Prevalence of Beta-Cell, Thyroid and Celiac Autoimmunity in North Indian Children with Recent Onset Type 1 Diabetes (T1D)
Devi Dayal1, Madhusudan Samprati2, Navchetan Kaur3, Ranjana Walker Minz4, Dhaarani Jayaraman5
1 Additional Professor, Pediatric Endocrinology & Diabetes Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
2 Registrar, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
3 Research Scholar, Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
4 Professor, Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
5 Registrar, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
NAME, ADDRESS, E-MAIL ID OF THE CORRESPONDING AUTHOR: Dr. Devi Dayal, Additional Professor, Pediatric Endocrinology & Diabetes Unit, Department of Pediatrics, Advanced Pediatrics Center, Postgraduate Institute of Medical Education and Research, Chandigarh-160012, India.
E-mail: drdevidayal@gmail.com; dayal.devi@pgimer.edu.in
There is wide variation in the prevalence of pancreatic and other major autoantibodies in different patient populations of Type 1 diabetes (T1D) across continents and even within countries. The data on frequency of associated autoimmunity Indian children with T1D is limited. A retrospective record review of 310 children aged 7.28±3.3 y (range 0.7-15 y) with recently diagnosed T1D attending our Pediatric Diabetes Clinic between April 2004 to September 2014, showed positivity for anti-GAD65, anti-IA2b, anti-TPO and anti-tTGA of 50% (64/128), 16% (12/72), 18.7% (23/123) and 22% (47/212) respectively. The male:female ratio in patients with anti-GAD, anti-TPO and anti-tTG positivity was 1.3, 0.7 and 0.6 respectively. In conclusion, our patient cohort exhibited a moderate prevalence of anti-GAD 65, low prevalence of anti-TPO and high prevalence of anti-tTGA autoantibodies as compared to previous reports. Male preponderance was noted in children with GAD65 positivity.
Introduction
T1D results from a complex interplay of genetic, immunological and environmental factors [1]. Although the disease is characterized by β cell destruction and presence of pancreatic autoantibodies, the autoimmune attack may involve other organs particularly thyroid, gut, adrenals and gastric parietal cells [1]. The presence of autoimmunity of other organs in patients with T1D influences the disease prognosis and screening for associated autoimmunity is therefore recommended [2]. Majority of the data on prevalence of autoimmunity in T1D has emerged from the developed countries. There is however wide variation in the frequencies of various autoantibodies in different populations of the world [3]. The prevalence of pancreatic autoantibodies is much lower in India as compared to other populations and has been considered to result from etiologic heterogeneity of T1D [3–8]. Majority of the patients of T1D are therefore labeled as Type 1B in India [9]. A higher prevalence of thyroid autoimmunity has also been noted in Indian patients as compared to other regions [2,10]. The prevalence of celiac autoimmunity in T1D, however appears to be similar to other reports [11,12]. In a recently published data from India, more than 50% of patients with T1D were noted to have associated clinical autoimmune disease, indirect evidence that autoantibodies are present in majority of patients [13]. The data on the frequency of various major associated autoantibodies in Indian children with T1D is limited. We thus aimed to conduct the present study in our large follow up cohort of children with T1D to determine the frequency of beta-cell, thyroid and celiac autoimmunity.
Materials and Methods
The retrospective record review of patients on follow up in Pediatric Diabetes Clinic of our hospital between April 2004 to September 2014 was performed. The diagnosis of diabetes was based on the ISPAD (The International Society for Pediatric and Adolescent Diabetes) criteria first published in 2000 and revised in 2009 [14]. Children aged <15 y with short history of osmotic symptoms, initial ketonuria, low C-peptide levels and absolute insulin dependence for maintaining normoglycemia, and who had their autoantibodies estimated within six months of diagnosis were included. Children with T2D, monogenic and secondary diabetes were excluded.
Autoantibodies to glutamic acid decarboxylase 65 (anti-GAD65), tyrosine phosphatase (IA-2b) and tissue transglutaminase IgA (anti-tTGA) were measured by enzyme immunoassay (ELISA) kits (Aeskulisa, Germany and Phadia, USA). The tests were performed as per manufacturers’ instructions. Anti-thyroid peroxidase (anti-TPO) antibodies were measured by using electrochemiluminiscence kits (Roche Diagnostics, Germany). Cut offs values were calculated by receiver operating curves and concentrations of >25 IU/ml for anti-GAD-65, >20 U/mL for ICA512, >34.0 U/l for anti-TPO and >8 U/mL for anti-tTG were considered positive.
Results
Of the 548 children with T1D registered in the clinic during the study period, 310 were found eligible; 181 (58%) were boys. The mean age was 7.28±3.3 y (range 0.7-15 y). Anti-GAD65 and anti-IA2 antibodies were positive in 64 (50%) of 128 and 12 (16%) of the 72 patients tested, respectively; the combined positivity was 54%. Anti-TPO antibodies were positive in 23 (18.7%) of the 123 patients. Anti-tTGA antibodies were positive in 47 (22%) of the 212 patients tested. The male: female ratio in patients with anti-GAD, anti-TPO and anti-tTG positivity was 1.3, 0.7 and 0.6 respectively.
Discussion
The presence of associated autoimmunity in T1D may result from a common genetic background (HLA antigens) as well as a defective immunoregulation or a poor ability to develop tolerance to autoantigens [1]. Timely additional work-up and intervention in cases of antibody positivity can improve clinical course of the disease [2]. The prevalence of beta-cell autoantibodies in our patients was higher as compared to data from other Indian centers [4–7] but lower than studies from West and South India [8,15] as well as from European countries [3,15]. The reasons for the worldwide differences in frequencies of various autoantibodies amongst patient populations of T1D are poorly understood. Timing of estimation from disease onset, differences in laboratory assays and threshold limits, patient recruitment procedures and small patient numbers have been cited as the potential causes for differences in the prevalence of pancreatic autoantibodies [8]. The higher prevalence in our study and the previous Indian studies could be due to the inclusion of patients with a recent onset of disease [8]. Frequency of pancreatic autoantibodies decreases with disease duration [16]. Conversely, thyroid autoimmunity is detected in about 29% of patients during first year of onset of T1D but its prevalence increases with disease duration [2,17]. The lower frequency in our study is similar to previous observations on an Indian cohort which exhibited anti-TPO prevalence of 25% in patients with disease duration of <2 y and 100% in those having disease for >6 y [10]. The higher prevalence of celiac autoantibodies in our patients as compared to previous studies may be explained by regional variations [11,12]. The female preponderance of anti-TPO and anti-tTGA positivity in our patients is similar to previous observations [18,19]. However, the observed sex ratio in GAD 65 positive patients was different from the previous reports [8]. We did not test for anti-adrenal and anti-parietal cell antibodies as their prevalence is too low in children with T1D to be cost-effective [18].
Conclusion
In conclusion, children with recently diagnosed T1D showed a moderate prevalence of anti-GAD65, low prevalence of anti-TPO and high prevalence of anti-tTGA autoantibodies. Male preponderance was noted in children with GAD65 positivity.
[1]. Pugliese A, Advances in the etiology and mechanisms of type 1 diabetes Discov Med 2014 18:141-50. [Google Scholar]
[2]. Kordonouri O, Klingensmith G, Knip M, Holl RW, Aanstoot HJ, Menon PS, Other complications and diabetes-associated conditions in children and adolescents Pediatr Diabetes 2014 15(Suppl 20):270-78. [Google Scholar]
[3]. Zimmet PZ, Rowley MJ, Mackay IR, Knowles WJ, Chen QY, Chapman LH, The ethnic distribution of antibodies to glutamic acid decarboxylase: presence and levels of insulin-dependent diabetes mellitus in Europid and Asian subjects J Diabetes Complications 1993 7:1-7. [Google Scholar]
[4]. Singh AK, Bhatia E, Dabadghao P, Bhatia V, Gellert SA, Colman PG, Role of islet autoimmunity in the aetiology of different clinical subtypes of diabetes mellitus in young north Indians Diabet Med 2000 17:275-80. [Google Scholar]
[5]. Fida S, Myers M, Mackay IR, Zimmet PZ, Mohan V, Deepa R, Antibodies to diabetes-associated autoantigens in Indian patients with Type 1 diabetes: Prevalence of anti-ICA512/IA2 and anti-SOX13 Diabetes Res Clin Pract 2001 52:205-11. [Google Scholar]
[6]. Goswami R, Kochupillai N, Gupta N, Kukreja A, Lan M, Maclaren NK, Islet cell autoimmunity in youth onset diabetes mellitus in Northern India Diabetes Res Clin Pract 2001 53:47-54. [Google Scholar]
[7]. Tandon N, Shtauvere-Brameus A, Hagopian WA, Sanjeevi CB, Prevalence of ICA-12 and other autoantibodies in north Indian patients with early-onset diabetes Ann N Y Acad Sci 2002 958:214-17. [Google Scholar]
[8]. Marita AR, Rane S, Mokal RA, Nair SR, Irani A, Autoantibodies against GAD65 and IA-2 in recently diagnosed Type 1 diabetic children from Western India Diabet Med 2004 21:956-57. [Google Scholar]
[9]. Balasubramanian K, Dabadghao P, Bhatia V, Colman PG, Gellert SA, Bharadwaj U, High frequency of type 1B (idiopathic) diabetes in North Indian children with recent-onset diabetes Diabetes Care 2003 26:2697 [Google Scholar]
[10]. Dosi RV, Tandon N, A study on prevalence of thyroid auto-immunity in type 1 diabetes mellitus J Indian Med Assoc 2010 108:349-50.:55-56. [Google Scholar]
[11]. Joshi AS, Varthakavi PK, Bhagwat NM, Chadha MD, Mittal SS, Coeliac autoimmunity in type I diabetes mellitus Arab J Gastroenterol 2014 15:53-57. [Google Scholar]
[12]. Adlercreutz EH, Svensson J, Hansen D, Buschard K, Lernmark A, Mortensen HB, Prevalence of celiac disease autoimmunity in children with type 1 diabetes: regional variations across the Øresund strait between Denmark and southernmost Sweden Pediatr Diabetes 2014 doi: 10.1111/pedi.12200 [Google Scholar]
[13]. Shaikh SB, Haji IM, Doddamani P, Rahman M, A Study of Autoimmune Polyglandular Syndrome (APS) in Patients with Type1 Diabetes Mellitus (T1DM) Followed Up at a Teritiary Care Hospital J Clin Diagn Res 2014 8:70-72. [Google Scholar]
[14]. Craig ME, Hattersley A, Donaghue KC, Definition, epidemiology and classification of diabetes in children and adolescents. ISPAD Clinical Practice Consensus Guidelines 2009 Compendium Pediatric Diabetes 2009 10(Suppl12):3-12. [Google Scholar]
[15]. Sanjeevi CB, Kanungo A, Das AK, Balaji V, Autoimmunity in Indian diabetics Int J Diabetes Dev Ctries 1998 18:102-12. [Google Scholar]
[16]. Kong YH, Kim MS, Lee DY, Comparison of the prevalence of islet autoantibodies according to age and disease duration in patients with type 1 diabetes mellitus Ann Pediatr Endocrinol Metab 2013 18:65-70. [Google Scholar]
[17]. Shun CB, Donaghue KC, Phelan H, Twigg SM, Craig ME, Thyroid autoimmunity in Type 1 diabetes: systematic review and meta-analysis Diabet Med 2014 31:126-35. [Google Scholar]
[18]. Warncke K, Fröhlich-Reiterer EE, Thon A, Hofer SE, Wiemann D, Holl RW, Polyendocrinopathy in children, adolescents, and young adults with type 1 diabetes: a multicenter analysis of 28,671 patients from the German/Austrian DPV-Wiss database Diabetes Care 2010 33:2010-12. [Google Scholar]
[19]. Wingren CJ, Agardh D, Merlo J, Sex differences in coeliac disease risk: a Swedish sibling design study Dig Liver Dis 2012 44:909-13. [Google Scholar]