A 1:1 matched case-control study: Are thyroid nodules related to iodine nutrition? Can thyroglobulin(Tg) serve as a functional biomarker for thyroid nodules?

doi:10.21203/rs.3.rs-2990755/v1

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A 1:1 matched case-control study: Are thyroid nodules related to iodine nutrition? Can thyroglobulin(Tg) serve as a functional biomarker for thyroid nodules?

https://doi.org/10.21203/rs.3.rs-2990755/v1

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Background

A significant increasing trend in the prevalence of thyroid nodules has resulted in shining a spotlight on whether thyroid nodules are related to the level of iodine nutrition. In this study, a 1:1 matched case-control study is conducted to investigate whether thyroid nodules are related to the level of iodine nutrition.

Methods

Selected three survey sites with median urinary iodine (MUI) < 100µg/L, 100–199µg/L, and 200–299µg/L. The residents who have lived there for at least 5 years with thyroid nodules were the case group, while those without nodules were the control group that matched 1:1 with the case group by age (± 3 years), gender and region. All subjects completed questionnaires, collected blood and urine samples.

Results

The MUI of the case group in the areas with more than adequate iodine intake was lower than that of the control group(P < 0.05); Only the level of Tg of the case group was higher than that of the control group in the areas with adequate iodine intake(P < 0.05).The conditional Logistic regression model resulted that there were statistically significant correlations between history of thyroid disorders, Tg, TgAb and thyroid nodules.

Conclusions

When in the areas with more than adequate iodine intake, a slight increase in urinary iodine may help inhibit the occurrence of nodules. History of thyroid disorders, increased Tg and TgAb levels were risk factors for thyroid nodules. Tg can serve as a functional biomarker for thyroid nodules.

thyroid nodules

iodine nutrition

thyroid function

thyroglobulin

Iodine is a trace element necessary for the synthesis of thyroxine (T4) and triiodothyronine (T3), which are essential for cell metabolism, growth and physical development, and thus adequate iodine is critical at all stages of life^[^]. Iodine deficiency can lead to iodine deficiency disorders (IDD), including miscarriage, stillbirth, endemic disease, neonatal cretinism, physical growth retardation in children and adolescents, endemic goiter and so on^[^,^]. Besides, excessive iodine intake is deemed to be associated with hyperthyroidism or hypothyroidism in some susceptible individuals^[^].

In order to eliminate the harm of iodine deficiency, international organizations including the World Health Organization and the United Nations Children’s Fund (UNICEF) advocated the universal salt iodization (USI) strategy in 1993, which received positive responses from member states and achieved remarkable results. The number of iodine-deficient countries decreased from 110 to 32 in 2012^[1]. Since the USI policy was implemented in China in 1995, the harm of iodine deficiency has been effectively controlled. Ten years later, the incidence of goiter has dropped to less than 5%. Thyroid-related diseases caused by iodine deficiency, including simple goiter, cretinism, psychiatric disorders and neuronal developmental disorders, were also significantly reduced^[^]. By 2000, China has basically achieved the goal of eliminating iodine deficiency disorders^[2].

About 80% of the iodine in the human body is excreted through urine. The urinary iodine concentration is an indicator that is currently internationally recognized, low-cost and easily obtained, which can reflect the recent nutritional status of iodine^[^]. National iodine monitoring data show that when the iodized salt concentration is 40–60 mg/kg in some provinces, the median urinary iodine concentration (mUIC) exceeds 300 µg/L. Therefore, the state lowered the concentration of iodized salt from 40-60mg/kg to 20-50mg/kg^[^]. However, it still maintains high urinary iodine levels in certain provinces due to high-salt diet^[^]. For the reason that salt consumption varies from regions, each province has been authorized to set its own iodized salt concentration standard according to its geography and the iodine nutrition of the population since March, 2012. To illustrate, Fujian Province sets the standard for iodized salt at 18–33 mg/kg^[2].The latest iodine nutrition survey in Fujian Province in 2017 showed that the iodine nutritional status of adults and children was generally at an appropriate level^[2].

Thyroid nodules are a common clinical thyroid disease. According to early reports, the incidence rate of thyroid nodules was 4%-7%, of which 5%-15% were malignant nodules or hidden thyroid cancer in benign nodules^[^,^]. With the development of society in recent years, the detection rate of thyroid nodules has shown an upward trend^[^,^,^], which can be as high as 19%-67% in the general population. The latest literature reports that the average detection rate of thyroid nodules in China is 38%, of which 45.2% for women and 31.2% for men^[^]. The sharp increase in the prevalence of thyroid nodules has aroused people’s wide concerns about the policy of iodizing salt, which causes a certain degree of impact on the sustainable development of the prevention and control of iodine deficiency diseases province-wide and even nationwide. Therefore, it is important and urgent to explore the relationship between thyroid nodules and iodine nutrition levels and other influencing factors.

This paper is intended to explore whether thyroid nodules are related to iodine nutrition level and other related influencing factors through a 1:1 matched case-control study with a strong causal argument. Moreover, a comparison of differences between thyroid function indicators with and without thyroid nodules is made to explore whether Tg can be a functional biomarker for thyroid nodules.

Selection of respondents

Villages with median urinary iodine (MUI) < 100µg/L, 100–199µg/L, and 200–299µg/L of the general population were selected as the survey sites. Inclusion criteria: The residents with thyroid nodules discovered for the first time and lived in the local area for at least 5 years were the case group, while the residents who matched 1:1 with the case group by age (± 3 years), gender, region, and the B-ultrasound examination with no nodules were the control group. In addition, the following groups should be excluded: pregnant women, lactating women, those currently suffering from thyroid nodule-related diseases, those with direct blood relationship with the case group, and those with a history of mental illness who could not correctly understand the questionnaire.

Estimation of samplesize

This study selected smoking as a factor for sample size estimation. Refer to two articals^[^,^]. The sample size estimation formula is as follows:

is the number of pairs of inconsistent exposure conditions, p = OR/(1 + OR), the total number of pairs required M = m /(p₀q₁ + p₁q₀), p₀ and p₁ respectively represent the estimated exposure rates of the control and case groups in the target population: p₁ = p₀OR/[1 + p₀(OR-1)]

In this study, α = 0.05, Z_α=1.96, β = 0.10, Z_β=1.282, and the values above are put into the formula to obtain the total number of pairs M = 103.

Thyroid B-ultrasound and questionnaire

Each respondent was examined by a trained physician using a B-type ultrasonic diagnostic apparatus with a probe frequency of 7.5MHZ. The examination was carried out according to the specification of ultrasonic diagnosis of thyroid nodules^[^]. A unified questionnaire was used and conducted by the trained investigators who used a one-to-one interview. A unified questionnaire was used and conducted by the trained investigators who used a one-to-one interview. The main contents of the questionnaire included (general information such as age and height; life behaviors such as smoking and drinking; diseases such as history of thyroid disorders and diabetes, radiations such as X radiation, CT, etc.)

Urine sample, blood collection and test of urine iodine and thyroid function

5mL random urine sample and 5mL peripheral venous blood were collected for each survey subject to detect urinary iodine using “As-Ce Catalytic Chromatography” method (WS/T 107–2016)^[^]. The US BECKMAN-access2 analyzer with the thyroid function diagnostic kit were used to detect 8 indicators of serum thyroid function, involving serum thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), Triiodothyronine (T3), total thyroxine (T4), thyroglobulin antibody (TgAb), thyroglobulin (Tg), thyroid peroxidase antibody (TPOAb).

Quality Control

This study was approved by the Medical Ethics Committee of the Fujian Provincial Center for Disease Control and Prevention (2017002), and all respondents have signed the informed consent. Clean polyethylene plastic containers with screw caps were used for urine sample collection, and at least one reference material was inserted before, during and after the detection of each batch of samples for quality control. The correlation coefficient of the standard curve of urine iodine detection was above 0.999. Blood required aseptic collection. More than 5 mL of blood was collected (without anticoagulant). After complete coagulation, it was centrifuged at low speed (2000–2800 rpm, 5–10 min), and serum was aliquoted in 2 mL cryovials.

Definitions and Reference Standards

The assessment of iodine nutritional status adopts the iodine nutritional status standard recommended by WHO^[^], in which the median urinary iodine < 100µg/L is iodine deficiency, 100–199µg/L is adequate iodine, 200–299µg/L is more than adequate iodine, and ≥ 300µg/L is excessive iodine. The reference ranges of thyroid function indicator were (provided by the kit used): TSH: 0.340-5.600uIU/mL, Tg:1.15-130.77µg/L, FT3:3.80-6.00pmol/L,

FT4: 7.85–14.40 pmo l/ L, TT3: 1.34-2.73nmol/L, TT4: 78.38-157.40nmol/L, TPOAb < 9.00IU/ml, TgAb < 4.00IU/ml.

Statistical analysis

SPSS software (SPSS 21.0) was used for data analysis.χ² tested the balance between the case and the control group in terms of marital status, educational level and occupation. The Enter method was used to conduct multivariate conditional Logistic regression analysis to further explore the influencing factors of thyroid nodules. Moreover, the MUI of the case group and the control group were tested by Wilcoxon rank sum test. Urinary iodine and thyroid function indicators that did not conform to the normal distribution were represented by median and interquartile range. The comparison of thyroid function between the case group and the control group was performed by the Wilcoxon rank sum test, and P < 0.05 was considered statistically significant.

General situation of the research object

A total of 327 cases of thyroid nodules and 327 controls were collected. It can be seen from Table 1 that there was no significant difference in general demographic characteristics between the two groups (P > 0.05). The two groups were balanced and comparable.

Table 1

Comparison of general demographic characteristics of case and control groups
General demographic characteristics	case group	control group	χ²	P
marital status			1.013	0.602
Unmarried n(%)	22(6.7)	23(7.0)
Married n(%)	283(86.6)	288(88.1)
Other n(%)	22(6.7)	16(4.9)
educational level			1.364	0.505
Elementary school and below n(%)	231(70.6)	223(68.2)
Middle school n(%)	84(25.7)	86(26.3)
College and above n(%)	12(3.7)	18(5.5)
occupation			0.077	0.782
Non-physical work n(%)	61(18.7)	60(18.3)
Manual labor n(%)	266(81.3)	267(81.7)

The relationship between urinary iodine concentration and thyroid nodules

There was no significant difference in MUI between the case group and the control group in the areas with adequate iodine intake, areas with mild iodine deficiency, and the whole population (P > 0.05). Nevertheless, the MUI of case group was lower than that of control group in the areas with more than adequate iodine intake(P < 0.05). (Table 2,Figs. 1 and Figs. 2.)

Table 2

The relationship between urinary iodine concentration and thyroid nodules
	case group MUI (µg/L)(P25-P75)	control group MUI (µg/L)(P25-P75)	Z	P
areas with adequate iodine intake	154.40(96.74-229.68)	141.96(83.40-199.47)	-1.672	0.094
areas with mild iodine deficiency	70.10(45.40–93.60)	63.90(45.80–91.50)	-0.239	0.811
areas with more than adequate iodine intake	218.10(142.81-313.36)	265.32(195.42-352.04)	-1.976	0.048
the whole population	121.18(69.20-209.35)	119.30(61.48-216.22)	-0.157	0.875

The K-S normality test was performed on the thyroid function indicators of the case group and the control group. The data of each indicator did not obey the normal distribution(P < 0.05).The Tg and FT4 levels of the case group in the areas with mild iodine deficiency, the areas with more than adequate iodine intake, and the whole population were higher than those in the control group(P < 0.05). Only the Tg level of the case group was higher than that of control group in the areas with adequate iodine intake (P < 0.05). Furthermore, other indicators had no statistical significance (Table 3).

Table 3

Comparison of various thyroid function indicators between the case group and the control group
Thyroid function indicators	areas with mild iodine deficiency		areas with adequate iodine intake		Areas with more than adequate iodine intake		the whole population
Thyroid function indicators	case group M(P25-P75)	control group M(P25-P75)	case group M(P25-P75)	control group M(P25-P75)	case group M(P25-P75)	control group M(P25-P75)	case group M(P25-P75)	control group M(P25-P75)
TSH(uIU/mL)	1.51(1.01–2.20)	1.62(1.26–2.19)	1.73(1.21–2.45)	1.79(1.22–2.60)	1.76(1.08–2.94)	1.98(1.47–3.01)	1.64(1.10–2.46)	1.79(1.34–2.57)
Tg(µg/L)	18.20(9.81–30.26)c	13.95(8.66–23.20)	12.97(7.23–24.40)b	9.79(4.82–15.86)	11.69(5.25–23.27)a	6.70(3.96–11.62)	14.10(7.35–25.16)d	9.70(5.16–16.69)
FT3(pmol/L)	5.21(4.70–5.70)	5.22(4.84–5.60)	5.04(4.70–5.57)	5.24(4.82–5.63)	5.32(5.00-5.76)	5.17(4.84–5.64)	5.22(4.81–5.70)	5.21(4.83–5.62)
FT4(pmol/L)	12.65(11.50-13.55)c	11.88(11.06–12.85)	12.31(11.16–13.32)	12.04(11.10-13.11)	12.64(11.55–13.66)a	12.11(11.33–13.30)	12.51(11.35–13.54)d	12.03(11.16–13.11)
TPOAb(IU/ml)	1.00(0.50–2.10)	1.10(0.50–2.50)	0.80(0.40–2.20)	1.25(0.50–3.70)	1.80(0.90-4.00)	1.60(0.80–3.27)	1.10(0.50-3.00)	1.20(0.60–3.20)
TT3 (nmol/L)	1.51(1.33–1.78)	1.55(1.39–1.78)	1.43(1.26–1.65)	1.32(1.32–1.68)	1.62(1.43–1.79)	1.57(1.40–1.72)	1.54(1.33–1.76)	1.55(1.37–1.72)
TT4( nmol/L)	97.75(81.65-109.01)	94.07(81.97–101.10)	92.17(80.65-104.96)	91.27(81.98–99.58)	100.49(86.50-117.75)	97.66(89.62-110.19)	96.20(82.57-111.01)	94.50(84.88-104.02)
Note: a represents the comparison of Tg and FT4 between the case group and the control group in the area with more than adequate iodine intake, P < 0.05; b represents the comparison of Tg between the case group and the control group in the area with adequate iodine intake, P < 0.05; c represents the comparison of Tg and FT4 between the case group and the control group in the area with mild iodine deficiency,P < 0.05;d represents the comparison of Tg and FT4 between the case group and the control group in the whole population,P < 0.05.

Multi-factor analysis

The multivariate conditional Logistic regression model was fitted by Enter method, and the results found that the history of thyroid disease, Tg, TgAb and thyroid nodules were statistically significantly associated (Table 4).

Table 4

Multivariate Conditional Logistic Regression Analysis of Influencing Factors of Thyroid Nodules
variable	Regression coefficients	standard error	Waldχ²	P	OR(95%CI)
history of thyroid disease
unknown	1.686	0.414	16.597	0.000	5.398(2.398–12.147)
history of thyroid disease	3.009	1.094	7.567	0.006	20.262(2.375-172.872)
Tg
below standard of Tg	-1.353	0.647	4.374	0.036	0.258(0.073–0.918)
TgAb
above standard of TgAb	1.146	0.572	4.010	0.045	3.146(1.025–9.660)

The results of this study showed that the difference in the MUI between the case group and the control group was statistically significant only in the areas with more than adequate iodine intake (P < 0.05). No matter in the areas with mild iodine deficiency, with adequate iodine intake, or with more than adequate iodine intake, the Tg level of the case group was higher than that of the control group (P < 0.05), which may suggest that Tg can be a specific indicator of thyroid nodules. Additionally, the multivariate conditional Logistic regression model showed that the history of thyroid disease, Tg, TgAb and thyroid nodules were significantly associated.

Studies on the relationship between iodine nutrition and thyroid nodules are currently inconsistent. Some scholars believe that high salt content in food increases the risk of thyroid cancer^[^]. Kim HJ mentioned that the risk of thyroid nodules was increased only when the iodine intake was low or extremely excessive in areas with sufficient iodine intake^[^]. Xiaoming Lou’s studies^[^] suggested that thyroid nodules had a U-shaped relationship with urinary iodine concentration. Compared with subjects with relatively low UIC (< 100µg/L), subjects with UIC between 200–399µg/L had less thyroid nodules, which the risk of thyroid nodules was reduced by about 37–57%. In addition, subjects with UIC between 100–199µg/L had a reduced risk of thyroid nodules. Besides, Teng W’s study found that when the urinary iodine concentration was less than 527µg/L, the thyroid nodules were negatively correlated with the urinary iodine concentration. On the contrary, when the urinary iodine concentration was ≥ 527µg/L, there was no statistical difference in the urinary iodine concentration with thyroid nodules^[^]. We found that in the areas with more than adequate iodine intake, the urine iodine concentration in the nodule group was lower than that in the non-nodule group, which may indicate that when in the areas with more than adequate iodine intake, a slight increase in urinary iodine concentration may help inhibit the occurrence of nodules. The results similar to the conclusion of other studies that thyroid nodules were related to iodine nutrition level. However, it was not clear when it reached the critical value would affect the thyroid nodule. Animal studies and prospective cohort studies could be used to further explore the critical value of iodine nutrition concentration affecting the thyroid nodule.

The results of multivariate conditional Logistic regression analysis showed that thyroid nodules were related to Tg, which was consistent with the results of other studies. Dellal FD found that Tg elevated after fine needle aspiration biopsy of thyroid nodules, and the Tg level of malignant thyroid nodules was significantly higher than that of suspected malignant and benign nodules^[^]. The higher the Tg concentration, the higher the risk of developing thyroid nodules, indicating that Tg can be used as a functional biomarker for thyroid nodules^[^]. Elevated Tg levels may impair the function of regulatory T cells, thereby increasing the risk of thyroid nodules and autoimmune thyroid disease^[^]. The literature has shown that positive serum TgAb test was an independent predictor of thyroid malignancy in thyroid nodules^[10], which was the same conclusion as this study.

The history of thyroid disease significantly increased the risk of thyroid nodules, OR = 20.262(2.375-172.872). Kitahara CM’s study also revealed that the prevalence of thyroid disease was positively correlated with the risk of thyroid nodules (malignancy)^[^]. Our study manifested that history of thyroid disease and thyroid nodules were significantly associated as well.

Some current studies have shown that obesity was associated with increased nodular thyroid disease^[^,^], however, this study did not draw this conclusion, which might be related to the rural areas with similar living habits selected in this study.

Several literatures have shown that thyroid nodules were related to gender and age^[^,^,^]. The prevalence of thyroid nodules in women was higher than that in men, and the prevalence of thyroid nodules increased with age. Our conclusion was the same as the literatures above.

The advantage of this study is that the control group was 1:1 matched with the case group by age (± 3 years), gender, and region, eliminating the influence of these three important confounding factors. The relationship between iodine nutrition and thyroid nodules, as well as other influencing factors is objectively explored. Previous studies were mostly limited to cross-sectional surveys or case-control studies with mismatched designs to explore the relationship between thyroid nodules, iodine nutrition and other influencing factors^[20,,^]. Additionally, this study is the first 1:1 matched case-control study in Fujian Province, which is more convincing in terms of causal argument. In addition to the common urine sample collection, blood samples from the survey subjects were also collected, which provided strong evidence for follow-up studies on whether there were differences in thyroid function of thyroid nodules. At present, there are relatively few studies on the relationship between Tg, thyroid nodules as well as iodine nutrition. This study found that Tg can be used as a sensitive functional indicator reflecting thyroid dysfunction, which is of great significance for the clinical diagnosis and treatment of thyroid nodules.

However, there are certain shortcomings in this study. Thyroid nodular diseases are not caused by a single factor, but are the result of the interactions of multiple factors such as heredity and environment^[^]. The 1:1 matched case-control study in this study is an analytical epidemiological study, and its causal argument is stronger than a cross-sectional study (descriptive epidemiological study) and a mismatched case-control study, however, the chronological sequence of causality cannot be determined, hence the causality cannot be further verified. Follow-up prospective cohort studies may be conducted to verify the causal relationship between thyroid nodules and iodine nutrition. In this study, the number of case-control pairs was obtained according to the sample size formula, and three survey sites were selected to meet the purpose of the study. However, under practical circumstances, the larger the sample size, the more convincing the research results. If the sample size and the sampling range can be expanded during the research, better research results will be obtained.

The difference in the MUI between the case group and the control group was statistically significant only in the areas with more than adequate iodine intake. When in the areas with more than adequate iodine intake, a slight increase in urinary iodine concentration may help inhibit the occurrence of nodules. History of thyroid diseases, elevated Tg and TgAb levels were risk factors for thyroid nodules.Tg can be used as a functional biomarker for thyroid nodules.

IDD:iodine deficiency disorders;mUIC:median urinary iodine concentration;

MUI:median urinary iodine;UIC:urinary iodine concentration;T4:thyroxine;

TSH:serum thyroid stimulating hormone;FT3:free triiodothyronine;FT4:free thyroxine;

TgAb:thyroglobulin antibody;Tg:thyroglobulin;TPOAb:thyroid peroxidase antibody;

WHO: World Health Organization;UNICEF:the United Nations Children’s Fund;

USI:Universal salt iodization.

Acknowledgements

The authors are grateful to all the participating children and their guardians, adults. The authors also thank the staff of county and district Center for Disease Control(CDCs) who managed urine and blood sample collection.

Consent for publication

The authors consent to the publication of the data.

Authors'contributions

Zhihui Chen and Qingying Lin conceived and designed the study.Qingying Lin took part in the field investigation and completed the laboratory analysis,collected and analysed the data, prepared for the first manuscript.Zhihui Chen gave advice and helped correct the first manuscript.Muhua Wang corrected English.Muhua Wang and Diqun Chen helped with thyroid ultrasound examination.Jiani Wu,Diqun Chen and Ying Lan helped with urine iodine test.All the authors took part in the field investigation.Qingdong Jin and Yanqing Chen had contribute to the literature.Qingying Lin and Muhua Wang contributed equally to this article.

Funding

This study was supported by Fujian provincial health technology project (2020CXA020) and Construction of Fujian Provincial Scientific and Technological Innovation Platform (2019Y2001).The funders had no role in the design, analysis or writing of this article.

Availability of data and materials

The datasets used during the current study are available from the first author on reasonable request.

Ethics approval and consent to participate

This study was conducted in accordance with the Declaration of Helsinki. Ethics approval was obtained from the Ethics Committee of Fujian Provincial CDC (No. 2017002). Written informed consent was obtained from every participant or the guardian of the children before their urine and blood samples were collected.

Conflict of Interest

None of the authors has conflict of interest to declare.

Authors’ details

¹The First Hospital of PuTian City, No. 389, Longdejing, PuTian 351199, Fujian, People’s Republic of China.

²The Department of Endemic Diseases, Fujian Center for Disease Control and Prevention, No. 386 Chong'an Road,Fuzhou 350012 ,Fujian, People’s Republic of China.

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A 1:1 matched case-control study: Are thyroid nodules related to iodine nutrition? Can thyroglobulin(Tg) serve as a functional biomarker for thyroid nodules?

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Abstract

Figures

Introduction

Methods

Estimation of samplesize

Thyroid B-ultrasound and questionnaire

Urine sample, blood collection and test of urine iodine and thyroid function

Quality Control

Definitions and Reference Standards

Statistical analysis

Results

The relationship between urinary iodine concentration and thyroid nodules

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

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