|Year : 2015 | Volume
| Issue : 3 | Page : 96-99
Thyroid dysfunction and autoantibodies in first degree relatives of North Indian children with autoimmune thyroiditis
Devi Dayal1, Sanjeev H Naganur2, Biman K Siakia3, Baljinder Singh4
1 Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh; Pediatric Endocrinology and Diabetes Unit, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
4 Department of Nuclear Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
|Date of Web Publication||16-Oct-2015|
Dr. Devi Dayal
Department of Pediatrics, Pediatric Endocrinology and Diabetes Unit, Advanced Pediatric Center, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
Background: Family studies in developed countries show an increased prevalence of thyroid autoantibodies in first degree relatives of children with autoimmune thyroiditis (AIT). Such data is scarce from developing country setups. Materials and Methods: Thyroid profiles and autoantibodies were evaluated in 50 first degree relatives of 50 children with AIT. Results: Eleven (22%) subjects had raised thyroid stimulating hormone (TSH); 4 fathers (42.5%), 3 mothers (12%), 1 brother (33%) and 3 (23%) sisters. Three (6%) showed thyroid profiles consistent with hypothyroidism. Levels of triiodothyronine (T 3 ) were raised in 7 (28%) mothers and 2 (15.4%) sisters while 2 (8%) mothers and 3 (23.1%) sisters also had increased thyroxine (T 4 ) levels; none had low TSH or clinical evidence of hyperthyroidism. Anti-thyroid peroxidase (TPO) antibodies were positive in 9 (18%) subjects; 4 mothers (4/25, 16%) 3 fathers (3/9, 33%) and 2 sisters (2/13, 15.4%). Mean T 3 levels were lower, mean T4 were similar and mean TSH levels were higher in TPO-positive as compared TPO-negative subjects. Anti-Tg antibody positivity was found in 32 (64%) subjects; 14 (56%) mothers, 7 (77.7%) fathers and 11 (84.6%) sisters. Mean thyroid hormone levels were similar in Anti-Tg positive and negative subjects. Two (8%) mothers, 1 (7.7%) sister and 2 (22.2%) fathers had both antibodies in their serum; their thyroid profiles were similar to subjects with anti-TPO positivity. Conclusions: Thyroid dysfunction is present in first degree relatives of North Indian children with AIT. Anti-TPO antibodies are less common but have strong correlation with thyroid dysfunction. Conversely, anti-thyroglobulin (TG) antibodies are commonly detected but correlate poorly with thyroid dysfunction.
Keywords: Autoimmune thyroiditis, children, first degree relatives, thyroid autoantibodies
|How to cite this article:|
Dayal D, Naganur SH, Siakia BK, Singh B. Thyroid dysfunction and autoantibodies in first degree relatives of North Indian children with autoimmune thyroiditis. Thyroid Res Pract 2015;12:96-9
|How to cite this URL:|
Dayal D, Naganur SH, Siakia BK, Singh B. Thyroid dysfunction and autoantibodies in first degree relatives of North Indian children with autoimmune thyroiditis. Thyroid Res Pract [serial online] 2015 [cited 2021 Apr 16];12:96-9. Available from: https://www.thetrp.net/text.asp?2015/12/3/96/157931
| Introduction|| |
Most patients of autoimmune thyroiditis (AIT) have detectable circulating antibodies to a variety of thyroid-specific antigens like thyroglobulin (Tg), colloid component other than Tg, thyroid peroxidase (TPO) enzyme, Na/I symporter protein, thyroid nuclei and TSH receptor.  Out of these, anti-TPO and anti-Tg are the most prevalent and most useful in diagnosis.  Thyroid autoantibodies are inherited as autosomal dominant trait in females with incomplete penetrance in males.  The disease has a marked predilection for females and previous studies suggest a familial aggregation.  The ability to form these antibodies is under polygenic control with moderate heritability approaching 50%.  About 20-60 immunosusceptibility genes, each with small effect, have been postulated for AIT.  Paternal HLA DQ alleles are also proposed to confer a higher risk for AIT.  The risk of developing hypothyroidism in subjects with antibody positivity is increased and their thyroid status needs to be checked periodically.  The disease can be detected in asymptomatic family members especially in mothers who may benefit from early intervention. 
There are only a few pediatric studies on familial prevalence of AIT. ,,, The data from the developing countries is limited. Two previous Indian studies on familial prevalence showed familial clustering of autoimmunity ranging between 43 and 67%. , In both these studies, a significant proportion of first degree relatives were detected to have overt (3.6%) and subclinical hypothyroidism (10-21%). The present study was conducted with an aim to obtain data on thyroid autoantibodies and detect subclinical or overt hypothyroidism in first degree relatives of children with AIT.
| Materials and Methods|| |
This Cross-sectional clinical and laboratory evaluation was conducted on parents and siblings of children with proven AIT (thyroid antibody positivity and/or FNAC confirmed AIT) who attended Pediatric Endocrinology Clinic of our hospital between July 2007 and June 2008.
Detailed history was elicited with special reference to thyroid related symptoms. Complete physical examination was done in all subjects and included weight, height and sexual maturity assessment in siblings. Goiter grading was done by WHO criteria as follows: Grade 0: no goiter, Grade 1 gland palpable but not visible with neck in normal position, Grade II: visible and palpable gland with neck in normal position. 
Thyroid function tests
Estimation of total triiodothyronine (T 3 ) and thyroxine (T 4 ) was done by standard radioimmunoassay having sensitivity of 0.22 ng/ml and 0.5 ng/ml and normal values of 0.7-2.0 ng/ml and 55-135 ng/ml respectively. TSH levels were estimated by ultra sensitive solid phase two-site immunoradiometric assay (IRMA) which can detect TSH levels as low as less than 0.1 µIU/ml. Normal values in our lab were 0.17-4.05 µIU/ml.
Thyroid antibody status
Anti-TPO antibodies were estimated by serodia-AMC, a semi-quantitative microtiter particle agglutination test based on the agglutination of gelatin particle carriers sensitized with microsomal antigen. Anti-Tg antibodies were detected by indirect noncompetitive enzyme immunoassay. Control sera were included with every run to ensure that all reagents and procedures were performing properly. Mean values and acceptable ranges for controls were established prior to the study. Results were interpreted as the ratio of absorbance (OD) of patient sample to cut off determined by positive control multiplied by a factor. A ratio of more than 1.4 was taken as positive.
| Results|| |
The study population comprised of 50 first degree relatives of 50 index cases (25 mothers, 09 fathers, 03 brothers and 13 sisters). All belonged to the Union Territory and its surrounding areas considered iodine sufficient regions in surveys conducted over the past decade. ,
[Table 1] shows the mean ages and thyroid hormone levels in the study group. Fathers had lower levels of T 3 and T 4 and higher TSH as compared to rest of the study population but the difference was not statistically significant. None of the fathers had clinical symptoms of hypothyroidism.
Manifest thyroid dysfunction in screened subjects
Majority (94%) of the family members studied were completely asymptomatic. Three (6%) of the subjects; 1 brother, 1 sister and 1 mother had recent onset of symptoms suggestive of hypothyroidism. All the three had increased weight gain, reduced appetite and increased sleep. One out of the 13 female siblings had goiter (WHO grade II) accounting for 2% of total subjects and 7.6% of female siblings having signs without symptoms.
Considering significant increase of TSH as > 5, we found 11 (22%) subjects having raised TSH; sub-analysis showed raised TSH in 4 fathers (42.5%), 3 mothers (12%), 1 brother (33%) and 3 (23%) sisters out of which 2 had low T 3 and T 4 also; 1 father and 1 brother each. T 3 levels alone were low in only 2 (4%) patients while 3 (6%) patients had low T 4 levels. Only 3 (6%) showed thyroid profiles consistent with a diagnosis of hypothyroidism based on low T 4 and raised TSH [Table 2].
Asymptomatic increase in thyroid hormones
Levels of T 3 were raised in 7 (28%) mothers and 2 (15.4%) sisters. Two (8%) mothers and 3 (23.1%) sisters had increased T 4 levels. None of these subjects had low TSH levels or clinical evidence of hyperthyroidism.
Anti-TPO antibodies were positive in 9 (18%) subjects which included 4 mothers (4/25, 16%) 3 fathers (3/9, 33%) and 2 sisters (2/13, 15.4%). None of the male siblings had antibodies in their sera. Analysis of relation between TPO antibodies and clinical symptoms showed 100% correlation in mothers (1/1) and sisters (1/1). However one symptomatic brother did not have anti-TPO antibodies in his serum. [Table 3] shows the mean total hormone levels in relation to TPO positivity. The mean levels of T 3 were significantly lower and TSH levels were significantly higher in TPO-positive as compared to TPO-negative subjects. However no difference was observed in the T 4 values in the antibody positive and negative subjects.
|Table 3: Relationship between TPO positivity and mean thyroid hormone levels|
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Anti-TPO and T 3 , T 4 and TSH levels
Among TPO antibody positive subjects none had increased T 3 or T 4 levels. One father (1/3, 33%) had low T 3 as well as T 4 levels while all others (67% of fathers, 100% of sisters and mothers) had normal T 3 and T 4 levels. No subject showed decreased TSH levels. Two (2/4, 50%) mothers, 2 (2/3, 66.6%) fathers and 2 (2/2, 100%) sisters had increased TSH levels.
Anti-Tg antibodies were positive in 32 (64%) subjects which included 14 (56%) mothers, 7 (77.7%) fathers and 11 (84.6%) sisters. None of the brothers were anti-Tg positive. None of the anti-Tg positive subjects had any thyroid related symptoms. However goiter was found in 1 asymptomatic female sibling. The mean thyroid hormone levels were also not significantly different in Anti-Tg positive and negative subjects [Table 4].
|Table 4: Relationship between Tg positivity and mean thyroid hormone levels|
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Anti-Tg and T 3 , T 4 and TSH levels
Among Anti-Tg positive subjects, 5 mothers (5/14, 35.7%) and 2 sisters (2/11, 18.2%) had increased T 3 levels. One father (1/7, 14.3%) had low T 3 levels, while others (85.7% of fathers, 73.8% of sisters and 64.3% of mothers) had normal T 3 levels. One (7.1%) mother and 3 (27.2%) sisters had increased levels of T 4 . One (14.2%) father had decreased T 4 levels and all others (85.8%% of fathers, 93% of mothers and 62.8% sisters) showed normal T 4 levels. Two (14.2%) mothers, 2 fathers (2/7, 28.6%) and 2 sisters (2/11, 18.2%) had increased TSH levels, while others (85.8% of mothers, 71.4% of fathers, 81.8% of sisters) had normal TSH levels.
Prevalence of both anti-TPO and anti-TG positivity
Two (8%) mothers, 1 (7.7%) sister and 2 (22.2%) fathers had presence of both antibodies in their serum. None of brothers had this feature. In total, only 5 out of 50 subjects tested positive for both antibodies. Mean T 3 was significantly lower in subjects having both antibodies in their sera (P value, 0.005) and mean TSH levels were increased in these subjects (P value, 0.011). However mean levels of T 4 were similar in the double antibody positive and antibody negative subjects. Only 1 (father) of these 5 subjects had increased T 3 and T 4 levels. Three (1 mother, 1 father and 1 sister) had elevated TSH levels.
| Discussion|| |
Autoimmune thyroiditis, first described by Hashimoto almost a century ago is the most common cause of acquired hypothyroidism in older children and adolescents.  Thyroid antibody positivity confers a higher risk of developing hypothyroidism.  In our study, 3 (6%) subjects were detected to have hypothyroidism. Other studies also have found similar rates of detection as seen by us. , In addition, as many as 22% family members had elevated levels of TSH. Two previous Indian studies have also shown the prevalence of this subclinical hypothyroid state between 10-17.6% thus emphasizing the need for a close follow up. , None of the subjects showed features of hyperthyroidism in our study which is similar to the previous observations. ,
We observed higher mean TSH levels in fathers although these were not statistically different from the other subject groups. This observation is different from the previous reports which showed more number of mothers to have subclinical hypothyroidism. , A possible explanation could be the age related decrease in thyroid function since fathers had a higher mean age as compared to other groups of study population.
Only 18% of the subjects in the study were found to be positive for anti-TPO antibodies. These results are similar to those observed in earlier studies particularly in non-goitrous subjects. ,, However a higher positivity has also been reported.  The strong correlation observed in our study between TPO positivity and clinical symptoms is similar to earlier findings. , The raised TSH levels in 67% of TPO positive subjects suggest that TPO positivity may herald impending thyroid failure and needs close monitoring of these subjects. 
Another significant observation in our study was a very high positivity rate for anti-Tg antibodies in the studied subjects. Such high positivity rates have been reported rarely.  Previous studies on Indian population have shown prevalences of 4.4% and 9.4%. , High sensitivity of the test itself may have contributed to high positivity.  Iodine induced immunomodulation may also have played a role by different mechanisms.  It is known that iodinated Tg produces more immune response as compared to less iodinated Tg molecules.  Iodine excess is thought to be linked to autoimmune thyroid disease partly by augmenting the antigenicity of Tg molecule through incorporation of iodine in the protein chain of Tg in addition to other mechanisms like production of cytokines and chemokines that can recruit immunocompetent cells to the thyroid and excess iodine processing in thyroid epithelial cells resulting in increased oxidative stress that leads to harmful lipid oxidation and thyroid tissue injuries.  Although our region is considered iodine sufficient, we did not check the iodine status of our subjects and whether excess iodine contributed to increased anti-Tg positivity in our subjects remains speculative. The weak correlation between Tg positivity and thyroid dysfunction as seen by us was similar to previous observations. 
Thyroid autoimmunity is said to be commoner in females.  No gender differences were observed by us although the number of subjects was too small for valid gender comparisons to be made. Similarly antibody negativity in all male sibs can be explained by low numbers. Due to financial constraints, the number of first-degree relatives who could be enrolled was low and this was a major limitation of our study.
In conclusion, a significant number (22%) of first degree relatives of children with AIT showed evidence of thyroid dysfunction; 6% had overt hypothyroidism. Anti-TPO and anti-Tg antibodies were detected in 18% and 64% of study subjects. Autoantibodies positivity was similar in males and females.
| References|| |
Brown RS. Autoimmune thyroiditis in childhood. J Clin Res Pediatr Endocrinol 2013;5 Suppl 1:45-9.
Davies TF. Really significant genes for autoimmune thyroid disease do not exist--so how can we predict disease? Thyroid 2007;17:1027-9.
Segni M, Pani MA, Pasquino AM, Badenhoop K. Familial clustering of juvenile thyroid autoimmunity: Higher risk is conferred by human leukocyte antigen DR3-DQ2 and thyroid peroxidase antibody status in fathers. J Clin Endocrinol Metab 2002;87:3779-89.
Desai MP, Karandikar S. Autoimmune thyroid disease in childhood: A study of children and their families. Indian Pediatr 1999;36:659-68.
Burek CL, Hoffman WH, Rose NR. The presence of thyroid antibodies in children and adolescents with autoimmune thyroid disease and their parents. Clin Immunol Immunopathol 1982;25:395-404.
Segni M, Wood J, Pucarelli I, Toscano V, Toscano R, Posquino AM. Clustering of autoimmune thyroid diseases in children and adolescents: A study of 66 families. J Pediatr Clin Endocrinol Metab 2001;14:1271-5.
Marwaha RK, Sen S, Tondon N, Sahoo M, Walia RP, Singh S, et al
. Familial aggregation of autoimmune thyroiditis in first degree relatives of patients with juvenile autoimmune thyroid disease. Thyroid 2003;13:297-300.
World Health Organization/United Nations Children′s Fund/International Council for control of Iodine Deficiency Disorders, author. Assessment of iodine deficiency disorders and monitoring their elimination. A Guide for Programme Managers. 3 rd
ed. Geneva: World Health Organization; 2007.
Harjeet A, Sahni D, Jit I, Aggarwal AK. Shape, measurements and weight of the thyroid gland in northwest Indians. Surg Radiol Anat 2004;26:91-5.
Das S, Bhansali A, Dutta P, Aggarwal A, Bansal MP, Garg D, et al
. Persistence of goitre in the post-iodization phase: Micronutrient deficiency or thyroid autoimmunity? Indian J Med Res 2011;133:103-9.
Kanga U, Tandon N, Marwaha RK, Khanna R, Bhattacharya B, Singh S, et al
. Immunogenetic associations and thyroid autoantibodies in juveule AITD in North India. Clin Endocrinol (Oxf) 2006;64:573-9.
Streider TG, Prummel MF, Tijssen JG, Endert E, Weirsinga WM. Risk factors for and prevalence of thyroid disorders in a cross sectional study among healthy female relatives of patients with autoimmune thyroid disease. Clin Endocrinol (Oxf) 2003;59:396-401.
Philips D, Prentce L, Upadhyaya MP, Chamberlin S, Roberts DF, McLachan S, et al
. Autosomal dominant inheritance of autoantibodies to thyroid peroxidase and thyroglobulin: Studies in families not selected for AITD. J Clin Endocrinol Metab 1991;72:975-8.
Ghoraishian SM, Hekmati Moghaddam SH, Afkhami-Ardekani M. Relationship between anti-thyroid peroxidase antibody and thyroid function test. Iran J Immunol 2006;3:146-9.
Prummel MF, Wiersinga WM. Thyroid peroxidase autoantibodies in euthyroid subjects. Best Pract Res Clin Endocrinol Metab 2005;19:1-15.
Sasaki N, Tsuyusaki T, Inomata H, Niimi H, Nakajima H. Significant fluctuation of thyroid function in children with chronic lymphocytic thyroiditis. Endocrinol Jpn 1983;30:219-28.
Sinclair D. Analytical aspects of thyroid antibodies estimation. Autoimmunity 2008;41:46-54.
Rose NR, Rasooly L, Saboori AM, Burek CL. Linking iodine with autoimmune thyroiditis. Environ Health Perspect 1999;107:749-52.
Saboori AM, Rose NR, Bresler HS, Vladut-Talor M, Burek CL. Iodination of human thyroglobulin alters its immunoreactivity. 1: Iodination alters multiple epitopes of human thyroglobulin. Clin Exp Immunol 1998;113:297-302.
Luo Y, Kawashima A, Ishido Y, Yoshihara A, Oda K, Hiroi N, et al
. Iodine excess as an environmental risk factor for autoimmune thyroid disease. Int J Mol Sci 2014;15:12895-912.
[Table 1], [Table 2], [Table 3], [Table 4]