|Year : 2021 | Volume
| Issue : 1 | Page : 15-20
Prevalence of organ-specific autoantibodies in children with type 1 DM in south central region of India
Chaitanya Konda, Vijay Sheker Reddy Danda, Srinivas Rao Paidipally, Krishna Reddy Thaduri
Department of Endocrinology, Gandhi Medical College, Musheerabad, Secundrabad, Telangana, India
|Date of Submission||21-Jul-2020|
|Date of Decision||10-Feb-2021|
|Date of Acceptance||19-Feb-2021|
|Date of Web Publication||19-May-2021|
Dr. Vijay Sheker Reddy Danda
Department of Endocrinology, 3rd Floor, Gandhi Hospital, Musheerabad, Secundrabad - 500003, Telangana
Source of Support: None, Conflict of Interest: None
Introduction: Type 1 diabetes mellitus (T1DM) is a long-standing metabolic disease caused by autoimmune beta cell destruction leading to absence or lowered insulin production. T1DM is associated with various other autoimmune disorders, including autoimmune thyroid disease, Celiac disease, and Addison disease. Detection of these antibodies is crucial to prevent morbidity related to unrecognized disease. Indian data regarding prevalence of these antibodies in T1DM is lacking, particularly antibodies against 21 hydroxylase.
Patients and Methods: Total 100 patients with T1DM were taken into the study, in all patients anti-transglutaminase (anti-tTG) IgA, anti-thyroid peroxidase (anti-TPO) were done, and 21 hydroxylase anti bodies were done in 86 cases. Descriptive statistics were reported using mean, SD, numbers, and percentages. Student's t-test was used to assess the differences between the groups.
Results: Fifteen cases were found to be TPOAb positive (eight had hypothyroidism, two had sub-clinical hypothyroidism, and five cases had normal thyroid function). tTGAb were positive in four cases, three were positive for 21-Hyroxylase antibody, and all had normal cortisol levels.
Conclusion: Organ-specific autoimmune antibodies were elevated in T1DM when compared to general population. Screening of all these antibodies in T1DM patient should become standard of care.
Keywords: Addison disease, anti-TPO antibody, celiac disease, type 1 diabetes
|How to cite this article:|
Konda C, Danda VS, Paidipally SR, Thaduri KR. Prevalence of organ-specific autoantibodies in children with type 1 DM in south central region of India. J NTR Univ Health Sci 2021;10:15-20
|How to cite this URL:|
Konda C, Danda VS, Paidipally SR, Thaduri KR. Prevalence of organ-specific autoantibodies in children with type 1 DM in south central region of India. J NTR Univ Health Sci [serial online] 2021 [cited 2022 Dec 10];10:15-20. Available from: https://www.jdrntruhs.org/text.asp?2021/10/1/15/316310
| Introduction|| |
Type 1 diabetes mellitus (T1DM) is a long-standing metabolic derangement characterized by autoimmune beta cell destruction leading to absence or lowered insulin production. T1DM is often associated with various other autoimmune disorders, including autoimmune thyroid disease (AIT) seen in 15–30%, Celiac Disease (CD) seen in 4–9%, and Addison's disease (AD) seen in 0.5%., These above-mentioned conditions have antibodies targeting specific organs.
Assays for anti-thyroid peroxidase antibodies (TPOAb) in AIT, anti-tissue transglutamase (tTGAb) in CD, and anti-21 alpha hydroxylase antibodies (21OHAb) may be used to screen asymptomatic disease, to identify the risk of progression to overt disease. Detection of these antibodies is crucial to prevent morbidity related to unrecognized disease. Previous studies have examined multiple autoantibodies (TPOAb, tTGAb, and 21OHAb) in cohorts of patients with T1DM. Indian data regarding prevalence of these antibodies in T1DM is lacking, particularly antibodies against 21 hydroxylase. This study focused on detection of these above-mentioned antibodies and how they link to the clinical presentation.
| Patients and Methods|| |
This study was conducted from January 2017 to February 2019. A total of 100 patients, less than 18 years old were diagnosed with diabetes as per the American Diabetes Association guidelines. Diagnosis of T1DM was made clinically.
A detailed medical history was taken followed by a thorough physical examination. Exclusion criteria were pancreatic calcification, history of chronic alcohol consumption, or any acute illness. All patients were subjected to investigations which included complete blood picture, fasting plasma glucose, HbA1c, thyroid stimulating hormone (TSH), serum calcium, albumin, and creatinine.
Blood samples were collected from all the patients. Written informed consent was taken from the parents or patients as deemed appropriate, based on the age of the patient. Ethical Committee clearance was taken. TPOAb and tTGAb were estimated for all the patients. TPOAb were estimated by using commercially available ELISA kits from Aesku diagnostics, Germany. Levels <60 IU/ml was considered negative and >60 IU/ml considered positive. Intra-assay and Inter-assay Coefficient Variation (CV) were 6.9 and 3.9, respectively. tTGAb were estimated by ELISA kits from Aesku diagnostics Germany. Levels <18 U/ml was considered negative and >18 U/ml was considered positive. Intra-assay and inter-assay CV were 7 and 4, respectively. 21OHAb were done in 86 cases and estimated by qualitative ELISA kits from Cusabio biotechnology company, Hubei, China. Both the intra- and inter-assay CV of this kits were <15%. Thermo Fischer scientific microplate reader was used for analysis of ELISA kits.
Descriptive statistics were reported using mean, Standard deviation (SD), numbers, and percentages. Clinical parameters such as duration of diabetes, height, hemoglobin, HbA1c, serum albumin, serum calcium was compared between groups using the independent t-test for normally distributed variables. A P value <0.05 was considered statistically significant.
| Results|| |
The patient's age ranged from 17 months to 18 years. Age at diagnosis of T1DM ranged from 1 to 16 years (8.74 ± 3.79). The duration of diabetes at the time of data collection was 0.08–13 years (3.96 ± 3.02 years). Female to male ratio was 1.43 (59 females and 41 males). Baseline characteristics of the patients are mentioned in [Table 1].
In our cohort, we analyzed 100 cases out of which 15 (15%) cases were found to be TPOAb positive and rest 85 cases were negative. Out of 15 cases, eight were found to have hypothyroidism, two were found to have SCH and five cases had normal TFT. 85 [85%] cases were found to be negative for TPOAb. However, hypothyroidism was present in seven cases, SCH in three cases, and normal TFT in 75 cases. TPOAb positivity ratio in male:female was 1:4 [Table 2].
In present study, tTGAb were positive in 4 out of 100 T1DM cases and the distribution of tTGAb positivity between male to female ratio was 3:1. In tTGAb positive group, none of them had symptoms suggestive of CD. Only one individual had both TPOAb and tTG AB positive.
Anti-21 alpha hydroxylase antibodies
In the present study, we analyzed 21OHAb in 86 cases. 3 cases were positive for antibody screening.
8 am Cortisol values in these three cases were found to be >15 mcg/dl. Hence, Synacthen stimulation test was not done. Clinically, these three did not experience episodes of crisis or symptoms related to primary adrenal insufficiency.
| Discussion|| |
T1DM is the most common cause of childhood diabetes, which develops as a result of autoimmune destruction of β cells leading to absolute insulin deficiency and hyperglycemia.
The overall prevalence of the associated antibodies was higher compared to the general population and it increased with the duration of diabetes.
In the present study, prevalence of TPOAb positivity was higher in T1DM patients (15%) compared to pediatric population (11.9%). The TPOAb positivity prevalence in T1DM as reported by numerous studies ranged from 7.3 to 59%.
The difference in prevalence in the population under study can be partly explained by average age of population under study, with increasing prevalence in old age. Variability in diagnostic criteria, iodine levels, and laboratory measurements, reference values for antibodies and TSH values are some factors which possibly explain the heterogeneity between studies. In many studies, only hypothyroid cases who were antibody positive were considered to have autoimmune hypothyroidism.,, We found 15 cases who were TPOAb positive. Like other studies, prevalence of TPOAb positivity was predominantly seen in females in this study.,
Clinical hypothyroidism was present in 53% of subjects with TPOAb positivity and 8.2% cases in negative group. Sub-clinical hypothyroidism was noted among 13.3% in the group with TPOAb positivity and 3.5% cases in the negative group. 63.3% of TPOAb positive were hypothyroid. In TPOAb negative group, 88.2% had normal Thyroid function.
In present study, most of positive cases were clinically hypothyroid compared to other studies where subclinical hypothyroidism was predominant in TPOAb positive group. Anti-thyroid antibodies in patients with T1DM are compared in [Table 3].
|Table 3: TPOAB, TTGAB, 21OHAB in Patients with T1DM Worldwide and Indian Studies in Comparison to Present Study|
Click here to view
Studies from India showed a relative higher percentage in northern state (Dayal et al., Menon et al., Goswami et al.,) compared to southern states (Shivaprasad et al.). Present study was conducted in southern city of Hyderabad, Telangana and was comparable to other studies conducted from South India.
The lower prevalence of TPOAb seen in our study could be partly explained by existing differences in HLA distribution. HLA DR3 is more common in South India compared to HLADR4 which is more common in North India.
In this study, duration of diabetes and female gender was significantly associated with TPOAb positivity when compared to T1DM with negative TPOAb. No statistical significance was observed for age, height, hemoglobin, and HbA1c values between these two groups [Table 4]. Even though our study did not find significant difference between two groups, hypothyroidism is known to increase the risk of hypoglycemia, anemia, and growth retardation. This could be explained as of some of our cases were already receiving levothyroxine and in euthyroid status.
|Table 4: Comparison Between TPOAB & TTGAB Positive and Negative Group of Different Metabolic Parameters And Auxology|
Click here to view
As thyroid hormones influence blood glucose levels, T1DM with new onset hypothyroidism are more prone for hypoglycemia.
As per the American Diabetes Association (ADA), TSH levels should be estimated in all individuals with newly diagnosed T1DM and every 1–2 years thereafter in euthyroid cases. Children with T1DM should better be screened for TPOAb and tTGAb soon after diagnosis.
In our study, the prevalence of CD in T1DM patient was higher than general population, which is around 0.5–1% in different parts of the world. Most studies determined the indication for duodenal biopsy based on antibody positivity. The proportion of patient screened with biopsy varied from 0.7 to 100%. In our study, none of the patients gave consent for biopsy.
The prevalence of CD antibodies abroad and India are depicted in [Table 3] ranged from 4.65 to 22% from various studies.,,,,,,,,, The prevalence of CD from northern states showed high prevalence which is comparable to Caucasians. The prevalence from southern states (Jacob et al., Annie et al.) is less in comparison to northern states. The prevalence in our study was like other studies from south India [Table 3].
The differences observed between South and North India may be because of dietary patterns as staple food is wheat in north and rice in south and because of different HLA haplotypes seen in north and south India. Most diabetic children with CD have silent or sub clinical form of illness. Only a small number of children are identified with symptoms classical of CD.
In the present study, comparison analysis between the two groups showed (celiac antibodies positive and negative) significant differences in height, hemoglobin, and calcium levels with P values of 0.03, 0.003, and 0.01, respectively. Other parameters like BMI, albumin, HbA1c, duration of diabetes showed no significant difference between two groups [Table 4]. This highlights the effect of CD in development of anemia, low calcium, and poor growth of children.
Bhadada et al. reported short stature was a manifestation in 52.3% of CD. CD should be suspected in T1DM cases in younger population, short stature, anemia, and also lower insulin requirement with frequent post-prandial hypoglycemia. Routine screening in T1DM patients for CD is to be considered after diagnosis. Periodic screening in asymptomatic individuals has been recommended, but the optimal frequency of screening is unclear.
Autoimmune adrenalitis is major cause of adrenal insufficiency in developed countries.
The increased prevalence of 21OHAb positivity seen in our study was slightly higher compared with other studies [Table 3] with no relation to age. Recently, one study conducted in south India with 170 subjects of T1DM showed 21 OHAb positivity in 1.1%. Adrenal insufficiency was observed in 0–4% of general population studies with a mean prevalence of 0.2%.
Comparison of 21 OHAb with different studies is shown below in [Table 3].
Effect of cortisol on glycemia is well known. In newly developed AD, decreased insulin requirement and frequent hypoglycemic episodes are seen.
Prospective follow-up is required in those cases at regular interval, along with plasma ACTH and renin which are found to be elevated before clinical adrenal insufficiency sets in. Measurement of renin and ACTH may be helpful in early identification of cases with positive 21 OHAb antibodies.
Limitations include a small sample size, cross-sectional study, no assent to duodenal biopsy. Confounding factors like glycemic control, restriction of food, etc., could not be eliminated in patients with short stature. In addition, IgA deficiency cases could not be ruled out.
| Conclusion|| |
Organ-specific autoimmune antibodies were elevated in T1DM when compared to general population. TPOAb positivity differed from other studies from India. tTGAb positivity was consistent with other South Indian studies but differed from North Indian population. 21OHAb positivity was slightly higher to other studies. Clinical hypothyroidism was high in TPOAb positive group. All tTGAb cases were asymptomatic or had manifestations like short stature, anemia, and hypocalcemia. All 21OHAb positive cases were asymptomatic and baseline cortisol was normal. As serological evidence for autoimmune diseases like AIT, CD, and AD was high in T1DM, screening of all T1DM patients should be standard of care.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Eisenbarth GS. Type 1 diabetes mellitus: A chronic autoimmune disease. N Engl J Med 1986;314:1360-8.
Barker JM. Clinical review: Type 1 diabetes-associated autoimmunity: Natural history, genetic associations, and screening. J Clin Endocrinol Metab 2006;91:1210-7.
Dayal D, Samprati M, Kaur N, Minz RW, Jayaraman D. Prevalence of beta-cell, thyroid and celiac autoimmunity in North Indian children with recent onset Type 1 diabetes (T1D). J Clin Diagn Res 2015;9:SM01-2.
Barker JM, Yu J, Yu L, Wang J, Miao D, Bao F, et al
. Autoantibody “subspecificity” in type 1 diabetes: Risk for organ-specific autoimmunity clusters in distinct groups. Diabetes Care 2005;28:850-5.
Amouzegar A, Gharibzadeh S, Kazemian E, Mehran L, Tohidi M, Azizi F. The Prevalence, incidence and natural course of positive antithyroperoxidase antibodies in a population-based study: Tehran thyroid study. PLoS One 2017;12:e0169283.
Shivaprasad C, Kolly A, Pulikkal A, Kumar KMP. High prevalence of organ specific autoantibodies in Indian type 1 diabetic patients. J Pediatr Endocrinol Metab 2017;30:707-12.
Metwalley KA, El-Saied AR. Thyroid abnormalities in Egyptian children and adolescents with type 1 diabetes mellitus: A single center study from Upper Egypt. Indian J Endocrinol Metab 2014;18:637-41.
Umpierrez GE, Latif KA, Murphy MB, Lambeth HC, Stentz F, Bush A, et al
. Thyroid dysfunction in patients with type 1 diabetes: A longitudinal study. Diabetes Care 2003;26:1181-5.
De Block CEM, De Leeuw IH, Vertommen JJF, Rooman RPA, Du Caju MVL, Van Campenhout CM, et al
. Beta-cell, thyroid, gastric, adrenal and coeliac autoimmunity and HLA-DQ types in type 1 diabetes. Clin Exp Immunol 2001;126:236-41.
Kakleas K, Paschali E, Kefalas N, Fotinou A, Kanariou M, Karayianni C, et al
. Factors for thyroid autoimmunity in children and adolescents with type 1 diabetes mellitus. Ups J Med Sci 2009;114:214-20.
Menon PS, Vaidyanathan B, Kaur M. Autoimmune thyroid disease in Indian children with type 1 diabetes mellitus. J Pediatr Endocrinol Metab 2001;14:279-86.
Goswami R, Marwaha RK, Goswami D, Gupta N, Ray D, Tomar N, et al
. Prevalence of thyroid autoimmunity in sporadic idiopathic hypoparathyroidism in comparison to type 1 diabetes and premature ovarian failure. J Clin Endocrinol Metab 2006;91:4256-9.
Sanyal D, Majumder A, Chaudhuri SR, Chatterjee S. Thyroid profile and autoantibodies in type 1 diabetes subjects: A perspective from Eastern India. Indian J Endocrinol Metab 2017;21:45-50.
Sharifi N, Khoshbaten M, Aliasgarzade A, Bahrami A. Celiac disease in patients with type-1 diabetes mellitus screened by tissue transglutaminase antibodies in northwest of Iran. Int J Diabetes Dev Ctries 2008;28:95-9.
Karavanaki K, Kakleas K, Paschali E, Kefelas N, Konstantopoulos I, Petrou V, et al
. Screening for associated autoimmunity in children and adolescents with type 1 diabetes mellitus (T1DM). Horm Res 2009;71:201-6.
Djuric Z, Stamenkovic H, Stankovic T, Milecevic R, Brankovic L, Ciric V, et al
. Celiac disease prevalence in children and adolescents with type 1 diabetes from Serbia. Pediatr Int 2010;52:579-83.
Agrawal RP, Rathore A, Joshi A, Chagal H, Kochar DK. Prevalence of celiac disease in type 1 diabetes mellitus in North West Rajasthan, India. Diabetes Res Clin Pract 2008;79:e15-6.
Joshi R, Madvariya M. Prevalence and clinical profile of celiac disease in children with type 1 diabetes mellitus. Indian J Endocrinol Metab 2015;19:797-803.
Tandon N, Shtauvere-Brameus A, Hagopian WA, Sanjeevi CB. Prevalence of ICA-12 and other auto antibodies in North Indian patients with early- onset diabetes. Ann N Y Acad Sci 2002;958:214-7.
Bhadada SK, Kochhar R, Bhansali A, Dutta U, Kumar PR, Poornachandra KS, et al
. Prevalence and clinical profile of celiac disease in type 1 diabetes mellitus in North India. J Gastroenterol Hepatol 2011;26:378-81.
Jacob A, Kumar S. Celiac disease in patients with type-1 diabetes mellitus screened by tissue transglutaminase antibodies in southern Kerala, India. Internet J Nutr Wellness 2008;8:1-5.
Pulikkal AA, Kolly A, Prasanna Kumar KM, Shivaprasad C. The seroprevalence of immunoglobulin A transglutaminase in type 1 diabetic patients of South Indian origin. Indian J Endocrinol Metab 2016;20:233-7.
Silva RC, Sallorenzo C, Kater CE, Dib SA, Falorni A. Autoantibodies against glutamic acid decarboxylase and 21-hydroxylase in Brazilian patients with type 1 diabetes or autoimmune thyroid diseases. Diabetes Nutr Metab 2003;16:160-8.
Ramakrishna BS. Celiac disease: Can we avert the impending epidemic in India? Indian J Med Res 2011;133:5-8.
] [Full text]
Johnson JL. Diabetes control in thyroid disease. Diabetes Spectr 2006;19:148-53.
American Diabetes Association. Introduction: Standards of medical care in diabetes—2019. Diabetes Care 2019;42(Suppl 1):S1-2.
Singh P, Arora A, Strand TA, Leffler DA, Catassi C, Green PH, et al
. Global prevalence of celiac disease: Systematic review and meta-analysis. Clin Gastroenterol Hepatol 2018;16:823-36.
Cerutti F, Bruno G, Chiarelli F, Lorini R, Meschi F, Sacchetti C. Younger age at onset and sex predict celiac disease in children and adolescents with type 1 diabetes: An Italian multicenter study. Diabetes Care 2004;27:1294-8.
Nederstigt C, Uitbeijerse BS, Janssen LGM, Corssmit EPM, de Koning EJP, Dekkers OM. Associated auto-immune disease in type 1 diabetes patients: A systematic review and meta-analysis. Eur J Endocrinol 2019;180:135-44.
Likhari T, Magzoub S, Griffiths MJ, Buch HN, Gama R. Screening for Addison's disease in patients with type 1 diabetes mellitus and recurrent hypoglycaemia. Postgrad Med J 2007;83:420-1.
[Table 1], [Table 2], [Table 3], [Table 4]