Autoimmune thyroiditis in children and adolescents with type 1 diabetes

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1 PRACE ORYGINALNE / Original articles Pediatric Endocrinology, Diabetes and Metabolism 2011, 17, 4, ISSN X Autoimmune thyroiditis in children and adolescents with type 1 diabetes Autoimmunologiczne zapalenie tarczycy u dzieci i młodzieży z cukrzycą typu 1 Ewa Piątkowska 1 1, 2, 3, Mieczysław Szalecki 1 The Third Department of Pediatrics (Endocrinology and Diabetology), Regional Children s Hospital, Kielce, Poland / III Oddział Chorób Dziecięcych (Endokrynologiczno-Diabetologiczny) Wojewódzkiego Specjalistycznego Szpitala Dziecięcego w Kielcach 2 Clinic of Endocrinology and Diabetology, Children s Memorial Health Institute, Warsaw, Poland / Klinika Endorynologii i Diabetologii Instytutu Pomnik-Centrum Zdrowia Dziecka 3 Faculty of Health Sciences, Jan Kochanowski University, Kielce, Poland / Wydział Nauk o Zdrowiu Uniwersytetu Jana Kochanowskiego w Kielcach Abstract Introduction: In children and adolescents with type 1 diabetes coexist some other autoimmune diseases such as autoimmune thyroiditis, celiac disease, Addison s disease or others. Aim of the study was to assess the incidence and risk factors for autoimmune thyroiditis in children and adolescents with type 1 diabetes at the moment of diagnosis. Material and methods: The study included 382 children, who in th e years 2001 to 2010 were diagnosed with type 1 diabetes. The concentrations of antibodies against thyroid peroxidase (anti- TPO), TSH and FT4 were measured and thyroid ultrasound examinations were performed. Children who had not initially shown the presence of anti-tpo had the test repeated at yearly intervals for 2-8 years. Results: At the time of diagnosi s of diab etes, elevated anti-tpo titres were found in 1 4.4% of patients, more often in girls than in b oys, p<0.01. Children with a positive anti-tpo titre were on average older than those whose anti-tpo levels were within the normal range, p<0.05. The incidence of elevated titers of anti-tpo increased with age, 20,5% of children above 10 years old had positive anti-tpo, compared to 8.3% of children less than 10 years old, p < At the time of the onset of diabetes, hypothyroidism was diagnosed in 14.5% of children with elevated anti-tpo, and in 2.1% of the whole group. 4.5% of patients whose levels of anti-tpo were initially normal, within the next 1-8 years had positive antibody titers. Conclusions: Due to the high incidence of the disease, it is necessary to carry out screenings for autoimmune thyroiditis in children with diabetes at the time of diagnosis and redo them in accordance with the recommendations. Key words: diabetes mellitus type 1, children, autoimmune thyroiditis, Hashimoto s disease, antibodies Streszczenie Address for correspondence: Ewa Piątkowska MD Poradnia Endokrynologiczna dla Dzieci Wojewódzkiego Specjalistycznego Szpitala Dziecięcego ul. Artwińskiego 3a Kielce, Poland phone: (+48) fax: (+48 41) epiatkowska@op.pl Wprowadzenie: U chorych na cukrzycę typu 1 współistnieją inne schorzenia o podłożu autoimmunologicznym, takie jak autoimmunologiczne zapalenie tarczycy, (azt), celiakia, choroba Addisona i inne. Celem pracy była ocena częstości występowania i czynników ryzyka azt u dzieci i młodzieży z cukrzycą typu 1 w momencie zachorowania na cukrzycę i w trakcie dalszej obserwacji klinicznej. Materiał i metody: Badaniami objęto 382 dzieci, w wieku 1 18 lat, u których w latach rozpoznano cukrzycę typu 1. U wszystkich oznaczano stężenie przeciwciał przeciwko peroksydazie tarczycowej (anty-tpo). U chorych z dodatnim mianem przeciwciał wykonywano TSH i FT4 oraz USG tarczycy. Dzieci, u których początkowo nie stwierdzano obecności anty-tpo miały powtarzane badania w odstępach rocznych przez okres 2-8 lat. Wyniki: W momencie rozpoznania cukrzycy podwyższone miano anty-tpo stwierdzono u 14,4% chorych, częściej u dziewcząt niż u chłopców, p<0,01. Dzieci z dodatnim mianem anty-tpo były starsze niż z anty-tpo w granicach normy, p<0,05. Częstość podwyższonego miana anty-tpo rosła z wiekiem, powyżej 10 r.ż. 20,5% dzieci miało dodatnie anty-tpo w porównaniu z 8,3% wśród dzieci poniżej 10 r.ż., p <0,001. W momencie ujawnienia cukrzycy niedoczynność tarczycy rozpoznano u 14,5% dzieci z podwyższonym stężeniem anty-tpo, a u 2,1% w całej grupie. U 4,5% dzieci, u których pierwotnie poziom anty-tpo mieścił się w granicach normy, w ciągu następnych 1-8 lat stwierdzono dodatnie miano przeciwciał. Wnioski: U dzieci chorych na cukrzycę, ze względu na dużą częstość występowania autoimmunologicznego zapalenia tarczycy, konieczne jest przeprowadzanie badań przesiewowych w tym 173

2 Zapalenie tarczycy u dzieci z cukrzycą Pediatric Endocrinology, Diabetes and Metabolism 2011, 17, 4 kierunku już w momencie rozpoznania choroby i ponawianie ich zgodnie z obowiązującymi zaleceniami. Słowa kluczowe: cukrzyca typu 1, dzieci, autoimmunologiczne zapalenie tarczycy, choroba Hashimoto, przeciwciała 174 Introduction In children and adolescents with t ype 1 diabetes coexist some other aut oimmune diseases such as aut oimmune thyroiditis, celiac disease, Addison s disease or others [1-3]. In these diseases similar immune r esponses can be obser ved, like the presence of specific autoantibodies in serum. In diabetes, most commonly found antibodies are those against glutamic acid decarboxylase (anti-gad), tyrosine phosphatase (IA2) and insulin (IAA); in other diseases against thyroid peroxidase (anti-tpo), thyroglobulin (anti-tg), TSH receptor, endomysium gastrointestinal smooth muscle, tissue transglutaminase, or 21-hydroxylase. Coexistence of diabetes and other aut oimmune diseases is conditioned by a common genetic factor of these diseases [4, 5]. Most commonly, diabetes is accompanied by chronic autoimmune thyroiditis. It is then possible to diagnose autoimmune polyglandular syndrome type 3 (APS 3), consisting of autoimmune thyroid disease and at least one of autoimmune diseases: type 1 diabetes (then it is of subt ype 3A), pernicious anemia, vitiligo, alopecia areata, celiac disease, hypogonadism, myasthenia gravis, and others (excluding Addison s disease). Autoimmune thyroiditis is associated with antibodies against anti-tpo and anti-tg and lymphocyte infiltrates in the thyroid, which can be observed with euthyroid or lead to hypothyroidism. It occurs in two forms with the presence of the goitre, as Hashimoto s disease, or as an atrophic form. Hashimoto s disease is the most common type of thyroiditis and the most c ommon cause of hypothyroidism. It occurs in all age g roups with a frequency of up to 2%, more frequently in women, but also in childr en, who are less likely than adults t o develop overt hypothyroidism [6, 7]. I n children with t ype 1 diabetes, elevated titres of antithyroid antibodies are found more frequently than in the general population, with a frequency of 7-40% [8]. I n a large, multicenter study, Kordonouri et al. in a group of 7097 children and adolescents from Germany and Austria with type 1 diabetes, found positive antithyroid antibodies in 21.6% of patients. Risk factors were: older age, longer duration of diabet es, later age at onset of diabet es and female gender [9]. I n the course of many years of observation, about 50% of the childr en with diabetes and elevated anti-tpo titres developed hypothyroidism requiring treatment with L -thyroxine [10-12]. Giv en the possibility of adverse effects of untreated hypothyroidism on the development of the child as w ell as on the metabolic c ontrol of diabetes, it is necessary to carry out screening for thyroid dysfunction and the presence of antibodies in these patients. Aim of the study The aim of the study was t o evaluate the incidenc e and risk factors for autoimmune thyroiditis in children and adolescents with newly diagnosed type 1 diabetes and to determine the incidence of autoimmune thyroiditis in the c ourse of several years of observation of patients who ha ve not previously shown the presence of antibodies. Material and methods The study included 382 children and adolescents, who in the years 2001 to 2010 were diagnosed with type 1 diabetes. The patients were under care of the Endocrinology and Diabetology Department of Regional Children s Hospital in Kielce. The group consisted of 186 girls (49%) and 196 boys (51%), aged 1-18 years (average of 9.3±4.4). I n all patients, after the initial metabolic c ontrol improvement stage, the c oncentration of antibodies against thyroid peroxidase was measured, in the years with radioimmunoassa y (Brahms, normal range 0-60 IU/ml), and sinc e 2007 with chemiluminescence (device Access 2, normal range IU/ml). I n the case of ele - vated titres of anti-tpo, thyroid activity was assessed by examining the level of thyroid stimulating hormone TSH (chemiluminescence method, device Access 2, normal range µiu/ml) and fr ee thyroxin FT4 (chemiluminesc ence method, device Access 2, normal range ng/dl), ultrasound of the thyroid gland was also per formed. The ultrasound examination was carried out with Esaot e Technos MPX and Philips iu22 devices using a 7.5 MHz transducer. Children who had not initially shown the presence of anti-tpo had the t est repeated at yearly intervals for 2-8 years. Statistical methods w ere used: two sample t-tests for a difference of means, two sample t-tests for a difference of proportions. Statistically significant was the value of t for which the p value was less than 0.05 (p <0.05). Results At diagnosis of diabetes, elevated titers of anti-tpo were found in 55 out of 382 patients 14.4%. Among the 55, ther e were 36 girls and 19 boys (36/186 equalling 19.4% f or girls, 19/196 equalling 9.7% f or boys, p<0.01). Age of children with diabetes and positive titre of anti-tpo was 3-18 y ears, with an average of 11.31±3.74 y ears, whereas the age of patients with anti-tpo levels in the normal range was between 1 to 18 years, on average 8.95±4.39 years, (p<0.05). The frequency of positive titers of anti-tpo increased with age, from 3% (2/65) in the age group of 0-4 y ears, 11% (14/127) f or the group aged 5-9 years, 20% (26/133) for those aged years, to 23% (13/57) in the age g roup of y ears. The group of children under the age of 10, 8.3% had positiv e anti-tpo, whereas for children above 10 years of age the fr equency of positive anti-tpo was already 20.5% (under 10 16/192, over 10 39/190, p<0.001). At the time of the diag nosis of diabetes 14.5% (8/55) of antibody-positive children were diagnosed with hypothyroidism, when in the whole study g roup the incidence of hypothyroidism on the backg round of autoimmune thyroiditis was 8/ %. TSH level at diagnosis of hypothyroidism was

3 Thyroiditis in children with diabetes Table I: Tabela I: Comparison between patients with positive and negative anti-tpo titers Porównanie pacjentów z dodatnim mianem anty-tpo z pacjentami z ujemnym mianem przeciwciał Positive anti-tpo / Dodatnie anty-tpo Negative anti-tpo / Ujemne anty-tpo t-test p value / Poziom istotności Female Płeć żeńska Male Płeć męska Female Płeć żeńska Number of patients / Liczba pacjentów Number of patients by sex Liczba pacjentów według płci Mean age at type 1 diabetes diagnosis Średni wiek rozpoznania cukrzycy typu 1 Standard deviation of age Odchylenie standardowe wieku anti-tpo antibodies against thyroid peroxidase / anty-tpo przeciwciała przeciwko peroksydazie tarczycowej Male Płeć męska p < p < % 20% 15% 10% Fig. 1. Ryc. 1. 5% 0% µiu/ml; these childr en did not pr esent clear clinical sig ns of hypothyroidism. 40 out of 55 (72.7%) of th yroid ultrasound images showed the characteristics of autoimmune thyroiditis in a heterogeneous, hypoechogenic parenchyma. In three girls, autoimmune thyroiditis presented as Hashimoto s disease was diagnosed between one to two years before the manifestation of type 1 diabetes, in the r emaining 52 cases, elevated titers of anti-tpo were detected during scr eening of childr en and adolescents with newly diag nosed diabetes. 17/382 children 4.5%, whose levels of anti-tpo were initially normal, within the next 1-8 years had positive antibody titers. These children, at the time of detection of elevated titers of anti-tpo were aged 6-18 years, an average of 12.35±3.41, and elevat ed titres presented after 1-8 years of duration of diabet es, an average of 4.35±2.03 years. The cumulative incidence of elevated anti-tpo in the whole group was 72/ %. Discussion anti-tpo antibodies against thyroid peroxidase anty-tpo przeciwciała przeciwko peroksydazie tarczycowej n number of patients in age groups 23% liczebność grup wiekowych 3% 0-4 n= 65 11% 5-9 n= 127 Age groups (years) / grupy wiekowe (lata) Frequency of elevated anti-tpo level depending on patient s age Częstość podwyższonego poziomu anty-tpo w zależności od wieku pacjentów Patients with diabetes have an increased risk of dev eloping thyroid dysfunction due to autoimmune thyroiditis. Antithyroid antibodies are found more frequently in children with 20% n= n= 57 type 1 diabetes than in the general population [8]. I n the Danish study, an elevated titer of antibodies was f ound in 17/105 children with diabetes 16.2%, compared with 2/ % in the clinical control group [13]. In our study, at the time of diag nosis of diabet es, presence of anti-tpo was found in 14.4% of childr en. A similar rate 14.6% was obser ved by Górska et al. among 130 children from the region of Małopolska in the study from 2005, Kakleas et al. 14,8% (anti-tpo and/or anti-tg) in the Gr eek study of 2009 and Kordonouri et al. 15,1% among 126 German children in the study of the 2005 [11, 14, 15]. Distinc tively less positive antibodies (anti-tpo and/or anti-tg) were detected by Lorini et al. 6.7% in the I talian study in 1996 [8]. A slightly higher rate 16.8 % of anti-microsomal antibodies (previously measured, later replaced by anti-tpo) showed Korpal-Szczyrska et al. in the study in 2002 on 119 children from the Pomeranian region [16]. We noted a higher incidence of elevated titers of anti-tpo in girls 19.4%, compared with boys 9.7% (p<0.01), which is c onsistent with the obser vations of the majorit y of authors [3, 9, 11, 15, 17 20]. The prevalence of girls is increasing especially during puberty, after 12 years of age as w ell as with longer duration of diabetes [11]. Also in the general population Hashimoto s disease occurs much more frequently (up to 95%) in females [6]. In our previous study on a group of 72 children and adolescents with aut oimmune thyroiditis treated at the Clinic of Endocrinology in K ielce 90.3% were girls [21]. The occurrence of a positive titer of antibodies significantly increases with age of patients with t ype 1 diabetes [9, 15, 18]. In the studied population, in the youngest group of children up to 5 years, elevated levels of anti-tpo appeared only in 3% of patients, whereas among adolescents aged years, almost in one in four patients 23%. Especially significant difference in frequency (p<0.001) occurred among children under 10, compared with the older ones. Very similar results were obtained in a German study by Holl et al. In 495 patients with type 1 diabetes, the incidence of elevated levels of anti-tg and/or anti-tpo in the age g roup below 5 years of age was 3.7%, and the age of years 25.3% [18]. The age at diag nosis of diabetes with a co-existing positive titer of anti-tpo was an a verage of 11.31±3.74 years, and was significantly higher (p<0.05) than in children without the pr esence of antibodies 8.95±4.39. Also, a significant difference in age of onset of diabet es has been 175

4 Zapalenie tarczycy u dzieci z cukrzycą Pediatric Endocrinology, Diabetes and Metabolism 2011, 17, shown, among others, in the A ustro-german study on a very large group of patients [22]. Anti-TPO concentrations are elevated in 98% of cases of autoimmune thyroiditis. But disc overing anti-tpo is not sufficient to identify aut oimmune thyroiditis, because of their increased concentrations observed in 5-10% of health y individuals [6]. To diagnose Hashimoto s disease w e must see an elevated antibody titer (especially anti-tpo, less important are the anti-tg) in people with goiter or hypothyroidism. The beginning of the disease usually pr esents with euthyroid, with time it comes to development of hypothyroidism requiring substitution with L-thyroxine [23]. At the time of diagnosis of diabetes in children, the incidence of hypothyroidism in patients with positive antibodies in our study was 8/ %, and in the whole group 8/ %. Similar proportions were observed by Górska et al. 15.7% and 2.3%, and c onsiderably lower by Korpal- Szczyrska et al. 2.6% and 0.8% [14, 16]. With the duration of diabetes increases the incidence of both positiv e thyroid antibodies and hypothyroidism on the background of autoimmune thyroiditis. In the largest study by Kordonouri et al. on a group of mean age of 12.4 y ears and average duration of diabetes 4.5 years, 21.6% (1530/7097) of patients with t ype 1 diabetes had elevated levels of antibodies and in 16% of them an elevat ed TSH level was obser ved [9]. I n the whole g roup hypothyroidism was diagnosed in 3.5% of patients. In a Polish study of Sz y- powska et al. in children with diabetes aged 11 on average and with a similar duration of diabet es an average 4 years, antibody-positive antibodies were found in 29%, and 23% of them required treatment with thyroxine because of h ypothyroidism, which constitutes 5% of the whole g roup [17]. In another study of 383 children, adolescents and y oung adults in Brazil, with longer-lasting diabetes (9.3 y ears), the incidenc e of elevat ed levels of th yroid antibodies was 16.7%, and h ypothyroidism was present in as much as 7.3% of all the patients [24]. I n our research, a majority (55/72) of positive anti-tpo were recognized at the time of diabet es diagnosis, and then in 17/382 childr en 4.5% were found after 1-8 years of diabetes duration, on average 4.35±2.03. Kordonouri et al. has similar observations at the beginning 15.1% among 126 children had positive anti-tpo, in the following 5 years they were discovered in 3.2% children [11]. Overt hypothyroidism, regardless the cause of the disease, is an absolute indication for use of substitution tr eatment. The drug of choice is the sodium salt of levorotatory thyroxine (L-T4) [6]. Some clinicians begin treatment of autoimmune thyroiditis in children and adolescents with L-thyroxine also in cases of subclinical hypothyroidism and/or presence of goitre (thyroid volume above 97 percentile for age and sex) with a typical ultrasound image of th yroid gland in the f orm of hypoechogenic parenchyma [11, 15, 25]. Our clinic also star ted the treatment in less advanc ed cases. The benefits of such tr eatment have been demonstrated in the study by Svensson et al., where treatment of 90 children and adolesc ents with aut oimmune thyroiditis with L-thyroxin led t o a goiter volume reduction, especially when enlarged thyroid was accompanied by hypothyroid, but also by euthyroid [26]. According to Karges et al. in another study, an L-T4 treatment in pediatric patients with type 1 diabetes and autoimmune thyroiditis resulted in a noticeable thyroid volume reduction, but there was no eff ect on thyroid function and lev els of antibodies [27]. I n the f ew studies on small groups of adult patients, treatment with L-thyroxine also resulted in lower titers of antibodies [28, 29]. Conclusions At the time of diag nosis of diabetes, an elevated thyroid peroxidase titer was found in up t o 14.4% of patients. During a follow-up another 4.5% shown positive titers of anti-tpo, on average after 4.4 years of the duration of the disease. Autoimmune thyroiditis is more common in girls and in children who fell ill after 10 years of age. The incidence of hypothyroidism on the background of autoimmune thyroiditis at the time of the diagnosis of diabetes was 2.1%. I n view of the high incidenc e of the disease, it is nec essary to carry out screening for autoimmune thyroiditis at the time of diag nosis of diabetes in all patients and repeat them in subsequent y ears in accordance with the recommendations. The study was presented at poster session at the XIII C ongress of Polish Diabetes Association in Krakow, May References 1. 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