Celiac disease is an important association of type 1 diabetes identified in 2-25% subjects [1]. The disease has significant impact on growth, bone density and glycemic control [2], emphasizing the need for timely detection. Non-specific features frequently result in delayed and missed diagnosis highlighting the need for screening [1]. The current guidelines differ in terms of initial and follow-up screening protocol for the condition [3-5]. Further, there is no information regarding time trend of celiac disease in Indian children and adolescents with type 1 diabetes. We, therefore, evaluated the time trend of celiac disease in Indian children and adolescents with type 1 diabetes with special emphasis on its predictors.

Case records of children and adolescents with type 1 diabetes presenting to our pediatric endocrinology clinic from August, 2008 to July, 2019 were reviewed after approval from the institutional ethics committee. All patients at our centre are advised IgA tissue transglutaminase antibody levels (TTG) at presentation and annually. IgA TTG is performed using Euro immune anti TTG IgA ELISA kit. Subjects without record of baseline TTG level within the first six months of diagnosis and those with incomplete records were excluded. Duodenal biopsy was advised when TTG levels were more than 20 RU/L and graded using modified Marsh criteria [6]. Celiac disease was diagnosed as per ESPGHAN 2012 recommendations [4]. TTG levels were repeated after 3, 6 and 12 months and annually in those not willing for biopsy, and celiac disease was diagnosed in subjects with TTG levels persistently above 200 RU/L. Information about age at diagnosis of type 1 diabetes, duration of follow-up, anthropometry, celiac disease status, thyroid profile, gastrointestinal symptoms and glycosylated hemoglobin (HBA1C) levels was recorded.

Data were entered and analyzed using IBM Statistical Package for Social Sciences (SPSS version 25.0, SPSS, Inc., Chicago, IL, USA) for Macintosh. Independent sample t test and Chi square test were used to compare continuous and categorical variables respectively, to identify predictors of celiac disease at presentation and on follow-up. P value less than 0.05 was considered significant.

Out of 262 children and adolescents with type 1diabetes (TID) presenting during the study period, 40 without baseline TTG levels and 14 with incomplete records were excluded from the study. The remaining 208 subjects (79.4%, 106 boys) included in the study were diagnosed at the median (IQR) age of 9.2 (6.4) years and followed up for median (IQR) 2.4 (4.4) years. Celiac disease was identified in 35 (16.8%).

Three patients had celiac disease 8.3 (8.1) months before the onset of diabetes, and TTG was positive in 21 (10.2%) at presentation. Celiac disease was histologically confirmed in 15 of these. Of the remaining six, three (2 boys) were diagnosed as celiac disease in view of persistently elevated IgA TTG levels above 200 RU/L. IgA TTG levels normalized over a median period of 4 months (3-12 months) in the other three. Biopsy proven celiac disease was diagnosed in 14 (7.5%) with negative initial screening after a median (IQR) 2.9 (2.7) years of diabetes onset. New onset celiac disease was identified in 12 (85.7%) within five years of diabetes diagnosis. Gastrointestinal symptoms were absent in all diagnosed within 10 years of diabetes but present in a boy identified after 12.6 years.

Those with celiac disease at baseline had significantly compromised weight and BMI, and worse HBA1C at diagnosis of T1D, as compared to both those with new onset celiac disease and those without celiac disease. No difference was observed in mean age at diagnosis of T1D, height SDS and insulin requirement. The difference in the gender and thyroid dysfunction between the three groups was not statistically significant (Table I).

Table I Comparison of Subjects with Celiac Disease at Presentation, Incident Disease on Follow-up and those without the disease

Findings of our study indicate high prevalence of celiac disease (16.8%) in Indian children with type 1 diabetes. This is substantially higher than Western reports and may reflect difference in the distribution of HLA genotypes [7].

Incident celiac disease contributed to 40% of subjects of our study resulting in higher prevalence than cross-sectional Indian studies (3.8-13.5%), despite similar baseline levels [1]. This is commensurate with a multi-centric follow-up study of 4322 Italian subjects [8], and a seroconversion rate of 2.8% over 3.6 years in an Australian study [9]. Gastrointestinal symptoms were absent in most diagnosed on follow-up, highlighting the need for periodic TTG levels over follow-up as suggested by previous studies [10]. The fact that 85% of these were identified within five years of diagnosis suggests annual screening till this period in line with ISPAD 2018 and ADA 2018 guidelines [3,5]. Symptom-based screening may be considered beyond this period.

Age at diagnosis, anthropometry, hemoglobin A1C level, thyroid dysfunction and gender did not predict celiac disease at presentation in contrast to higher risk in younger children and female gender in the multi-centric trial in Italy [8]. Compromised weight and glycemic control in subjects with new onset celiac disease indicates the potential adverse effect of the disease.

Our study is limited by its retrospective nature; but uniform implementation of institutional protocol with high concordance of TTG IgA testing and availability of detailed growth and glycemic control data provided real life information about time trend of celiac status. Importantly, over 80% of subjects on active follow-up underwent TTG levels at each time point. Further, small sample size and no data on HLA subtypes add to the limitations of our study.

Our study confirms the high prevalence of celiac disease in Indian children and adolescents with type 1 diabetes. The identification of the disease in asymptomatic children with negative initial serology highlights the need for annual screening till at least five years of diagnosis.

Ethical clearance: Regency Hospital Limited; RHL-IEC-16035 dated September 11, 2019.

Contributors: NA,CD,RP: data collection; NA: literature review, statistical analysis and drafted the initial manuscript; RS,AB: patient management; AB: conceptualized and planned the study, conducted statistical analysis, critically reviewed the manuscript and would act as guarantor of the paper.

Funding: None; Competing interest: None stated.

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