Graves’ disease in children in the two decades following implementation of an iodine prophylaxis programme

Introduction

Grave’s disease (GD) is a form of thyroid autoimmune disease characterised by hyperthyroidism. It is a rare clinical problem in paediatrics, and the incidence is estimated at 0.1-3 per 10,000 children [1]. On the other hand, it is the most common cause of thyrotoxicosis in developmental age [1]. GD in prepubertal children is less common, but its course is usually more severe and more often requires radical therapy [2]. Development of disease is the result of genetic susceptibility and some environmental factors. Genetic predisposition is usually multifactorial, but some monogenic diseases are also associated with increased risk of GD, such as 21 trisomy [3, 4], Turner syndrome [5], or DiGeorge syndrome [6]. One of the best documented environmental factors involved in thyroid autoimmunity is iodine excess [7]. Increased incidence of autoimmune thyroid diseases was observed in countries after the introduction of iodine prophylaxis [8-10]. Higher incidence was noted after iodine fortification of salt, and it concerns especially young subjects with a genetic predisposition [11].
In Poland, mandatory salt iodination was introduced in 1997. Table salt is obligatorily enriched in iodine 30 ±10 mg KJ/1 kg NaCl [12]. Studies performed 10 years after introducing iodination classified Poland’s status as iodine-sufficient in the general population [13].
The aim of our study was to analyse the clinical course and the response to pharmacological treatment in children diagnosed in our centre with Graves’ disease in the first two decades after mandatory salt iodination.

Material and methods

We analysed retrospectively the records of 94 children diagnosed with GD in the Department of Paediatrics and Endocrinology, Medical University of Warsaw, in the years 1998-2017. The diagnosis was established on the basis of clinical symptoms of hyperthyroidism and confirmed by hormonal tests and the presence of TSH receptor antibodies (TRAb). Clinical and biochemical features were analysed at diagnosis: age at onset, the most common symptoms and complaints, biochemical abnormalities in laboratory test, anti-thyroid antibodies, and thyroid ultrasound. The response to antithyroid drug therapy and its side effects were assessed. Medical data of patients were compared between two decades following implementation of an iodine prophylaxis programme in Poland in the periods 1998-2007 (first-decade group – FDG) and 2008-2017 (second-decade group – SDG); 34 and 60 patients, respectively. Medical data of FDG was obtained from archival records and previous analysis performed in 2006 [14]. Data of 60 patients from SDG were obtained from currently available medical records.
Free thyroxine (fT4, normal range: 0.78-1.31 ng/dl) and triiodothyronine (fT3, normal range: 2.33-4.35 pg/ml), thyroid stimulating hormone (TSH, normal range: 0.53-3.59 µIU/ml), anti-thyroid peroxidase antibodies (anti-TPOAb, normal range < 5.6 IU/ml), and anti-thyroglobulin antibodies (anti-TGAb, normal range < 4.1 IU/ml) were evaluated by chemiluminescence immunoassay (Architect i1000SR, Germany). The value of TSH receptor antibodies (TRAb) was measured by electrochemiluminescence immunoassay (Cobas e601, Roche); a positive value was considered as > 1.75 IU/l. Thyroid ultrasound was performed in each patient at the time of diagnosis.
Results were statistically analysed using Microsoft Excel software and reported as mean and standard deviation, median, maximal, and minimal values. Comparisons between groups was conducted using the Independent Samples T-test performed with Statistica 11 software. A p-value < 0.05 was considered statistically significant.

Results

Clinical features of Graves’ disease at diagnosis

The symptoms at diagnosis were characteristic for hyperthyroidism and did not differ in FDG and SDG children. The most common clinical feature at diagnosis observed in children from SDG was tachycardia (Table 1), in four cases accompanied by cardiac arrhythmia, and in one case cardiac arrhythmia was not connected with tachycardia. The most frequent complaints were fine, wet skin and tremor. Polydipsia, dysphagia, vomiting, and pruritus were reported as first symptoms extremely rarely. Twenty-six per cent (10/39) of pubertal girls reported irregular menses (Table 1).
The frequency of newly diagnosed GD for each month in a year was analysed, and the tendency of increased newly diagnosed cases was observed from the end of spring to the end of autumn with a peak incidence in May (Fig. 1).
In SDG children the median TRAb value was 9.77 IU/l, range: from 2.46 to > 40 IU/l. Anti-TGAb and/or anti-anti-TPOAb concentrations at diagnosis were elevated in almost all tested patients (93%, Table 2); median values were 102.90 IU/ml (range 1.2-3488 IU/ml) and 226.55 IU/ml (range 0.2-6656 IU/ml), respectively.

Evaluation of treatment and side effects

The majority of SDG patients (n = 59) were treated with methimazole (MMI), only one patient received propylthiouracil (PTU) as initial therapy. Adverse drug reactions occurred in 13 patients (21.67%): hive (n = 3), pruritus (n = 1), leucopaenia (n = 4), elevated liver enzymes (n = 4), and purpuric skin lesions (n = 1). Thirty-two children (53%) developed hypothyroidism during the first course of ATD treatment and simultaneously received supplementation with L-thyroxin.
Remission was defined as being euthyroid for one year after cessation of therapy [2]. Relapse was defined as recurrence of hyperthyroidism at any time during the treatment or after withdrawal of thyrostatics.
In 56 children under observation longer than three months after starting ATD treatment, prolonged TSH suppression (> 3 months) was found in 18 (32%) patients. In 31 children observed ≥ 24 months, relapses after first-line treatment occurred in 10 patients (32%), and relapses after completion of antithyroid drug therapy occurred in six patients (19%). In children observed < 24 months (n = 29) relapses after first-line treatment were found in 14 patients (48%). Ten patients were referred for radioiodine therapy, and one patient was qualified for strumectomy.
Comparison of medical data of patients diagnosed with Graves’ disease in two decades following implementation of iodine prophylaxis programme
In our centre there were 34 newly diagnosed patients in FDG and 60 patients in SDG. No statistically significant difference in the mean age and sex contribution at diagnosis between groups was found. Familial prevalence of GD was significantly more frequent in FDG than in SDG (29% vs. 7%; p = 0.004). The mean value of TRAb was higher in SDG, but no statistical significance was found (p > 0.05). Occurrence of thyroid autoimmune ophthalmopathy (TAO) in the second decade decreased (44% vs. 28.3%); however, the difference was not statistically significant (p > 0.05). Severe side effects of ATDs were observed significantly more often in FDG than in SDG (p < 0.05). All other clinical features of GD between FDG and SDG did not differ significantly (Table 3).

Discussion

In our study, the two-fold higher number of patients in SDG suggests increasing incidence of GD in children in the last 10 years. However, the study was a single-centre observation, hence it does not have epidemiological value. The next finding was significantly more frequent familial prevalence of GD in FDG than in SDG (29% vs. 7%; p = 0.004). The increased frequency of GD in children without familial (genetic) susceptibility suggests a significant influence of some environmental factors. Temporal relationship with the introduction of salt iodination justifies the conjecture that it had impact on GD development. Higher incidence of autoimmune thyroid disorder was detected in several countries after the start of mandatory salt iodination [8-11]. Polish authors [15] reported a significant increase of frequency of cytologically diagnosed autoimmune thyroiditis (AIT) in fine-needle aspiration biopsy in the years after initiation of iodine supplementation, and the difference was more pronounced in children than in adults (from 3% in 1992 up to 16% in 1999). Similar data were reported by authors from Greece [16] and from Argentina [17]. The impact of increased iodine supply on thyroid autoimmunity is confirmed in an animal model [18]. This phenomenon is elucidated by higher immunostimulatory properties of more iodinated thyroglobulin. In concert with this hypothesis Bulow et al. reported the increased prevalence of anti-TPOAb and anti-TGAb after 4-5 years of salt iodination [19]. The increased iodine supply is not the only environmental factor involved in autoimmunity. It is well known that some viral infections, vaccination, drugs, chemical pollution, and stress can be trigger factors in autoimmune thyroid disease development. We cannot definitely exclude the influence of the other factors; nevertheless, in our study children were not on special diets, were not treated for other chronic diseases, and were vaccinated according to a mandatory vaccination program.
The temporary association with introduction of mandatory salt iodination and the concordance with observations of other authors [15] support our conclusions that it could be responsible for changes in the autoantibodies profile in GD in our study group. In classical pathogenesis of GD anti-TPOAb and anti-TGAb appears secondary to TRAb, and their levels are lower than in Hashimoto thyroiditis (HT). The presence of anti-TPOAb and anti-TGAb is mainly associated with HT, but it can be present also in 70-90% of GD patients [20, 21]. In our study elevated values of TRAb were accompanied by anti-TPOAb and/or anti-TGAb in 97% patients at the time of diagnosis, and concentrations of these antibodies varied from slightly elevated to very high amounts. It might suggest that autoimmune processes in our patients with GD were primarily not only directed against TSH receptor but also involved other thyroid antigens at the onset of the disease. This may indicate that the pathogenesis of hyperthyroidism in these patients is similar to HT, and it could be named autoimmune hyperthyroidism rather than classical GD. What is more, recently some reports suggest a conversion of GD to HT [22, 23] and vice versa [24].
TAO occurs in one third of children with GD [25]. It occurs more frequent in female and post-pubertal patients [26, 27]. In our study a decreasing prevalence of TAO was observed in SDG, but the difference was not statistically significant (p = 0.11). However, this beneficial tendency might be connected with the decreasing popularity of smoking in Poland reported in recent years and decreased exposure to passive nicotinism in public areas [28]. Smoking has been proven as one of the strongest risk factors of TAO [29, 30].
In children, the recommended initial treatment of choice is antithyroid drug therapy with methimazole (MMI). Propylthiouracil (PTU) should not be prescribed in paediatric patients due to reports of PTU-induced ANCA-positive vasculitis and rapidly progressive PTU liver failure with a low chance of reversibility. In contrast, MMI is not associated with severe liver failure in children [31] or with high prevalence of MPO-ANCA [32]. Adverse events during MMI therapy are dose-dependent and affect up to 20% of children [33]. In our study, side effects of ATDs were reported by 17% to 21.7% of children in FDG and SDG, respectively. We observed significantly less frequent severe adverse drug events in SDG (p < 0.05). Probably this is connected with decreased use of PTU in recent years. In SDG only one patient was treated with PTU; in FDG more patients received PTU as initial treatment, and more severe effects were reported in that group. Many studies support the observation that pharmacological treatment of GD in children is not very effective [34]. It allows long-term remission only in 30% of patients [35, 36]. One of the most important relapse risk factors is lack of TSH normalisation during the first three months of treatment [37, 38]. In our study among SDG patients prolonged TSH suppression was found in 32% of children. The same percentage of children treated ≥ 24 months had relapses after first-line treatment. However, prolonged TSH suppression highlights a low chance of remission and can indicate candidate patients requiring definitive therapy in the future.
Our paper supports other authors’ data regarding the seasonality of new diagnosis of GD with increased incidence from the end of spring to the end of autumn [37]. The hypotheses explaining this phenomenon include viral infections [37], allergic sensitisation [38], and decreased vitamin D concentration [39]. Seasonality is also observed in relapses of GD after completion of anti-thyroid drug therapy, with higher rates in spring and summer in comparison to autumn and winter [40].

Conclusions

We realise that our study has some limitations because of its retrospective character. We analysed medical records that were not originally designed for the study. Nevertheless, we can conclude that:
In our study, after mandatory salt iodination, a tendency of an increase in newly diagnosed GD in children without family susceptibility was observed.
The antibody profile in our group of GD children indicates the significant contribution of autoimmune processes involving all thyroid antigens; therefore, the term “autoimmune hyperthyroidism” seems to be more appropriate than classical GD in this group of patients.
The first-choice treatment with MMI rarely causes adverse events during the therapy, and they have benign character.

The authors declare no conflict of interest.

References

1. Lavard L, Ranlov I, Perrild H, et al. (1994): Incidence of juvenile thyrotoxicosis in Denmark, 1982-1988. A nationwide study. Eur J Endocrinol 130: 565-568.
2. Ross DS, Burch HB, Cooper DS, et al. (2016): American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and other causes of Thyrotoxicosis. Thyroid 26: 1343-1421.
3. Goday-Arno A, Cerda-Esteva M, Flores-Le-Roux JA, et al. (2008): Hyperthyroidism in a population with Down syndrome (DS). Clin Endocrinol (Oxf) 71: 110-114.
4. De Luca F, Corrias A, Salerno M, et al. (2010): Peculiarities of Graves’ disease in children and adolescents with Down’s syndrome. Eur J Endocrinol 162: 591-595.
5. Wasniewska M, Corrias A, Messina MF, et al. (2010): Graves’ disease prevalence in a young population with Turner syndrome. J Endocrinol Invest 33: 69-70.
6. Brown JJ, Datta V, Browning MJ, Swift PG (2004): Graves’ disease in DiGeorge syndrome: patient report with a review of endocrine autoimmunity associated with 22q11.2 deletion. J Pediatr Endocrinol Metab 17: 1575-1579.
7. Luo Y, Kawashima A, Ishido Y, et al. (2014): Iodine Excess as an Environmental Risk Factor for Autoimmune Thyroid Disease. Int J Mol Sci 15: 12895-12912.
8. Vučinić M, Kušec V, Dundović S, et al. (2018): The effect of 17 years of increased salt iodization on the prevalence and nature of goiter in Croatian schoolchildren. J Pediatr Endocrinol Metab Jul 28. pii: /j/jpem.ahead-of-print/jpem-2018-0129/jpem-2018-0129.xml. doi: 10.1515/jpem-2018-0129.
9. Zois C, Stavrou I, Kalogera C, et al. (2003): High Prevalence of Autoimmune Thyroiditis in Schoolchildren After Elimination of Iodine Deficiency in Northwestern Greece. Thyroid 13: 485-489.
10. Fernando RF, Chandrasinghe PC, Pathmeswaran AA (2012): The prevalence of autoimmune thyroiditis after universal salt iodisation in Sri Lanka. Ceylon Med J 57: 116-119.
11. Bülow Pedersen I, Laurberg P, Knudsen N, et al. (2006): Increase in Incidence of Hyperthyroidism Predominantly Occurs in Young People after Iodine Fortification of Salt in Denmark. J Clin Endocrinol Metab 91: 3830-3834.
12. Zarządzenie Ministra Zdrowia i Opieki Społecznej z dnia 24 lipca 1996 roku w sprawie zakazu produkcji i wprowadzania do obrotu w celach spożywczych niektórych rodzajów soli. http://www.monitorpolski.gov.pl/mp/1996/s/48/462 (pol).
13. Szybiński Z (2009): Iodine prophylaxis in Poland in the lights of the WHO recommendation on reduction of the daily salt intake. Pediatr Endocrinol Diabetes Metab 15: 103-107.
14. Kucharska A, Wrzosek A, Franas, Izabela A, et al. (2006): The factors determining the effectiveness of antithyroid drug therapy of Graves’ disease in children. Pediatr Endocrinol 4: 15-21.
15. Słowińska-Klencka D, Klencki M, Sporny S, Lewiński A (2002): Fine-needle aspiration biopsy of the thyroid in an area of endemic goitre: influence of restored sufficient iodine supplementation on the clinical significance of cytological results. Eur J Endocrinol 146: 19-26.
16. Doufas AG, Mastorakos G, Chatziioannou S, et al. (1999): The predominant form of non-toxic goiter in Greece is now autoimmune thyroiditis. Eur J Endocrinol 140: 505-511.
17. Harach HR, Williams ED (1995): Thyroid cancer and thyroiditis in the goitrous region of Salta, Argentina, before and after iodine prophylaxis. Clin Endocrinol (Oxf) 43: 701-706.
18. Rasooly L, Burek CL, Rose NR (1996): Iodine-induced autoimmune thyroiditis in NOD-H-2h4 mice. Clin Immunol Immunopathol 81: 287-292.
19. Bülow Pedersen I, Knudsen N, Carle A, et al. (2011): A cautious iodization program bringing iodine intake to a low recommended level is associated with an increase in the prevalence of thyroid autoantibodies in the population. Clin Endocrinol (Oxf) 75: 120-126.
20. Ogawa T, Sakata S, Nakamura S, et al. (1994): Thyroid hormone autoantibodies in patients with Graves’ disease: effect of anti-thyroid drug treatment. Clin Chim Acta 228: 113-122.
21. Mariotti S, Caturegli P, Piccolo P, et al.(1990): Antithyroid peroxidase autoantibodies in thyroid diseases. J Clin Endocrinol Metab 71: 661-669.
22. Umar H, Muallima N, Adam JM, Sanusi H (2006): Hashimoto’s thyroiditis following Graves’ disease. Acta Med Indones 42: 31-35.
23. Ohye H, Nishihara E, Sasaki I, et al. (2006): Four cases of Graves’ disease which developed after painful Hashimoto’s thyroiditis. Intern Med 45: 385-389.
24. Pak S, Valencia D, Fershko A (2017): Transformation of Hashimoto thyroiditis to Graves’ disease. Res Rev Insights. doi: 10.15761/RRI.1000117.
25. Krassas GE, Segni M Wiersinga WM (2004): Childhood Graves’ ophthalmopathy: results of a European questionnaire study. Eur J Endocrinol 153: 515-520.
26. Acuna OM, Athannassaki I, Paysse EA (2007): Association between thyroid-stimulating immunoglobulin levels and ocular findings in pediatric patients with Graves’ disease. Trans Am Ophthalmol Soc 105: 146-150; discussion: 150-151.
27. Lazar L, Kalter-Leibovici O, Pertzelan A, et al. (2000): Thyrotoxicosis in prepubertal children compared with pubertal and postpubertal patients. J Clin Endocrinol Metab 85: 3678-3682.
28. Główny Urząd Statystyczny. Zdrowie i zachowania zdrowotne mieszkańców Polski w świetle badania EHIS 2014. https://stat.gov.pl/obszary-tematyczne/zdrowie/zdrowie/zdrowie-i-zachowania-zdrowotne-mieszkancow-polski-w-swietle-badania-ehis-2014,10,1.html (pol).
29. Villanueva R, Inzerillo AM, Tomer Y, et al. (2000): Limited Genetic Susceptibility to Severe Graves’ Ophthalmopathy: No Role for CTLA-4 But Evidence for an Environmental Etiology. Thyroid 10: 791-798.
30. Hegediüs L, Brix TH, Vestergaard PJ (2004): Relationship between cigarette smoking and Graves’ ophthalmopathy. Endocrinol Invest 27: 265-271.
31. Rivkees SA, Mattison DR (2009): Propylthiouracil (PTU) Hepatoxicity in Children and Recommendations for Discontinuation of Use. Int J Pediatr Endocrinol 2009: 132041. doi: 10.1155/2009/132041.
32. Sato H, Hattori M, Fujieda M, et al. (2000): High prevalence of antineutrophil cytoplasmic antibody positivity in childhood onset Graves’ disease treated with propylthiouracil. J Clin Endocrinol Metab 85: 4270-4273.
33. Rivkees SA, Stephenson K, Dinauer C (2010): Adverse events associated with methimazole therapy of graves’ disease in children. Int J Pediatr Endocrinol 2010: 176970. doi: 10.1155/2010/176970.
34. John M, Sundrarajan R, Gomadam SS (2015): Anti thyroid drugs in pediatric Graves’ disease. Indian J Endocrinol Metab 19: 340-346.
35. Kaguelidou F, Alberti C, Castanet M, et al. (2008): Predictors of autoimmune hyperthyroidism relapse in children after discontinuation of antithyroid drug treatment. J Clin Endocrinol Metab 93: 3817-3826.
36. Glaser NS, Styne DM (1997): Predictors of early remission of hyperthyroidism in children. J Clin Endocrinol Metab 82: 1719-1726.
37. Dong YH, Fu DG (2014): Autoimmune thyroid disease: mechanism, genetics and current knowledge. Eur Rev Med Pharmacol Sci 18: 3611-3618.
38. Nagata K, Kumata K, Nakayama Y, et al. (2017): Epstein-Barr Virus Lytic Reactivation Activates B Cells Polyclonally and Induces Activation-Induced Cytidine Deaminase Expression: A Mechanism Underlying Autoimmunity and Its Contribution to Graves’ Disease. Viral Immunol 30: 240-249.
39. Xu MY, Cao B, Yin J, et al. (2015): Vitamin D and Graves’ disease: a meta-analysis update. Nutrients 7: 3813-3817.
40. Misaki T, Iida T, Kasagi K, Konishi J (2003): Seasonal variation in relapse rate of Graves’ disease after thionamide drug treatment. Endocr J 50: 669-672.