariani P, Ballati G, et al. Diabetes-related autoantibodies do appear in children with coeliac disease. Acta Paediatrica 1992; 81: Schober E, Granditsch G. IDDM and coeliac disease. Diabetes Care 1994; 17: Saukkonen T, Savilahti E, Reijonen H, Ilonen J, et al. Coeliac disease: frequent occurrence after clinical onset of insulin-dependent diabetes mellitus. Diabetic Medicine 1996; 13: Cronin CC, Shanahan F. Insulin-dependent diabetes mellitus and coeliac disease. Lancet 1997; 349: Thain ME, Hamilton J, Ehrlich RM. Coexistence of diabetes mellitus and coeliac disease. J Pediatr 1974; 85: Sires JM, de Majo SF. Diabetes mellitus and coeliac disease in children. Pediatr Adolesc Endocr 1977; 2: Maki M, Hallstrom O, Vesikari T, Visakorpi JM. Evaluation of serum IgA-class reticulin antibody test for the detection of childhood coeliac disease. J Pediatr 1984; 105: Savilahti E, Simell O, Koskimies S, Rilva A, et al. Coeliac disease in insulin-dependent diabetes mellitus. J Pediatr 1986; 108: Cacciari E, Salardi S, Volta U, Biasco G, et al. Prevalence and characteristics of coeliac disease in type 1 diabetes mellitus. Acta Paediatr Scand 1987; 76: Koletzko S, Burgin-Walff A, Koletzko B, Knapp M, et al. Prevalence of coeliac disease in diabetic children and adolescents. A multicentre study. Eur J Pediatr 1988; 148: Barera G, Bianchi C, Calisti L, Cerutti F, et al. Screening of diabetic children for coeliac disease with antigliadin antibodies and HLA typing. Arch Dis Child 1991; 66: Gadd S, Silink M, Ramanand K, Skerritt JH. Co-existence of coeliac disease and insulin-dependent diabetes mellitus in children: screening sera using an ELISA test for gliadin antibody. Aust N Z J Med 1992; 22: Rossi TM, Albini CH, Kumar V. Incidence of coeliac disease identified by the presence of serum endomysial antibodies in children with chronic diarrhea, short stature, or insulin-dependent diabetes mellitus. J Pediatr 1993; 123: Sigurs N, Johansson C, Elfstrand PO, Viander M, et al. Prevalence of coeliac disease in diabetic children and adolescents in Sweden. Acta Paediatr Scand 1993; 82: Maki M, Huupponen T, Holm K, Hallstrom O. Serum reticulin autoantibody production and development of coeliac disease is triggered by onset of IDDM. Diabetes in the Young 1993; 68, Abstract. 16. Chowdry MMU, Burden AC, Burden ML, Sherk K. IDDM and coeliac disease. Diabetes Care 1994; 17: Pocecco M, Ventura A. Coeliac disease and insulin dependent diabetes mellitus: a casual association? (Italian Multicentre Study). Acta Paediatr 1995; 84: Rensh MJ, Merenich JA, Lieberman M, Long BD, et al. Gluten sensitive enteropathy in patients with insulin-dependent diabetes mellitus. Ann Int Med 1996; 124: De Vitis I, D Addesa S, Ghirlanda G, Gasbarrini G. Coeliac disease (CD) and insulin-dependent diabetes mellitus (IDDM): a multicentre study. Gastroenterology 1996; 110 (suppl) A13, Abstract. 20. Acerini CL, Ahmed ML, Rossi KM, Sullivan PB,

5 December 1998 Coeliac Disease and IDDM in Children 129 et al. Coeliac disease in children and adolescents with IDDM: clinical characteristics and response to gluten-free diet. Diabet Med 1998; 15: Lorini R, Scotta MS, Avanzini MA, Vitali L. IgA antibodies to gliadin, reticulin, and endomysium for coeliac disease screening in children with insulin-dependent diabetes mellitus. J Pediatr 1994; 124: Walker-Smith J. Revised criteria for diagnosis of coeliac disease. Reporting of Working Group of the European Society to Paediatric Gastroenterology and Nutrition. Arch Dis Child 1990; 65: Lorini R, Scotta MS, Cortona L, Avanzini MA, et al. Coeliac disease and type 1 (insulin dependent) diabetes mellitus in childhood: follow-up study. J Diab Comp 1996; 10: Lepore L, Pennesi M, Ventura A, Torre G, et al. Anti-alpha-gliadin antibodies are not predictive of coeliac disease in juvenile chronic arthritis. Acta Paediatr 1993; 82: Pellegrini G, Scotta MS, Soardo S, Avanzini MA, et al. Elevated IgA anti-gliadin antibodies in juvenile chronic arthritis. Clin Exp Rheumatol 1991; 9:

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

Medical Journal of the Islamic Republic of Iran H. Moayeri and S.H. Bahremand Volume 18 Number 1 Spring 1383 May 2004 PREVALENCE OF CELIAC DISEASE IN CHILDREN AND ADOLESCENTS WITH TYPE I DIABETES MELLITUS