The Prevalence of Single and Multiple Thyroid Nodules and Its Association with Metabolic Diseases in Chinese: A Cross-Sectional Study

Purpose The present study aims to investigate the prevalence of single and multiple thyroid nodules and its association with metabolic diseases in subjects who participated in the heath examination in China. Methods This is a cross-sectional study. The participants who attend the physical examination at the Health Management Center of Southwest Hospital, Army Military Medical University, between January 2014 and December 2018, were included. Thyroid nodules were diagnosed by thyroid ultrasound. Multivariable logistic regression was used to investigate the association between metabolic diseases and nodular thyroid disease. Results A total of 9,146 subjects were included in this study; of them, 2,961 were diagnosed with thyroid nodules, with a prevalence of 32.4%. The prevalence in women was significantly higher than that in men (45.2% vs 26.0%; χ2 = 339.56, P < 0.001), and the prevalence was gradually increased with age (Z = 20.05, P < 0.001), and the prevalence was gradually increased with age ( Conclusions The prevalence of thyroid nodules was relatively high. Age, female gender, and diabetes are positively associated with nodular thyroid disease. High LDL cholesterolemia is more likely to be associated with multiple thyroid sarcoidosis.


Introduction
yroid nodules are one or more lumps made up of abnormal clusters of thyroid cells in the thyroid gland with a variety of etiologies, which can be cystic, solid, or mixed, and are the most common thyroid diseases in clinical settings [1,2]. yroid nodules can be complicated by various thyroid diseases because of its insidious onset, and most of the patients are asymptomatic in the early stage [3,4]. e prevalence of thyroid nodules among males and females was 29.49% and 33.15% in Southeast China, respectively [2]. With lifestyle and dietary changes, diabetes, hypertension, metabolic diseases such as hyperlipidemia, fatty liver, hyperuricemia, and obesity are the main chronic diseases affecting the health of residents in China [5][6][7][8]. Previous studies show certain metabolic diseases were significantly associated with thyroid diseases, but the results are not consistent [5][6][7][8][9][10][11]. By investigating the prevalence of thyroid nodules and its association with metabolic diseases in participants in Southwest China, we conducted a cross-sectional study based on the subjects participating in the health checkup center, to investigate whether the potential metabolic factors are associated with thyroid nodules in the different populations.

Subjects.
Subjects who participated in the health checkup of the Health Management Center of Southwest Hospital between January 2014 and December 2018 were included in the present study. During this period, a total of 13,773 subjects received thyroid ultrasound; 4627 of them were excluded from the study as no sufficient information were available concerning US examination results. Overall, 9,146 subjects were included in this study.
is study protocol was approved by the Institutional Review Board of Southwest Hospital, Army Military Medical University (KY2019103). Informed consent was confirmed by the board.

Inclusion and Exclusion Criteria.
e inclusion criteria included people receiving thyroid ultrasound, abdominal ultrasound examination, with complete data involving height, weight, waist circumference, hip circumference, blood pressure, fasting blood glucose, 2-hour postprandial blood sugar, four blood lipid measurements, and blood uric acid. e individuals who had a diagnosis of thyroid disease or surgery, with serious illness, taking antithyroid drugs (iodine), and the pregnant or lactating women were excluded.

Body Measurements.
e medical history and physical examination results of the subjects were collected by the professional nursing staff. e subject was placed on the health analyzer (SK-X80) after taking off the shoes. e system automatically generates the report about height, weight, and body mass index (BMI) of the subject. Blood pressure in the right arm was measured at rest (Omron electronic sphygmomanometer HBP-9021, Omron Healthcare, Kyoto, Japan). e waist circumference was measured according to the international standard. For hip circumference, the most prominent circumference of the pelvic ring was measured.

Biochemical Indicator Test.
e subject was fasted for 8 hours at night, and 10 ml of blood specimen was taken in the morning. Fasting blood glucose (FBG) and 2-hour postprandial blood glucose (2 hPG) were detected by the hexokinase method. Triglyceride (TG) content was detected by the GPO-POD method, total cholesterol (TC) was detected by the enzymatic method, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were detected by the direct method, and blood uric acid (UA) was detected by the uricase peroxidase method. After completing the fasting tests (such as abdominal B-ultrasound), the subjects were asked to take glucose powder orally (75 g) and the glucose tolerance was tested, and they were not allowed to drink or eat for 2 hours, after that the 2 hPG was taken on time.

yroid Ultrasound Examination.
e subjects took the supine position to fully expose the neck. e measurement was performed by a professional sonographer, who conducted a multisectional scanning of the thyroid gland to record in detail the location, size, shape, boundary, internal structure, echo, and blood flow of the thyroid nodules. e sonographer also carefully described the possibility of malignant nodules and the state of regional lymph nodes.

Abdominal Ultrasound Examination.
Subjects took the supine position to fully expose their abdomen. A professional sonographer performed the examination and observed the degree of hepatic steatosis. Abdominal ultrasound was performed using Philips Color Super EPIQ 7 (probe frequency 3.5-5 MHz/50 mm).

Diagnostic Criteria for Fatty Liver.
Diffuse fatty liver can be diagnosed if two of the following three items are confirmed: (1) the near-field echo of liver is diffusely enhanced and is stronger than that of the kidney. (2) e structure of intrahepatic duct is not clearly displayed. (3) e far-field echo of liver is gradually attenuated [14].

e Cutoff Points of Dyslipidemia.
is study confirms that the reference ranges are as follows: (1)

Statistical Analysis.
Sample size and its percentage were used for describing qualitative indicators, such as gender. Chi-square test or rank-sum test was used for analysis of intergroup differences. Cochran-Armitage analysis was used to analyze the trend of thyroid nodule prevalence changes with growing age. e association between metabolic diseases and thyroid nodules was first analyzed by univariable logistic regression, and the variables with P < 0.05 were included in multivariable logistic regression analysis. SPSS 22.0 statistical software was used, and the significant level was defined as two-tailed P < 0.05.

Basic Information and Prevalence of yroid Nodules of the Subjects.
A total of 9,146 subjects were enrolled in the study, with 6,119 men and 3,027 women, with an average age of 46.09 ± 9.75 years (14-89 years). A total of 2961 patients were diagnosed with thyroid nodules, with prevalence of 32.4%. e prevalence in male and female were 26.0% (N � 1593) and 45.2% (N � 1368), respectively, and the prevalence in women was significantly higher than that in men (χ 2 � 339.56, P < 0.001). According to age stratification, there was a significant difference in the prevalence of thyroid nodules between different age groups (Z � 20.05, P < 0.001) ( Table 1), and the prevalence increased with growing age (Z � 20.71, P < 0.001). Among patients with thyroid nodules, those with single nodule accounted for 56.9% (N � 1685) and those with multiple nodules accounted for 43.1% (N � 1276).

Association between Metabolic Diseases and Multiple
yroid Nodules Risk. In patients with thyroid nodules (N � 2961), univariable logistic regression showed that hypertension, high LDL cholesterolemia, IGR, and diabetes were significantly associated with onset of multiple thyroid nodules, while other factors suggested no association. e stratified analysis showed that BMI and hypertension were significantly associated with multiple thyroid nodules in men, while higher BMI, central obesity, hypertriglyceridemia, hypercholesterolemia, high LDL    International Journal of Endocrinology cholesterolemia, low HDL cholesterolemia, hyperuricemia, IGR, diabetes, metabolic syndrome, and fatty liver were significantly associated with multiple thyroid nodules in women (Table 4). Multivariate logistic regression analysis showed that gender, age, and high LDL cholesterolemia were positively associated with multiple thyroid nodules risk in the general population (Table 5). When stratified by gender, results indicate that advanced age and obesity were positively associated with multiple thyroid nodules in men, and advanced age, high LDL cholesterolemia, low HDL cholesterolemia, and hyperuricemia were positively associated with multiple thyroid nodules risk in women (P < 0.01) (Tables 6 and 7).

Discussion
yroid nodule is a common disease in the general population. e prevalence of thyroid nodule diagnosis is closely related with the means of examination. e diagnosis rate by doctor's palpation is 3%-7% [20], but now it reaches as high as 50-60% in the health examination [21]. In this crosssectional study, the prevalence of thyroid nodules in health checkup participants in Southwest China was 32.4%, which   is slightly higher than that in mainland China (22.8%) [22]. ere are also other countries with high prevalence of thyroid nodules (France 34.7%, Germany 23.4%, Brazil 17.0%, and Korea 13.4%) [23][24][25][26][27]. A number of epidemiological investigations worldwide show that the prevalence of thyroid nodules increases with age, which is consistent with the results of this study [5,11,[28][29][30]. e mechanism may be that with the increase of age, the thyroid will undergo degenerative changes, leading to diffuse compensatory hyperplasia of the thyroid and eventually the nodules [31]. erefore, thyroid ultrasound screening of the elderly should receive special attention in the future health checkup.
e results of this study show that gender is an independent risk factor for thyroid nodule, and its prevalence in women is significantly higher than that in men, which is consistent with the previous reports [22,32,33]. e high incidence of thyroid nodules in women is associated with increased demand for thyroid hormones during pregnancy, breastfeeding, and menstruating; estrogen can also affect the development of thyroid nodules [34].
In recent years, whether other factors contribute to the high incidence of thyroid nodules needs further investigation. Studies have shown that the incidence of thyroid nodules in patients with type 2 diabetes is significantly higher than that in healthy people [35]. It is also shown that type 2 diabetes often coexists with thyroid nodules [36,37]. Ayturk et al. found that insulin resistance promotes the development of thyroid nodules, leading to a higher prevalence [38,39]. Rezzonico et al. found that insulin is a growth factor for thyroid gland; therefore, high levels of insulin in the blood circulation can promote the proliferation of thyroid cells through the insulin receptor, leading to thyroid nodules [40]. Kimura showed that insulin-like growth factor (IGF-1) can stimulate the proliferation and differentiation of thyroid cells, which partially explains the high prevalence of thyroid nodules in diabetic patients [41]. e results of this study showed that the prevalence of thyroid nodules in the diabetic group was higher than that in the control group.
In addition, the gender stratification analysis showed that the risk factors were different between men and women. In men, diabetes and central obesity are significantly associated with the risk of thyroid nodules; in women, fatty liver has association with thyroid nodules. Studies have found that central obesity is associated with both diabetes and insulin resistance [42]. Jornayvaz et al. [10] found that insulin resistance can cause an increase in body fat, making excessive adipose tissue release nonlipidized fatty acids, and excessive fatty acids will enter the liver to induce fatty liver. e incidence of fatty liver is related to insulin resistance, which has a correlation with thyroid nodules. erefore, in  e results showed that compared with patients with single thyroid nodule, gender, age, and high LDL cholesterolemia are significantly associated with the risk of multiple thyroid nodules in general patients. e stratified analysis showed that age and obesity were positively associated with the prevalence of multiple thyroid nodules in men, while age, high LDL cholesterolemia, low HDL cholesterolemia, and hyperuricemia were positively associated with the prevalence of multiple thyroid nodules in women.
Previous studies reported that thyroid nodule is closely related to hypertension, BMI, and metabolic syndrome [11,43]. Our results showed that the prevalence of thyroid nodules in the patients with hypertension, BMI, and metabolic syndrome groups was higher than that in the control group, but no association was found between hypertension, BMI, metabolic syndrome, and thyroid nodules. Possible explanations include the research data are from one-time physical examination, and complete data need to be collected before enrollment. And there are differences in the research subjects (the sample size is small). Studies with large sample size will be conducted in the future to confirm the results of current study.

Conclusions
In summary, the prevalence of thyroid nodules in Southwest China is slightly higher than the average in mainland China. Age, female gender, and diabetes are positively associated with thyroid nodules risk, and high LDL cholesterolemia is more likely to associated with multiple thyroid nodules. In the future, we will conduct regular physical examinations in women and the elderly, pay attention to the screening of thyroid nodules, and identify patients with thyroid nodules early.

Data Availability
e data used to support the findings of this study are restricted by the Institutional Review Board of Southwest Hospital, Army Military Medical University, in order to protect patient privacy. Data are available from Southwest Hospital, Army Military Medical University, for researchers who meet the criteria for access to confidential data.

Conflicts of Interest
e authors declare that they have no conflict of interest.