Five-Year Prospective Evaluation of Thyroid Function Test Evolution in Children with Hashimoto's Thyroiditis Presenting with Either Euthyroidism or Subclinical Hypothyroidism

Abstract

Background:

Whether the course of thyroid function in Hashimoto's thyroiditis (HT) differs in children who present with either euthyroidism or subclinical hypothyroidism (SH) has been incompletely investigated.

Aim:

Using a five-year prospective evaluation of 234 children with HT and no prognostic risk factors, this study investigated whether the evolution of the thyroid status is influenced by the biochemical pattern at initial diagnosis.

Results:

In the entire series, thyrotropin values significantly increased during follow-up, while free thyroxine values decreased and the proportion of children with a thyroid dysfunction increased from 27.3% to 47.4% (p = 0.0001). An increasing proportion of cases with severe thyroid dysfunction was identified, especially among the 64 patients presenting with SH (group B), but also among the 170 children presenting with euthyroidism (group A) at initial diagnosis. At the end of follow-up, the prevalence of children with overt hypothyroidism was 12.3% in group A compared with 31.2% in group B (p = 0.0007). In the overall population, however, the majority of patients (52.6%) exhibited biochemical euthyroidism at the end of follow-up.

Conclusions:

Children with HT may develop a deterioration of thyroid status during the first five years of disease. Such a trend may be observed, even in the patients who initially present with a mild biochemical picture (either SH or euthyroidism). A total of 57.1% of initially euthyroid children remain euthyroid, and 40.6% of patients with initial SH normalize thyroid function within five years after HT diagnosis. The patients presenting with SH are more prone to the risk of developing severe thyroid dysfunction over time.

Introduction

Hashimoto's thyroiditis (HT) is a relatively common disease, and its prevalence in the pediatric age has been reported to range around 3%, achieving its peak during adolescence (1). It is by far the most common form of thyroiditis in childhood (2) and the most frequent cause of pediatric thyroid disease in iodine-replete areas of the world (3,4).

At diagnosis, children and adolescents with HT may be asymptomatic, and the main reasons for referral are goiter and association with extrathyroidal autoimmune disorders (5). Thyroid function at presentation may range from euthyroidism to frank hypothyroidism (6) or, occasionally, overt or subclinical hyperthyroidism (SH) (7 –11). The biochemical findings which are most frequently observed at HT diagnosis in the pediatric age are euthyroidism (in 52.1% of cases) and either frank or SH (in 41.4% of cases) (12).

However, although the recent literature includes many reports on the biochemical presentation of HT in children (7 –20), only few studies have specifically addressed whether the biochemical pattern at diagnosis may in any way affect the subsequent evolution of thyroid function over time. In particular, it has been only sporadically investigated whether the long-term course of thyroid function may significantly differ in the children who initially presented with either euthyroidism or SH (5,13), that is, the two biochemical pictures of thyroid function that are most frequently found at diagnosis of juvenile HT (9,18).

The aim of the present study was to investigate, by means of a five-year prospective evaluation, whether the evolution of the thyroid status is influenced by the biochemical pattern at initial diagnosis.

Patients and Methods

Study population

The study cohort consisted of 234 children (177 girls), aged between 2.5 and 17.4 years at the time of HT diagnosis. They were identified in three pediatric endocrinology centers of Northern and Southern Italy during the period 2000–2008, and were admitted to this prospective study according to the following inclusion and exclusion criteria.

The inclusion criteria were: (i) age <18 years; (ii) positivity for serum thyroglobulin and/or thyroid peroxidase autoantibodies (TGAbs and TPOAbs, respectively) at titers above the upper limits of the laboratory reference ranges (30 and 20 IU/mL, respectively); (iii) a hypoechogenic pattern on ultrasonography (US), consistent with autoimmune thyroid disease (AITD); and (iv) a biochemical pattern of thyroid function at HT diagnosis of either euthyroidism or SH.

The exclusion criteria were: (i) association with other causes of thyroid dysfunction or enlargement, such as concomitant therapies with antiepileptic agents, glucocorticoids and iodinated drugs, or individuals originating from iodine-deficient areas; (ii) association with either Turner syndrome (TS) or Down syndrome (DS), that is, two chromosomopathies that are known to be linked with an increased risk of AITDs (21 –27); and (iii) a biochemical picture of thyroid function at HT diagnosis consistent with either overt hypothyroidism or hyperthyroidism, or SH.

All the recruited children were in good clinical condition and clinically euthyroid at HT diagnosis, and the main clinical reasons for the referral were: (i) mild thyroid enlargement with palpable lobes (58.5% of cases); (ii) association with extrathyroidal autoimmune illnesses (24.8% of cases); and (iii) a family history of thyroid disease in first-degree relatives (22.2% of cases). The main clinical and biochemical data of these patients at HT diagnosis are reported in Table 1.

Table 1.

Median Ages (and Ranges), Prevalence Rates of Pubertal Patients, Mean Thyroid Volume (±SD), Mean fT4 (±SD), Median TSH, and TPOAbs and TGAbs Serum Levels (and Ranges) at Diagnosis of Hashimoto's Thyroiditis in the Entire Study Population and in the Two Groups of Children Presenting with Either Euthyroidism (Group A) or Subclinical Hypothyroidism (Group B)

	Age (years)	Pubertal patients (%)	Thyroid volume (SD score ^a )	fT4 (pmol/L)	TSH (mIU/mL)	TPOAbs (mIU/L)	TGAbs (mIU/L)
Entire population (n = 234)	10.5 (2.5–17,4)	53.0	+1.04 ± 0.54	15.0 ± 3.5	3.8 (0.5–19.3)	340 (40–29,950)	200 (35–8348)
Group A (n = 170)	10.5 (2.5–17.4)	55.3	+1.00 ± 0.55	15.4 ± 3.5	2.7 (0.5–4.0)	362 (40–29,950)	204 (37–8348)
Group B (n = 64)	10.1 (3.9–15.9)	46.9	+1.15 ± 0.50	14.1 ± 3.2	5.9 (5.0–19.3)	283 (40–6375)	200 (35–3000)
p ^b	0.40	0.25	0.067	0.012	0.0001	0.36	0.28

According to the ultrasonographic standards for age of Aydiner et al. (32).

Between groups A and B.

fT4, free thyroxine; TSH, thyrotropin; TPOAbs, serum thyroid peroxidase autoantibodies; TGAbs, serum thyroglobulin autoantibodies.

The 234 subjects were divided into two groups, according to whether they exhibited, at HT diagnosis, a biochemical thyroid status consistent with either euthyroidism (group A) or SH (group B). Group A consisted of 170 children (133 girls) aged between 2.5 and 17.4 years, while group B consisted of 64 children (44 girls) aged between 3.9 and 15.9 years at HT diagnosis.

Study design

All the children who were diagnosed in the authors' centers during the period 2000–2008 as having HT and who fulfilled the above-reported inclusion and exclusion criteria were consecutively recruited for this study.

From the time of recruitment, all of them were followed as outpatients every 12 months for a pre-established period of five years, and only those who completed the overall follow-up period were taken into consideration for this study.

At each examination, thyrotropin (TSH), free thyroxine (fT4), TPOAb, and TGAb serum levels were measured. In the children who exhibited an increase in TSH levels to >10 mIU/L and/or a pathological decrease of fT4 levels to <10.3 pmol/L at the annual investigations, levothyroxine (LT4) therapy (1 μg/kg/day) was begun immediately, according to the authors' guidelines (28) and other literature recommendations (29,30). In the individuals who exhibited a dramatic fall in TSH serum level to <0.3 mIU/L and a concomitant increase of fT4 to >24.4 pmol/L during follow-up, methimazole treatment (0.5–1 mg/kg/day, maximal dose 30 mg/day) was begun immediately, as generally recommended (31). In the cases undergoing LT4 or methimazole treatment, doses were periodically (every three months) adjusted on the basis of clinical and biochemical assessments.

With regard to the thyroid function at the time of recruitment and at the end of follow-up, children from both groups were evaluated according to TSH and fT4 serum levels and classified into the following biochemical groups: (i) euthyroidism (both TSH and fT4 within normal limits); (ii) SH (normal fT4 and elevated TSH); (iii) overt hypothyroidism (elevated TSH with low fT4); and (iv) hyperthyroidism (suppressed TSH and elevated fT4). The prevalence rates of the above biochemical conditions in the two groups were compared between them at the end of follow-up.

All the children who were on LT4 treatment at the end of follow-up were analyzed six weeks after therapy withdrawal. Those who were under methimazole therapy at the end of follow-up were considered as patients who shifted over time from HT to Graves' disease (GD), provided that TSH receptor autoantibodies (TRAbs) were positive.

Both at entry and five years later, all the patients from both groups underwent a thyroid US aiming at evaluating thyroid echogenicity and volume.

The study design was approved by the ethical committees of the hospitals participating in the study, and the children's parents gave informed consent. For the few subjects who came of age (≥18 years) during follow-up, the patients' informed consent was also obtained after oral and written explanation of the study. Appropriate consent was also obtained earlier from the Study Group for thyroid diseases of the Italian Society for Pediatric Endocrinology and Diabetology.

Methods

TSH (reference range 0.3–4.5 mIU/L) and fT4 (reference range 10.3–24.4 pmol/L) levels were measured by radioimmunoassays. TPOAbs (reference range 0–20 IU/mL) and TGAbs (reference range 0–30 IU/mL) were measured by chemiluminescent immunometric assays (12).

TRABs were measured by a radioreceptor assay only in those patients who developed a hyperthyroid picture and underwent methimazole therapy during follow-up. For the used method, values >1.5 IU/mL are considered positive (10).

Thyroid US was performed in all cases with a high-resolution 7.5 MHz linear transducer. Both at diagnosis and five years later, thyroid volume was assessed by the same operators. Gland volume was expressed as SD scores (SDS), according to the US age-specific standards recently reported by Aydiner et al. (32).

Statistical analysis

Results are expressed as mean ± SD or median and range values, as appropriate. Comparisons between groups were performed by Student's unpaired and paired t-test (normally distributed data) or Mann–Whitney and Wilcoxon test (non-normally distributed data), as appropriate. Frequency rates were compared using the chi-square test. Correlations between quantitative variables were assessed using Pearson's correlation analysis. The level of significance was set at 0.05 for all the statistical analyses.

Results

Main data at diagnosis of HT

The female predominance in the overall population was 75.6%, with no significant differences between the two patient groups (78.2 vs. 68.8%; p = 0.132). The median age was not significantly different in the children of group A compared to those of group B (Table 1). Even though expressed as mean ± SD, patients' age at entry was similar in the two groups. Furthermore, the prevalence rates of pubertal children at HT diagnosis did not significantly differ between the two groups (Table 1). Mean thyroid volume was not significantly different in the patients of groups A and B (Table 1). In group B, median TSH values were higher than they were in group A, while mean fT4 values were lower (Table 1). Both TPOAb and TGAb serum levels were not significantly different in the two groups (Table 1).

Main data at the end of follow-up

Median ages were very similar in the children of groups A (15.5 years; range 7.6–22.4 years) and B (15.0 years; range 8.9–19.5 years), and no significant differences were detected, even though age was expressed as mean ± SD. Furthermore, the prevalence rates of pubertal patients did not significantly differ between groups A and B (94.7% vs. 87.7%, respectively; p = 0.058).

Mean thyroid volume SDS significantly increased from HT diagnosis to the end of follow-up, both in the overall population and in the patients of group A, whereas such an increase did not achieve statistical relevance in the children of group B (Table 2). However, at the end of follow-up, as well as at study entry, the mean thyroid volume SDS did not significantly differ between the patients of groups A and B (Table 2).

Table 2.

Mean Thyroid Volume (±SD), Mean fT4 (±SD), Median TSH, and TPOAbs and TGAbs Serum Levels (and Ranges) at the End of a Five-Year Follow-Up in the Entire Study Population and in the Two Groups of Patients Presenting with Either Euthyroidism (Group A) or Subclinical Hypothyroidism (Group B)

	Thyroid volume (SD score ^a )	p^b	fT4 (pmol/L)	p^b	TSH (mIU/mL)	p^b	TPOAbs (mIU/L)	p^b	TGAbs (mIU/L)	p^b
Entire population (n = 234)	+1.38 ± 0.81	0.0001	14.3 ± 3.5	0.020	4.0 (0.07–99)	0.001	251 (6–8945)	0.036	119 (5–6443)	0.003
Group A (n = 170)	+1.42 ± 0.80	0.0001	15.1 ± 3.3	0.190	3.4 (0.5–99)	0.001	286 (6–8945)	0.102	120 (5–6443)	0.077
Group B (n = 64)	+1.31 ± 0.84	0.134	13.3 ± 3.6	0.186	6.2 (0.07–14.3)	0.192	194.5 (19–2854)	0.048	110.5 (20–700)	0.0001
p ^c	0.349		0.0001		0.0001		0.089		0.080

According to the ultrasonographic standards for age of Aydiner et al. (32).

Compared with the corresponding level measured at the start of follow-up.

Between groups A and B.

In the whole population, mean fT4 serum levels significantly decreased from entry to the end of follow-up, whereas the median TSH values significantly increased during the same period (Table 2). A relevant increase of median TSH values from entry onwards was also recorded in the children of group A but not in those of group B (Table 2). In both these groups, mean fT4 values did not significantly change during follow-up (Table 2). At the end of follow-up as well as at study entry, TSH serum levels were significantly higher and fT4 values significantly lower in the patients of group B compared with those of group A (Table 2).

For the patients of both groups who were treated with LT4, the results in Table 2 reflect thyroid function and autoimmunity tests after six weeks of therapy withdrawal. During follow-up, median TPOAb and TGAb serum levels significantly decreased in the overall population (Table 2), with no differences between the patients who received LT4 therapy and those who were not treated. At the end of follow-up, both TPOAbs and TGAbs were not significantly different in groups A and B (Table 2).

Thyroid function patterns at the end of follow-up

As a consequence of the changes in thyroid function tests, which were recorded throughout follow-up, the proportion of children with a biochemical pattern of euthyroidism, in the entire population, significantly decreased over time (from 72.6% to 52.6%; p = 0.0001), whereas the proportion of patients who developed a biochemical picture of overt hypothyroidism during the same period significantly increased (from 0% to 17.5%; p = 0.0001).

Finally, the rates of children with either SH or hyperthyroidism did not substantially change during follow-up in the overall series (from 27.4% to 29.1% for SH and from 0% to 0.8% for hyperthyroidism). In the entire study population, the proportion of children with a thyroid dysfunction significantly increased throughout follow-up from 27.3% to 47.4% (χ² = 20.16; p = 0.0001).

When the evolution over time of thyroid function patterns was separately analyzed in the context of the two different study groups, it became apparent that the majority of group A children (97/170) remained biochemically euthyroid, even at the end of follow-up, whereas the thyroid status deteriorated in 73/170 with the development of either SH (52/73 cases) or overt hypothyroidism (21/73 cases).

Among the 64 children of group B, 26 became euthyroid over time, 20 developed a biochemical picture of overt hypothyroidism, 16 remained SH, and the remaining two shifted over time from HT to GD. In the overall study population, shifting from HT to GD was recorded only in these two patients.

At the end of the observation period, the prevalence of children with euthyroidism was significantly higher in group A, while the prevalence of children with either overt hypothyroidism or hyperthyroidism was significantly higher in group B (Table 3). Due to the relevant percentage (40.6%) of patients with initial SH who became euthyroid five years later, the prevalence of children with SH was very similar in the two groups at the conclusion of follow-up (Table 3).

Table 3.

Prevalence Rates (%) of the Different Biochemical Patterns of Thyroid Function Detected at the End of a Five-Year Follow-Up in the Entire Population and in the Two Groups of Children with Hashimoto's Thyroiditis Presenting with Either Euthyroidism (Group A) or Subclinical Hypothyroidism (Group B)

	Euthyroidism	Subclinical hypothyroidism	Overt hypothyroidism	Hyperthyroidism	Overall dysfunctions
Entire population (n = 234)	52.6	29.1	17.5	0.8	47.4
Group A (n = 170)	57.1	30.6	12.3	0	42.9
Group B (n = 64)	40.6	25.0	31.2	3.2	59.4
p ^a	0.025	0.400	0.0007	0.020	0.025

Between groups A and B.

Median levels (and ranges) of both TPOAbs and TGAbs at HT diagnosis were not significantly different in the patients who developed a biochemical picture of overt hypothyroidism during follow-up compared to those who were still euthyroid or SH at the end of the observation period (311 mIU/L [range 40–6400] vs 357 mIU/L [range 34–29,950], p = 0.254, for TPOAbs; 101 mIU/L [range 40–4809) vs. 222 mIU/L [range 35–8348], p = 0.075, for TGAbs).

Discussion

In adults, HT has been extensively investigated, even in the last 20 years (33 –39), and follow-up studies indicate that its natural history in adulthood is often characterized by a progressive shift toward SH or overt hypothyroidism from euthyroidism (34,35,37).

In children and adolescents, the natural course of HT may be quite variable (5,9,15,17,19,40 –42) and might be dependent on the TSH serum levels at the time of HT presentation (15,34,37). In fact, in the four-year follow-up study by Radetti et al. (15), the majority of euthyroid patients remained euthyroid, while those with SH were found to develop overt hypothyroidism over time.

The present study compared the long-term evolution of thyroid function tests in two selected study populations of children with HT, who initially presented with either biochemical euthyroidism or SH. According to the study design, patients who presented with either overt hypothyroidism or hyperthyroidism were not taken into consideration for this study. Moreover, all the patients with either TS or DS were excluded (i.e., two chromosomopathies that are known to be able to significantly affect the course of HT by increasing the risk of a thyroid function deterioration over time) (43 –45).

This study design gave us the opportunity of evaluate whether the development of HT may have a negative impact on the long-term evolution of thyroid function in children and adolescents, irrespective of other concomitant prognostic risk factors. According to the results, it might be argued that the course of thyroid function in young patients with HT may be not infrequently characterized by a spontaneous deterioration over time, even in the cases who initially present with a mild biochemical picture (i.e., either euthyroidism or SH). This inference is supported by both the increasing median TSH levels and the decreasing mean fT4 levels that were recorded in the entire study population from HT diagnosis onwards. This trend was observed both in the patients who were biochemically euthyroid at HT diagnosis and in those who presented with SH, which suggests that the evolution of the thyroid status in children with HT is not significantly affected by thyroid function pattern at diagnosis over time, at least in the cases who initially present with a mild biochemical picture.

The significant deterioration of thyroid status that occurred from HT diagnosis onwards in the present study population was also substantiated by the concomitant increase in thyroid volume SDS, which was recorded in the patient series during follow-up.

It has to be emphasized, however, that the evolution of the thyroid status in children with HT is not necessarily unfavorable over time. Of note, at the end of the five-year follow-up, 57.1% of initially euthyroid patients remained euthyroid, and 40.6% of those who presented with SH spontaneously normalized their thyroid function. Such a percentage of SH patients who became euthyroid throughout follow-up was even higher than that reported by other authors in pediatric cohorts with HT-related SH (30,46,47), but lower than that observed by Lazar et al. during a five-year follow-up in a very large pediatric population with SH (48). However, it has to be considered that the vast majority of children included in that important study did not have an underlying AITD (48).

When the patients in the present series who had presented with SH were compared with those who were initially euthyroid, the only substantial difference in terms of biochemical outcomes was that SH children were prone to a higher risk of developing severe thyroid dysfunction over time, either overt hypothyroidism or hyperthyroidism. This is not very surprising, considering that underlying HT is known to affect the evolution of SH in the pediatric age negatively (30,44,46,47,49,50).

In the present study, 0.8% of children with HT developed a biochemical and clinical picture of GD over time, a sequence of events that has been reported just recently to occur more frequently in young patients with TS and DS (51). Such a change from HT to GD is known to occur, even in the general pediatric population (52 –56).

The majority of long-term follow-up studies including quantitative thyroid autoantibody measurements were performed on small samples of adults (36,38,39,57 –60). According to the results of those studies, a significant decrease of TPOAb and/or TGAb serum levels may be frequently observed over time, particularly in adult patients receiving LT4 therapy (36,39,59). On the basis of the present results, it is concluded that a decrease in autoantibody serum levels may be recorded, even in juvenile HT over time, irrespective of whether children are treated. Such a decrease involves both TPOAbs and TGAbs.

Finally, from a methodological view, it is known that age-specific reference ranges should possibly be employed when measuring TSH and fT4 in children. During very early life, the levels of these hormones may vary widely, making it challenging to interpret measurements in infants and, particularly, newborns (61). In the present study, however, the median ages of the patients included in the two study groups were very similar, and no patients <2.5 and >17.4 years were recruited in the overall study series.

Conclusions

Children with HT may develop a deterioration of thyroid status during the first five years of disease. Such a trend may be observed, even in the patients who initially present with a mild biochemical picture (either SH or euthyroidism). A total of 57.1% of initially euthyroid children remain euthyroid, and 40.6% of patients with initial SH normalize thyroid function within five years after HT diagnosis. Patients presenting with SH are more prone to the risk of developing severe thyroid dysfunction over time.

Footnotes

Author Disclosure Statement

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

References

Akamizu

, Amino

, DeGroot

. 2013. Hashimoto's thyroiditis. In: De Groot

, Beck-Peccoz

, Chrousos

, Dungan

, Grossman

, Hershman

, Koch

, McLachlan

, New

, Rebar

, Singer

, Vinik

, Weickert

(eds) Endotext [Internet]. MDText.com, Inc., South Dartmouth, MA.

Wasniewska

, Vigone

, Cappa

, Aversa

, Rubino

, De Luca

. 2007. Acute suppurative thyroiditis in childhood: relative frequency among thyroid inflammatory diseases. J Endocrinol Invest, 30:346–347.

Lafranchi

. 1992. Thyroiditis and acquired hypothyroidism. Pediatr Ann, 21:32–39.

Kabelitz

, Liesenkötter

, Stach

, Willgerodt

, Stäblein

, Singendonk

, Jäger-Roman

, Litzenbörger

, Ehnert

, Grüters

. 2003. The prevalence of anti-thyroid peroxidase antibodies and autoimmune thyroiditis in children and adolescents in an iodine replete area. Eur J Endocrinol, 148:301–307.

de Vries

, Bulvik

, Phillip

. 2009. Chronic autoimmune thyroiditis in children and adolescents: at presentation and during long-term follow-up. Arch Dis Child, 94:33–37.

De Luca

, Aversa

, Salzano

, Zirilli

, Sferlazzas

, Wasniewska

. 2015. Autoimmune thyroiditis. In: Bona

, De Luca

, Monzani

(eds) Thyroid Diseases in Childhood: Recent Advances from Basic Science to Clinical Practice. Springer International Publishing, Switzerland, pp 181–194.

Nabhan

, Kreher

, Eugster

. 2005. Hashitoxicosis in children: clinical features and natural history. J Pediatr, 146:533–536.

Williamson

, Greene

. 2010. Incidence of thyrotoxicosis in childhood: a national population based study in the UK and Ireland. Clin Endocrinol (Oxf), 72:358–363.

Özen

, Berk

, Şimşek

, Darcan

. 2011. Clinical course of Hashimoto's thyroiditis and effects of levothyroxine therapy on the clinical course of the disease in children and adolescents. J Clin Res Pediatr Endocrinol, 3:192–197.

10.

Wasniewska

, Corrias

, Salerno

, Lombardo

, Aversa

, Mussa

, Capalbo

, De Luca

, Valenzise

. 2012. Outcomes of children with hashitoxicosis. Horm Res Paediatr, 77:36–40.

11.

Aversa

, Valenzise

, Corrias

, Salerno

, Mussa

, Capalbo

, Salzano

, De Luca

, Wasniewska

. 2014. Subclinical hyperthyroidism when presenting as initial manifestation of juvenile Hashimoto's thyroiditis: first report on its natural history. J Endocrinol Invest, 37:303–308.

12.

Wasniewska

, Corrias

, Salerno

, Mussa

, Capalbo

, Messina

, Aversa

, Bombaci

, De Luca

, Valenzise

. 2012. Thyroid function patterns at Hashimoto's thyroiditis presentation in childhood and adolescence are mainly conditioned by patients' age. Horm Res Paediatr, 78:232–236.

13.

Mäenpää

, Raatikka

, Räsänen

, Taskinen

, Wager

. 1985. Natural course of juvenile autoimmune thyroiditis. J Pediatr, 107:898–904.

14.

Zak

, Noczyńska

, Wasikowa

, Zaleska-Dorobisz

, Golenko

. 2005. Chronic autoimmune thyroid disease in children and adolescents in the years 1999–2004 in Lower Silesia, Poland. Hormones, 4:45–48.

15.

Radetti

, Gottardi

, Bona

, Corrias

, Salardi

, Loche

; Study Group for Thyroid Diseases of the Italian Society for Pediatric Endocrinology (SIEDP/ISPED). 2006. The natural history of euthyroid Hashimoto's thyroiditis in children. J Pediatr, 149:827–832.

16.

Gopalakrishnan

, Chugh

, Chhillar

, Ambardar

, Sahoo

, Sankar

. 2008. Goitrous autoimmune thyroiditis in a pediatric population: a longitudinal study. Pediatrics, 122:e670–674.

17.

Demirbilek

, Kandemir

, Gonc

, Ozon

, Alikasifoglu

. 2009. Assessment of thyroid function during the long course of Hashimoto's thyroiditis in children and adolescents. Clin Endocrinol, 71:451–454.

18.

Skarpa

, Kousta

, Tertipi

, Anyfandakis

, Vakaki

, Dolianiti

, Fotinou

, Papathanasiou

. 2011. Epidemiological characteristics of children with autoimmune thyroid disease. Hormones, 10:207–214.

19.

Radetti

, Maselli

, Buzi

, Corrias

, Mussa

, Cambiaso

, Salerno

, Cappa

, Baiocchi

, Gastaldi

, Minerba

, Loche

. 2012. The natural history of the normal/mild elevated TSH serum levels in children and adolescents with Hashimoto's thyroiditis and isolated hyperthyrotropinaemia: a 3-year follow-up. Clin Endocrinol, 76:394–398.

20.

De Luca

, Santucci

, Corica

, Pitrolo

, Romeo

, Aversa

. 2013. Hashimoto's thyroiditis in childhood: presentation modes and evolution over time. Ital J Pediatr, 30:39–48.

21.

Livadas

, Xekouki

, Fouka

, Kanaka-Gantenbein

, Kaloumenou

, Mavrou

, Constantinidou

, Dacou-Voutetakis

. 2005. Prevalence of thyroid dysfunction in Turner's syndrome: a long-term follow-up study and brief literature review. Thyroid, 15:1061–1066.

22.

Fukuda

, Hizuka

, Kurimoto

, Morita

, Tanaka

, Yamakado

, Takano

. 2009. Autoimmune thyroid diseases in 65 Japanese women with Turner syndrome. Endocr J, 56:983–986.

23.

Goday-Arno

, Cerda-Esteva

, Flores-Le-Roux

, Chillaron-Jordan

, Corretger

, Cano-Pérez

. 2009. Hyperthyroidism in a population with Down syndrome (DS). Clin Endocrinol, 71:110–114.

24.

De Luca

, Corrias

, Salerno

, Wasniewska

, Gastaldi

, Cassio

, Mussa

, Aversa

, Radetti

, Arrigo

. 2010. Peculiarities of Graves' disease in children and adolescents with Down's syndrome. Eur J Endocrinol, 162:591–595.

25.

Wasniewska

, Corrias

, Messina

, Crisafulli

, Salzano

, Valenzise

, Mussa

, De Luca

. 2010. Graves' disease prevalence in a young population with Turner syndrome. J Endocrinol Invest, 33:69–70.

26.

Gawlik

, Gawlik

, Januszek-Trzciakowska

, Patel

, Malecka-Tendera

. 2011. Incidence and dynamics of thyroid dysfunction and thyroid autoimmunity in girls with Turner's syndrome: a long-term follow-up study. Horm Res Paediatr, 76:314–320.

27.

Valenzise

, Aversa

, Corrias

, Mazzanti

, Cappa

, Ubertini

, Scarano

, Mussa

, Messina

, De Luca

, Wasniewska

. 2014. Epidemiology, presentation and long-term evolution of Graves' disease in children, adolescents and young adults with Turner syndrome. Horm Res Paediatr, 81:245–250.

28.

Arrigo

, Wasniewska

, Crisafulli

, Lombardo

, Messina

, Rulli

, Salzano

, Valenzise

, Zirilli

, De Luca

. 2008. Subclinical hypothyroidism: the state of the art. J Endocrinol Invest, 31:79–84.

29.

Cooper

. 2001. Clinical practice. Subclinical hypothyroidism. N Engl J Med, 345:260–265.

30.

Lazarus

, Brown

, Daumerie

, Hubalewska-Dydejczyk

, Negro

, Vaidya

. 2014. European thyroid association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J, 3:76–94.

31.

Cooper

. 2005. Antithyroid drugs. N Engl J Med, 352:905–917.

32.

Aydıner

, Karakoç Aydıner

, Akpınar

, Turan

, Bereket

. 2015. Normative data of thyroid volume—ultrasonographic evaluation of 422 subjects aged 0–55 years. J Clin Res Pediatr Endocrinol, 7:98–101.

33.

Romaldini

, Biancalana

, Figueiredo

, Farah

, Mathias

. 1996. Effect of L-thyroxine administration on antithyroid antibody levels, lipid profile, and thyroid volume in patients with Hashimoto's thyroiditis. Thyroid, 6:183–188.

34.

Wang

, Crapo

. 1997. The epidemiology of thyroid disease and implications for screening. Endocrinol Metab Clin North Am, 26:189–218.

35.

Vanderpump

, French

, Appleton

, Tunbridge

, Kendall-Taylor

. 1998. The prevalence of hyperprolactinaemia and association with markers of autoimmune thyroid disease in survivors of the Whickham Survey cohort. Clin Endocrinol, 48:39–44.

36.

Padberg

, Heller

, Usadel

, Schumm-Draeger

. 2001. One-year prophylactic treatment of euthyroid Hashimoto's thyroiditis patients with levothyroxine: is there a benefit?. Thyroid, 11:249–255.

37.

Vanderpump

, Tunbridge

. 2002. Epidemiology and prevention of clinical and subclinical hypothyroidism. Thyroid, 12:839–847.

38.

Aksoy

, Kerimoglu

, Okur

, Canpinar

, Karaağaoğlu

, Yetgin

, Kansu

, Gedik

. 2005. Effects of prophylactic thyroid hormone replacement in euthyroid Hashimoto's thyroiditis. Endocr J, 52:337–343.

39.

Schmidt

, Voell

, Rahlff

, Dietlein

, Kobe

, Faust

, Schicha

. 2008. Long-term follow-up of antithyroid peroxidase antibodies in patients with chronic autoimmune thyroiditis (Hashimoto's thyroiditis) treated with levothyroxine. Thyroid, 18:755–760.

40.

Moore

. 1996. Natural course of “subclinical” hypothyroidism in childhood and adolescence. Arch Pediatr Adolesc Med, 150:293–297.

41.

Wang

, Tung

, Tsai

, Lee

, Hsiao

. 2006. Long-term outcome of hormonal status in Taiwanese children with Hashimoto's thyroiditis. Eur J Pediatr, 165:481–483.

42.

Lee

, Hwang

. 2014. The natural course of Hashimoto's thyroiditis in children and adolescents. J Pediatr Endocrinol Metab, 27:807–812.

43.

Aversa

, Messina

, Mazzanti

, Salerno

, Mussa

, Faienza

, Scarano

, De Luca

, Wasniewska

. 2015. The association with Turner syndrome significantly affects the course of Hashimoto's thyroiditis in children, irrespective of karyotype. Endocrine, 50:777–782.

44.

Wasniewska

, Aversa

, Salerno

, Corrias

, Messina

, Mussa

, Capalbo

, De Luca

, Valenzise

. 2015. Five-year prospective evaluation of thyroid function in girls with subclinical mild hypothyroidism of different etiology. Eur J Endocrinol, 173:801–808.

45.

Aversa

, Lombardo

, Valenzise

, Messina

, Sferlazzas

, Salzano

, De Luca

, Wasniewska

. 2015. Peculiarities of autoimmune thyroid diseases in children with Turner or Down syndrome: an overview. Ital J Pediatr, 15:39–41.

46.

Monzani

, Prodam

, Rapa

, Moia

, Agarla

, Bellone

, Bona

. 2012. Endocrine disorders in childhood and adolescence. Natural history of subclinical hypothyroidism in children and adolescents and potential effects of replacement therapy: a review. Eur J Endocrinol, 168:R1–R11.

47.

Bona

, Prodam

, Monzani

. 2013. Subclinical hypothyroidism in children: natural history and when to treat. J Clin Res Pediatr Endocrinol, 5 Suppl 1:23–28.

48.

Lazar

, Frumkin

, Battat

, Lebenthal

, Phillip

, Meyerovitch

. 2009. Natural history of thyroid function tests over 5 years in a large pediatric cohort. J Clin Endocrinol Metab, 94:1678–1682.

49.

Aversa

, Valenzise

, Corrias

, Salerno

, De Luca

, Mussa

, Rezzuto

, Lombardo

, Wasniewska

. 2015. Underlying Hashimoto's thyroiditis negatively affects the evolution of subclinical hypothyroidism in children irrespective of other concomitant risk factors. Thyroid, 25:183–187.

50.

Monzani

, Prodam

, Bellone

, Bona

. 2015. Subclinical hypothyroidism. In: Bona

, De Luca

, Monzani

(eds) Thyroid Diseases in Childhood: Recent Advances from Basic Science to Clinical Practice. Springer International Publishing, Switzerland, pp 195–202.

51.

Aversa

, Lombardo

, Corrias

, Salerno

, De Luca

, Wasniewska

. 2014. In young patients with Turner or Down syndrome, Graves' disease presentation is often preceded by Hashimoto's thyroiditis. Thyroid, 24:744–747.

52.

Champion

, Gopinath

, Ma

, El-Kaissi

, Wall

. 2008. Conversion to Graves' hyperthyroidism in a patient with hypothyroidism due to Hashimoto's thyroiditis documented by real-time thyroid ultrasonography. Thyroid, 18:1135–1137.

53.

Ludgate

, Emerson

. 2008. Metamorphic thyroid autoimmunity. Thyroid, 18:1035–1037.

54.

Wasniewska

, Corrias

, Arrigo

, Lombardo

, Salerno

, Mussa

, Vigone

, De Luca

. 2010. Frequency of Hashimoto's thyroiditis antecedents in the history of children and adolescents with Graves' disease. Horm Res Paediatr, 73:473–476.

55.

Kamath

, Young

, Kabelis

, Sanders

, Adlan

, Furmaniak

, Rees Smith

, Premawardhana

. 2012. Thyrotrophin receptor antibody characteristics in a woman with long-standing Hashimoto's who developed Graves' disease and pretibial myxoedema. Clin Endocrinol, 77:465–470.

56.

Troisi

, Novati

, Sali

, Colzani

, Monti

, Cardillo

, Tesauro

. 2013. Graves' hyrotoxicosis following Hashimoto's thyroiditis. Res Rep Endocr Disord, 3:13–15.

57.

Rieu

, Richard

, Rosilio

, Laplanche

, Ropion

, Fombeur

, Berrod

. 1994. Effects of thyroid status on thyroid autoimmunity expression in euthyroid and hypothyroid patients with Hashimoto's thyroiditis. Clin Endocrinol, 40:529–535.

58.

Vitti

, Mariotti

, Marcocci

, Chiovato

, Giachetti

, Fenzi

, Pinchera

. 1990. Thyroid autoimmunity and thyroid autonomy. Acta Med Austriaca, 17 Suppl 1:90–92.

59.

Mariotti

, Caturegli

, Piccolo

, Barbesino

, Pinchera

. 1990. Antithyroid peroxidase autoantibodies in thyroid diseases. J Clin Endocrinol Metab, 71:661–669.

60.

Hegedüs

, Hansen

, Feldt-Rasmussen

, Hansen

, Høier-Madsen

. 1991. Influence of thyroxine treatment on thyroid size and anti-thyroid peroxidase antibodies in Hashimoto's thyroiditis. Clin Endocrinol, 35:235–238.

61.

Verburg

, Kirchgässner

, Hebestreit

, Steigerwald

, Lentjes

, Ergezinger

, Grelle

, Reiners

, Luster

. 2011. Reference ranges for analytes of thyroid function in children. Horm Metab Res, 43:422–426.