Can “VAI” Better Indicate Metabolic Syndrome Compared with Other Metabolic Syndrome-Related Parameters in Patients with Thyroid Nodules? A Study from Turkey

Abstract

Background:

To investigate the relationship between visceral adiposity index (VAI) and other metabolic syndrome (MetS)-related parameters, and thyroid nodules.

Methods:

This single-center, prospective, case–control study included 67 patients with thyroid nodules and 48 healthy volunteers with similar age, sex, and body mass index (BMI). Biochemical parameters were obtained from medical charts. Anthropometric measurements and total body composition analysis were performed to calculate VAI and other MetS parameters. The parenchymal structure was evaluated according to VESINC (Volume, Echogenicity, Sonographic texture, Infiltration of pseudonodular Nodules, Cysts) system on thyroid ultrasound and nodule characteristics were also detected. MetS was defined according to International Diabetes Federation criteria.

Results:

We examined a total of 67 patients with thyroid nodule and 48 healthy volunteers. Sixty-one (91%) were female in the patient group; and 43 (90%) were female in the control group. The mean age was 48.5 ± 11.6 years in the patient group; 47.2 ± 9.5 years in the control. The median VAI was significantly higher in the patient group than the control group [4.1 interquartile range (IQR: 2.6–5.9) vs. 3 (IQR: 2–4.3), P = 0.024]. There was a positive correlation between VAI and BMI, waist/hip ratio (WHpR), waist/height ratio (WHtR), and homeostasis of model assessment of insulin resistance (HOMA-IR). On the other hand, there was no significant correlation between VAI and thyroid function tests and autoantibodies and thyroid volume.

Conclusions:

In conclusion, we demonstrated that MetS was more common in patients with thyroid nodules. Although VAI and HOMA-IR levels were significantly different between the two groups, we found no significant difference in terms of waist circumference, WHpR, and WHtR. This might suggest that VAI compared with these parameters, better predicts the risk of MetS in patients with thyroid nodules.

Introduction

Thyroid nodules are increasingly more commonly detected in parallel with the technological developments in the diagnosis and treatment of thyroid disorders. The frequency of thyroid nodules has been reported as 4%–7% with palpation and 19%–67% with ultrasound.¹ Several factors, such as sex, age, thyroid-stimulating hormone (TSH), and iodine intake, play a role in the formation of thyroid nodules.² The association of thyroid nodules with metabolic syndrome (MetS) and adiposity has been addressed in many studies.^3

–6

MetS is a metabolic dysfunction involving multiple risk factors and increases the risk of developing diabetes and cardiovascular disease in the future. Several parameters, such as body mass index (BMI), waist circumference (WC), waist/hip ratio (WHpR), waist/height ratio (WHtR), homeostasis model assessment of insulin resistance (HOMA-IR), and triglyceride (TG)/high-density lipoprotein cholesterol (HDL), and finally visceral adiposity index (VAI) have been used in clinical practice as possible predictors of MetS.

It is well known that metabolic disorders have a stronger association with visceral adipose tissue as compared with subcutaneous tissue. On the other hand, BMI and central obesity as assessed by the measurement of the WC have some caveats and do not reliably reflect visceral adiposity.^7,8 Currently, the VAI is successfully used as an indicator of visceral adipose tissue, which functions to predict insulin resistance and cardiometabolic risk factors.^9

–14 The VAI is a mathematical index, based on WC, BMI, TG, and HDL levels.¹⁰

Thyroid hormones have an important effect on energy homeostasis, lipid and glucose metabolism, and blood pressure. Therefore, it is hypothesized that functional and morphological changes in the thyroid gland might be associated with MetS and its related components, including obesity, insulin resistance, lipid and glucose metabolism abnormalities, and increased blood pressure.¹⁵ As the underlying pathophysiological mechanism, dysregulation between the hypothalamic/pituitary/thyroid axis and adipose tissue has been blamed.^16,17

To date, many studies have been conducted on the relationship between MetS and thyroid volume and nodule frequency.^5,18

–21 However, in patients with thyroid nodules, the VAI, which better reflects visceral adipocyte function and insulin sensitivity and thus better predicts cardiometabolic risk, has not yet been studied. Therefore, we aimed to investigate the relationship between VAI and other MetS parameters, and thyroid nodules.

Materials and Methods

Patients and study design

This single-center, prospective, case–control study included 58 patients with thyroid nodules who were consecutively admitted to the Endocrinology and Metabolism outpatient clinic of Istanbul University-Cerrahpasa, Cerrahpasa Medical School between April 2019 and October 2019. As the control group, 57 euthyroid healthy volunteers without any known chronic disease were consecutively recruited from patients admitted to the Internal Medicine outpatient clinic for routine examination purposes in the same period. The controls were matched to patients in terms of age, sex, and BMI. Thyroid nodules were detected in nine healthy volunteers and they were transferred to the patient group. Sixty-seven patients and 48 healthy controls were included in the final analysis.

The inclusion criteria were as follows: being between 18 and 65 years of age, having thyroid function tests within the normal reference range (TSH: 0.27–4.2 μIU/mL; free T3: 2–4.4 pg/mL; and free T4: 0.93–1.7 ng/dL), and the detection of thyroid nodules in the patient group. Participants with any of the following characteristics were excluded from the study: the presence of any chronic disease; thyroid hormone replacement; and a history of antithyroid, antihyperlipidemic, antidiabetic, oral contraceptive, corticosteroid, and immunosuppressive drug use.

MetS was defined according to the International Diabetes Federation (IDF) criteria in 2006.²² MetS is diagnosed in the presence of abdominal obesity (defined as a WC >94 cm in men and >80 cm in women for Turkish people, with other values for other ethnicities) plus any two of the following four factors: (1) serum TGs ≥150 mg/dL; (2) serum HDL <40 mg/dL in men and <50 mg/dL in women; (3) blood pressure ≥130/85 mmHg; and (4) fasting plasma glucose ≥100 mg/dL.

Laboratory measurement

Biochemical parameters, which were collected in fasting status, such as TSH, free T3, free T4, antithyroid peroxidase (anti-TPO), antithyroglobulin (anti-TG), insulin, glucose, uric acid, total cholesterol, low-density lipoprotein (LDL) cholesterol, TG, HDL, and C-reactive protein (CRP) were obtained from medical charts.

TSH, using sandwich technique, using two different monoclonal antibodies labeled with biotin or ruthenium complex; free T3 and free T4 using competitive technique, using a specific monoclonal antibody labeled with a ruthenium complex were measured by the electrochemiluminescence immunoassay (ECLIA) method. These parameters were analyzed using Elecsys Test Kits in Roche cobas e 602 systems. Also, anti-TPO and anti-TG using competitive technique, and insulin using sandwich technique were measured by the ECLIA method. Glucose, uric acid, total cholesterol, LDL-cholesterol, TG, and HDL were measured by enzymatic colorimetric method. CRP was measured by immunoturbidimetric method. These parameters were analyzed in Roche/Hitachi cobas c systems (Roche Diagnostics GmbH, Mannheim, Germany).

Anthropometric measurements

Height (m), weight (kg), WC (cm) (the minimum size between the iliac crest and lateral costal margin), and hip circumference (cm) (the widest point over the buttocks) were measured by a single person to calculate MetS-related parameters, such as VAI, BMI, WHpR, and WHtR.

Total body fat and water composition analysis were performed by the same person, using a body composition analyzer (Tanita T 6360; Tanita Corp., Tokyo, Japan, 2009).

VAI levels were calculated using the following formula: (WC/[39.68 + (1.88 × BMI)]) × (TG/1.03) × (1.31/HDL) for males; (WC/[36.58 + (1.89 × BMI)]) × (TG/0.81) × (1.52/HDL) for females.¹⁰

Sonography and VESINC system

First, the patients were positioned to hyperextend their neck following the standard sonographic protocol. Then, each thyroid lobe was separately scanned in the axial, longitudinal, and transverse planes by the same physician using a LOGIQ e Ultrasound (software version R9.1.2; General Electric Company, China, 2016). A 6–12-MHz linear transducer was used. B mode sonography was used combined with color Doppler sonography to evaluate vascularity.

Thyroid volume was calculated according to the ellipsoid formula: volume (mL): depth (cm) × width (cm) × length (cm) × π/6.²³ Normal thyroid volume was defined as 10 mL.²⁴

The parenchymal structure was evaluated according to the VESINC (Volume, Echogenicity, Sonographic texture, Infiltration of pseudonodular Nodules, Cysts) sonographic classification system. VESINC is a new classification system that was defined by Willms et al.²⁵ for a rapid and objective sonographic evaluation of thyroid parenchyma. The VESINC parameters were as follows: V: volume in cubic centimeters (mL); E: echogenicity (E₁, isoechoic; E₂, mildly hypoechoic or E₃, hypoechoic); S: sonographic texture (S₁, homogeneous or S₂, heterogeneous); I: pseudonodular hypoechoic infiltration (I₀, no or I₁, yes); N: nodules (N₀, no or N₁, yes); C: cysts (C₀, no or C₁, yes). Also, nodule characteristics, such as location, size, shape, structure, echogenicity, borders, vascularity, presence of calcification, longest diameter, and the total number of nodules were detected using sonography.

Ethics issues

The study was approved by the local Ethics Committee of Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty (Decision No: 39143 dated March 08, 2019). All procedures performed in studies involving human participants were in accordance with ethical standards of the Institutional and/or National Research Committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Statistical analyses

Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) software (version 21.0). Data were first analyzed for normality using the Kolmogorov–Smirnov test. Continuous variables are expressed as mean ± standard deviation and/or medians [interquartile range (IQR)]. Student's t-test was used to compare mean between groups. Medians were compared using the Mann–Whitney U test. Spearman's rank-order test and Pearson's correlation test were used for calculating correlation coefficients between continuous variables. Frequencies were compared using Pearson's and Fisher's exact tests. A P value <0.05 was considered statistically significant. Based on the control group VAI levels in the reference article,²⁶ in two-sample t-test power analysis, the sample size was calculated as 45 people in each group with 95% confidence intervals and 85% statistical power.

Results

Participants' characteristics

We examined a total of 67 patients with thyroid nodules and 48 healthy volunteers. Sixty-one (91%) were female in the patient group and 43 (90%) were female in the control group. The mean age was 48.5 ± 11.6 years in the patient group and 47.2 ± 9.5 years in the control group. There was no significant difference between the two groups for sex and age (P = 0.999 P = 0.517, respectively) (Table 1).

Table 1.

The Demographic, Clinical, and Biochemical Characteristics of Patients with Thyroid Nodules and Control Group

Variables	Patient group (n = 67)	Control group(n = 48)	P
Variables	n (%) or mean ± SD or median (IQR 25–75)		P
Age, years	48.5 ± 11.6	47.2 ± 9.5	0.517
Sex
Male	6 (9)	5 (10.4)	0.999
Female	61 (91)	43 (89.6)
Systolic blood pressure, mmHg	124.9 ± 15.5	118.3 ± 12	0.020
Diastolic blood pressure, mmHg	82.1 ± 10.2	78.7 ± 9	0.049
Total cholesterol, mg/dL	187 (170–219)	193.5 (174.3–214.8)	0.468
LDL-cholesterol, mg/dL	119 (103–153)	131.5 (114.5–154.5)	0.102
Triglyceride, mg/dL	127 (99–179)	99 (77.8–126)	0.008
HDL-cholesterol, mg/dL	56 (44–66)	58 (47–68.8)	0.662
Glucose, mg/dL	89 (82–99)	83 (78–90.8)	0.008
Insulin, μU/mL	11.1 (8–17.2)	8.2 (5.7–13.9)	0.011
Uric acid, mg/dL	4.1 (3.4–4.8)	4.2 (3.5–4.9)	0.921
CRP, mg/L	2.3 (1.1–3.9)	1.7 (0.9–2.7)	0.092
TSH, μIU/mL	1.4 (0.7–2.2)	2 (1.4–2.8)	0.001
Free T3, pg/mL	3.4 (3.1–3.6)	3.3 (3.1–3.5)	0.213
Free T4, pg/mL	1.2 (1.2–1.3)	1.2 (1.1–1.3)	0.057
Anti-TPO, IU/mL	11.8 (9.6–17.7)	14.6 (9.3–21)	0.624
Anti-TPO positivity	9 (13.4)	5 (10.4)	0.843
Anti-TG, IU/mL	11.3 (10–18.3)	13.3 (10–20.4)	0.324
Anti-TG positivity	8 (11.9)	4 (8.3)	0.753

All the P values which was considered statistically significant (<0.05) are identified in bold.

Anti-TG, antithyroglobulin; Anti-TPO, antithyroid peroxidase; CRP, C-reactive protein; HDL-cholesterol, high-density lipoprotein-cholesterol; IQR, interquartile range; LDL, low-density lipoprotein; SD, standard deviation; TSH, thyroid-stimulating hormone.

On physical examination, the mean systolic (124.9 ± 15.5 mmHg vs. 118.3 ± 12 mmHg) and diastolic (82.1 ± 10.2 mmHg vs.78.7 ± 9 mmHg) blood pressures of patients were higher than those of the control group (P = 0.02, P = 0.049, respectively).

Participants' biochemical characteristics are summarized in Table 1.

Thyroid parenchyma features according to the VESINC system

The mean total thyroid volume was 12.6 ± 7 mL in the patient group and 6.7 ± 2.3 mL in the control group (P < 0.001). A total of 26 (38.8%) patients had isoechoic, 36 (53.7%) had mildly hypoechoic, and 5 (7.5%) had hypoechoic thyroid parenchyma in terms of echogenicity. In the control group, 36 (75%) had isoechoic and 12 (25%) had mildly hypoechoic parenchyma (P < 0.001). In terms of sonographic texture, the number of patients with heterogeneous parenchyma was higher in the patient group than in the control group [43 (64.2%) vs. 10 (20.8%), P < 0.001]. Pseudonodular hypoechoic infiltration was significantly more frequent in patients compared with the controls [46 (68.7%) vs. 7 (14.6%), P < 0.001]. The presence of cysts was not different between the groups [patients; 24 (35.8%) vs. controls; 12 (25%), P = 0.303]. All of these findings were shown in Table 2.

Table 2.

Comparison of the Thyroid Parenchyma Features in Patients with Thyroid Nodules and Control Groups

Variables	Patient group	Control group	P
	(n = 67)	(n = 48)
	n (%) or mean ± SD
Volume, mL	12.6 ± 7	6.7 ± 2.3	<0.001
Echogenicity
Isoechoic	26 (38.8)	36 (75)	<0.001
Mildly hypoechoic	36 (53.7)	12 (25)
Hypoechoic	5 (7.5)	0
Sonographic texture
Homogeneous	24 (35.8)	38 (79.2)	<0.001
Heterogeneous	43 (64.2)	10 (20.8)
Pseudonodular infiltration
No	21 (31.3)	41 (85.4)	<0.001
Yes	46 (68.7)	7 (14.6)
Cysts
No	43 (64.2)	36 (75)	0.303
Yes	24 (35.8)	12 (25)

All the P values which was considered statistically significant (<0.05) are identified in bold.

Characteristics of thyroid nodules in the patient group

The median total number of nodules was 2 (min–max = 1–7), and the median longest diameter was 17 (IQR = 12–24) mm. The most common features of the dominant nodule were as follows: right lobe located, 10–19 mm in size, longer mediolateral diameter, solid, hypoechoic, with regular borders and peripheral vascularity, and without any calcification.

Comparison of MetS-related parameters between the patient and control groups

The median VAI was significantly higher in the patient group than in the control group [4.1 (IQR: 2.6–5.9) vs. 3 (IQR: 2–4.3), P = 0.024]. The number of subjects with MetS was significantly higher in the patient group than in the control group (34.3% vs. 10.4%, P = 0.006). Also, the groups were significantly different in terms of TG/HDL and HOMA-IR. These parameters were higher in the patients than in controls [2.4 (IQR: 1.5–3.3) vs. 1.9 (IQR: 1.2–2.6), P = 0.04; 2.3 (IQR: 1.7–4) vs. 1.8 (IQR: 1.1–2.6), P = 0.008; respectively]. Also, there was no significant difference in terms of MetS-related parameters such as body fat percentage, visceral fat ratio, WC, WHpR, and WHtR between the patient and control groups (P > 0.05 for all) (Table 3).

Table 3.

Anthropometric Measurements, Visceral Adiposity Index, and Other Metabolic Syndrome-Related Parameters in the Patient and Control Groups

Variables	Patient group	Control group	P
	(n = 67)	(n = 48)
	n (%) or mean ± SD or median (IQR 25–75)
Weight, kg	72.4 ± 14.3	70.9 ± 14.4	0.602
Height, cm	159.6 ± 8.9	161.2 ± 7.4	0.323
BMI, kg/m²	28.5 ± 5.4	27.3 ± 4.9	0.192
Waist circumference, cm	87.9 ± 13.4	84.5 ± 11.6	0.166
Hip circumference, cm	108.3 ± 9.5	105.7 ± 9.2	0.155
WHpR	0.8 ± 0.1	0.8 ± 0.07	0.449
WHtR	0.6 ± 0.1	0.5 ± 0.07	0.086
% fat	32.9 ± 7.3	32.1 ± 7.7	0.545
Visceral fat rate	7.7 ± 3.4	6.9 ± 3.2	0.225
VAI	4.1 (2.6–5.9)	3 (2–4.3)	0.024
TG/HDL	2.4 (1.5–3.3)	1.9 (1.2–2.6)	0.040
HOMA-IR	2.3 (1.7–4)	1.8 (1.1–2.6)	0.008
Presence of MetS	23 (34.3)	5 (10.4)	0.006

All the P values which was considered statistically significant (<0.05) are identified in bold.

BMI, body mass index; HOMA-IR, homeostasis model assessment of insulin resistance; MetS, metabolic syndrome [according to International Diabetes Federation (IDF) criteria in 2006]; WHpR, waist/hip ratio; WHtR, waist/height ratio; VAI, visceral adiposity index; TG/HDL, triglyceride/HDL-cholesterol.

Relationship between MetS-related parameters and the VESINC system

In all participants, according to the VESINC sonographic classification system, the median VAI was significantly higher in subjects with heterogeneous thyroid parenchyma as compared with those with homogeneous parenchyma [4 (2.6–5.9) vs. 3.4 (1.9–4.8); P = 0.03]. Subjects with pseudonodular hypoechoic infiltration [4.3 (2.7–6) vs. 2.8 (1.9–4.4)] or nodules [4.1 (2.6–5.9) vs. 3 (2–4.3)] had significantly higher VAI than those without (P = 0.001; P = 0.024, respectively). However, VAI did not correlate with thyroid volume, and did not differ according to the presence of parenchymal echogenicity and cysts (P > 0.05 for all) (Table 4).

Table 4.

Relationship Between VESINC Sonographic Classification System and Metabolic Syndrome Parameters

	VAI	BMI	WHpR	WHtR	Visceral fat rate	TG/HDL	HOMA-IR	MetS
n (%) or mean ± SD or median (IQR 25–75)
V_olume
<10 mL	3.6 (2.3–5.2)	27.4 ± 5.4	0.80 ± 0.07	0.53 ± 0.08	6.9 ± 3	2 (1.3–3.3)	2.1 (1.3–3.4)	14 (50)
>10 mL	3.6 (2.1–5.1)	29 ± 5.4	0.81 ± 0.1	0.55 ± 0.09	8.1 ± 3.7	2.1 (1.3–3)	2.2 (1.5–3.5)	14 (50)
P	0.796	0.144	0.448	0.335	0.086	0.890	0.451	0.213
E_CHOGENICITY ^a
Isoechoic	3.5 (2–5)	27.4 ± 5	0.80 ± 0.08	0.53 ± 0.08	7 ± 3.3	2 (1.2–3.1)	1.9 (1.3–2.7)	8 (29.6)
Mildly hypoechoic	4 (2.5–5.9)	29 ± 5.4	0.81 ± 0.09	0.55 ± 0.09	8 ± 3.4	2.3 (1.5–3.3)	2.4 (1.6–3.5)	19 (70.4)
P	0.191	0.116	0.589	0.147	0.115	0.314	0.048	0.003
S_{ONOGRAPHIC TEXTURE}
Homogeneous	3.4 (1.9–4.8)	27.5 ± 5.2	0.79 ± 0.07	0.53 ± 0.08	6.8 ± 3.3	1.9 (1.1–2.9)	1.8 (1.3–2.6)	8 (28.6)
Heterogeneous	4 (2.6–5.9)	28.8 ± 5.2	0.83 ± 0.09	0.56 ± 0.09	8.2 ± 3.2	2.4 (1.6–3.3)	2.5 (1.8–4)	20 (71.4)
P	0.03	0.193	0.044	0.047	0.035	0.039	0.001	0.004
I_{NFILTRATION OF PSEUDONODULAR}
No	2.8 (1.9–4.4)	27.2 ± 4.9	0.79 ± 0.07	0.52 ± 0.07	6.8 ± 3.2	1.7 (1.1–2.7)	1.7 (1.2–2.4)	6 (21.4)
Yes	4.3 (2.7–6)	29 ± 5.4	0.83 ± 0.09	0.56 ± 0.09	8 ± 3.4	2.5 (1.6–3.4)	2.7 (1.9–4.3)	22 (78.6)
P	0.001	0.061	0.02	0.007	0.059	0.002	<0.001	<0.001
N_ODULES
No	3 (2–4.3)	27.3 ± 4.9	0.80 ± 0.07	0.53 ± 0.07	6.9 ± 3.2	1.9 (1.2–2.6)	1.8 (1.1–2.6)	5 (17.9)
Yes	4.1 (2.6–5.9)	28.5 ± 5.4	0.81 ± 0.09	0.55 ± 0.09	7.7 ± 3.4	2.4 (1.5–3.3)	2.3 (1.7–4)	23 (82.1)
P	0.024	0.192	0.449	0.086	0.225	0.04	0.008	0.006
C_YSTS
No	3.6 (2.3–5)	28.1 ± 5.3	0.81 ± 0.08	0.54 ± 0.08	7.4 ± 3.4	2 (1.3–3.1)	2.1 (1.4–3.5)	19 (67.9)
Yes	3.9 (1.9–5.7)	27.8 ± 5	0.80 ± 0.09	0.54 ± 0.08	7.2 ± 3.3	2.1 (1.1–3.2)	2.48 (1.6–3.4)	9 (32.1)
P	0.840	0.751	0.695	0.999	0.713	0.849	0.484	0.999

All the P values which was considered statistically significant (<0.05) are identified in bold.

Due to the small number of hypoechoic thyroid parenchyma (n = 5), no comparison was performed between this group and other echogenicity subgroups.

Relationship between MetS-related parameters and features of nodules

When the patients were divided into two groups according to nodule size (≤2 or >2 cm), the presence of hypoechogenecity, or central vascularity and microcalcification, there was no significant difference for VAI, WHpR, WHtR, and HOMA-IR between the groups (P > 0.05 for all).

When nodules were classified as having regular or irregular borders, the median VAI [6.1 (IQR: 3.5–9.3) vs. 3.9 (IQR: 2.3–5.3)] and TG/HDL [3.5 (IQR: 2–5) vs. 2.3 (IQR: 1.4–3)] were significantly higher in patients with nodules with irregular borders than those without (P = 0.027; P = 0.024, respectively). However, WHpR, WHtR, and HOMA-IR were similar (P > 0.05 for all).

Intercorrelation among MetS-related parameters and some study variables

When we consider all of the participants, there was a positive correlation between VAI and BMI, WHpR, WHtR, visceral fat ratio, TG/HDL, HOMA-IR, systolic and diastolic blood pressure, uric acid, and CRP. On the other hand, there was no significant correlation between VAI and TSH, free T3, free T4, anti-TPO, anti-TG, and thyroid volume.

When we consider only patients with thyroid nodules, there was positive correlation between VAI and BMI (r = 0.458, P < 0.001), WHpR (r = 0.533, P < 0.001), WHtR (r = 0.531, P < 0.001), visceral fat ratio (r = 0.409, P = 0.001), TG/HDL (r = 0.988, P < 0.001), HOMA-IR (r = 0.413, P = 0.001), systolic blood pressure (r = 0.394, P = 0.001), uric acid (r = 0.454, P < 0.001), and CRP (r = 0.506, P < 0.001). On the other hand, there was no significant correlation between VAI and diastolic blood pressure, TSH, free T3, free T4, anti-TPO, anti-TG, and thyroid volume (P > 0.05 for all) (Table 5).

Table 5.

Correlation Analyses of Some Study Variables in the Patients with Thyroid Nodules and Control Groups Separately

	2	3	4	5	6	7	8	9	10	11	12	13	14	15
1. VAI	0.46^‡	0.53^‡	0.53^‡	0.41^†	0.99^‡	0.41^†	0.39^†	0.19	0.45^‡	0.51^‡	0.18	−0.02	−0.01	−0.13
1. VAI	0.60^‡	0.46^†	0.62^‡	0.52^‡	0.98^‡	0.54^‡	0.06	0.30	0.28	0.27	−0.09	−0.1	−0.23	0.15
2. BMI		0.57^‡	0.88^‡	0.84^‡	0.44^‡	0.30^*	0.42^‡	0.39^†	0.58^‡	0.54^‡	0.21	−0.04	−0.21	0.11
2. BMI		0.40^†	0.84^‡	0.85^‡	0.59^‡	0.55^‡	0.23	0.37^†	0.46^†	0.54^‡	−0.08	−0.24	−0.10	0.07
3. WHpR			0.83^‡	0.66^‡	0.52^‡	0.42^‡	0.39^†	0.14	0.54^‡	0.48^‡	0.08	−0.1	−0.13	0.13
3. WHpR			0.74^‡	0.52^‡	0.45^†	0.40^†	0.13	0.31^*	0.29^*	0.45^†	0.03	−0.07	−0.07	0.12
4. WHtR				0.85^‡	0.51^‡	0.37^†	0.44^‡	0.29^*	0.63^‡	0.57^‡	0.18	−0.12	−0.27^*	0.06
4. WHtR				0.74^‡	0.58^‡	0.56^‡	0.16	0.42^†	0.39^†	0.62^‡	−0.07	−0.27	−0.11	0.01
5. Visceral fat rate					0.40^†	0.36^†	0.45^‡	0.41^†	0.71^‡	0.50^‡	0.26^*	−0.13	−0.2	0.05
5. Visceral fat rate					0.53^‡	0.52^‡	0.35^*	0.35^*	0.57^‡	0.52^‡	−0.01	−0.02	−0.14	0.13
6. TG/HDL						0.43^‡	0.38^†	0.19	0.48^‡	0.49^‡	0.16	−0.08	0.02	−0.09
6. TG/HDL						0.49^‡	0.04	0.26	0.28	0.22	−0.06	0.12	−0.27	0.15
7. HOMA-IR							0.26^*	0.08	0.44^‡	0.44^‡	0.12	0.09	0.06	0.02
7. HOMA-IR							0.18	0.22	0.39^†	0.44^†	−0.35^*	0.05	0.07	0.1
8. Systolic B.P.								0.66^‡	0.37^†	0.49^‡	0.04	0.2	−0.04	0.18
8. Systolic B.P.								0.67^‡	0.27	0.14	−0.09	−0.02	0.17	−0.11
9. Diastolic B.P.									0.29^*	0.33^†	0.21	0.03	−0.13	0.02
9. Diastolic B.P.									0.27	0.23	−0.22	−0.04	0.05	−0.08
10. Uric acid										0.57^‡	0.19	0.01	−0.12	0.04
10. Uric acid										0.42^†	−0.09	0.13	0.06	−0.07
11. CRP											0.03	−0.09	−0.1	0.19
11. CRP											−0.14	−0.02	0.11	−0.02
12. TSH												−0.27	0.1	−0.56^‡
12. TSH													−0.02	−0.2
13. Anti-TPO													0.43^‡	−0.05
13. Anti-TPO													0.34^†	0.13
14. Anti-TG														−0.01
14. Anti-TG														0.08
15. Thyroid volume

The correlation coefficients in the patient group were shown in the first line of each variable, whereas the coefficients in the control group were shown in the second line. All of these study variables were analyzed by univariate methods.

P < 0.05; ^† P < 0.01; ^‡ P < 0.001.

B.P., blood pressure.

When we consider only healthy controls, there were positive correlations between VAI and BMI (r = 0.598, P < 0.001), WHpR (r = 0.463, P = 0.001), WHtR (r = 0.622, P < 0.001), visceral fat ratio (r = 0.524, P < 0.001), TG/HDL (r = 0.982, P < 0.001), and HOMA-IR (r = 0.538, P < 0.001). On the other hand, there was no significant correlation between VAI and systolic and diastolic blood pressure, uric acid, CRP, TSH, free T3, free T4, anti-TPO, anti-TG, and thyroid volume (P > 0.05 for all) (Table 5).

We performed a multivariate analysis by VAI components, such as BMI, WC, TG, and HDL. Altogether these variables could predict 68.7% of the cases with thyroid nodules. Among these variables, TG levels were the only significantly associated factor that predicted nodule formation (odds ratio: 1.017, confidence interval: 1.006–1.028, P = 0.003).

Discussion

In this study, we primarily demonstrated that MetS was more common in patients with thyroid nodules. Also, we detected that systolic and diastolic blood pressure and TG levels were higher in patients with nodules than in those without. We revealed that patients with thyroid nodules had higher VAI and HOMA-IR levels than controls, but there was no difference in the WC, WHpR, and WHtR between the two groups. Also, we determined that although the VAI levels were positively correlated with all other MetS-related parameters, they were not correlated with thyroid volume, thyroid function tests, and autoantibodies. Finally, according to the VESINC classification system, we found that VAI levels were higher in patients with heterogeneous thyroid parenchyma, pseudonodular infiltration, and nodules.

MetS is the sum of risks that significantly increase the occurrence of cardiovascular disease, such as abdominal obesity, high blood pressure, lipid abnormalities, and impaired glucose metabolism.²⁷ All these risk factors are also strong predictors of cardiometabolic risk.²⁸ To date, the relationship of thyroid nodules with MetS and adiposity has been demonstrated in many studies.^{3

–6,18

–21} Accordingly, in our study, we found that MetS was more common in individuals with thyroid nodules than in controls. Several studies reported a relationship between obesity and thyroid morphologic changes supporting the hypothesis that the hypothalamo/pituitary/thyroid/adipose tissue axis was disrupted.^16,17 Primarily, the relationship between leptin and thyroid hormones has been blamed. Leptin acts as a negative regulator for thyroid hormones. Leptin secretion increases exponentially with increasing fat mass and counteracts the effects of insulin. Therefore, insulin resistance and increased fat mass in patients with MetS may contribute to increased serum TSH levels through leptin.^29,30 In our study, we included only euthyroid patients and controls to examine the relationship between thyroid nodules and MetS, independent of thyroid disorders. This might explain the lack of association among MetS, obesity, and TSH levels.

In our study, we determined that systolic and diastolic blood pressure were higher in patients with thyroid nodules as compared with controls. Our results were consistent with the reports by Song et al.³¹ By contrast, in another study, it was shown that systolic blood pressure was higher in patients with thyroid nodules, and diastolic blood pressure was not different between the groups.³² On the other hand, we determined that triglycerides were significantly higher in patients with thyroid nodules. Whereas, Yang et al. reported that the results were similar for lipid profile components, such as TG, total cholesterol, LDL, and HDL among those with or without thyroid nodules.³² Hypertriglyceridemia can also induce thyroid cell hyperplasia, similar to hyperinsulinemia and hyperglycemia.⁵ Also, the central obesity that develops as a result of hypertriglyceridemia may be the first sign of progression to MetS. On the other hand, we found that TG levels are the only relevant factor predicting nodule formation within the components of the VAI formula that indicate visceral fat tissue. Although we do not know exactly how hypertension and hypertriglyceridemia contribute to the formation of nodules, they have appeared as a risk factor in many previous studies.^4,19,33

In a previous study, although WC was detected to be significantly higher in patients with thyroid nodules, there was no association after adjusting for insulin resistance between groups.¹⁹ On the other hand, in our study, we found that HOMA-IR,³⁴ one of the parameters, indicate insulin resistance that was higher in patients with thyroid nodules, but there was no significant difference between the groups for WC. These results may suggest that HOMA-IR is a better marker than WC in the formation of thyroid nodules. Also, it is suggested that insulin resistance contributes to the development and increase in the number of blood vessels in thyroid nodules.³⁵ Differences in vascularization cause an increase in the thyroid nodules' growth rate.³⁵ In some previous studies, patients with IR had a higher risk of thyroid nodule formation and larger thyroid volumes.^19,36

In our study, we revealed that VAI levels were higher in patients with thyroid nodules than in controls. On the other hand, we found no significant difference between the patient and control groups in terms of MetS-related parameters, such as WC, WHpR, and WHtR. This may suggest that VAI compared with WC, WHpR, and WHtR better predict the risk of Mets in patients with thyroid nodules. Our findings are consistent with some but not all studies. Song et al. reported that BMI was not correlated with thyroid nodule risk, and recommended against its use to determine visceral adiposity in patients with thyroid nodule.³¹ The authors suggested measuring WC rather than BMI. In contrast, in some studies, a negative relationship between BMI and thyroid nodules was reported.^6,37

The relationship between VAI and BMI, WHpR, WHtR, HOMA-IR, thyroid function tests, and thyroid volume has been discussed in many studies. However, none of these studies consisted of individuals with thyroid nodules as the sample group. In our study, despite VAI being positively correlated with all other MetS-related parameters, inflammation markers, such as uric acid and CRP, it was not correlated with thyroid volume, thyroid function tests, or autoantibodies. In Durmus et al.'s study involving patients with polycystic ovary syndrome, VAI was positively correlated with WHpR, HOMA-IR, uric acid, and CRP levels.³⁸ In other studies, VAI levels were reported to be positively correlated with HOMA-IR.^39

–42 These results once again reveal the strong relationship between visceral fat and insulin resistance. On the other hand, in a previous study, analyses showed a positive correlation between TSH and VAI levels.²⁶ Even if TSH is within the normal range, it has been found to be positively associated with VAI.^43,44 This situation indicates that TSH levels rise in parallel with the increase in visceral fat and insulin resistance. On the contrary, in our study, we determined that TSH was not correlated with VAI, BMI, WC, WHpR, or WHtR. Moreover, TSH levels were higher in the healthy controls than in the patients with thyroid nodules. These levels may be affected by fasting-satiety status, the time of blood collection due to its circadian rhythm, steroids, oral contraceptives etc. But, in our study, the blood samples were collected between 08:00 and 10:00 in the morning and all of the participants were not using any drugs that affect TSH levels. At the same time, in our country, which is an endemic region, iodine deficiency has contributed to the formation of thyroid nodules and these nodules may have started to gain autonomy. This finding can be interpreted better if thyroid nodules that gained autonomy are shown by repeated TSH measurements and thyroid scintigraphy in a follow-up study.

In our study, according to the VESINC classification system, we found that VAI levels were higher in patients with heterogeneous thyroid parenchyma, pseudonodular infiltration, and nodules. Although we cannot show a significant correlation between thyroid autoantibodies and VAI, inflammatory thyroid parenchymal changes seem to be associated with MetS.

The weaknesses of our study can be summarized as follows: our study was a case–control study and had a limited number of patients and controls. For more precise results, our findings need to be tested with a larger number of patients in prospective studies. To evaluate visceral fat tissue, we used a mathematical index, VAI. To measure true visceral fat tissue, the use of imaging modalities, such as computed tomography, magnetic resonance imaging, and dual-energy X-ray absorptiometry are recommended. On the other hand, due to the radiation risk and cost, they are not used in clinical practice on a routine basis.^45,46 Finally, the normal limits for VAI levels are still unknown. In a retrospective study involving 1764 patients, Amato et al. reported cutoff values of VAI according to age groups.⁴⁷ However, in our study, there was no significant difference between the groups for age; therefore, we did not evaluate VAI according to age groups separately. In addition, VAI levels were higher in both the patient and control groups as compared with Amato et al.'s study's cutoffs.

The strengths of our study can be summarized as follows: to the best of our knowledge, this is the first study to evaluate the relationship between VAI and thyroid nodules. Also, we used a new sonographic classification system, VESINC, in thyroid nodules and revealed its relationship with MetS-related parameters.

In the literature, there are many studies addressing the relationship between thyroid nodules and MetS.^5,18

–21 Diagnosis of MetS in someone with any thyroid disease can prevent the formation of new thyroid nodules or goiter. Even, there are studies showing that thyroid volume and nodules shrink or disappear with metformin treatment.^48

–51 For this reason, it is important to define MetS in individuals with thyroid disease. On the other hand, the VAI is successfully used as an indicator of visceral adipose tissue, which functions to predict insulin resistance and cardiometabolic risk factors. Additionally, the VAI is an easily calculated mathematical index. The most valuable aspect is that it predicts visceral adipose tissue and cardiometabolic risk without requiring an invasive method.

We demonstrated that MetS was more common in patients with thyroid nodules. Although VAI and HOMA-IR levels were significantly different between the two groups, we found no significant difference in terms of WC, WHpR, and WHtR. This might suggest that VAI, compared with these parameters, better predicts the risk of MetS in patients with thyroid nodules.

Footnotes

Authors' Contributions

All authors made substantial contributions to conception and design, and/or acquisition of data, and/or analysis and interpretation of data; participated in drafting the article or revising it critically for important intellectual content; and gave final approval of the version to be submitted.

Author Disclosure Statement

The authors declare no conflicts of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding Information

No funding was received for this article.

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