Abstract
Objectives: The reference values for thyroid volume (Tvol) determined by ultrasound require supportive data of normal Tvol from local iodine-sufficient populations. This study aimed to explore new reference values for Tvol in Chinese adults and comprehensively evaluate the factors associated with enlarged Tvol. Methods: A cross-sectional study was conducted in Tianjin, China. Tvol was measured by ultrasound in adults with long-term iodine sufficiency. Blood and urine samples were collected to evaluate biochemical indexes, thyroid function, and iodine status. Results: A total of 1,991 adults from the urban and suburban areas were analysed. The trend of Tvol increasing with age was observed in men under age 40 years and in women under age 52 years. In the quantile regression analyses, we found that body surface area (BSA) (β = 7.22, 95% CI: 5.33, 9.12), thyroid-stimulating hormone (TSH) (β = −1.48, 95% CI: −2.39, −0.57), thyroid nodules (TNs) (β = 6.70, 95% CI: 2.19, 11.22), and metabolic syndrome (MetS) (β = 1.40, 95% CI: 0.63, 2.17) had a strong effect on Tvol at higher percentiles in males. The dominant factors influencing Tvol were BSA (β = 9.64, 95% CI: 2.66, 16.61), TSH (β = −0.78, 95% CI: −1.16, −0.39), and TNs (β = 1.11, 95% CI: 0.43, 1.79) in females. The largest reference values for Tvol based on BSA were 20.18 (17.79, 24.32) mL in males and 15.31 (14.05, 16.70) mL in females. Conclusions: Quantile regression analyses showed that a high BSA index, a decreased TSH level, and the prevalence of TNs were essential factors associated with the enlargement of the thyroid gland. Our findings reported the new reference values for Tvol determined by ultrasound based on gender and BSA in Chinese adults.
Introduction
Thyroid volume (Tvol) and total goitre rate have been regarded as sensitive indicators reflecting long-term population iodine nutrition [1]. Iodine deficiency and iodine excess are associated with marked differences in goitre prevalence and thyroid abnormalities on ultrasound analysis [2]. Goitre is a functional biomarker that can be applied to assessing iodine status in individuals and populations [3]. The definition of goitre needs reliable volumetric data from local iodine-sufficient populations.
Chinese goitre standard published in 2007 [4] was based on European data from 1993 [5]. As the universal salt iodization programme has been mandatory since 1994 in China, iodine status has been greatly improved [6]. A previous study showed that raising the iodine intake in iodine-deficient (ID) populations reduced Tvol and decreased the incidence of thyroid enlargement [7]. Some scholars have found that the current goitre standard in China was inaccurate [8]. New reference values for Tvol in Chinese children have been proposed [8]. It is necessary to update the goitre standard for adults. Some factors such as age, sex, parity, smoking status, ethnicity, genetic causes, and geographic region affecting Tvol have been described [9-13]. It is recommended that the area- and population-specific references are needed to evaluate the normative values of Tvol [14].
Few studies have investigated the factors influencing Tvol by quantiles, which could demonstrate the continuous effects of variables on Tvol. Moreover, metabolic syndrome (MetS) has become a major health hazard in the modern world [15]. It was found to be related to functional/morphological abnormalities of the thyroid gland [16]. The association between MetS and Tvol may be explored. This study aimed to evaluate the factors influencing Tvol overall and at the quantile level, and establish updated reference values for Tvol in euthyroid adults in China.
Participants and Methods
Participants
From March to October 2015, 2,655 subjects were recruited from urban and suburban areas in Tianjin to assess adults’ iodine nutritional status. The exclusion criteria were set as follows: (1) age younger than 18 years; (2) participants who lived locally for <5 years; (3) participants who were taking iodine-containing drugs or had received iodine contrast agent examination within the prior 3 months; and (4) pregnant or lactating women. All of the participants provided written informed consent before the study. In the final analyses, we excluded participants who were missing Tvol data and those with thyroid dysfunction or a history of thyroid diseases. Figure 1 illustrates the selection of subjects for the study.
Questionnaire Survey
A questionnaire was designed to obtain basic information, including age, sex, chronic disease history, current medication use, and smoking and drinking status. The investigators of the questionnaire have been professionally trained.
Anthropometric Measurements
Height, weight, waist circumference (WC), and blood pressure were measured using standardized procedures. Body mass index (BMI) and body surface area (BSA) were calculated according to the following formulas: BMI = weight (kg)/height (m)2 and BSA = weight (kg)0.425 × height (cm)0.725 × 0.007184.
Thyroid Function and Biochemistry Measurements
Fasting venous blood samples (4–5 mL) were collected from the cubital vein of the forearm and stored in a clean glass tube. Samples were spun and the serum was separated within 2 h from taking the blood sample, and the aliquots were frozen at −20°C until further analysis. The concentrations of thyroid-stimulating hormone (TSH) were measured with the ADVIA Centaur system. Biochemical measurements, including fasting blood glucose, triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol, were measured with a Roche automatic biochemistry analyser (C8000). All of the blood samples were tested in the clinical laboratory of Tianjin Medical University General Hospital.
Thyroid Ultrasonography
A single trained operator performed the thyroid ultrasound examination using a 7.5-MHz transducer (Madison Portable B-SA-600) with the participants in the supine position. Before the study, the technique of the operator was validated against that of an experienced radiologist who specializes in ultrasound. During the study, the Tvol of 30 randomly selected adults were measured twice to monitor measurement reliability. There was no significant difference in Tvol between 2 measurements. Measurements of the thyroid gland were obtained in 3 dimensions (width, length, and depth). The maximal width was measured in the transverse section, and the maximal length and depth were determined in the longitudinal section. The volume of each lobe was calculated by the following formula: volume (mL) = 0.479 × length × width × depth (mm)/1,000. Tvol was the sum of the volume of each lobe. The isthmus was not included. Thyroid nodules (TNs) were described as additional ultrasound structural focal abnormalities. The location, number, echogenicity, boundary, diameter >1 cm or not, and calcification of TNs were recorded.
Urinary Iodine
In the morning, the midstream urine samples were collected to determine the urinary iodine concentrations (UIC) by ammonium persulfate digestion with spectrophotometric detection of the Sandell-Kolthoff reaction at the Key Laboratory of Hormone and Development (Ministry of Health), Metabolic Diseases Hospital and the Tianjin Institute of Endocrinology, Tianjin Medical University.
Diagnosis of MetS
According to the International Diabetes Federation [17], the definition of MetS was abdominal adiposity (WC ≥90 cm and WC ≥80 cm for Chinese men and women) plus at least 2 of the following factors:
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triglyceride concentrations >1.7 mmol/L or specific treatment for this lipid abnormality;
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high-density lipoprotein cholesterol concentrations <1.03 mmol/L in men and 1.29 mmol/L in women or specific treatment for this lipid abnormality;
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blood pressure >130/85 mm Hg or treatment of previously diagnosed hypertension;
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fasting plasma glycaemia >5.6 mmol/L or previous diagnosis of type 2 diabetes.
Statistical Analysis
The Kolmogorov-Smirnov test was performed to assess the normality of variables. Normally distributed data are expressed as the mean ± standard deviation (SD), while non-normally distributed data are expressed as the median (IQR). A t test or Mann-Whitney U test was used to compare 2 continuous variables. The rates were compared between groups using the χ2 test. Spearman rank correlation was used to examine the factors associated with Tvol, and we adjusted for the confounding factors to calculate the partial correlation coefficient. We used a generalized additive model to identify the nonlinear relationship between age and Tvol. A 2-piece-wise regression model was used to examine the threshold effect of the age on Tvol in terms of a smoothing plot. Multivariate linear regression analyses were applied to identify the factors affecting Tvol with LN transformation. Quantile regression was then used to estimate the effects of BSA, TSH, TNs, UIC, MetS, and smoking status on Tvol across different quantiles, including 2.5th, 25th, 50th, 75th, and 97.5th quantiles. Data transformations were not conducted as quantile regression is semiparametric in nature (i.e., makes no assumptions about the distributions of errors and is accordingly more robust to non-normal distributions and outliers) and invariant to monotonic data [18]. Such a model enabled us to explore various forms of heterogeneity associated with the covariates under less stringent distributional assumptions [19, 20]. The 95% confidence interval (CI) of quantiles of Tvol was derived from 1,000 bootstrapped replications. The statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA), Empower (R) (www.empowerstats.com, X&Y Solutions, Inc., Boston, MA, USA) and R (http://www.R-project.org). All statistical tests were 2-tailed, and a p value <0.05 was considered statistically significant.
Results
Baseline Data
A total of 1,991 adults were included in the final analyses: 1,004 subjects were from an urban area, and 987 subjects were from a suburban area. Baseline data are shown in Table 1. There was no significant difference in age distribution among men and women (p = 0.45). The median of UIC indicated adequate iodine nutrition of the population [1]. The medians of Tvol in men and women were 10.1 (8.3–12.6) mL and 7.5 (6.0–9.4) mL, respectively. The prevalence of MetS was significantly higher in males (34.3%) than in females (21.0%) (p < 0.001). More than 70% of the subjects with nodules had multiple nodules. The proportion of TNs >1 cm was 27.2%. The echogenicity of the nodules was as follows: hypoechoic (19.8%), hyperechoic (10.2%), isoechoic (47.8%), anechoic (10.0%), and mixed echogenicity (12.2%).
Baseline characteristics of participants
Exploration of the Factors Associated with Tvol
A nonlinear relationship between age and Tvol is shown in Figure 2. Tvol increased with age up to the turning points (age 40 years for men and 52 years for women). To the left of the turning points, the upward trends were significant in both men and women (p < 0.001 and p = 0.002, respectively). However, the downward trend was significant in men but not in women to the right of turning points (Table 2). Tvol was significantly associated with anthropometric indices including height (r = 0.39), weight (r = 0.49), WC (r = 0.45), BMI (r = 0.37), and BSA (r = 0.50). These trends remained after adjusting for confounders (data not shown). In the multiple linear regression model, BSA, TNs, MetS, and smoking status were significantly positively correlated with Tvol, and TSH was inversely correlated with Tvol in males. However, no significant correlations between Tvol and MetS or smoking status were found in females (Table 3). When including the information of pregnancy history and menopause status in female analyses, the statistical significance of the relationships between Tvol and age, BSA, TSH, TNs, UIC, MetS, and smoking status did not change (data not shown). Moreover, online suppl. Figure 1 (see www.karger.com/doi/10.1159/000513494 for all online suppl. material) shows no significant difference in Tvol in women without and with pregnancy history or in premenopausal women and postmenopausal women.
Threshold effect analyses of age on Tvol using a 2-piece-wise linear regression mode
Multiple linear regression analyses on the relationship between Tvol and related variables
The association between age and Tvol in males and females. A threshold, nonlinear association between age and Tvol was found (p < 0.001 in males and p = 0.03 in females) in a generalized additive model. The solid black line represents the fitted smooth curve. The dotted lines represent the 95% CI.
Citation: European Thyroid Journal 10, 6; 10.1159/000513494
Quantile Regression Results for Assessing Factors Associated with Tvol
The influences of the factors changed at different quantiles of Tvol (online suppl. Table 1). The effects of BSA on Tvol continued to increase from low quantiles to high quantiles in both sexes. The relationship with TSH was inverse and significant for almost all percentiles of Tvol. The effects of MetS and smoking status on Tvol were found in males at the lower percentiles. However, we did not find a significant effect of pregnancy history or menopause status on Tvol across all the percentiles in women (data not shown).
Reference Values of Tvol Based on Bootstrapping
The values of the Tvol obtained by excluding subjects with TNs were smaller than those in subjects with TNs (online suppl. Tables 2, 3). BSA-adjusted Tvol by gender is presented in Table 4. The quantile-specific Tvol increased with an increase in BSA in all population groups. Males had significantly greater Tvol over the entire range of quantiles than did females.
The reference values for Tvol based on bootstrapping in subjects without TNs by BAS quartiles
Discussion
In this study, the median of UIC was 138 μg/L, which indicates sufficient iodine nutrition [1]. Subjects recruited in our study had spent at least 5 years in a longstanding iodine-sufficient area [21]. This ensures the representativeness of the population for establishing reference values.
We demonstrated an age-related increase trend in Tvol. Similar results were found in a previous study that evaluated the effect of mandatory iodization of salt on Tvol. Tvol increased with age within a specific age range both before and after the iodization of salt [7]. However, a negative relationship between Tvol and age in the female group was found in a French study [22]. One possible reason for the difference was that the subjects were all over 35 years old in the French study. We also found a significant interaction between the effects of age on Tvol and other factors. The variation in Tvol that the effect of age accounted for was negligible when adjusting for BSA, TSH, TNs, UIC, MetS, and smoking status in the multiple linear regression analyses.
We found considerable effects of anthropometric parameters on Tvol. Weight, WC, BMI, and BSA had an interactive effect on Tvol and explained >30% of the variation in Tvol in both males and females. Kayastha et al. [23] also suggested that BSA is the best indicator for the assessment of Tvol. As for TSH, although several earlier studies showed that there was a lack of significant correlation between TSH levels and Tvol [24, 25], a negative relationship between them was later confirmed in other studies [22, 26], as well as in our study. The correlation between Tvol and UIC is well recognised in ID populations, while the relationship is likely diminished in iodine-replete populations [10, 27]. In our study, a modest correlation between UIC and Tvol was found in females but not in males. Thyroglobulin (Tg) was not measured in our study. A cross-sectional study found that Tg was also associated with Tvol, and the prevalence of thyroid enlargement was 11.43% in the Tg-above-77-μg/L group [28].
Additionally, smoking as a risk factor was frequently investigated for Tvol progression and goitre [13, 29, 30]. Our data showed a significant correlation between smoking status and Tvol only in males. We speculate that the reason for this difference was that a far higher proportion of the men studied were smokers. The same trend was also found in the relationship between MetS and Tvol. Previous studies have elucidated the potential pathological basis between MetS and enlarged Tvol [31]. Insulin resistance forms the basis for the development of MetS [32], and higher circulating levels of insulin increase thyroid proliferation, which manifests as increased Tvol [16]. Moreover, parity has been reported in relation to Tvol in ID areas [12, 33, 34]. However, Gomez et al. [26] found no association between Tvol and parity among 134 randomly selected healthy females in an iodine-sufficient area. In the female analyses, no statistical differences in Tvol between nulligravida and those with the pregnancy history, or premenopausal women and postmenopausal women were found. The possible reason is that our study population was iodine sufficient.
It has been mentioned in previous studies that the mean of Tvol was similar in different ethnic and racial groups with sufficient iodine intake [5]. Our measured means of Tvol agreed with the reported values of Adibi et al. [11], Berghout et al. [25], and Maravall et al. [35]. The values were 10.31 mL in males and 7.70 mL in females in our data, 10.73 and 7.71 mL in Iran [11], 12.7 and 8.7 mL in the Netherlands [25], and 9.87 and 6.57 mL in Spain [35]. Subjects with a higher Tvol tended to be found in ID areas. A Danish study published in 1983 reported the means of Tvol of 19.6 and 17.5 mL in males and females, respectively. Denmark was moderately to mildly ID at that time [36]. Subsequently, the medians of Tvol of 12.7 mL in women and 15.8 mL in men in mildly ID areas and 14.2 mL in women and 19.5 mL in men in moderately ID areas were reported in 1998 in Denmark. After the implementation of mandatory salt iodization programme, the medians of Tvol of 11.8 mL in women and 14.1 mL in men in formerly mildly ID areas and 12.3 mL in women and 16.9 mL in men in formerly moderately ID areas were reported in 2005 in Denmark [7]. This reflects the decreasing trend in Tvol with the improvement in iodine status [37]. In the existing standards, the values of Tvol >25 mL in men and 18 mL in women are considered goitre [4]. The new reported reference values for Tvol in our study were smaller than those for the existing goitre criteria [4]. Based on published studies, we concluded that this change is reasonable. The data source for goitre criteria in China was based on the background of iodine deficiency in Europe [5, 36]. Tvol is increased with iodine deficiency. In addition, iodine status has been greatly improved in China, and along with the transition of iodine status from iodine deficiency to iodine sufficiency, there was a corresponding change in Tvol. Shan et al. [6] found that the prevalence of goitre significantly decreased from 5.02% to 2.9% after implementing a mandatory universal salt iodization programme for 16 years in China. Another study conducted in an iodine-sufficient area in China has begun to use the new goitre definition values of 18.8 mL for males and 14.4 mL for females [38]. All of these studies suggest that the current reference values for Tvol should be redefined in China.
There are some limitations to this study. Tg as a sensitive biomarker of iodine status was not measured, and parity information was not collected in our study. The influence of Tg and parity on Tvol should be taken into account in subsequent studies. We only included an iodine-adequate area in China. It would be better represented if the populations from multiple iodine-sufficient regions in China were included. However, we have a guaranteed sufficient sample size and age range compared to other studies that established reference values [9, 25, 39]. Subjects in rural and urban areas were included to ensure the sample’s representativeness. Moreover, we assessed factors affecting Tvol at the quantile level. To our knowledge, this is the first reference data of Tvol measured by ultrasonography based on a large adult sample in China.
In summary, the new reference values of Tvol for adults were proposed in this study. Quantile regression identified strong relationships between the upper percentiles of Tvol and BSA, TSH, and TNs in both sexes.
Acknowledgements
We gratefully acknowledge all the participants in this study, along with Tianjin Medical University General Hospital, for their assistance in collecting and examining the biochemical samples.
Statement of Ethics
This study was conducted and approved by the medical Ethics Committee of China Medical University (serial number: IRB [2013]115). All procedures performed in the studies were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All participants were informed about the purpose and procedure of the study, and they declared their voluntary attendance by signed written consent.
Conflict of Interest Statement
All authors and companies or organizations do not have any conflicts of interests.
Funding Sources
This work was supported by the National Natural Science Foundation of China (Grant No.: 81330064, 81920108031, 71774115 and 81703218) and Tianjin Education Committee Social Science Major Project (Grant No.: 2017JWZD35).
Author Contributions
W.Z. and L.T. designed the research; Y.C., L.F., and C.D. conducted the research and collected the data; M.Z. and H.W. provided essential reagents or essential materials; W.G. and Y.J. analysed the data and wrote the statistical analyses plan; and W.G. and S.D. wrote the first draft of the paper. W.Z. had primary responsibility for the final content.
Footnotes
verified
References
- 1↑
WHO/UNICEF/ICCIDD. Assessment of iodine deficiency disorders and monitoring their elimination: a guide for programme managers. 3rd ed. 2007.
- 2↑
Knudsen N , Bülow I, Jorgensen T, Laurberg P, Ovesen L, Perrild H. Goitre prevalence and thyroid abnormalities at ultrasonography: a comparative epidemiological study in two regions with slightly different iodine status. Clin Endocrinol. 2000;53(4):479–85.http://dx.doi.org/10.1046/j.1365-2265.2000.01121.x.
- 3↑
Zimmermann MB , Andersson M. Assessment of iodine nutrition in populations: past, present, and future. Nutr Rev. 2012;70(10):553–70.http://dx.doi.org/10.1111/j.1753-4887.2012.00528.x.
- 4↑
Ministry of Health of the People's Republic of China. Diagnostic criteria for endemic goiter (WS 276-2007). Beijing, China.
- 5↑
Gutekunst R , Martin-Teichert C. Requirements for goiter surveys and the determination of thyroid size, in iodine deficiency in Europe. In: Delange F, Dunn JT, Glinoer D, editors. Boston, MA: Springer USA; 1993.
- 6↑
Shan Z , Chen L, Lian X, Liu C, Shi B, Shi L, et al.. Iodine status and prevalence of thyroid disorders after introduction of mandatory universal salt iodization for 16 years in china: a Cross-Sectional Study in 10 cities. Thyroid. 2016;26(8):1125–30.
- 7↑
Vejbjerg P , Knudsen N, Perrild H, Carlé A, Laurberg P, Pedersen IB, et al.. Effect of a mandatory iodization program on thyroid gland volume based on individuals' age, gender, and preceding severity of dietary iodine deficiency: a prospective, population-based study. J Clin Endocrinol Metab. 2007;92(4):1397–401.http://dx.doi.org/10.1210/jc.2006-2580.
- 8↑
Chen W , Zhang Q, Wu Y, Wang W, Wang X, Pearce EN, et al.. Shift of reference values for thyroid volume by ultrasound in 8- to 13-year-olds with sufficient iodine intake in China. Thyroid. 2019;29(3):405–11.http://dx.doi.org/10.1089/thy.2018.0412.
- 9↑
Sahin E , Elboga U, Kalender E. Regional reference values of thyroid gland volume in Turkish Adults. Srp Arh Celok Lek. 2015;143(3–4):141–5..
- 10↑
Zimmermann MB , Hess SY, Molinari L, De Benoist B, Delange F, Braverman LE, et al.. New reference values for thyroid volume by ultrasound in iodine-sufficient schoolchildren: a World Health Organization/Nutrition for Health and Development Iodine Deficiency Study Group Report. Am J Clin Nutr. 2004;79(2):231–7.http://dx.doi.org/10.1093/ajcn/79.2.231.
- 11↑
Adibi A , Mehri S, Aminorroaya A, Ehsan R, Mohsen M, Fallah Z, et al.. Normal values of thyroid gland in Isfahan, an iodine replete area. J Res Med Sci. 2008;13:55–60.
- 12↑
Knudsen N , Bülow I, Laurberg P, Ovesen L, Perrild H, Jørgensen T. Parity is associated with increased thyroid volume solely among smokers in an area with moderate to mild iodine deficiency. Eur J Endocrinol. 2002;146(1):39–43.http://dx.doi.org/10.1530/eje.0.1460039.
- 13↑
Vejbjerg P , Knudsen N, Perrild H, Carlé A, Laurberg P, Pedersen IB, et al.. The impact of smoking on thyroid volume and function in relation to a shift towards iodine sufficiency. Eur J Epidemiol. 2008;23(6):423–9.http://dx.doi.org/10.1007/s10654-008-9255-1.
- 14↑
Mo Z , Lou X, Mao G, Wang Z, Zhu W, Chen Z, et al.. Larger thyroid volume and adequate iodine nutrition in Chinese School children: local normative reference values compared with WHO/IGN. Int J Endocrinol. 2016;2016:8079704.http://dx.doi.org/10.1155/2016/8079704.
- 15↑
Saklayen MG . The global epidemic of the metabolic syndrome. Curr Hypertens Rep. 2018;20(2):12.http://dx.doi.org/10.1007/s11906-018-0812-z.
- 16↑
Rezzonico J , Rezzonico M, Pusiol E, Pitoia F, Niepomniszcze H. Introducing the thyroid gland as another victim of the insulin resistance syndrome. Thyroid. 2008;18(4):461–4.http://dx.doi.org/10.1089/thy.2007.0223.
- 17↑
Alberti KG , Zimmet P, Shaw J. The metabolic syndrome: a new worldwide definition. Lancet. 2005;366(9491):1059–62.http://dx.doi.org/10.1016/S0140-6736(05)67402-8.
- 19↑
Koenker R . Quantile regression for longitudinal data. J Multivar Anal. 2004;91(1):74–89.http://dx.doi.org/10.1016/j.jmva.2004.05.006.
- 20↑
Lipsitz SR , Fitzmaurice GM, Molenberghs G, Zhao LP. Quantile regression methods for longitudinal data with drop-outs: application to CD4 Cell counts of patients infected with the human immunodeficiency virus. J R Stat Soc Ser C. 1997;46(4):463–76.
- 21↑
Gao M , Chen W, Sun H, Fan L, Wang W, Du C, et al.. Excessive iodine intake is associated with formation of thyroid nodules in pregnant Chinese women. Nutr Res. 2019;66:61–7.http://dx.doi.org/10.1016/j.nutres.2019.02.009.
- 22↑
Barrere X , Valeix P, Preziosi P, Bensimon M, Pelletier B, Galan P, et al.. Determinants of thyroid volume in healthy French adults participating in the SU.VI.MAX cohort. Clin Endocrinol. 2000;52(3):273–8.
- 23↑
Kayastha P , Paudel S, Shrestha D, Ghimire R, Pradhan S. Study of thyroid volume by ultrasonography in clinically euthyroid patients. J Inst Med. 2010;32:36–43.
- 24↑
Hegedus L , Perrild H, Poulsen LR, Andersen JR, Holm B, Schnohr P, et al.. The determination of thyroid volume by ultrasound and its relationship to body weight, age, and sex in normal subjects. J Clin Endocrinol Metab. 1983;56(2):260–3.
- 25↑
Berghout A , Wiersinga WM, Smits NJ, Touber JL. Determinants of thyroid volume as measured by ultrasonography in healthy adults in a non-iodine deficient area. Clin Endocrinol. 1987;26(3):273–80.http://dx.doi.org/10.1111/j.1365-2265.1987.tb00784.x.
- 26↑
Gomez JM , Maravall FJ, Gomez N, Guma A, Soler J. Determinants of thyroid volume as measured by ultrasonography in healthy adults randomly selected. Clin Endocrinol. 2000;53(5):629–34.
- 27↑
Zou Y , Ding G, Lou X, Zhu W, Mao G, Zhou J, et al.. Factors influencing thyroid volume in Chinese children. Eur J Clin Nutr. 2013;67(11):1138–41.http://dx.doi.org/10.1038/ejcn.2013.173.
- 28↑
Du Y , Gao YH, Feng ZY, Meng FG, Fan LJ, Sun DJ. Serum thyroglobulin-A sensitive biomarker of iodine nutrition status and affected by thyroid abnormalities and disease in adult populations. Biomed Environ Sci. 2017;30(7):508–16.http://dx.doi.org/10.3967/bes2017.067.
- 29↑
Ittermann T , Schmidt CO, Kramer A, Below H, John U, Thamm M, et al.. Smoking as a risk factor for thyroid volume progression and incident goiter in a region with improved iodine supply. Eur J Endocrinol. 2008;159(6):761–6.http://dx.doi.org/10.1530/EJE-08-0386.
- 30↑
Knudsen N , Laurberg P, Perrild H, Bülow I, Ovesen L, Jørgensen T. Risk factors for goiter and thyroid nodules. Thyroid. 2002;12(10):879–88.http://dx.doi.org/10.1089/105072502761016502.
- 31↑
Guo W , Tan L, Chen W, Fan L, Chen Y, Du C, et al.. Relationship between metabolic syndrome and thyroid nodules and thyroid volume in an adult population. Endocrine. 2019;65(2):357–64.http://dx.doi.org/10.1007/s12020-019-01901-4.
- 32↑
Blanc E , Ponce C, Brodschi D, Nepote A, Barreto A, Schnitman M, et al.. Association between worse metabolic control and increased thyroid volume and nodular disease in elderly adults with metabolic syndrome. Metab Syndr Relat Disord. 2015;13(5):221–6.http://dx.doi.org/10.1089/met.2014.0158.
- 33↑
Rotondi M , Amato G, Biondi B, Mazziotti G, Del Buono A, Rotonda Nicchio M, et al.. Parity as a thyroid size-determining factor in areas with moderate iodine deficiency. J Clin Endocrinol Metab. 2000;85(12):4534–7.http://dx.doi.org/10.1210/jcem.85.12.7002.
- 34↑
Farahati J , Wegscheider K, Christ K, Gilman E, Oing W. Gender-specific determinants of goiter. Biol Trace Elem Res. 2006;113(3):223–30.http://dx.doi.org/10.1385/BTER:113:3:223.
- 35↑
Maravall FJ , Gómez-Arnáiz N, Gumá A, Abós R, Soler J, Gómez JM. Reference values of thyroid volume in a healthy, non-iodine-deficient Spanish population. Horm Metab Res. 2004;36(9):645–9.
- 36↑
Nyström HF , Brantsæter AL, Erlund I, Gunnarsdottir I, Hulthén L, Laurberg P, et al.. Iodine status in the Nordic countries: past and present. Food Nutr Res. 2016;60:31969.http://dx.doi.org/10.3402/fnr.v60.31969.
- 37↑
Rasmussen LB , Carlé A, Jørgensen T, Knudsen N, Laurberg P, Pedersen IB, et al.. Iodine intake before and after mandatory iodization in Denmark: results from the Danish Investigation of Iodine Intake and Thyroid Diseases (DanThyr) study. Br J Nutr. 2008;100(1):166–73.
- 38↑
Liu Y , Huang H, Zeng J, Sun C. Thyroid volume, goiter prevalence, and selenium levels in an iodine-sufficient area: a cross-sectional study. BMC Public Health. 2013;13:1153.http://dx.doi.org/10.1186/1471-2458-13-1153.
- 39↑
Aydıner Ö , Karakoç Aydıner E, Akpınar İ, Turan S, Bereket A. Normative data of thyroid volume-ultrasonographic evaluation of 422 subjects aged 0-55 years. J Clin Res Pediatr Endocrinol. 2015;7(2):98–101.http://dx.doi.org/10.4274/jcrpe.1818.
Footnotes
Wenxing Guo, Long Tan, and Shuyao Dong contributed equally as co-first authors.
