Authors:  Hummel M. Bonifacio E. Stern M. Dittler J. Schimmel A. Ziegler AG.
Institution:  Diabetes Research Institute and 3rd Medical Department, Academic Teaching Hospital Manchen-Schwabing, Munich, Germany.
Title:  Development of celiac disease-associated antibodies in offspring of parents with type I diabetes.
Source:  Diabetologia. 43(8):1005-11, 2000 Aug.

Abstract
AIMS/HYPOTHESIS: The aim of this study was to determine the frequency and temporal development of antibodies related to celiac disease in offspring of parents with Type I (insulin-dependent) diabetes mellitus. METHODS: Sera from 913 offspring of parents with Type I diabetes prospectively followed from birth to the age of 8 years were tested for IgG-transglutaminase antibodies (IgG-tTGCAs), endomysial IgA antibodies (EMA) and gliadin antibodies. RESULTS: We found tTGCAs in 32 (3.5%) of the 913 relatives. Prevalence was related to age and reached 6.5% at age 8 years. Endomysial IgA antibodies were detected in 44% of the relatives with tTGCAs and 0.6% of tTGCA negative relatives and were also most prevalent (5 %) in those aged 8 years. Both tTGCAs and EMAs were more frequent in relatives with the HLA DRB1*03 DQA1*0501 DQB1*02 haplotype (7.1% and 7.2%, respectively; p < 0.005). Antigliadin antibodies were common in both tTGCA positive (42%) and negative (23%) relatives, did not show a relation with age and were less prevalent in relatives with HLA DR3 (p < 0.05). There was no association between the presence of antibodies associated with celiac disease and islet autoantibodies in these relatives. Of the relatives 15 (1.6%) had tTGCAs plus EMAs. In two of these, anti-gliadin antibodies were detected before the detection of tTGCAs and EMAs at the age of 9 months whereas none of the remainder had any antibodies associated with celiac disease before age 2 years. In three there were no detectable antigliadin antibodies in any of the samples tested. Celiac disease without clinical symptoms was diagnosed in 9 of 12 by intestinal biopsy. CONCLUSION/INTERPRETATION. A statistically significant proportion of relatives of patients with Type I diabetes have celiac disease-associated autoimmunity and the silent form of celiac disease early in life. These relatives should, therefore, be considered for celiac antibody screening.

Authors:  Gillett PM. Gillett HR. Israel DM. Metzger DL. Stewart L. Chanoine JP. Freeman HJ.
Institution:  British Columbia's Children's Hospital, Vancouver, Canada.
Title: High prevalence of celiac disease in patients with type 1 diabetes detected by antibodies to endomysium and tissue transglutaminase.
Source:  Canadian Journal of Gastroenterology. 15(5):297-301, 2001 May.

Abstract
OBJECTIVE: To establish the prevalence of celiac disease (CD) in children with type 1 diabetes in British Columbia. PATIENTS AND METHODS: Two hundred thirty-three children with type 1 diabetes were prospectively screened for CD using blind testing with the current 'gold standard', immunoglobulin A endomysium antibody (EmA), and the novel immunoglobulin A tissue transglutaminase (tTG) antibody. Those children with positive results were offered small bowel biopsy; a gluten-free diet was recommended if CD was confirmed. RESULTS: Nineteen children were positive for EmA and had an elevated tTG level. One patient from this group was already known to have CD, and the other 18 patients consented to biopsy. One biopsy was normal, three biopsies demonstrated elevated intraepithelial lymphocyte counts with normal morphology and 14 biopsies had morphological changes consistent with CD. Growth parameters were normal in all patients, and nine of 19 children who were positive for EmA were asymptomatic. Seven patients had mild elevation of tTG levels alone. Two children from this latter group had normal biopsies, and five declined biopsy. CONCLUSIONS: At least 14 new cases of CD were detected in addition to four known cases, yielding an overall biopsy-confirmed prevalence of CD of 7.7% (18 of 233). The present study confirms that CD is as prevalent in the pediatric type 1 diabetic population in British Columbia as it is in Europe. Serological screening of these children is important because many children have no symptoms or signs suggestive of CD. This study suggests that tTG serology may also be useful in monitoring response and compliance with a gluten-free diet.

Authors:  Lampasona V. Bonfanti R. Bazzigaluppi E. Venerando A. Chiumello G.
Bosi E. Bonifacio E.
Title:  Antibodies to tissue transglutaminase C in type I diabetes. [see comments].
Comment in: Diabetologia. 2000 Jun;43(6):815-6
Source:  Diabetologia. 42(10):1195-8, 1999 Oct.

Abstract
AIMS/HYPOTHESIS: Silent coeliac disease is a gluten driven autoimmune disease which is relatively frequent in patients with Type I (insulin-dependent) diabetes mellitus. To determine the extent of gluten associated autoimmunity in Type I diabetes, autoantibodies to tissue transglutaminase C, a major autoantigen in coeliac disease, were measured in patients with new-onset Type I diabetes. METHODS: We measured IgG and IgA tissue transglutaminase C autoantibodies using human recombinant antigen and radio-binding assays in a cohort of 287 patients with new-onset Type I diabetes, 119 with Type II (non-insulin-dependent) diabetes mellitus and in 213 control subjects. RESULTS: We found IgA and IgG tissue transglutaminase C antibodies in 24 (8 %) patients with Type I diabetes; 97 (33 %) patients had IgG antibodies only and 1 IgA antibodies only. Antibody concentrations were highest in those with both IgA and IgG antibodies. Only 2 (2 %) patients with Type II diabetes and 2 (1 %) control subjects had either IgG or IgA tissue transglutaminase C antibodies. Patients with HLA DRB1(*)04 alleles had the highest prevalence of IgG tissue transglutaminase C antibodies. CONCLUSION/INTERPRETATION:
These data show that almost 10 % of patients have autoimmunity typical of coeliac disease and that another 30 % have low level tissue transglutaminase C antibody binding. This high prevalence suggests either involvement of the gut in the pathogenesis of Type I diabetes or that transglutaminase is a secondary autoantigen resulting from beta-cell destruction. [Diabetologia (1999) 42: 1195-1198]

Authors:  Matteucci E. Cinapri V. Quilici S. Lucchetti A. Mugnaini P. Giampietro O.
Institution:  Dipartimento di Medicina Interna, University of Pisa, Italy.
Title:  Screening for coeliac disease in families of adults with Type 1 diabetes based on serological markers.
Source:  Diabetes, Nutrition & Metabolism - Clinical & Experimental. 14(1):37-42, 2001 Feb.

Abstract
The prevalence of coeliac disease (CD) in the adult population is unknown because silent and latent stages do exist. Type 1 diabetes mellitus may be associated with CD because of common genetic background and/or shared pathogenetic mechanisms. We investigated 74 adults with type 1 diabetes (32+/-11 yr, disease duration 13+/-9 yr), 69 parents of diabetic probands (56+/-10 yr), 59 siblings (30+/-11 yr) and 50 healthy controls (35+/-10 yr) for the presence of circulating islet cell antibodies (ICA), anti-glutamic acid decarboxylase antibodies (GADA65), anti-gliadin immunoglobulins A and G (IgA- and IgG-AGA). All patients with raised AGA, performed also IgA anti-endomysium antibody (EmA) indirect immunofluorescence assay. Samples were positive for ICA in 19 diabetics (26%), 4 parents (6%), 4 siblings (7%), 0 controls (p<0.001); for GADA in 34 diabetics (46%), 4 parents (6%), 1 sibling (2%), 0 controls (p<0.001). Twenty-five diabetic patients (34%), 10 parents (14%), 5 siblings (8%), 3 controls (6%) (p<0.001) had raised IgA-AGA (>4.4 mg/l). Four diabetic patients (5%), 5 parents (7%), 0 siblings (0%), 4 controls (8%) had raised IgG-AGA (>18 mg/l). Both IgA- and IgG-AGA were detected in 1 diabetic and 2 parents. The prevalence of ICA, GADA, and IgA-AGA positivity in Type 1 diabetes patients was significantly higher than in controls (p<0.001). Finally, 50 AGA-positive subjects performed EmA test: only 2 of them resulted EmA-positive, a diabetic patient and a sibling. The patient with Type 1 diabetes had a small-bowel biopsy specimen consistent with CD and, as sole evidence of malabsorption, sideropenic anaemia. EmA-positive sibling also showed severe iron deficiency, yet refused endoscopy. We conclude that: 1) CD cannot be diagnosed on the basis of associated IgA-and IgG-AGA alone. Nevertheless, detection of such antibodies is useful, in combination with EmA, in screening for endoscopic biopsy; 2) too high rate of detection of IgA-AGA in Type 1 diabetic patients in comparison with other groups excludes a false positivity of the test itself, while suggests a pathogenetic association of both immunological disorders, perhaps related to abnormal gammadelta TCR-bearing intraepithelial lymphocytes.

Authors:  Mohn A. Cerruto M. Lafusco D. Prisco F. Tumini S. Stoppoloni O. Chiarelli F.
Institution:  Department of Paediatrics, University of Chieti, Italy. amohn@unich.it
Title:  Celiac disease in children and adolescents with type I diabetes: importance of hypoglycemia.
Source:  Journal of Pediatric Gastroenterology & Nutrition. 32(1):37-40, 2001 Jan.

Abstract
BACKGROUND: Symptomatic hypoglycemia is an unavoidable problem in the treatment of type I diabetes. Celiac disease is associated with malabsorption and may therefore represent an important risk factor. METHODS: The frequency of symptomatic hypoglycemia in patients with type I diabetes and celiac disease (cases) was compared with those of patients who had diabetes without celiac disease (controls). For this purpose, each case was matched for age, sex, and duration of disease with one to two control patients. Indices of metabolic control (hemoglobin [Hb]A1c, frequency of hypoglycemia, and total insulin requirement) were retrieved for the 18 months before and after diagnosis of celiac disease. RESULTS:  Eighteen patients (6 males and 12 females) had diagnosed celiac disease and were matched with 26 control patients (10 males and 16 females). There was no difference in age (11.0 years; range, 1.8-21.9 vs. 13.1 years; range, 2.3-22; P = 0.3) and duration of disease (8.4 years; range, 1.2-19.3 vs. 8.3 years; range, 1.1-18.7; P = 0.3) between the two groups. During the 6 months before and after diagnosis of celiac disease the cases had significantly more hypoglycemic episodes than the controls (means +/-SD; 4.5+/-4 vs. 2.0+/-2.2 episodes/months, P = 0.01). This was reflected by a progressive reduction in insulin requirement over the 12 months before diagnosis reaching a nadir at time 0 (0.6+/-0.2 vs. 0.9+/-0.3, P = 0.05). CONCLUSION: These data suggest that underlying celiac disease is associated with an increased risk of symptomatic hypoglycemia and that the introduction of a gluten-free diet with normalization of the intestinal mucosa may reduce its frequency.

Authors:  Aktay AN. Lee PC. Kumar V. Parton E. Wyatt DT. Werlin SL.
Institution:  Division of Gastroenterology, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA.
Title:  The prevalence and clinical characteristics of celiac disease in juvenile diabetes in Wisconsin.
Source:  Journal of Pediatric Gastroenterology & Nutrition. 33(4):462-5, 2001 Oct.

Abstract
BACKGROUND: The relationship between celiac disease and juvenile diabetes has long been known. Only a single study in the United States, from Buffalo, New York, has reported the prevalence of celiac disease in a pediatric diabetic population. This study was conducted to determine the prevalence and clinical presentation of celiac disease in children and adolescents with juvenile diabetes in Wisconsin, USA, using serum antiendomysial antibody as a screening test. METHODS: Two hundred eighteen patients with diabetes (113 males; age range, 4-21 years) and 117 age-and gender-matched control participants were tested for immunoglobulin A endomysial antibody. Patients with positive results were offered a small bowel biopsy. A questionnaire regarding abdominal pain, diarrhea, and growth failure was completed by the parents. RESULTS: Seventeen of 218 diabetic patients (7.7%) had positive endomysial antibody. All control participants had negative results for the endomysial antibody. Small bowel biopsy was performed in 14 patients. Ten patients had villous atrophy. In one patient without villous atrophy, a repeat biopsy 2 years later showed villous atrophy, and two patients had increased intraepithelial lymphocytes without villous atrophy. Seventy percent of the patients with celiac disease were asymptomatic. The reported symptoms were abdominal pain and diarrhea (n = 1) and growth failure (n = 2). Two patients with celiac disease had Down syndrome. CONCLUSIONS: The prevalence of celiac disease in children with juvenile diabetes in Wisconsin is at least 4.6%, which is comparable with European and Canadian studies. Because patients without villous atrophy may have latent celiac disease, the prevalence may be even higher. All children with juvenile diabetes should be screened for celiac disease.

Authors:  Hansen D. Bennedbaek FN. Hansen LK. Hoier-Madsen M. Hegedu LS.  Jacobsen BB. Husby S.
Institution:  Departments of Paediatrics, University Hospital, Odense, Denmark. dorte.hansen@dadlnet.dk
Title:  High prevalence of coeliac disease in Danish children with type I diabetes mellitus. [see comments.].
Comments:  Comment in: Acta Paediatr. 2001 Nov;90(11):1217-20 ; 11808887
Source:  Acta Paediatrica. 90(11):1238-43, 2001 Nov.

Abstract
The purpose of this population-based study was to determine the prevalence of coeliac disease (CD) in 106 Danish children (age 2-18 y) with type I diabetes mellitus compared with 106 age- and sex-matched healthy controls. Serum samples were analysed for immunoglobulin A (IgA) and IgG gliadin antibodies by enzyme-linked immunosorbent assay (ELISA), for IgA endomysium antibodies (EMA) by immunofluorescence and for IgA tissue transglutaminase antibodies (tTGA) by ELISA. None of the controls had EMA or tTGA. Two diabetics previously diagnosed with CD were antibody negative on a gluten-free diet. Ten diabetics had both EMA and tTGA. Intestinal biopsy was performed in nine of them. All biopsies showed a histological picture of partial or total villous atrophy confirming the diagnosis of CD. Diabetics with CD were significantly younger (p = 0.026). had an earlier onset of diabetes (p = 0.005), had a lower height standard deviation score (p = 0.019) and more often had thyroid antibodies (p = 0.040) compared with diabetics without CD. CONCLUSION: A high prevalence of CD of 10.4% (95% confidence interval 4.6-16.2%) was found in young Danish diabetics. Early onset of diabetes may predispose to CD. Routine serological screening for CD may be valuable in patients with type I diabetes mellitus.

Authors:  Barera G. Bonfanti R. Viscardi M. Bazzigaluppi E. Calori G. Meschi F. Bianchi C. Chiumello G.
Institution:  Department of Pediatrics, Scientific Institute H San Raffaele, Milan, Italy. barera.graziano@hsr.it
Title:  Occurrence of celiac disease after onset of type 1 diabetes: a 6-year prospective longitudinal study. [see comments.].
Comments:  Comment in: Pediatrics. 2002 May;109(5):952-4 ; 11986459
Source:  Pediatrics. 109(5):833-8, 2002 May.

Abstract
OBJECTIVE: To investigate the prevalence of celiac disease in a large cohort of children and adolescents at the onset of type 1 diabetes and the occurrence of new cases during a 6-year follow-up. METHODS: We prospectively studied, by repeated serologic screening, 274 consecutive patients at the onset of type 1 diabetes (age [mean +/- standard deviation]: 8.28 +/- 4.65 years) for 6 subsequent years. One patient had a diagnosis of celiac disease before the onset of diabetes. The immunoglobulin A-antiendomysium antibody test was selected as the screening test; patients with positive results (++ or +++) or with 2 consecutive weak positive tests (+) were considered appropriate for the jejunal biopsy. RESULTS: At diabetes onset, 15 (5.5%) of 273 patients tested positive with the antiendomysium test; jejunal biopsy was performed in 10, and celiac disease was diagnosed in 9. The prevalence of biopsy-confirmed celiac disease at the manifestation of diabetes was 3.6% (10 of 274 patients). Twelve more patients with a negative antiendomysium antibody test at diabetes onset tested positive during the follow-up within 4 years; 10 of them had biopsies performed, and 7 had celiac disease. Therefore, the overall prevalence of biopsy-confirmed celiac disease in the entire cohort of patients was 6.2%. The age at diabetes onset in patients with and without celiac disease was not different (7.88 +/- 5.69 vs 8.3 +/- 4.58 years). The majority of cases of celiac disease were asymptomatic in their presentation, and no signs of overt malnutrition were documented. CONCLUSIONS: The prevalence of celiac disease in patients with type 1 diabetes is approximately 20 times higher than in the general population. Sixty percent of cases are already present at diabetes onset, mostly undetected, but an additional 40% of patients develop celiac disease a few years after diabetes onset. Extending screening programs for celiac disease after the onset of type 1 diabetes is recommended, even in the absence of clinical symptoms.

Authors:  Holmes GK.
Institution:  Department of Medicine, Derbyshire Royal Infirmary, Derby, UK. GeoffreyHolmes@compuserve.com
Title:  Screening for coeliac disease in type 1 diabetes. [Review] [63 refs]
Source:  Archives of Disease in Childhood. Online. 87(6):495-8, 2002 Dec.

Abstract
The average prevalence of coeliac disease among children with diabetes mellitus in 26 reports was 4.5% (0.97-16.4%). Malabsorption, unstable diabetes, and growth failure, indicate that coeliac disease may be present. Even those who are apparently asymptomatic may have subtle complaints indicative of coeliac disease if a careful history is taken. Ill health may only be recognised in retrospect following the benefits conferred by a gluten free diet. For these reasons it is recommended that a screening programme should be instituted to detect coeliac disease in these children. Parents and where possible children themselves, should be fully involved at all stages of the screening, diagnostic, and treatment process. [References: 63]