Potential implications of thyroid autoantibodies in children, adolescents, and young adults with thyroid nodules in Japan: The Fukushima Health Management Survey

Abstract

There have been no systematic epidemiological evaluations of the relationship between thyroid autoimmunity and the clinical background of young patients with thyroid nodules. We aimed to clarify the clinical features associated with thyroglobulin or thyroperoxidase antibodies (thyroid autoantibodies [Tabs]) in children and young adults with nodules. We performed a cross-sectional study using data from 3,018 participants of 3–29 years of age with nodules, including thyroid cancer, from the Fukushima Health Management Survey. After stratification of the data for body mass index (BMI) and the bilateral width and thickness of the area (BWTAR) as indicators of thyroid volume for age, sex, body surface area (BSA), and sex-adjusted standard deviation score (SDS), trend analyses were performed. A logistic regression analysis was performed using tab-positivity as an objective variable. The overall prevalence of tab-positivity is 13.9%. It was high in females (17%), participants with diffuse goiter (DG) (19.2%), and those with papillary thyroid carcinoma (PTC) (12.8%). The age- and sex-adjusted odds ratios (95% confidence intervals) for BMI-SDS, BWTAR-SDS, presence of DG, diagnosis of PTC, and TSH concentrations were 0.962 (0.863–1.073), 1.263 (1.171–1.361), 7.357 (4.816–11.239), 2.787 (1.965–4.014), and 1.403 (1.257–1.564), respectively. Tab positivity was independently associated with a large thyroid, the presence of DG, the presence of PTC, and a high TSH concentration in patients with nodules. Based on the systematic epidemiologic evidence shown in young patients, Tab positivity might complement ultrasonography for the assessment of the thyroid function and identification of malignancy in younger patients with asymptomatic thyroid nodules.

Introduction

Hashimoto’s thyroiditis (HT) is the most common disorder among middle-aged [1]. Although assays used to identify thyroid autoimmunity and clinically diagnose HT have different specificities and sensitivities for anti-thyroglobulin (Tg) and anti-thyroperoxidase (TPO) antibodies, both antibodies (thyroid autoantibodies; Tabs) are associated with the development of HT [2]. Histological examination revealed lymphocyte infiltration of the thyroid, accompanied by heterogeneous ultrasonographic findings in the enlarged thyroid gland (diffuse goiter; DG) [3]. A clinical diagnosis of HT is made in the presence of DG accompanied by positive Tab titers and euthyroid or hypothyroid status [4]. Numerous epidemiological and histopathological studies have shown an association between HT and malignancy, especially PTC in adults [5, 6]. Several clinical studies on the prevalence of PTC in HT and HT in PTC have reported only a few cases in children and adolescents [7-10]. However, none of the studies systematically demonstrated the clinical features of children with positive Tabs who had asymptomatic thyroid nodules, including thyroid cancer, using conventional ultrasonographic examination.

To elucidate the clinical implications of Tab positivity in children, adolescents, and young adults, we aimed to analyze data obtained during the Fukushima Health Management Survey, which commenced after the Fukushima Daiichi nuclear power plant accident, because of the need for careful management of health and social problems and anxiety among the residents of Fukushima prefecture following this accident [11]. One of the main components of the survey, the thyroid ultrasound examination (TUE) program, was initiated in October 2011, with the intention of repeating this every 2 or 5 years [12]. Thyroid nodules of ≥5.1 mm in diameter were screened. Thyroid function testing and confirmatory ultrasonography were performed during the second examination. Previously, we found a relationship between the thyroid function and ultrasonographic findings associated with nodules and cysts in the data collected during the confirmatory screening of Tab-negative participants [13, 14]. We have also reported that the prevalence of DG increases with age and that a high BMI, the absence of cysts, and the presence of nodules may be associated with ultrasonographic findings of DG in young individuals [15]. Although no association has been identified between radioactive contamination and the prevalence of PTC during the TUE program, careful monitoring of Fukushima residents is continuing [16].

In this study, we calculated the prevalence of Tab positivity and identified the factors associated with Tab positivity in participants in the Fukushima Health Management Survey with nodules. These findings may inform clinical management of thyroid nodules in younger patients.

Materials and Methods

Study participants

The participants were approximately 360,000 children who lived or were staying in Fukushima Prefecture at the time of the nuclear accident and were ≤18 years of age on March 11, 2011 [11]. The TUE program was planned to be repeated every 2 or 5 years. Currently, a sixth-round examination is in progress. Thyroid nodules of ≥5.1 mm were principally screened using portable ultrasonographic devices during the first screening. In the second screening, namely a second confirmatory survey, serum thyroid function tests, such as TSH, free T3 (fT3), free T4 (fT4), thyroglobulin, anti-thyroglobulin antibody, and anti-thyroperoxidase antibody were performed, in addition to confirmatory ultrasound examination. Data from 789,459 sets were analyzed during the first, second, and third rounds of TUE (Fig. 1). Since the subjects were identical, the age of the subjects increased depending on the round of the survey. Of the 6,025 participants who were recommended to undergo a second confirmatory survey, 5,035 underwent complete examinations, including thyroid ultrasonography and blood testing, to establish a definitive diagnosis (Fig. 1). We excluded 269 (5.3%) participants in whom the thyroid size and presence or absence of DG were not assessed during the first survey. After the confirmatory ultrasonographic examination, the findings were re-assessed and the participants were re-categorized. Thus, 982 participants were excluded because they did not have nodules in the confirmatory survey. FNAC was performed in participants with nodules according to the published criteria [17]. As this was a cross-sectional study, only the data collected at the earliest visit by each participant were analyzed, and 766 (15.2%) sets of data collected during the second and third examinations were excluded. Eleven participants (0.36%) had a medical history of thyroid diseases. Among them, 4 participants (0.13%) were taking thyroid medications.

Fig. 1  Flow chart describing the selection of the participants

Ultrasonographic diagnosis

Diagnoses were made based on ultrasonographic findings by the examiners, who were mostly board-certified fellows of various Japanese medical associations, as previously described [12]. During the TUE program, apparent DG was recorded as a subsidiary finding alongside the main findings regarding nodules. No validated reference values or indices for the diagnosis of DG were available; therefore, DG was defined as an apparently large thyroid gland with a lumpy or uneven surface, along with diffuse low thyroid echogenicity, as previously described [18]. Thyroid volume was assessed using a previously described method [19]. Briefly, the width of the thyroid was multiplied by its thickness for each lobe and these values were added to yield the bilateral width multiplied by the thickness area (BWTAR).

Calculation of the standard deviation scores (SDS) for BMI (BMI-SDS) and BWTAR (BWTAR-SDS)

The mean and standard deviation (SDs) of the BMIs of the populations depended on sex and age distribution. Furthermore, BWTAR, an index of thyroid volume, was found to be closely related to body surface area (BSA) and sex. Therefore, we assessed BMI and BWTAR after standardization of the data according to the means and SDs of the participants for each year of age and 0.1 m² increase in BSA for each sex, using the participants’ previous measurements [15, 19].

Measurements of serum thyroid hormone, TSH concentrations, and thyroglobulin and thyroperoxidase antibody titers

fT3, fT4, and TSH levels were measured by a chemiluminescence immunoassay using ChemilumiFT3 (reference range 2.13–4.07 pg/mL), ChemilumiACSE-FT4 (reference range 0.95–1.74 ng/dL), and ChemilumiACS-TSHIIIultra (reference range 0.340–3.880 μIU/mL) (Siemens Healthcare Diagnostics, Munich, Germany). The inter-assay coefficients of variation for the fT3, fT4, and TSH assays were 4.0%, 6.0%, and 4.0%, respectively. Anti-thyroglobulin autoantibody (TgAb) and anti-thyroperoxidase autoantibody (TPOAb) levels were measured using ECLusys Anti-Tg and Anti-TPO, respectively (Roche Diagnostics GmbH, Mannheim, Germany). TgAb and TPOAb positivity were defined by titers of >28.0 IU/mL and >16.0 IU/mL, respectively. Tabs positivity was defined as positivity for TgAbs and/or TPOAb. The serum TSH concentration of the 10 participants (0.36%) in whom it was <0.001 μIU/mL was defined as 0.001 μIU/mL. The fT3 concentration in a single participant (0.033%) with a concentration of >20 pg/mL was defined as 20 pg/mL. Forty-eight participants (1.6%) who had a high TSH concentration of 3.89–34.9 μIU/mL and 102 (3.4%) with a low TSH concentration of 0.001–0.339 μIU/mL were included. Four participants (0.14%) with an fT3 concentration of <2.13 pg/mL and 409 (13.6%) with an fT3 concentration >4.07 pg/mL were also included. In addition, 81 participants (2.7%) with an fT4 concentration of <0.95 ng/dL and 24 (0.8%) with an fT4 concentration of >1.74 ng/dL fT4 were included.

Statistical analysis

Fisher’s exact test was used to analyze categorical data. To exclude arbitrariness in categorizing age groups, we divided the participants of each sex into quartile-based age groups. Age-dependent biological changes, such as those described by Tanner stages, were not considered in the study. The indicated values of each age group and each sex were compared according to the presence or absence of Tabs using the Mann–Whitney U test (Tables 1 and 2). A nonparametric test for trends across ordered groups was used to analyze the trends shown in Table 3. A logistic regression analysis was used to determine whether age, sex, BMI-SDS, BWTAR-SDS, DG, diagnosis of PTC, and/or thyroid function independently affected the Tab status. Five different adjustments were made for confounding factors.

Table 1 Characteristics of participants with nodules in the study

		Thyroid autoantibodies		p-value
		+	–
total; n (%)	3,018	421 (13.9)	2,597 (86.1)
Age; n (%)				0.684
	3–14 years	107 (13.7)	673 (86.3)
	15–17 years	130 (13.7)	816 (86.3)
	18–19 years	78 (13.0)	520 (87.0)
	20–29 years	106 (15.3)	588 (84.7)
Sex				<0.001
	female; n (%)	342 (17.0)	1,670 (83.0)
	male; n (%)	79 (7.9)	927 (92.1)
Thyroid function #1
	TSH (mIU/L)	1.30 [0.80, 1.97]	1.08 [0.75, 1.60]	<0.001
	fT4 (ng/dL)	1.21 [1.10, 1.34]	1.23 [1.12, 1.33]	0.048
	fT3 (pg/mL)	3.37 [3.10, 3.65]	3.49 [3.20, 3.85]	<0.001
DG n (%)#3		81 (19.2)	49 (1.9)	<0.001
Obesity#2 n (%)#3		22 (5.2)	128 (4.9)	0.809
PTC n (%)#3		54 (12.8)	138 (5.3)	<0.001

DG; diffuse goiter PTC; papillary thyroid carcinoma

#1; Median and interquartile range were shown.

#2; BMI 95 percentile or higher for age and sex

#3; percentage expressed by ratio of the indicated numbers to total numbers of positive (421) or negative (2,597) thyroid autoantibodies

Table 2 Prevalences of thyroid autoantibody positivity and median and interquartile range of the indicated values in the age-stratified groups of each sex

Thyroid autoantibody positivity		female			male
		+	–	p	+	–	p
n (%)				0.344			0.286
	3–14 years	89 (17.1)	430 (82.9)		18 (6.9)	243 (93.1)
	15–17 years	107 (17.0)	521 (83.0)		23 (7.2)	295 (92.8)
	18–19 years	54 (14.2)	325 (85.8)		24 (11.0)	195 (89.0)
	20–29 years	92 (18.9)	394 (81.1)		14 (6.7)	194 (93.3)
BMI (kg/m2)
	3–14 years	18.8 [17.6, 20.4]	18.6 [16.8, 20.4]	0.314	19.3 [17.4, 20.9]	18.4 [16.7, 20.7]	0.531
	15–17 years	20.4 [19.1, 21.7]	20.5 [19.2, 22.4]	0.554	20.5 [19.4, 22.6]	20.6 [19.0, 22.6]	0.967
	18–19 years	21.1 [18.9, 22.8]	20.8 [19.4, 22.2]	0.626	22.5 [20.0, 25.0]	21.1 [19.5, 23.4]	0.130
	20–29 years	20.2 [19.1, 22.5]	21.0 [19.4, 22.8]	0.405	21.6 [20.0, 26.5]	21.4 [20.0, 23.9]	0.413
BWTAR (mm2)
	3–14 years	413 [332, 556]	347 [289, 420]	<0.001	376 [294, 464]	326 [269, 415]	0.201
	15–17 years	434 [353, 526]	384 [323, 447]	<0.001	490 [406, 546]	420 [368, 499]	0.051
	18–19 years	420 [343, 519]	383 [320, 445]	0.016	502 [423, 681]	433 [365, 504]	0.005
	20–29 years	448 [369, 534]	391 [324, 462]	<0.001	577 [352, 766]	472 [393, 546]	0.264
TSH (mIU/L)
	3–14 years	1.50 [1.22, 2.15]	1.11 [0.77, 1.69]	<0.001	1.66 [1.21, 2.34]	1.40 [1.01, 2.05]	0.140
	15–17 years	1.16 [0.75, 1.72]	0.94 [0.70, 1.42]	0.034	1.34 [0.72, 1.94]	1.17 [0.80, 1.75]	0.658
	18–19 years	1.24 [0.79, 1.98]	0.93 [0.64, 1.34]	0.005	1.21 [0.77, 1.68]	1.12 [0.79, 1.83]	0.860
	20–29 years	1.16 [0.67, 2.11]	1.07 [0.74, 1.55]	0.591	1.47 [1.36, 4.89]	1.09 [0.82, 1.61]	0.008
fT4 (ng/dL)
	3–14 years	1.20 [1.11, 1.34]	1.22 [1.12, 1.30]	0.989	1.33 [1.19, 1.39]	1.24 [1.16, 1.34]	0.095
	15–17 years	1.16 [1.08, 1.28]	1.18 [1.09, 1.27]	0.410	1.33 [1.21, 1.44]	1.33 [1.19, 1.43]	0.974
	18–19 years	1.14 [1.06, 1.29]	1.19 [1.10, 1.30]	0.336	1.39 [1.20, 1.47]	1.31 [1.21, 1.42]	0.502
	20–29 years	1.21 [1.08, 1.29]	1.19 [1.09, 1.28]	0.414	1.26 [1.13, 1.47]	1.32 [1.22, 1.45]	0.637
fT3 (pg/mL)
	3–14 years	3.53 [3.32, 3.84]	3.66 [3.35, 4.01]	0.038	4.06 [3.69, 4.35]	4.09 [3.87, 4.41]	0.384
	15–17 years	3.28 [3.09, 3.46]	3.28 [3.10, 3.48]	0.557	3.79 [3.58, 4.17]	3.88 [3.63, 4.17]	0.581
	18–19 years	3.12 [2.83, 3.34]	3.21 [3.03, 3.43]	0.013	3.68 [3.52, 3.90]	3.72 [3.50, 3.91]	0.877
	20–29 years	3.19 [2.94, 3.36]	3.17 [2.95, 3.38]	0.957	3.81 [3.40, 3.94]	3.61 [3.39, 3.87]	0.426

BMI; body mass index

BWTAR; bilateral width multiplied by the thickness of the area

Table 3 Number of participants and percentage by BMI-SDS and BWTAR-SDS and the number and percentage of positive Tabs in the indicated groups

Degree of BMI-SDS	All participants					Female					Male
	n	% #1	Tabs n	% #2	p	n	% #1	Tabs n	% #2	p	n	% #1	Tabs n	% #2	p
					0.990					0.780					0.860
<–‍2.5SD	1	0.03	0	0.0		1	0.05	0	0.0		0	0.0	0	—
–2.5SD ≤ <–‍1.5SD	26	0.9	4	15.4		22	1.1	4	18.2		4	0.4	0	0.0
–1.5SD ≤ <1.5SD	2,701	89.5	377	14.0		1,804	89.7	306	17.0		897	89.2	71	7.9
1.5SD ≤ <2.5SD	187	6.2	25	13.4		117	5.8	19	16.2		70	7.0	6	8.6
2.5SD≤	103	3.4	15	14.6		68	3.4	13	19.1		35	3.5	2	5.7
Total	3,018	100	421	13.9		2,012	100	342	17.0		1,006	100	79	7.9
Degree of BWTAR-SDS	All participants					Female					Male
	n	% #1	Tabs n	% #2	p	n	% #1	Tabs n	% #2	p	n	% #1	Tabs n	% #2	p
					<0.001					<0.001					<0.001
<–‍2.5SD	0	0.0	0	—		0	0.0	0	—		0	0.0	0	—
–2.5SD ≤ <–‍1.5SD	21	0.7	1	4.8		10	0.5	0	0.0		11	1.1	1	9.1
–1.5SD ≤ <1.5SD	2,283	75.7	248	10.9		1,517	75.4	201	13.2		766	76.1	47	6.1
1.5SD ≤ <2.5SD	417	13.8	72	17.3		284	14.1	62	21.8		133	13.2	10	7.5
2.5SD≤	297	9.8	100	33.7		201	10	79	39.3		96	9.5	21	21.9
Total	3,018	100	421	13.9		2,012	100	342	17.0		1,006	100	79	7.9

#1 Percentage of the number of participants in the indicated cohorts.

#2 Percentage of the number of participants with positive TAbs in the indicated each degree of SDS group.

SDS; standard deviation score Tabs; Thyroid autoantibodies

BMI; body mass index

BWTAR; bilateral width multiplied by the thickness of the area

Ethics

The survey was approved by the Ethics Review Committee of Fukushima Medical University (No. 1318). Written informed consent was obtained from the participants, their parents, or the guardians of the surveyed participants. The raw data used to create the tables and figures in the present study cannot be made available to other researchers owing to a restriction in the informed consent agreement.

Results

Tab positivity was more common in females and in patients with DG or PTC

Of the 3,018 participants with nodules, including those with PTC, 421 (13.9%) were Tab-positive (Table 1). The age distributions of the participants who were Tab-negative or Tab-positive did not differ to a statistically significant extent (p = 0.684). Of the participants who were Tab-positive, 342 (17.0%) were female and 79 (7.9%) were male; thus, female participants were more likely to be Tab-positive than male participants (p < 0.001). The median TSH concentration was significantly higher and the median concentrations of fT4 and fT3 were significantly lower in Tab-positive participants. There were 81 (19.2%) and 49 (1.9%) cases of DG among the participants who were Tab-positive or Tab-negative, respectively (p < 0.001). However, there was no significant difference in the prevalence of Tab positivity between 22 (5.2%) and 128 (4.9%) obese cases (p = 0.809). In addition, 54 (12.8%) and 138 (5.3%) instances of PTC were found among participants who were Tab-positive or Tab-negative, respectively. Tab positivity was more common than Tab-negativity among participants with PTC (p < 0.001).

The prevalence of Tab positivity, and the median and interquartile ranges for BMI, BWTAR, TSH, fT4, and fT3 in the age-stratified groups of participants of each sex with nodules (Table 2)

The prevalence of Tab positivity was 14.2%–18.9% and 6.7%–11.0% for the age-stratified groups of female and male participants, respectively (Table 2; p = 0.344 and p = 0.286). There was no difference in the BMI of Tab-positive participants among the age-stratified groups of both sexes. There was a tendency for BWTAR to be higher in Tab-positive participants of both sexes, but the differences were not statistically significant in 3–14-, 15–17-, and 20–29-year-old males. The median TSH concentrations were high in all age groups for both sexes, although there were no significant differences in females of 20–29-years of age and males of 3–14, 15–17, and 18–19 years of age. There were no differences in the fT4 and fT3 concentrations in the various age groups, except that the fT3 concentrations of Tab-positive female participants were lower in those of 3–14 years of age and 18–19 years of age.

BMI-SDS was not associated with the prevalence of Tab positivity, while BWTAR-SDS was positively associated with Tab positivity in males and females

To evaluate the relationship between the prevalence of Tab positivity and BMI and BWTAR, we divided the participants into 5 groups according to the SDS of a series of values calculated using the means and SDs for each age/sex and BSA/sex group, respectively, as previously described [15, 17]. There were 1 (0.03%) and 0 (0.0%) participants in the BMI-SDS <–2.5 SD and BWTAR-SDS <–2.5 SD groups, respectively (the lowest value groups), and 103 (3.4%) and 297 (9.8%) in the BMI-SDS ≥2.5 SD and BWTAR-SDS ≥2.5 SD, respectively (the highest value groups) (Table 3). There was no association between the prevalence of Tab positivity and BMI-SDS scores in either sex or in the defined groups. In contrast, there were linear relationships between the prevalence of Tab positivity and BWTAR-SDS across all participants and for each sex.

Tab positivity was independently associated with sex, BWTAR-SDS, DG, a diagnosis of PTC, and the concentrations of TSH, but not age, BMI-SDS, or the concentrations of fT4 and fT3 in the logistic regression analysis

To determine whether sex, age, BMI, BWTAR, the presence of DG, a diagnosis of PTC, and thyroid function significantly affected Tab status, we conducted logistic regression analyses and calculated ORs and 95% CIs for Tab positivity according to sex, age, BMI-SDS, BWTAR-SDS, DG, PTC diagnosis, and thyroid function (Graphical Abstract). Positive relationships between Tab positivity and female sex were identified in Model 1. However, BMI-SDS was not associated with Tab positivity after correcting for age and sex (p = 0.580). Both BWTAR-SDS and the presence of DG were independently associated with Tab positivity in Model 2. High TSH and a diagnosis of PTC were independently associated with Tab positivity after correction for age, sex, BMI-SDS, BWTAR-SDS, and the presence of DG in Model 3. However, there were no associations between Tab positivity and fT4 or fT3 concentrations after the same corrections as in Model 3 (fT4, p = 0.191; fT3, p = 0.578). Age and BMI-SDS did not affect Tab status in any of the five models.

Graphical Abstract  Odds ratios and confidence intervals of positive thyroid autoantibodies for sex, age, BMI-SDS, BWTAR-SDS, DG, PTC and the thyroid function

A logistic regression analysis was used to determine whether age, sex, BMI-SDS, BWTAR-SDS, DG, diagnosis of PTC, and/or thyroid function independently affected the Tab status. Five different adjustments were made for the confounding factors. Model 1 was adjusted for age, sex, and BMI SDS score. Model 2 was adjusted for age, sex, BWTAR-SDS, and presence of DG. Model 3 was adjusted for the PTC diagnosis, TSH concentration, age, sex, BMI-SDS, BWTAR-SDS, and the presence of DG. In Models 4 and 5, instead of TSH concentration, fT4 and fT3 were included, in addition to age, sex, BMI SDS, BWTAR-SDS, the presence of DG, and a diagnosis of PTC.

Discussion

In the present study, we found a Tab positivity prevalence of 13.9% in children and adolescents with thyroid nodules >5.0 mm in diameter. We also found that tab-positivity was more common in females and young people with DG or PTC, consistent with previous findings in adults [4]. During general health screening of 12–19-year-olds in the US, the mean prevalence of TPOAb or TgAb positivity was found to be 2.9–7.3%, although the mean prevalence for Mexican Americans was relatively high, at 3.0–9.7% [20]. However, an appropriate cutoff value for Tab positivity has not yet been validated. The apparently higher prevalence in this study may have been, at least in part, the result of a selection bias because all participants had thyroid nodules.

Previous studies of children with DG have shown that it is more common in people who are positive for Tabs [21, 22], and Tab positivity was also found to be associated with DG in the present study, indicating that there is an association between Tab positivity and DG in children, adolescents, and young adults with thyroid nodules. Previously, we showed an age-related increase in the prevalence of DG and its relationship with thyroid nodules in children, especially in younger children [15]. According to a large population-based study in the UK, there have been various age-related changes in the incidence of autoimmune diseases [23]. While there is currently limited strong evidence of an age-related increase in the occurrence of Tab positivity within the general pediatric population, a gradual increase in prevalence throughout childhood would not be unexpected. Meanwhile, comorbid thyroid autoimmunity and nodule formation may be present in children because the prevalence of nodules also increases with age in this age group [24]. In the present study, no age-related increase of Tab positivity was identified in participants with nodules. Taken together with the possible age-dependent increase in Tab positivity in the general population, thyroid autoimmunity may be associated with nodule formation rather than aging itself in the case of nodules found in children, adolescents, and young adults.

Autoimmune thyroiditis is associated with obesity in children and adults [25]. We have previously shown a relationship between DG and high BMI in children and adolescents [15]. In the present study, there was no difference in the BMI of participants with or without Tab positivity in either sex (Table 2). Tab positivity did not vary significantly among the BMI-SDS-stratified groups (Table 3), and Tab positivity was not found to be associated with BMI-SDS in the participants with nodules (Graphical Abstract). These results indicated that autoimmune thyroiditis may not be associated with obesity in individuals with thyroid nodules. It is worth noting that there was only one participant (0.03%) in the lowest BMI group (BMI SDS <–2.5 SD), whereas there were 103 (3.4%) in the highest BMI group (2.5 SD< BMI-SDS) (Table 3), implying that obesity itself may be associated with the presence of nodules, as previously shown [26, 27].

In contrast to the lack of a relationship between BMI and Tab positivity, high thyroid volume was found to be associated with Tab positivity (lower part of Table 3). The thyroid volume has been reported to be associated with age, sex, and BSA in childhood [28]. The thyroid volume is conventionally assessed using BWTAR, and the mean and SD for every 0.1-m² increase in BSA has been published for each sex [19]. As shown in Table 2, the thyroid volumes of Tab-positive participants were high, and this was especially true for females. The frequency of Tab positivity increased linearly across the BWTAR-SDS-stratified groups (Table 3), and Tab positivity was independently associated with a high BWTAR-SDS after adjustment for the presence of DG (Graphical Abstract). Taken together, these data suggest a positive epidemiologic relationship between thyroid autoimmunity and volume in children and adolescents with nodules. However, the reason for this has not yet been clearly determined. Thyroid volume, however, is affected not only by TSH but also by other hormones, such as estrogen, IGF-1, and cytokines [29]. In addition, stress may be associated with thyroid autoimmunity [30]. Consequently, these factors may be directly or indirectly associated with the thyroid autoimmunity. In addition to the possible association between thyroid autoimmunity and volume, there were no participants in the lowest BWTAR-SDS group (BWTAR-SDS <–2.5 SD), while there were 297 (9.8%) participants in the highest group (2.5 SD< BWTAR-SDS) (Table 3), which implies that children and adolescents with nodules have large thyroid glands overall. The reported median urinary iodine concentration in Fukushima Prefecture is 204 mg/L [31], which suggests that sufficient iodine intake is unlikely to affect the thyroid volume.

Previously, we showed that the circulating TSH concentration decreased with age in children and adolescents who did not have Tabs or nodules [13]. This change is thought to be associated with the maturation of the pituitary–thyroid axis feedback response [14]. As shown in Graphical Abstract, Tab positivity was found to be associated with a high TSH concentration after adjustment for age, whereas there were no changes in fT4 or fT3 concentrations. Although TSH concentration is affected by sex and age in childhood, our results suggest that subclinical hypothyroidism may be present in Tab-positive children with nodules.

Although no association between the prevalence of PTC and HT was identified in a systematic literature review performed by Hershman et al., HT has been shown to be associated not only with thyroid cancer but also with breast, lung, and urogenital cancers in observational studies of the relationship between HT and malignancy in adults [32, 33]. The prevalence of PTC has been reported to be between 0.67% and 7.87% in children with HT [10]. Anti-Tg and TPO antibody positivity were both found to be significantly more prevalent in 927 young adults with PTC than in 927 age- and sex-matched controls [34]. The prevalence of HT diagnosed histopathologically was 44.1% (19/43) in symptomatic patients with thyroid carcinoma who were aged >18 years [35]. Therefore, the development of HT may be associated with the development of PTC in younger people as well as in adults. This association between HT and PTC was also observed in children and adolescents with asymptomatic nodules in the present study.

The present study has two principal limitations. First, we could not exclude individuals with thyroid dysfunction, such as those caused by hypothyroidism or thyrotoxicosis, because reference values for a number of thyroid function-related indices do not currently exist for children, even though both age and sex affect these values in children and adolescents, as previously shown [13]. Second, individuals with nodules of ≤5.0 mm in size were not included because of the design of the protocol for the second screening session of the survey, as described previously [12]. In conclusion, we calculated the prevalence of Tab positivity in children, adolescents, and young adults with thyroid nodules >5 mm in diameter, including PTC. Tab positivity was independently associated with a high thyroid volume, presence of DG, presence of PTC, and high TSH concentration in children and adolescents with thyroid nodules. Thus, PTC development may be associated with HT in children and adolescents with asymptomatic thyroid nodules. These results provide epidemiological evidence that Tab positivity can complement ultrasonographic findings and the thyroid function, as it does in cases of asymptomatic nodules identified by chance, even in younger people.

Acknowledgments

We express our gratitude to all participants of the Fukushima Health Management Survey. We thank Ms. Miyuki Konno for her excellent secretarial assistance. We thank Professor Kenneth E. Nollet at the Radiation Medical Science Center for the Fukushima Health Management Survey for editing the manuscript draft. The findings and conclusions of this article are solely the responsibility of the authors, and do not represent the official views of the Fukushima Prefecture government.

Author Contributions

Rina Tazaki: review and editing (equal); Conceptualization (supporting), Yurie Kobashi: review and editing (equal); formal analysis (supporting), Mahiro Asano: review and editing (equal); provision of the data set (supporting), Norikazu Abe: review and editing (equal); provision of the data set (supporting), Haruka Ejiri: review and editing (equal); verification (supporting), Ayako Sato: review and editing (equal); verification (lead), Nana Nakahata: review and editing (equal); provision of the data set (supporting), Natsuki Nagamine: review and editing (equal); provision of the data set (lead), Chisato Takahashi: review and editing (equal); verification (supporting), Yukie Yamaya: review and editing (equal); verification (supporting), Satoshi Suzuki: review and editing (equal); data curation (supporting), Satoru Suzuki: Conceptualization (lead); writing-original draft (lead); data curation (lead); formal analysis (lead); writing-review and editing (equal), Manabu Iwadate: review and editing (equal), Takashi Matsuzuka: review and editing (equal), Hiroki Shimura: review and editing (equal), Tetsuya Ohira: review and editing (equal), Fumihiko Furuya: review and editing (equal), Shinichi Suzuki: review and editing (equal), Susumu Yokoya: review and editing (equal), Shunichi Yamashita: review and editing (equal); writing-review and editing (equal), Hitoshi Ohto: review and editing (equal), Seiji Yasumura: review and editing (equal), project administration (lead).

Disclosure Statement

The authors have no conflicts of interest to declare.

Funding

This survey was conducted as part of Fukushima Prefecture’s post-disaster recovery plans and was supported by the national “Health Fund for Children and Adults Affected by the Nuclear Incident.”

Appendix

Other participating expert committee members, advisors, and staff members in the Fukushima Health Management Survey: Kenji Kamiya, Kumiko Tsuboi, Masaharu Maeda, Keiya Fujimori, Tetsuo Ishikawa, Shigehira Saji, Michio Shimabukuro, Mitsuaki Hosoya, Masaharu Maeda, Masaharu Tsubokura, Hiroshi, Zaima, Shinji Meguro, Mizuki Sekino, Toshie Sakagami, Masahiko Henmi, Sakiko Meguro, Yuko Namekata, Hinako Itou, Yuka Hamaya, Ryouko Hata, Takako Takahashi and Noriko Seto.

References

• 1   Amino  N,  Lazarus  JH,  DeGroot  LJ (2015) Chronic (Hashimoto’s) Thyroiditis. In: Jameson JL, DeGroot LJ (eds) Endocrinology: adult and pediatric (7th), Saunders, Philadelphia, USA: 1515–1539.
• 2   Spencer  CA (2023) Laboratory thyroid tests: a historical perspective. Thyroid 33: 407–419.
• 3   Filetti  S,  Tuttle  RM,  Leboulleux  S,  Alexander  EK (2020) Nontoxic diffuse goiter, nodular thyroid disorders, and thyroid malignancies. In: Melmed S, Auchus RJ, Goldfine AB, Koenig RJ, Rosen CJ (eds) Williams Textbook of Endocrinology (14th). Saunders, Philadelphia, USA: 433–477.
• 4   Akamizu  T,  Amino  N (2017) Hashimoto’s Thyroiditis. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, et al. (eds) Endotext [Internet]. MDText.com, Inc., South Dartmouth, USA. https://www.ncbi.nlm.nih.gov/books/NBK285557/ accessed on August 20, 2024.
• 5   Lee  JH,  Kim  Y,  Choi  JW,  Kim  Y (2013) The association between papillary carcinoma and histologically proven Hashimoto’s thyroiditis: meta-analysis. Eur J Endocrinol 168: 343–349.
• 6   Liang  J,  Zeng  W,  Fang  F,  Yu  T,  Zfao  Y, et al. (2017) Clinical analysis of Hashimoto thyroiditis coexistent with papillary thyroidcancer in 1,392 patients. Acta Otorhinolaryngol Ital 37: 393–400.
• 7   DeBoer  MD,  LaFranchi  S (2008) Differential presentation for children with autoimmune thyroiditis discovered because of symptom development or screening. J Pediat Endocrinol Metab 21: 753–761.
• 8   de Vries  L,  Bulvik  S,  Phillip  M (2009) Chronic autoimmune thyroiditis in children and adolescents: at presentation and during long-term follow-up. Arch Dis Child 94: 33–37.
• 9   Skarpa  V,  Kousta  E,  Tertipi  A,  Anyfandakis  A,  Vakaki  M, et al. (2011) Epidemiological characteristics of children with autoimmune thyroid disease. Hormones (Athens) 10: 207–214.
• 10   Sur  ML,  Gaga  R,  Lazăr  C,  Lazea  C,  Aldea  C, et al. (2020) Papillary thyroid carcinoma in children with Hashimoto’s thyroiditis—a review of the literature between 2000 and 2020. J Pediatr Endocrinol Metab 33: 1511–1517.
• 11   Yasumura  S,  Hosoya  M,  Yamashita  S,  Kamiya  K,  Abe  M, et al. (2012) Study protocol for the Fukushima Health Management Survey. J Epidemiol 22: 375–383.
• 12   Suzuki  S,  Yamashita  S,  Fukushima  T,  Nakano  K,  Midorikawa  S, et al. (2016) The protocol and preliminary baseline survey results of the thyroid ultrasound examination in Fukushima [Rapid Communication]. Endocr J 63: 315–321.
• 13   Suzuki  S,  Nakamura  I,  Suzuki  S,  Ohkouchi  C,  Mizunuma  H, et al. (2016) Inappropriate suppression of thyrotropin concentrations in young patients with thyroid nodules including thyroid cancer: The Fukushima Health Management Survey. Thyroid 26: 717–725.
• 14   Suzuki  S,  Suzuki  S,  Iwadate  M,  Matsuzuka  T,  Shimura  H, et al. (2022) Possible association between thyroid nodule formation and developmental alterations in the pituitary-thyroid hormone axis in children and adolescents: The Fukushima Health Management Survey. Thyroid 32: 1316–1327.
• 15   Nakahata  N,  Asano  M,  Abe  N,  Ejiri  H,  Ota  H, et al. (2024) Prevalence of thyroid diffuse goiter and its association with body mass index and the presence of cysts and nodules in children and adolescents: The Fukushima Health Management Survey. Endocr J 71: 383–393.
• 16   Ohira  T,  Shimura  H,  Hayashi  F,  Nagao  M,  Yasumura  S, et al. (2020) Absorbed radiation doses in the thyroid as estimated by UNSCEAR and subsequent risk of childhood thyroid cancer following the Great East Japan Earthquake. J Radiat Res 61: 243–248.
• 17   Shimura  H,  Matsuzuka  T,  Suzuki  S,  Iwadate  M,  Suzuki  S et al. (2021) Fine needle aspiration cytology implementation and malignancy rates in children and adolescents based on Japanese guidelines: The Fukushima Health Management Survey. Thyroid 31: 1683–1692.
• 18   Pedersen  OM,  Aardal  NP,  Larssen  TB,  Varhaug  JE,  Myking  O, et al. (2000) The value of ultrasonography in predicting autoimmune thyroid disease. Thyroid 10: 251–259.
• 19   Ejiri  H,  Asano  M,  Nakahata  N,  Suzuki  S,  Sato  A, et al. (2023) Ultrasonography-based reference values for the cross-sectional area of the thyroid gland in children and adolescents: The Fukushima Health Management Survey. Clin Pediatr Endocrinol 32: 52–57.
• 20   Hollowell  JG,  Staehling  NW,  Flanders  WD,  Hannon  WH,  Gunter  EW, et al. (2002) Serum TSH, T(4), and thyroid antibodies in the United States population 1988 to 1994: National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 87: 489–499.
• 21   Kambalapalli  M,  Gupta  A,  Prasad  UR,  Francis  GL (2015) Ultrasound characteristics of the thyroid in children and adolescents with goiter: a single center experience. Thyroid 25: 176–182.
• 22   Lorini  R,  Gastaldi  R,  Traggiai  C,  Perucchin  PP (2003) Hashimoto’s thyroiditis. Pediatr Endocrinolo Rev Suppl 2: 205–211.
• 23   Conrad  N,  Misra  S,  Verbakel  JY,  Verbeke  G,  Molenberghs  G, et al. (2023) Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: a population-based cohort study of 22 million individuals in the UK. Lancet 401: 1878–1890.
• 24   Shimura  H,  Sobue  T,  Takahashi  H,  Yasumura  S,  Ohira  T, et al. (2018) Findings of thyroid ultrasound examination within 3 years after the Fukushima nuclear power plant accident: The Fukushima Health Management Survey. J Clin Endocrinol Metab 103: 861–869.
• 25   Song  RH,  Wang  B,  Yao  QM,  Li  Q,  Jia  X, et al. (2019) The impact of obesity on thyroid autoimmunity and dysfunction: a systematic review and meta-analysis. Front Immunol 10: 2349.
• 26   Mu  C,  Ming  X,  Tian  Y,  Liu  Y,  Yao  M, et al. (2022) Mapping global epidemiology of thyroid nodules among general population: a systematic review and meta-analysis. Front Oncol 12: 1029926.
• 27   Ohira  T,  Nagao  M,  Hayashi  F,  Shimura  H,  Suzuki  S, et al. (2024) Effects of overweight on risk of thyroid nodules in children and adolescents: the Fukushima Health Management Survey. J Clin Endocrinol Metab doi: 10.1210/clinem/dgae161. Online ahead of print.
• 28   Suzuki  S,  Midorikawa  S,  Fukushima  T,  Shimura  H,  Ohira  T, et al. (2015) Systematic determination of thyroid volume by ultrasound examination from infancy to adolescence in Japan: the Fukushima Health Management Survey. Endocr J 62: 261–268.
• 29   Demetriou  E,  Fokou  M,  Frangos  S,  Papageorgis  P,  Economides  PA, et al. (2023) Thyroid nodules and obesity. Life (Basel) 13: 1292.
• 30   Mizokami  T,  Wu Li  A,  El-Kaissi  S,  Wall  JR (2004) Stress and thyroid autoimmunity. Thyroid 14: 1047–1055.
• 31   Tsubokura  M,  Nomura  S,  Watanobe  H,  Nishikawa  Y,  Suzuki  C, et al. (2016) Assessment of nutritional status of iodine through urinary iodine screening among local children and adolescents after the Fukushima Daiichi Nuclear Power Plant Accident. Thyroid 26: 1778–1785.
• 32   Jankovic  B,  Le  KT,  Hershman  JM (2013) Clinical review: Hashimoto’s thyroiditis and papillary thyroid carcinoma: is there a correlation? J Clin Endocrinol Metab 98: 474–482.
• 33   Hu  X,  Wang  X,  Liang  Y,  Chen  X,  Zhou  S, et al. (2022) Cancer risk in Hashimoto’s thyroiditis: a systematic review and meta-analysis. Front Endocrinol (Lausanne) 13: 937871.
• 34   Liu  Y,  Li  C,  Zhao  W,  Wang  Y (2017) Hashimoto’s thyroiditis is an important risk factor of papillary thyroid microcarcinoma in younger adults. Horm Metab Res 49: 732–738.
• 35   Ren  PY,  Liu  J,  Xue  S,  Chen  G (2019) Pediatric differentiated thyroid carcinoma: the clinicopathological features and the coexistence of Hashimoto’s thyroiditis. Asian J Surg 42: 112–119.