|Year : 2017 | Volume
| Issue : 1 | Page : 45-50
Thyroid profile and autoantibodies in Type 1 diabetes subjects: A perspective from Eastern India
Debmalya Sanyal1, Anirban Majumder1, Soumyabrata Roy Chaudhuri1, Sudip Chatterjee2
1 Department of Endocrinology, KPC Medical College, Kolkata, West Bengal, India
2 Department of Endocrinology, Park Clinic, Kolkata, West Bengal, India
|Date of Web Publication||19-Dec-2016|
36 Block H, New Alipore, Kolkata - 700 053, West Bengal
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Context: There has been a rise in the incidence of type 1 diabetes mellitus (T1DM) in India. The prevalence of thyroid autoantibodies and thyroid dysfunction is common in T1DM. Aims: The aim of this study is to determine the incidence of thyroid dysfunction and thyroid autoantibodies in T1DM subjects, without any history of thyroid disease, and the prevalence of glutamic acid decarboxylase (GAD) antibody, Islet antigen-2 antibody (IA2), thyroid peroxidase (TPO), and thyroglobulin autoantibodies (Tg-AB) in T1DM subjects. Settings and Design: This was a cross-sectional clinical-based study. Subjects and Methods: Fifty subjects (29 males, 31 females) with T1DM and without any history of thyroid dysfunction were included in the study. All subjects were tested for GAD antibody, IA2 antibody, TPO antibody, thyroglobulin antibody, free thyroxine, and thyroid-stimulating hormone. Statistical Analysis Used: A Chi-square/pooled Chi-square test was used to assess the trends in the prevalence of hypothyroidism. A two-tailed P< 0.05 was considered statistically significant. Results: The mean age of the subjects was 23.50 years. 9.8% of subjects were below the age of 12 years, 27.45% of subjects were of age 12–18 years, 37.25% of subjects were of age 19–30 years, and 25.49% of subjects were above 30 years. 78% were positive autoantibody for GAD, 30% for IA-2, 24% for TPO, and 16% were positive for Tg-AB. A total of 6.0% of T1DM subjects had evidence of clinical hypothyroidism, but the prevalence of subclinical hyperthyroidism (SCH) varied from 32% to 68.0% for we considered different definitions of SCH as advocated by different guidelines. All subjects with overt hypothyroidism had positive GAD and thyroid autoantibodies. One (2%) subject had clinical hyperthyroidism with strongly positive GAD, TPO, and Tg-AB. Conclusions: We found a high prevalence of GAD, IA2, TPO, and Tg-AB in our T1DM subjects. A substantial proportion of our subjects had undiagnosed thyroid dysfunction with a preponderance of subclinical hypothyroidism. All T1DM subjects with overt hypothyroidism or hyperthyroidism had positive GAD and thyroid autoantibodies. The high prevalence of undiagnosed thyroid dysfunction highlights the importance of regular thyroid screening in T1DM subjects.
Keywords: Anti-glutamic acid decarboxylase antibody, free thyroxine, IA-2 antibody, TG Antibody, thyroid peroxidase antibody, thyroid-stimulating hormone, type 1 diabetes mellitus
|How to cite this article:|
Sanyal D, Majumder A, Chaudhuri SR, Chatterjee S. Thyroid profile and autoantibodies in Type 1 diabetes subjects: A perspective from Eastern India. Indian J Endocr Metab 2017;21:45-50
|How to cite this URL:|
Sanyal D, Majumder A, Chaudhuri SR, Chatterjee S. Thyroid profile and autoantibodies in Type 1 diabetes subjects: A perspective from Eastern India. Indian J Endocr Metab [serial online] 2017 [cited 2017 Jan 24];21:45-50. Available from: http://www.ijem.in/text.asp?2017/21/1/45/195998
| Introduction|| |
There has been a substantial increase in the incidence of type 1 diabetes mellitus (T1DM) in the last few years, growing at a rate of 3%–5% every year., India is no exception, with a South India-based Karnataka type 1 diabetes registry reporting an incidence of 3.7/100,000 in boys and 4.0/100,000 in girls, over 13 years. Recently, Kalra et al. reported a high prevalence (10.20/100,000 population) of T1DM in Karnal district in North India. T1DM is recognized to be due to autoimmune destruction of beta cells in the majority of cases., Other autoimmune diseases such as thyroid dysfunction are more common in T1DM. Immunological markers, such as the pancreatic islet cell antibodies (now known as Islet antigen-2 [IA2]), glutamic acid decarboxylase (GAD65) antibodies, and insulin autoantibodies have been documented to be present at diagnosis and may even predict future T1DM in siblings of affected subjects.,,,, The appearance of antithyroid peroxidase (TPO), antithyroglobulin (TG) autoantibodies in T1DM precedes thyroid dysfunction. TPO antibodies are one of the major secondary antibodies associated with autoimmune thyroid disease and can be used as a diagnostic marker. The prevalence of thyroid autoantibodies and thyroid dysfunction is increased in subjects with nonthyroid autoimmune diseases such as T1DM. Screening for antithyroid antibodies in T1DM may help in early detection of autoimmune thyroid disorders. Clinically, thyroid dysfunction can cause metabolic disturbances and may undermine diabetes control. Hyperthyroidism may worsen glycemic control while hypothyroidism alters carbohydrate metabolism. Therefore, regularly screening in T1DM subjects allows early detection and treatment of thyroid dysfunction.
To study the prevalence of previously undiagnosed thyroid dysfunction in T1DM subjects and to determine the prevalence of positive autoantibodies, i.e., GAD, IA2, TPO, and Tg-AB in T1DM subjects.
| Subjects and Methods|| |
Study design and enrolment criteria
Subjects with T1DM without any previously history or symptoms of thyroid dysfunction were included in the study. Criteria for diagnosis of diabetes were as per the standard American Diabetes Association guidelines. Participants were excluded if they were pregnant or had any acute or chronic systemic illnesses as judged by the investigator or if they were receiving drugs (such as lithium or steroids) that could interfere with thyroid function tests.
Total fifty subjects with T1DM were included in the study.
All subjects were tested for GAD antibody, IA2 antibody, TPO Antibody, and Tg-AB using standard kits by standard methods. The thyroid profile of subjects: free thyroxine (FT4) and thyroid-stimulating hormone (TSH) were also tested. GAD antibody (Ab) was estimated by (radioimmunoassay) RIA (DLD Diagnostika, GMBH); IA-2 Ab by RIA (DLD Diagnostika, GMBH); TPO-Ab by CLIA (Roche, Germany-Cobas e 411); Tg-Ab by CLIA (Roche, Germany-Cobas e 411).
Based on thyroid function test results, participants were classified using following definitions: Overt hypothyroid: low serum-FT4 (i.e., <0.9 ng/dL) and TSH >10 µU/ml); subclinical hyperthyroidism (SCH): Normal serum FT4 (0.9–1.7 ng/dL); and suppressed TSH (i.e., <0.3 µU/ml). For subclinical hypothyroidism, we considered a normal serum FT4 (0.9-1.7 ng/dL) along with TSH >4.2 mIU/mL (based on Clinical Practice Guidelines for Hypothyroidism in Adults: the American Association of Clinical Endocrinologists [AACE] and American Thyroid Association [ATA] 2012) or TSH >2.50 mIU/mL (based on National Academy of Clinical Biochemistry laboratory guideline). Anti-TPO antibody positive: the presence of anti-TPO antibodies above 34 IU/ml. Anti-TG antibody positive: the presence of anti-TG antibodies above 115 IU/ml. GAD antibody positive: the presence of GAD antibodies above 1 IU/ml. IA-2 antibody positive: The presence of IA-2 antibodies above 1 IU/ml.
All statistical calculations were performed using the Statistical Package for Social Sciences (SPSS Complex Samples) Version 21.0 for windows (SPSS, Inc., Chicago, IL, USA). Statistical methods used were descriptive to calculate mean ± standard deviation. The prevalence of hypothyroidism and other thyroid disorders was summarized as counts and percentages. A Chi-square/pooled Chi-square test was used to assess the trends in the prevalence of hypothyroidism. A two-tailed P < 0.05 was considered statistically significant.
| Results|| |
The baseline characteristics of subjects are given in [Table 1]. Of the total 50 subjects, 29 were male, and 21 were female. Their age ranged 5–52 years (mean 23.50 years), [Table 1]. Around 9.8% of subjects were below the age of 12 years, 27.45% between age 12 and 18 years, 37.25% between age 19 and 30 years, and 25.49% above 30 years. The prevalence of hypothyroidism in the study sample is shown in [Table 2]. Positive GAD antibody (Ab) was detected in 39 subjects (78.0%), IA2 Ab was present in 15 (30.0%) subjects, 12 (24.0%) subjects had TPO-Ab and 8 (16.0%) had Tg-Ab, 13 (26.0%) subjects showed positivity of both GAD-Ab and IA2-Ab, and 8 (16.0%) subjects showed positivity of both TPO and Tg-Ab. The presence of all four antibodies was observed in only two subject's, i.e., 4.0% [Table 3]. The prevalence of hypothyroidism among autoantibodies is depicted in [Table 4] and [Table 5]. All subjects overt hypothyroidism had positive GAD and thyroid autoantibodies. The one subject with hyperthyroidism had positive GAD, Tg-AB, and TPO autoantibodies. If we consider the upper normal limit of TSH as 4.2 mIU/mL (based on our kit reference as well as Clinical Practice Guidelines for Hypothyroidism in Adults: AACE and ATA 2012), a total of 38% of T1DM subjects had previously undiagnosed thyroid dysfunction with 32% having SCH while 6.0% had overt hypothyroidism. As per the recent National Academy of Clinical Biochemistry laboratory guideline, considering the TSH cutoff 2.5 mIU/mL, the prevalence of overt hypothyroidism remained unchanged at 6%, but the prevalence of SCH soared significantly to 68%. Consequently, SCH was found to be significantly higher in the GAD antibody-positive subjects, P = 0.043. There was no significant difference in the prevalence of subclinical hypothyroidism between IA2, TG, IA2, TPO, and TG antibody positive or negative T1DM subjects. There was only one (2%) subject with overt hyperthyroidism due to Graves' disease as confirmed by radionuclide technetium scan. None of the subjects had polygrandular atrophy. Further the age-wise stratification of thyroid autoantibodies in different age groups of type 1 diabetes mellitus subjects is depicted in [Table 6].
|Table 4: Association of glutamic acid decarboxylase and islet antigen-2 antibody between clinical and sub clinical hypothyroidism|
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|Table 5: Association of antibody between clinical and subclinical hypothyroidism|
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|Table 6: Age-wise stratification of thyroid autoantibodies in different age groups of type 1 diabetes mellitus subjects|
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| Discussion|| |
The prevalence of 26%–61% of autoantibody positivity in T1DM subjects has been reported from North India, with very few dual positive subjects.,, Low antibody seropositivity is a consistent feature of T1DM in Asia, particularly in India, compared to Western T1DM population.,, The majority of our subjects were positive for one or more autoantibodies, and this is similar to what has been shown by other landmark studies such as the SEARCH for Diabetes in the Young Study and the Finnish DIPP Study., In our study, GAD antibody was present in 78.0% followed by 30% positivity for IA2 and 26.0% had both GAD and IA2 antibodies. The level of autoimmunity reported in the present study was among the highest reported so far compared to other Indian studies. Kochupillai and Goswami have shown 38% anti-GAD positivity while Singh et al. reported 61% GAD antibody and/or IA-2 antibody positive in T1DM subjects.,
The prevalence of thyroid autoimmunity in children and adolescents with T1DM has been reported between 3.9% and 50% in various studies, and they include Hashimoto's thyroiditis and Graves' disease., In the present study, 24.0% subjects had positive TPO antibody, and 16.0% had Tg-AB while 16.0% subjects were positive for both TPO and Tg-AB. The presence of all four (GAD, IA2, TPO, and TG) antibodies was observed in only 2 (4%) subjects. Age-wise stratification of thyroid autoantibodies in different age groups of our subjects revealed statistically significant higher thyroid autoantibodies positivity (both TPO and TG) in age group <18 years.
The management of hypothyroidism differs to a great extent in children (<12 years) and adults >12 years with different diagnostic goals. In our study, only 10% of subjects were below 12 years of age. Present, there is lack of unanimity and ever growing debate and controversy regarding the definition of normal reference range of TSH. With the availability of highly sensitive assay methods and appreciation of the fact that populations previously considered normal according to conventional TSH cutoffs, they were polluted with individuals with various degrees of thyroid dysfunction that served to increase mean TSH levels for the whole group. Noteworthy, recent laboratory guidelines from the National Academy of Clinical Biochemistry argued that more than 95% of normal individuals have TSH levels below 2.5 mIU/m. Furthermore, the early detection and treatment of thyroid dysfunction in diabetes may improve outcomes. Even early treatment of SCH should be considered in T1DM, especially in children. Hence, we also considered a TSH cutoff of 2.5 mIU/mL as per the National Academy of Clinical Biochemistry laboratory guideline  which led to a substantial proportion (76%) of our study subjects qualifying for undiagnosed thyroid dysfunction with 68% having subclinical hypothyroidism while 6.0% had overt hypothyroidism and 2% had hyperthyroidism. However, if we consider the Clinical Practice Guidelines for Hypothyroidism in Adults: AACE and ATA 2012 our subjects qualifying for SCH significantly drops to 32%. We did not consider separate TSH cutoffs for the adult and the children as recommended by different guidelines. Particularly, a large scale Indian epidemiological study by Marwaha et al. clearly suggested not to increase the upper normal limit of TSH in children compared to the adult population. As per the European thyroid association guideline for the management of subclinical hypothyroidism in pregnancy and in children published in 2014, normalization is achieved in more than 70% of children with TSH >5.5–10 mu/L while it rarely deteriorates for the remaining population with elevated TSH. In the same line, the AACE and ATA, 2012 clinical practice guidelines for hypothyroidism does not recommend different normative ranges of TSH for the adults and the children. A large-scale epidemiological study (n = 4409) also considered an upper normal limit of 4.2 for TSH.
Rattarasarn et al. reported subclinical hypothyroidism in 6.3% of 16 subjects who were either TPO-AB or Tg-AB positive. Betterle et al. found 18.9% subclinical hypothyroidism in 37 T1DM subjects with TPO-AB and/or Tg-AB. Fernández-Castañer et al. found 5 (19.2%) subjects with subclinical hypothyroidism. Roldán et al. reported clinical hypothyroidism in 2.8% of 36 T1DM subjects with TPO-AB or Tg-AB positive. Burek et al. reported hypothyroidism in 26% of 53 subjects with Tg-AB and/or TPO-AB; those with hypothyroidism all had both TPO and Tg-AB. Fernández-Castañer et al. found 4 (15.4%) with clinical hypothyroidism out of their 26 TPO-AB positive T1DM subjects. In our study, all T1DM subjects with overt hypothyroidism had positive GAD and thyroid autoantibodies. In our study, SCH was found in 58.3% with GAD antibody positivity and 50.0% of T1DM subjects with positive TPO-AB and Tg-AB, respectively. 50% of our T1DM subjects with both TPO and Tg-AB positive had SCH. There was no significant difference in the prevalence of SCH between GAD, IA2, TPO, and TG antibody positive or negative T1DM subjects. Overt hypothyroidism was present in 16.7 and 25.0% of our subjects with positive TPO-AB and Tg-AB antibody, respectively while 25% of the present study subjects with both Tg-AB and TPO-AB positive had overt hypothyroidism. The prevalence of SCH was also found to be significantly higher in the GAD antibody-positive subjects. However, we found no significant difference in the prevalence of SCH between IA2, TPO, and TG antibody positive or negative T1DM subjects. The one subject with hyperthyroidism had positive GAD, TG, and TPO autoantibodies.
| Conclusions|| |
A substantial proportion of our T1DM subjects had previously undiagnosed thyroid dysfunction with majority having subclinical hypothyroidism. There was high prevalence of GAD, IA2, TPO, antithyroglobulin autoantibodies, with anti-GAD being the most commonly detected one. TPO was the most common thyroid antibody detected. Both TPO and Tg antibodies were higher in the age group <18 years. All T1DM subjects with overt hypothyroidism or hyperthyroidism had positive GAD and thyroid autoantibodies. The high prevalence of undiagnosed thyroid dysfunction highlights the importance of regular thyroid screening in T1DM subjects.
The authors would like to thank Mr. Kingshuk Bhattacharjee for statistical analysis of the data.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
DIAMOND Project Group. Incidence and trends of childhood Type 1 diabetes worldwide 1990-1999. Diabet Med 2006;23:857-66.
TEDDY Study Group. The environmental determinants of diabetes in the young (TEDDY) study: Study design. Pediatr Diabetes 2007;8:286-98.
Kumar P, Krishna P, Reddy SC, Gurappa M, Aravind SR, Munichoodappa C. Incidence of type 1 diabetes mellitus and associated complications among children and young adults: Results from Karnataka Diabetes Registry 1995-2008. J Indian Med Assoc 2008;106:708-11.
Kalra S, Kalra B, Sharma A. Prevalence of type 1 diabetes mellitus in Karnal district, Haryana state, India. Diabetol Metab Syndr 2010;2:14.
Steck AK, Johnson K, Barriga KJ, Miao D, Yu L, Hutton JC, et al
. Age of islet autoantibody appearance and mean levels of insulin, but not GAD or IA-2 autoantibodies, predict age of diagnosis of type 1 diabetes: Diabetes autoimmunity study in the young. Diabetes Care 2011;34:1397-9.
Das AK, Shtauvere-Brameus A, Sanjeevi CB. GAD65 and ICA512 antibodies in undernourished and normally nourished South Indian patients with diabetes. Ann N
Y Acad Sci 2002;958:247-50.
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.
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;958:214-7.
Harrison LC, Honeyman MC, DeAizpurua HJ, Schmidli RS, Colman PG, Tait BD, et al
. Inverse relation between humoral and cellular immunity to glutamic acid decarboxylase in subjects at risk of insulin-dependent diabetes. Lancet 1993;341:1365-9.
Kaufman DL, Clare-Salzler M, Tian J, Forsthuber T, Ting GS, Robinson P, et al
. Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature 1993;366:69-72.
Orban T, Sosenko JM, Cuthbertson D, Krischer JP, Skyler JS, Jackson R, et al
. Pancreatic islet autoantibodies as predictors of type 1 diabetes in the Diabetes Prevention Trial-Type 1. Diabetes Care 2009;32:2269-74.
Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, et al
. Clinical practice guidelines for hypothyroidism in adults: Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid 2012;22:1200-35.
Roldán MB, Alonso M, Barrio R. Thyroid autoimmunity in children and adolescents with Type 1 diabetes mellitus. Diabetes Nutr Metab 1999;12:27-31.
Wenzlau JM, Juhl K, Yu L, Moua O, Sarkar SA, Gottlieb P, et al
. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci U S A 2007;104:17040-5.
Lan MS, Wasserfall C, Maclaren NK, Notkins AL. IA-2, a 23. Transmembrane protein of the protein tyrosine phosphatase family, is a major autoantigen in insulin-dependent diabetes mellitus. Proc Natl Acad Sci USA 1996;93:6367-70.
Dabelea D, Pihoker C, Talton JW, D'Agostino RB Jr., Fujimoto W, Klingensmith GJ, et al
. Etiological approach to characterization of diabetes type: The SEARCH for Diabetes in Youth Study. Diabetes Care 2011;34:1628-33.
Kimpimäki T, Kulmala P, Savola K, Kupila A, Korhonen S, Simell T, et al
. Natural history of beta-cell autoimmunity in young children with increased genetic susceptibility to type 1 diabetes recruited from the general population. J Clin Endocrinol Metab 2002;87:4572-9.
Kochupillai N, Goswami R. Youth-Onset Diabetes in India: 6. Nature of Diabetes and Use of Bovine Insulin in Their Treatment. RSSDI Textbook of Diabetes; April, 2002. Available from: http:// www.iddtindia.org/youth.asp
. [Last accessed on 2016 Apr 19].
Burek CL, Rose NR, Guire KE, Hoffman WH. Thyroid autoantibodies in black and in white children and adolescents with type 1 diabetes mellitus and their first degree relatives. Autoimmunity 1990;7:157-67.
Wartofsky L, Dickey RA. The evidence for a narrower thyrotropin reference range is compelling. J Clin Endocrinol Metab 2005;90:5483-8.
Marwaha RK, Tandon N, Desai A, Kanwar R, Grewal K, Aggarwal R, et al
. Reference range of thyroid hormones in normal Indian school-age children. Clin Endocrinol (Oxf) 2008;68:369-74.
Lazarus J, Brown RS, Daumerie C, Hubalewska-Dydejczyk A, Negro R, Vaidya B. 2014 European thyroid association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J 2014;3:76-94.
Marwaha RK, Tandon N, Ganie MA, Kanwar R, Sastry A, Garg MK, et al
. Status of thyroid function in Indian adults: Two decades after universal salt iodization. J Assoc Physicians India 2012;60:32-6.
Rattarasarn C, Diosdado MA, Ortego J, Leelawattana R, Soonthornpun S, Setasuban W, et al
. Thyroid autoantibodies in Thai type 1 diabetic patients: Clinical significance and their relationship with glutamic acid decarboxylase antibodies. Diabetes Res Clin Pract 2000;49:107-11.
Betterle C, Zanette F, Pedini B, Presotto F, Rapp LB, Monciotti CM, et al
. Clinical and subclinical organ-specific autoimmune manifestations in Type 1 (insulin-dependent) diabetic patients and their first-degree relatives. Diabetologia 1984;26:431-6.
Fernández-Castañer M, Molina A, López-Jiménez L, Gómez JM, Soler J. Clinical presentation and early course of type 1 diabetes in patients with and without thyroid autoimmunity. Diabetes Care 1999;22:377-81.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]