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

Abstract

The main cause of diffuse thyroid goiter is autoimmune chronic thyroiditis, otherwise known as Hashimoto’s thyroiditis. Thyroid hormones play pivotal roles in growth and development during childhood. However, the prevalence of diffuse goiter and the relationships between diffuse goiter, thyroid volume, cysts and nodules, and anthropometric measurements in children are not well known. Among 789,459 participants who participated in thyroid ultrasound examinations, 320,206 participants (male: 161,728; female: 158,478) aged 1–23 years were analyzed. Logistic regression analyses were conducted to calculate the odds ratios of the standard deviation score of body mass index (BMI-SDS), the SDS of bilateral width multiplied thickness area (BWTAR-SDS) as a provisional determination of thyroid volume, and the presence of nodules or cysts for positive diffuse goiter compared with negative diffuse goiter after correction for sex and age. The prevalence of diffuse goiter increased in a female-dominant manner with aging. Compared with the absence of diffuse goiter, the age- and sex-adjusted odds ratios (95% confidence intervals) for BMI-SDS (1 SD), BWTAR-SDS (1 SD), cysts, and nodules were 1.24 (1.21–1.27), 3.21 (3.13–3.29), 0.53 (0.50–0.58), and 1.38 (1.17–1.64), respectively. The odds ratios of nodules for positive diffuse goiter were 4.18 (1.08–16.08), 1.76 (1.01–3.07), 1.80 (1.32–2.45), and 1.34 (1.08–1.67) in the age groups 1–7, 8–11, 12–15, and 16–23 years, respectively. The age-dependent increase in the prevalence of diffuse goiter was independently associated with increased BMI and positive prevalence of nodules in young individuals.

THYROID HORMONES are essential and play pivotal roles in growth and development during childhood [1]. Using sonography as a screening method, the prevalence of goiter has been reported to be as high as 30%–50% in the adult population [2]. Preliminary systematic determination of diffuse goiter showed a rate of 1.4% in data obtained from 4,365 children aged 3–18 years in Japan [3]. However, the precise characterization of cases of diffuse goiter is not well known, especially in childhood.

The Fukushima Health Management Survey was started after the Fukushima Daiichi Nuclear power plant accident [4]. One of the main projects in the survey, the thyroid ultrasound examination (TUE) program, was started in October 2011 and was planned to be repeated every 2 or 5 years [5]. The subjects included approximately 360,000 children who lived or were staying in Fukushima Prefecture at the time of the accident and were aged 18 years or younger on 11 March 2011 [5]. Currently, the sixth-round examination is underway.

Ultrasonography may be of value in diagnosing autoimmune thyroid disease as it may detect a diffuse reduction in thyroid echogenicity [6]. Ultrasonographic findings can distinguish two clinical forms of chronic autoimmune thyroiditis, including goitrous Hashimoto’s disease and atrophic thyroiditis [6]. Although a reduction in ultrasonographic echogenicity is not directly suggestive of autoimmune thyroiditis, and may also be observed in subacute thyroiditis of non-autoimmune origin, high specificity was reported for the diagnosis of Graves’ and Hashimoto’s thyroiditis [7].

In the present study, we initially evaluated the prevalence of diffuse goiter in participants aged 1–23 years. We also analyzed the features of anthropometric measurements in children and adolescents with or without diffuse goiter at different ages. Finally, the association between diffuse goiter development and nodule or cyst formation was evaluated in children and adolescents.

Methods

Participants

The data were obtained from participants who received their first examination in the first, second, or third round of the TUE program (Fig. 1). A total of 789,459 participants (male: 397,909, female: 391,550) were analyzed in the first (n = 299,900), second (n = 269,649), and third (n = 219,910) rounds of the TUE program. We excluded 7,209 participants because of invalid height, weight, and thyroid-size determination, as well as 36,927 participants because diffuse goiter was not systematically assessed in the initial period between 9 October 2011 and 12 April 2012. All participants were 1 year old or older when recording of diffuse goiter commenced on 13 April 2012 [5, 8]. Among the remaining participants, 424,658 (56.9%) underwent two or three examinations. As this was a cross-sectional study, only the record from the earliest visit of each participant was analyzed, and the results of the second and third examinations were excluded. We also excluded 648 participants who were 24 years of age or older. We finally analyzed 320,206 (male: 161,728, female: 158,478) participants who were 1–23 years of age (Tables 1–4).

Fig. 1

Flow chart of participant selection

Table 1

Characteristics of participants with and without diffuse goiter

Variable	diffuse goiter				p-Value
	+		–
n (%)	3,908	(1.2)	316,298	(98.8)
Age (years) #1	14.0 [12.0, 17.0]		11.0 [6.0, 15.0]		<0.001
Sex:					<0.001
Male, n (%)	1,208	(0.7)	160,520	(99.3)
Female, n (%)	2,700	(1.7)	155,778	(98.3)
Age distribution:					<0.001
1–7 years, n (%)	130	(0.1)	99,700	(99.9)
8–11 years, n (%)	816	(1.1)	74,891	(98.9)
12–15 years, n (%)	1,315	(1.8)	72,673	(98.2)
16–23 years, n (%)	1,647	(2.3)	69,034	(97.7)
Obesity #2	399	(10.2)	15,611	(4.9)	<0.001
cysts: n (%) #3	1,592	(40.7)	159,198	(50.3)	<0.001
nodules: n(%) #4	255	(6.5)	4,128	(1.3)	<0.001

#1; Median and interquatile range were shown.

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

#3; percentage to the number of cysts detected in the presence of absence of diffuse goiter.

#4; percentage to the number of nodules detected in the presence of absence of diffuse goiter.

Table 2

Number of participants and percentage by Height-SDS, Weight-SDS, BMI-SDS and BWTAR-SDS, and the number and percentage of diffuse goiter in the indicated groups

Degree of Height-SDS	All residents				Male				Female
	n	diffuse goiter n	% #1	p#2	n	diffuse goiter n	%	p	n	diffuse goiter n	%	p
				0.009				0.543				0.003
–2.5SD > Height-SDS	3,164	37	1.2		2,028	16	0.8		1,136	21	1.8
–1.5SD > Height-SDS ≥ –2.5SD	17,168	176	1.0		9,051	53	0.6		8,117	123	1.5
1.5SD > Height-SDS ≥ –1.5SD	277,868	3,393	1.2		138,625	1,052	0.8		139,243	2,341	1.7
2.5SD > Height-SDS ≥ 1.5SD	18,936	264	1.4		10,111	73	0.7		8,825	191	2.2
Height-SDS ≥ 2.5SD	3,070	38	1.2		1,913	14	0.7		1,157	24	2.1
Total	320,206	3,908	1.2		161,728	1,208	0.7		158,478	2,700	1.7
Degree of Weight-SDS	All residents				Male				Female
	n	diffuse goiter n	%	p	n	diffuse goiter n	%	p	n	diffuse goiter n	%	p
				<0.001				<0.001				<0.001
–2.5SD > Weight-SDS	131	1	0.8		37	1	2.7		94	0	0.0
–1.5SD > Weight-SDS ≥ –2.5SD	7,887	40	0.5		3,532	14	0.4		4,355	26	0.6
1.5SD > Weight-SDS ≥ –1.5SD	288,702	3,334	1.2		145,761	1,001	0.7		142,941	2,333	1.6
2.5SD > Weight-SDS ≥ 1.5SD	16,084	342	2.1		8,392	116	1.4		7,692	226	2.9
Weight-SDS ≥ 2.5SD	7,402	191	2.6		4,006	76	1.9		3,396	115	3.4
Total	320,206	3,908	1.2		161,728	1,208	0.7		158,478	2,700	1.7
Degree of BMI-SDS	All participants				Male				Female
	n	diffuse goiter n	%	p	n	diffuse goiter n	%	p	n	diffuse goiter n	%	p
				<0.001				<0.001				<0.001
–2.5SD > BMI-SDS	549	1	0.2		264	0	0.0		285	1	0.4
–1.5SD > BMI-SDS ≥ –2.5SD	6,766	47	0.7		2,927	13	0.4		3,839	34	0.9
1.5SD > BMI-SDS ≥ –1.5SD	288,737	3,300	1.1		145,958	993	0.7		142,779	2,307	1.6
2.5SD > BMI-SDS ≥ 1.5SD	15,899	347	2.2		8,232	120	1.5		7,667	227	3.0
BMI-SDS ≥ 2.5SD	8,255	213	2.6		4,347	82	1.9		3,908	131	3.4
Total	320,206	3,908	1.2		161,728	1,208	0.7		158,478	2,700	1.7
Degree of BWTAR-SDS	All participants				Male				Female
	n	diffuse goiter n	%	p	n	diffuse goiter n	%	p	n	diffuse goiter n	%	p
				<0.001				<0.001				<0.001
–2.5SD > BWTAR-SDS	72	0	0		39	0	0.0		33	0	0
–1.5SD > BWTAR-SDS ≥ –2.5SD	8,893	4	0.04		4,733	2	0.04		4,160	2	0.05
1.5SD > BWTAR-SDS ≥ –1.5SD	278,544	1,314	0.5		140,463	453	0.3		138,081	861	0.6
2.5SD > BWTAR-SDS ≥ 1.5SD	23,918	976	4.1		12,181	301	2.5		11,737	675	5.8
BWTAR-SDS ≥ 2.5SD	8,779	1,614	18.4		4,312	452	10.5		4,467	1,162	26.0
Total	320,206	3,908	1.2		161,728	1,208	0.7		158,478	2,700	1.7

#1 Percentage of the number of participants with diffuse goiter in the indicated each degree of SDS group.

#2 Cochran-Armitage test of trend.

SDS; standard deviation score, BMI; body mass index, BWTAR; bilateral width multiplied by thickness area

Table 3

Distribution of cysts and nodules in the presence or absence of diffuse goiter

Variable	diffuse goiter				p-Value
	+		–
	n	frequency	n	frequency
cysts
male, n (%)
1–7 years, n (%)	13	(35.1)	16,627	(32.4)	0.724
8–11 years, n (%)	91	(48.4)	22,081	(57.4)	0.013
12–15 years, n (%)	196	(48.3)	21,242	(56.6)	<0.001
16–23 years, n (%)	252	(43.8)	17,382	(52.3)	<0.001
total, n (%)	552	(45.7)	77,332	(48.2)	0.086
female, n (%)
1–7 years, n (%)	35	(37.6)	17,140	(35.4)	0.654
8–11 years, n (%)	256	(40.8)	22,380	(61.5)	<0.001
12–15 years, n (%)	348	(38.3)	22,159	(63.0)	<0.001
16–23 years, n (%)	401	(37.5)	20,187	(56.4)	<0.001
total, n (%)	1,041	(38.4)	82,015	(52.6)	<0.001
nodules
male, n (%)
1–7 years, n (%)	0	(0.0)	176	(0.3)	NA
8–11 years, n (%)	4	(2.1)	210	(0.5)	0.004
12–15 years, n (%)	15	(3.7)	390	(1.0)	<0.001
16–23 years, n (%)	39	(6.8)	745	(2.2)	<0.001
total, n (%)	58	(4.8)	1,521	(0.9)	<0.001
female, n (%)
1–7 years, n (%)	4	(4.3)	155	(0.3)	<0.001
8–11 years, n (%)	22	(3.5)	299	(0.8)	<0.001
12–15 years, n (%)	58	(6.4)	674	(1.9)	<0.001
16–23 years, n (%)	113	(10.6)	1,479	(4.1)	<0.001
total, n (%)	197	(7.3)	2,607	(1.7)	<0.001

NA; not applicable

Table 4

Odds ratios and confidence intervals of diffuse goiter for sex, age, BSA-sex specific BWTAR, and the presence of cysts and nodules

Model 1

	Odds ratio	95% CI	p-Value
Sex (Female sex)	2.21	[2.06–2.37]	<0.001
Age, (1 year)	1.15	[1.15–1.16]	<0.001

Model 2

	Odds ratio	95% CI	p-Value
Sex (Female sex)	2.36	[2.19–2.55]	<0.001
Age, (1 year)	1.15	[1.15–1.16]	<0.001
BMI-SDS (1 SD)	1.25	[1.22–1.28]	0.012
BWTAR-SDS (1 SD)	3.22	[3.14–3.30]	<0.001

Model 3

	Odds ratio	95% CI	p-Value
Total:
Sex (Female sex)	2.38	[2.20–2.56]	<0.001
Age, (1 year)	1.15	[1.14–1.16]	<0.001
BMI-SDS (1 SD)	1.24	[1.21–1.27]	<0.001
BWTAR-SDS (1 SD)	3.21	[3.13–3.29]	<0.001
cysts	0.53	[0.50–0.58]	<0.001
nodules	1.38	[1.17–1.64]	<0.001
1–7 years:
Sex (Female sex)	2.77	[1.84–4.18]	<0.001
Age, (1 year)	1.74	[1.52–2.00]	<0.001
BMI-SDS (1 SD)	1.23	[1.06–1.44]	0.008
BWTAR-SDS (1 SD)	3.36	[3.05–3.71]	<0.001
cysts	0.51	[0.34–0.75]	<0.001
nodules	4.18	[1.08–16.08]	0.038
8–11 years:
Sex (Female sex)	3.65	[3.05–4.37]	<0.001
Age, (1 year)	1.32	[1.23–1.42]	<0.001
BMI-SDS (1 SD)	1.58	[1.49–1.69]	<0.001
BWTAR-SDS (1 SD)	3.53	[3.34–3.73]	<0.001
cysts	0.41	[0.35–0.48]	<0.001
nodules	1.76	[1.01–3.07]	0.047
12–15 years:
Sex (Female sex)	2.32	[2.04–2.64]	<0.001
Age, (1 year)	1.07	[1.01–1.13]	0.029
BMI-SDS (1 SD)	1.33	[1.26–1.40]	<0.001
BWTAR-SDS (1 SD)	3.30	[3.16–3.45]	<0.001
cysts	0.48	[0.43–0.54]	<0.001
nodules	1.80	[1.32–2.45]	<0.001
16–23 years:
Sex (Female sex)	1.95	[1.74–2.19]	<0.001
Age, (1 year)	0.96	[0.93–0.995]	0.023
BMI-SDS (1 SD)	1.18	[1.13–1.22]	<0.001
BWTAR-SDS (1 SD)	3.17	[3.05–3.31]	<0.001
cysts	0.52	[0.47–0.58]	<0.001
nodules	1.34	[1.08–1.67]	0.008

CI, confidence interval; BMI, body mass index; BWTAR, bilateral width multiplied by thickness area

Model 1: adjusted only for age and sex

Model 2: adjusted for age, sex, BMI-SDS, and BWTAR-SDS

Model 3: adjusted for age, sex, BMI-SDS, BWTAR-SDS, cysts and nodules

Ultrasonographic diagnosis

Ultrasonographic examinations were performed by board-certified fellows from various Japanese medical associations, as previously described [5]. In the TUE program, diffuse goiter was defined as goitrous form with diffuse reduced thyroid echogenicity [6]. Although no clear reference values or indices for the diagnosis of diffuse goiter were available, goitrous form was defined as an apparent large thyroid gland with a lumpy or rugged surface, as previously described [6]. The frequency of apparent large thyroid was shown to be 23% among cases with reduced thyroid echogenicity [6]. Cases with a simple enlarged thyroid gland with nodules or cysts were therefore not classified as diffuse goiter. Thyroid volume can be calculated as width x thickness x longitudinal length [9]. However, measuring the longitudinal length of the thyroid gland is challenging when the neck length is short or when the thyroid length exceeds that of an ultrasound probe. To compensate for the uncertainty of thyroid volume measurement, we used bilateral width × thickness area (BWTAR) to represent thyroid volume, as previously described [10].

Calculation of standard deviation scores (SDSs) for body height, body weight, body mass index (BMI), and BWTAR

We assessed body height, weight, and BMI using standardization with means and standard deviations (SDs), namely SDS, at each age and for each sex. The means and SDs of body height, body weight and BMI at the ages of 1–23 years are shown in Supplementary Table 1. There was no apparent difference between our dataset and the standard Japanese population. The Spearman’s rank correlation coefficient for BWTAR and body surface area (BSA) was the highest (r = 0.835, p < 0.001), followed by those for BWTAR and age (r = 0.801, p < 0.001), and BWTAR and BMI (r = 0.664, p < 0.001). The means and SDs of every 0.1 m² BSA-sex specific BWTAR were available in Supplementary Table 4 of the previous study [10]. We used BSA-sex specific BWTAR as a categorical BWTAR-SDS to assess thyroid volume in Tables 2 and 4.

Statistical analysis

We divided the participants into quartile-based age groups in each sex. The chi-square test was used to analyze categorical data. We used the Cochran-Armitage test to analyze trends in the prevalence of diffuse goiter in SDS-stratified groups (Table 2). A logistic regression analysis was used to determine whether sex, age, BMI-SDS, BWTAR-SDS, and the presence of cysts and nodules independently affect the presence or absence of diffuse goiter. Three different approaches were used to adjust for confounding factors. Model 1 adjusted only for sex and age. Model 2 included BMI-SDS and BWTAR-SDS, in addition to sex and age. Model 3 included cysts and nodules in addition to sex, age, BMI-SDS, and BWTAR-SDS. All probability values for statistical tests were two-tailed, and p-values <0.05 were considered statistically significant.

Ethical statement

The current study was approved by the Ethics Committee of Fukushima Medical University (No. 1318). Written informed consent was obtained from the surveyed participants or the parents or guardians of the participants if they were younger than 16 years of age. The raw data used to create all figures and tables in this study are unavailable because of a restriction outlined in the informed consent.

Results

Demographic features of thyroid diffuse goiter in childhood and adolescence

Table 1 shows the characteristics of the participants with and without diffuse goiter. The prevalence of diffuse goiter was 1.2%. Female sex was dominant, and the prevalence of diffuse goiter gradually increased in older age groups (p < 0.001). Obesity, defined as a BMI in the 95^th percentile or higher for the corresponding age and sex, was seen in 10.2% of the group with diffuse goiter. Obesity was only seen in 4.9% of the group without diffuse goiter. Cysts were seen in 40.7% of the group with diffuse goiter, which is less than the 50.3% seen in the group without diffuse goiter. In contrast, nodules were seen in 6.5% of the group with diffuse goiter, which is higher than the 1.3% seen in the group without diffuse goiter. The prevalence of diffuse goiter tended to increase in an age-dependent manner in male and female participants (Fig. 2). The prevalence of diffuse goiter was higher in female participants than in male participants at all ages, except for those aged 1–4 years.

Fig. 2

Age distribution of children and adolescents with diffuse goiter. Blue and red columns represent male and female participants, respectively

Associations between the prevalence of diffuse goiter and categorical groups depending on SDS calculated with age- and sex-specific height, weight, BMI, and BSA- and sex-specific BWTAR

To evaluate the associations between the prevalence of diffuse goiter and height, weight, and BMI, we categorized the participants into five groups depending on the SDSs of a series of measurements calculated using means and SDs of each sex and at each age in the cohort. We also show the association between the prevalence of diffuse goiter and BWTAR-SDS in the bottom panel of Table 2.

The frequency of diffuse goiter linearly increased from the lowest SDS groups to the highest SDS groups in the weight, BMI and BWTAR categories in the entire cohort and each sex (Table 2). Although the frequency of diffuse goiter in the height categories of the entire cohort increased linearly, no associations were observed among the height (Height-SDS) groups in the male group.

Association between the prevalence of diffuse goiter and the frequency of cysts or nodules in quartile age groups

The prevalence of cysts and nodules was evaluated in the presence or absence of diffuse goiter (Table 3). The prevalence of cysts was significantly lower in the presence of diffuse goiter in females but not in males. There were no differences in the prevalence of cysts in the presence and absence of diffuse goiter in either the male or female 1–7-year-old groups. In contrast, the prevalence of cysts was significantly lower in the presence of diffuse goiter for both sexes in the 8–11-year-old and older groups. The prevalence of nodules was high in the presence of diffuse goiter in both sexes in all age groups, except for in the 1–7-year-old male group, which had no cases of diffuse goiter with nodules.

Logistic regression analysis of sex, age, BMI-SDS, BWTAR-SDS, and the presence of cysts and nodules in relation to the presence and absence of diffuse goiter

To clarify whether BMI and the presence of cysts or nodules significantly affect the prevalence of diffuse goiter, we conducted a logistic regression analysis to calculate odds ratios and 95% confidence intervals (CIs) of positive diffuse goiter for age, sex, BMI-SDS, BWTAR-SDS, and the presence of cysts and nodules (Table 4). Positive individual relationships between the presence of diffuse goiter and age or female sex were observed in Model 1. A higher BMI-SDS was associated with an increased prevalence of diffuse goiter after correction by age, sex, and BWTAR-SDS in Model 2. A higher BMI-SDS, the absence of cysts, and the presence of nodules were independently associated with an increased prevalence of diffuse goiter after correction by age, sex, and BWTAR-SDS in Model 3. Furthermore, age group-stratified analyses were performed in a similar manner to the main analyses. There were similar significant associations of diffuse goiter with individual BMI-SDS, the absence of cysts, and the presence of nodules in all age groups. In addition, odds ratios of nodules for positive diffuse goiter tended to decrease in an age-dependent manner (4.18 at 1–7 years, 1.76 at 8–11 years, 1.80 at 12–15 years, and 1.34 at 16–23 years).

Discussion

In this study, we determined the prevalence of diffuse goiter by ultrasonographic examination, and evaluated its association with sex, age, BMI, thyroid volume, and cysts and nodules in children and adolescents.

We diagnosed 3,908 participants with diffuse goiter among 320,206 participants aged 1–23 years with a TUE conducted in three surveys. The prevalence of diffuse goiter was 1.2%. This prevalence gradually increased in an age-dependent manner in both sexes. Previous studies showed that the prevalence of diffuse goiter as shown by ultrasound was 16.3%, 18.8%, and 35.6% in adults; however, the definition of diffuse goiter has not been standardized and access to health screening may have varied among the studies [11-13]. Additionally, a preliminary systematic determination of diffuse goiter showed a rate of 1.4% at the ages of 3–18 years [3]. Although the prevalence of diffuse goiter in our study is low compared with that in adults, and the peak seems to be reached at approximately 17 years of age in males and approximately 12 years of age in females, and then plateaus, the prevalence in female participants at 23 years of age was nearly 4%. The prevalence, however, gradually increased in the age-stratified groups as shown in Table 1, this finding suggests that the frequency of diffuse goiter may increase further with age.

When BMI was categorized by SDS, the frequency of diffuse goiter linearly increased with BMI. Therefore, lean participants had a low frequency of diffuse goiter, and participants with obesity had a high frequency of diffuse goiter. Generally, the relationship between BMI and the probability of disease development shows a J-curve [14]. Not only high body mass, but also low body mass, may affect disease development. The linear relationship between BMI and the prevalence of diffuse goiter in our study suggests that weight loss or a lean status may suppress the development of diffuse goiter and obesity-related diffuse goiter, at least in childhood. This positive relationship was also seen between the frequency of diffuse goiter and BWTAR-SDS, implying that cases with diffuse goiter might have enlarged thyroid glands.

As shown in Table 3, the prevalence of cysts and nodules was significantly lower and higher, respectively, in the presence of diffuse goiter for both sexes in all age groups except the youngest 1–7-year-old group. Previous findings indicate low prevalence of diffuse goiter, and cysts and nodules in infants and toddlers, suggesting that small sample size may affect the results in the 1–7-year-old group [15].

The prevalence of Hashimoto’s thyroiditis associated with diffuse goiter is female- and adult-dominant [16]. In this study, logistic regression analysis showed that increasing age and female sex were independently associated with the presence of diffuse goiter in Model 1 (Table 4). This finding indicates that aging and multiple sex-related factors, including estrogen, may affect the development of diffuse goiter in childhood and adulthood.

The diagnosis of diffuse goiter based on the definition in this study may be affected by thyroid volume. In addition, there may be a positive association between BMI and BWTAR in children, because a strong association between BSA and BWTAR was previously shown in children [10]. A positive association between diffuse goiter and increasing BMI-SDS after adjusting for age, sex and BWTAR-SDS was shown in Model 2 (Table 4), suggesting that increasing BMI is independently associated with increased frequency of diffuse goiter in children and adolescents.

Although a linear relationship between BMI and diffuse goiter has been shown in the study, the association between obesity and autoimmunity has not been well investigated, especially in children. A possible association between obesity and autoimmune thyroiditis was previously demonstrated in children, but these studies included less than 1,000 participants [17, 18].

Previous research showed that the prevalence of cysts increased until 11–12 years of age, while that of nodules gradually increased after puberty (>10 and >14 years in female and male individuals, respectively) [15]. Using age, sex, BMI-SDS, and the detection of cysts and nodules as explanatory variables in Model 3, a low prevalence of cysts was associated with a high prevalence of diffuse goiter in all age groups. This finding suggests that cyst formation itself suppresses the development of diffuse goiter. Alternatively, diffuse goiter may decrease the development of cysts via an autoimmune reaction in children and adolescents. In addition, ultrasonographic detection of cysts may be affected by the background of diffuse findings. Therefore, the detection of cysts may be more difficult in participants with diffuse goiter. Consequently, technical bias may be another reason for the inverse relationship between diffuse goiter and the prevalence of cysts.

The odds ratio of nodules in the 1–7 year old group was the highest among the age quartile groups and gradually tended to decrease in subsequent age groups. This finding suggests that the association between nodule formation and the development of diffuse goiter may be strong at younger ages. Other factors, especially puberty-related hormones, may positively affect nodule formation in the older age groups [15]. As a result, the risk of diffuse goiter associated with nodules may decrease in the older age groups.

Because this study used data from the Fukushima-based population, two predisposing factors for diffuse goiter should be carefully considered, namely iodide consumption and radiation exposure. The reported median urinary iodine concentration in Fukushima Prefecture is 204 mg/L [19], which suggests that iodine intake is unlikely to affect thyroid volume. The association between low-dose radiation exposure in the Fukushima prefecture and thyroid cancer is currently under investigation. However, the United Nations Scientific Committee on the Effects of Atomic Radiation 2020 report found no association between radiation exposure and the incidence of childhood thyroid cancer, and estimated a low thyroid-absorbed radiation dose in Fukushima [20].

There are three limitations to this study. First, this was a cross-sectional study. We showed the relationship between diffuse goiter and related factors, but did not elucidate causal relationships. Second, although the diagnosis of diffuse goiter was made by experienced examiners, some inter-observer variation may have affected diagnosis. Third, according to the dataset policy, the unit of age was 1 year. Therefore, the anthropometric measurements may have shown some heterogeneity, especially in the rapid growth period of study participants.

In conclusion, this study shows the prevalence and features of diffuse goiter in children and adolescents. A high BMI and BWTAR, the absence of cysts, and the presence of nodules may be associated with the development of diffuse goiter in young individuals. The precise molecular mechanisms of the association between body mass and thyroid autoimmunity need to be investigated in children and adolescents.

Acknowledgements

We express our gratitude to all participants who participated in the Fukushima Health Management Survey. We also thank Ms. Miyuki Konno for her excellent secretarial assistance. 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. We thank Barbara Garbers, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Author Contribution

Nana Nakahata: review and editing (equal); conceptualization (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), Hisashi Ota: review and editing (equal); verification (supporting), Satoshi Suzuki: review and editing (equal); data curation (supporting), Ayako Sato: review and editing (equal); verification (lead), Rina Tazaki: 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), 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: writing-original draft (supporting); review and editing (equal), Fumihiko Furuya: review and editing (equal), Shinichi Suzuki: review and editing (equal), Seiji Yasumura: writing-original draft (supporting); review and editing (equal), Susumu Yokoya: review and editing (equal), Hitoshi Ohto: writing-original draft (supporting); writing-review and editing (equal), Kenji Kamiya: review and editing (equal), project administration (lead).

Disclosure Statement

The authors have nothing to disclose. There is no conflict of interest in this study.

Fund

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: Hiroyuki Yaginuma, Kenneth E. Nollet, 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, Tomoko Ito, Kunio Shibayama, Yuka Hamaya, Ryouko Hata, Takako Takahashi, Noriko Seto, Naoto Nihonmatsu and Yurie Kobashi.

Supplementary Table 1

Mean and standard deviation of body height (BH), body weight (BW) and BMI, at the ages of 1 to 23 yr, in male and female

male	n	BH		BW		BMI
age		mean	SD	mean	SD	mean	SD
1	1,124	80.5	4.5	10.6	1.2	16.4	1.8
2	5,036	87.9	4.8	12.5	1.5	16.1	1.6
3	8,537	95.0	4.6	14.4	1.8	15.9	1.5
4	8,580	101.7	5.1	16.3	2.1	15.7	1.5
5	7,825	108.4	5.3	18.3	2.7	15.6	1.7
6	9,733	115.3	5.6	21.1	3.7	15.8	2.1
7	10,497	121.2	5.8	23.8	4.7	16.1	2.4
8	9,860	126.9	5.9	27.1	5.8	16.7	2.7
9	9,395	132.4	6.3	30.8	7.1	17.4	3.1
10	9,704	137.6	6.5	34.5	8.2	18.1	3.3
11	9,726	143.6	7.3	38.8	9.4	18.7	3.5
12	10,107	150.8	8.2	43.7	10.3	19.1	3.4
13	10,060	158.2	8.0	48.7	10.3	19.3	3.2
14	10,080	163.9	7.1	53.5	10.6	19.8	3.2
15	7,672	167.4	6.3	57.7	10.5	20.5	3.3
16	7,693	169.3	6.0	60.3	10.5	21.0	3.3
17	8,631	170.2	5.8	62.1	10.7	21.4	3.4
18	6,789	170.8	5.9	63.4	10.8	21.7	3.4
19	4,671	171.0	5.9	63.7	10.7	21.7	3.4
20	3,582	171.0	6.0	64.0	11.2	21.9	3.6
21	1,566	171.4	6.0	65.7	12.1	22.3	3.8
22	614	171.2	6.3	65.9	12.1	22.5	3.8
23	246	170.9	5.9	65.5	11.5	22.4	3.8
Total	161,728
female	n	BH		BW		BMI
age		mean	SD	mean	SD	mean	SD
1	1,004	78.9	4.5	10.1	1.2	16.2	1.7
2	4,656	86.7	4.8	12.0	1.5	15.9	1.6
3	8,106	94.2	4.6	13.9	1.8	15.7	1.5
4	8,138	101.0	5.2	15.9	2.1	15.6	1.6
5	7,498	107.8	5.4	18.0	2.7	15.5	1.7
6	9,174	114.5	5.6	20.5	3.4	15.6	2.0
7	9,922	120.6	5.7	23.2	4.3	15.9	2.2
8	9,594	126.0	5.9	26.1	5.3	16.4	2.5
9	8,886	132.1	6.6	29.8	6.6	17.0	2.8
10	8,951	138.5	7.1	33.7	7.6	17.4	2.9
11	9,591	145.2	7.1	38.4	8.2	18.1	2.9
12	9,516	150.7	6.2	43.1	8.5	18.9	3.1
13	9,518	153.9	5.6	46.2	7.9	19.5	2.9
14	9,571	155.7	5.4	48.8	7.7	20.1	2.9
15	7,464	156.6	5.3	50.4	7.6	20.6	2.8
16	7,983	157.1	5.3	51.5	7.5	20.8	2.7
17	8,648	157.5	5.4	52.1	7.6	21.0	2.8
18	7,074	157.6	5.4	52.4	8.0	21.1	3.0
19	5,631	157.7	5.4	52.3	7.9	21.0	2.9
20	4,437	157.8	5.3	52.4	7.9	21.0	2.9
21	2,028	158.0	5.5	52.8	8.3	21.1	3.1
22	751	157.7	5.4	53.3	9.0	21.4	3.4
23	337	157.9	5.4	53.6	9.2	21.5	3.5
Total	158,478

References

• 1   Fisher  DA,  Nelson  JC,  Carlton  EI,  Wilcox  RB (2000) Maturation of human hypothalamic-pituitary-thyroid function and control. Thyroid 10: 229–234.
• 2  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.
• 3   Hayashida  N,  Imaizumi  M,  Shimura  H,  Okubo  N,  Asari  Y, et al. (2013) Thyroid ultrasound findings in children from three Japanese prefectures: Aomori, Yamanashi and Nagasaki. PLoS One 8: e83220.
• 4   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.
• 5   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.
• 6   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.
• 7   Pishdad  P,  Pishdad  GR,  Tavanaa  S,  Pishdad  R,  Jalli  R (2017) Thyroid ultrasonography in differentiation between Graves’ disease and Hashimoto’s thyroiditis. J Biomed Phys Eng 7: 21–26.
• 8   Suzuki  S,  Suzuki  S,  Fukushima  T,  Midorikawa  S,  Shimura  H, et al. (2016) Comprehensive survey results of childhood thyroid ultrasound examinations in Fukushima in the first four years after the Fukushima daiichi nuclear power plant accident. Thyroid 26: 843–851.
• 9   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.
• 10   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.
• 11   Miao  K,  Zhang  L,  Dong  X,  Qi  Y,  Kong  D, et al. (2020) Iodine nutrition and prevalence of sonographic thyroid findings in adults in the Heilongjiang Province, China. Ann Transl Med 8: 1439.
• 12   Reiners  C,  Wegscheider  K,  Schicha  H,  Theissen  P,  Vaupel  R, et al. (2004) Prevalence of thyroid disorders in the working population of Germany: ultrasonography screening in 96,278 unselected employees. Thyroid 14: 926–932.
• 13   Brander  A,  Viikinkoski  P,  Nickels  J,  Kivisaari  L (1989) Thyroid gland: US screening in middle-aged women with no previous thyroid disease. Radiology 173: 507–510.
• 14   Aune  D,  Sen  A,  Prasad  M,  Norat  T,  Janszky  I, et al. (2016) BMI and all cause mortality: systematic review and non-linear dose-response meta-analysis of 230 cohort studies with 3.74 million deaths among 30.3 million participants. BMJ 353: i2156.
• 15   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.
• 16   Hu  X,  Chen  Y,  Shen  Y,  Tian  R,  Sheng  Y, et al. (2022) Global prevalence and epidemiological trends of Hashimoto’s thyroiditis in adults: a systematic review and meta-analysis. Front Public Health 10: 1020709.
• 17   Bhowmick  SK,  Dasari  G,  Levens  KL,  Rettig  KR (2007) The prevalence of elevated serum thyroid-stimulating hormone in childhood/adolescent obesity and of autoimmune thyroid diseases in a subgroup. J Natl Med Assoc 99: 773–776.
• 18   Räisänen  L,  Lommi  S,  Engberg  E,  Kolho  KL,  Viljakainen  H (2022) Central obesity in school-aged children increases the likelihood of developing paediatric autoimmune diseases. Pediatr Obes 17: e12857.
• 19   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.
• 20  (2021) UNSCEAR 2020/2021 Report to the General Assembly with Scientific Annexes, Vol.Ⅱ, Scientific Annex B. United Nations Scientific Committee on the Effects of Atomic Radiation. United Nations Scientific Committee on the effects of Atomic Radiation. https://www.unscear.org/unscear/uploads/documents/unscear-reports/UNSCEAR_2020_21_Report_Vol.II.pdf accessed on November 1, 2023.