Thyroid Function Assessment in Saudi Males with Metabolic Syndrome.

Background: Metabolic Syndrome (MetS) is a multifactor condition associated with cardiovascular risk. Thyroid hormones regulate MetS components via controlling energy homeostasis, lipids, and glucose metabolism. The risk ratio for MetS and related disorders changes between males and females. Aim and
Objectives: Study aim to access thyroid functions in Saudi population with metabolic syndrome. Materials and
Methods: The current study sought to evaluate the impact of thyroid stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) in predicting the risk of MetS. A total of 200 (MetS 100 and control 100) Saudi Arabian males were enrolled for the study, and after applying eligibility criteria, the eligible study size was examined for the physical test (chest, abdominal, and general examination with stress on blood pressure measurement) and anthropometric parameters (bodyweight, body mass index, and waist circumference).
Results: In the present study, the biochemical parameters, such as TSH, FT3, FT4, total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), high-density lipoprotein (LDL), fasting glucose, and fasting insulin were measured in the study group, and statistical analysis was also performed. The results revealed that the MetS and control differ in terms of physical, anthropometric, and biochemical markers. The study showed that thyroid dysfunction (TD) and MetS are closely associated with the difference in physical, anthropometric, and metabolic characteristics.
Conclusion: The result demonstrated hypothyroidism major risk factor due to TD in MetS. These findings provide a scientific basis for diagnosis and the management of TD, associated MetS, and cardiovascular disease (CVD). Copyright:

INTRODUCTION

Metabolic syndrome (MetS) and insulin resistance (IR) act as the causative factor for high triglyceride levels, low high-density lipids (HDL) cholesterol, hypertension, and high fasting plasma glucose level. Although fairly similar, threshold criteria for all measurements vary from one organization to the other, such as the International Diabetes Federation,[1] Adult Treatment Panel III, the National Cholesterol Education Program,[2] and the WHO.[3] These clusters of metabolic abnormalities are related to an increased risk of Type 2 diabetes mellitus, cardiovascular disease (CVD), and atherosclerosis.[4] The global burden of MetS is significantly high, i.e., 25%; every single individual out of four. The prevalence of MetS reported significantly high in South Asian populations, including Saudi Arabia, due to several epidemiological risk factors.[567]

Thyroid dysfunction (TD) is recognized by a variation in plasma level of thyroid stimulating hormone (TSH) with normal or altered thyroid hormones (FT3) and (FT4).[8] TD is also associated with MetS and CVD risk factors where thyroid hormone plays a critical role in lipid and glucose metabolism affecting blood pressure.[9] Studies have also demonstrated that the incidence of MetS was reported much higher with subclinical hypothyroidism than in a normal population.[10] Both MetS and hypothyroidism may act result in “additive effects” by raising the risk of CVD.[11] A higher serum level of TSH (TSH >10 mIU/l) along with subclinical hypothyroidism enhances the prevalence of MetS but not incidence.[1213] Association between TD and MetS components is complex.[14] The present work was designed to investigate thyroid function and associated abnormalities in MetS patients in the Saudi Arabian male population.

SUBJECTS AND METHODS

The present study was carried out at Islamic University Medical Centre in outpatients during the follow-up period during January–September 2020. A total 200 male participants were enrolled for the present study with MetS patients (n = 100) and control (n = 100). The age range of the enrolled participants, including MetS patients and the control group, is 25–65 years. The registered MetS patients were diagnosed in compliance with the National Cholesterol Education: Adult Panel III (ATP III). ATP III has appeared as the most widely applied definition because it provides a relatively simple method for diagnosing MetS by employing easily appreciable risk factors.[215] ATP III distinguishes MetS with three to five threat variables:

The presence of central obesity is measured by waist circumference (WC) of ≥ 102 cm for men and ≥88 cm for females

↑ triglycerides level: ≥150 mg/dl, or special treatment for this lipid irregularity

↓ HDL cholesterol: <40 mg/dl in males, or <50 mg/dl in females

↑ blood pressure: systolic BP ≥130 or diastolic BP ≥85 mmHg

↑fasting plasma glucose ≥110 mg/dl.

MetS patients were deemed to have TD if patients' thyroid hormones level outside the reference range (free T3 (2.7–5.3 pg/ml), free T4 (0.70–2.0 ng/dl), and TSH level (0.40–5.0 μIU/ml). If all thyroid hormone levels were within the standard range, the patient was considered to be euthyroid. Overt hypothyroidism was characterized as TSH >5 μIU/ml and free T4 <0.70 ng/dl. TSH >5 IU/ml and free T4 in the standard range were considered subclinical hypothyroidism. Again, subclinical hyperthyroidism was characterized with TSH 0.46 IU/ml and free T3 and free T4 levels within the standard range.[816] TSH and FT4 together are recommended by the American Thyroid Society as the optimal blood tests for ambulatory and hospitalized patients' diagnosis and follow-up.[8]

Exclusion criteria

We excluded patients with thyroid diseases or receiving medications that may change lipid levels or thyroid functions, CVD, renal disease, liver disease, corticosteroid use, and other endocrinal problems. Enrolled and eligible participants, including MetS patients and control qualified for exclusion criteria, were subjected to laboratory, physical, and anthropometric examinations.

Physical examination and anthropometric measurements

In the present study, enrolled and eligible participants, including MetS and control, were subjected to physical examination, including chest, abdominal, and general examination with stress on blood pressure measurement. Anthropometric measures were done according to standard protocols, including body weight, body mass index (BMI), and WC.

Laboratory measurements

Blood samples were collected from enrolled and eligible participants, including MetS and control, after 12 h overnight fast. Centrifugation was used to separate the serum from blood samples drawn from the antecubital vein. Biochemical markers were also measured according to standard methodology, including serum TSH, FT3, FT4, total cholesterol (TC), total triglyceride (TG), HDL cholesterol, low-density lipids (LDL) cholesterol, fast glucose, and fasting insulin. The automatic Siemens Dimension (RXL Max) Clinical Chemistry System was used to establish lipoprotein lipids and glucose levels utilizing conventional biochemical laboratory techniques. FT3, FT4, and TSH and were examined using the VITROS reagent packs and calibrators on the Vitro 3600 immunodiagnostic system.[171819] The fasting insulin in human serum or plasma was examined using a chemical luminescent microparticle enzyme immuno-survey (Abbott Architect System, ALAMEDA, CA, USA).[2021] Homeostasis model assessment of IR (HOMA-IR) was used to measure IR from fasting insulin and fasting glucose levels using the equation: (Insulin [μU/ml]) (fasting glucose [mg/dl])/405. IR exceeded 2.5 as HOMA-IR.[22]

Statistical analysis

SPSS version 25 was used for statistical analysis (SPSS Inc., Chicago, IL, USA). Descriptive features for contributors were transferred as mean, standard deviation, number, and percent for conclusive data. Student t-tests were performed to explore differences between MetS patients and the control group in the basic attributes. Coefficients of Pearson correlation were determined to evaluate any significant link between parameter MetS components and thyroid hormone parameters (TSH and FT4 levels). A Analysis of variance (ANOVA) was used to make the comparison between four types of TD.

RESULTS

The Group 1 (control group) and the Group 2 (MetS group) present their clinical and biochemical features in Table 1. The study did not show any statistical differences in age between the two groups (47.56 ± 7.45 vs. 47.09 ± 7.68, P = 0.65). However, BMI shows a significant statistical difference in both groups including MetS and control (27.77 ± 0.92 vs. 31.06 ± 1.25, P = 0.00). Further results have shown a significantly high difference in WC in MetS and control group (97.58 ± 5.06 vs. 105.40 ± 2.17, P = 0.00). Both systolic and diastolic blood pressure (DBP) values were shown to be significantly different between MetS and controls (118.86 ± 3.20 vs. 130.44 ± 2.82, P = 0.00) and (79.28 ± 1.94 vs. 88.17 ± 2.82 mmHg, P = 0.00). Similarly, as the result shown here, the biochemical parameters, i.e., fasting blood glucose (FBG) and fasting insulin had shown a significant difference in both the group including MetS and control (100.5 ± 5.71 vs. 117.46 ± 3.16, P = 0.00) and (15.44 ± 1.68 vs. 22.75 ± 3.30, P = 0.00). In the present study, HOMA-IR mean of MetS group (4.29 ± 0.51) is significantly high than the control (1.99 ± 0.31) with P = 0.00. As the result shown in Table 1, the lipid profile between MetS and control shown significant difference; for cholesterol (169.00 ± 16.16 vs. 186.00 ± 9.09, P = 0.001) and triglycerides (118.40 ± 12.58 vs. 171.52 ± 12.47, P = 0.00. There are statistical differences in the mean of serum HDL-cholesterol between the two groups (45.50 ± 3.14 vs. 36.50 ± 3.03, P = 0.00). There are statistical differences in the mean of serum LDL cholesterol between the two groups (103.40 ± 16.20 vs. 169.32 ± 13.08, P = 0.00). There are no significant differences in FT3 between the two groups (3.85 ± 0.55 vs. 3.50 ± 0.79, P = 0.96). There are no significant changes in FT4 between the two groups (1.32 ± 0.344 vs. 1.31 ± 0.45, P = 0.99). There are highly statistical differences in TSH between the two groups (2.72 ± 0.95 vs. 4.90 ± 1.45mU/ml, P = 0.00). Clinical and biochemical markers of Type 2 diabetes mellitus patients in both groups were analyzed.

Table 1

Anthropometric measures and biochemical parameters data of patients with metabolic syndrome (Group 2) and healthy control persons (Group 1)

Variable	Group 1 Nonmetabolic syndrome (n=100), mean±SD	Group 2 Metabolic syndrome (n=100 ), mean±SD	P
Age (years)	47.56±7.45	47.09±7.68	0.65 NS
BMI (kg/m2)	27.77±0.92	31.06±1.25	0.00** !
WC (cm)	97.58±5.06	105.40±2.17	0.00**
SBP (mmHg)	118.86±3.20	130.44±2.82	0.00**
DBP (mmHg)	79.28±1.94	88.17±2.82	0.00**
FBG (mg/dl)	100.5±5.71	117.46±3.16	0.00**
Fasting insulin (mU/ml)	15.44±1.68	22.75±3.30	0.00**
HOMA-IR	1.99±0.31	4.29±0.51	0.00**
TC (mg/dl)	169.00±16.16	186.00±9.09	0.00**
TGs (mg/dl)	118.40±12.58	171.52±12.47	0.00**
HDL-cholesterol (mg/dl)	45.50±3.14	36.50±3.03	0.00**
LDL-cholesterol (mg/dl)	103.40±16.20	169.32±13.08	0.00**
FT3 (2.7-5.3 pg/mL)	3.85±0.55	3.50.79	0.96 NS
FT4 (0.70-2.0 ng/dL)	1.32±0.34	1.31±0.45	0.99 NS
TSH (0.40-5.0 µIU/mL)	2.72±0.95	4.90±1.45	0.00**

*Significant (P<0.05) - **Highly significant (P<0.01). WC: Waist circumference, SBP: Systolic blood pressure, DBP: Diastolic blood pressure, FBG: Fasting blood glucose, HOMA-IR: Homeostasis model assessment of insulin resistance, TC: Total cholesterol, TGs: Triglycerides, HDL: High-density lipoprotein, LDL: Low-density lipoprotein, TSH: Thyroid-stimulating hormone, FT3: Free triiodothyronine, FT4: Free thyroxine, SD: Standard deviation, NS: Nonsignificant (P>0.05)

As shown in Figure 1 and Table 2, a clear difference MetS component was reported among TD subgroups. Based on thyroid function tests, Group 2 or MetS patients (100) were classified as euthyroid (N = 78, 78%), subclinical hypothyroidism (N = 16, 16%), Overt hypothyroidism (N = 4, 4%), and subclinical hyperthyroidism (N = 2, 2%). The results indicated that systolic blood pressure (SBP), DBP, fasting blood sugar (FBS), HDL cholesterol, and WC were to be nonsignificantly different between MetS subgroups as well. The result also shows [Table 2] a significant difference in lipid profile, i.e., triglycerides in TD subgroup. Pearson correlation coefficients analysis data shown in Table 3 demonstrates a positive correlation of MetS component with TSH and free T4. Study reports a nonsignificant (P > 0.05) correlation between WC and high plasma TSH level while systolic and DBP were reported in negative correlation with high plasma TSH (P > 0.05). It should be noted here that FBS and TSH plasma were significantly correlated (P = 0.03). WC is closely associated with lipid profile and here in present study result shows TGs and high TSH remain in positive correlation with P > 0.05, i.e., nonsignificant. On the contrary, HDL-cholesterol and high TSH remain in a negative correlation with P < 0.01, i.e., significant. Given the research group's greater FT4 levels, WC showed a negative connection (P < 0.01) and a positive correlation (P > 0.05) with systolic and DBP. Similarly, high FT4 level reported in a differential relation with FBS (negative and nonsignificant), TG (negative and nonsignificant), and HDL-cholesterol (positive and nonsignificant).

Figure 1

Thyroid dysfunction subgroups of group

Table 2

Differences in components of metabolic syndrome among thyroid dysfunction subgroups of Group 2 (the metabolic syndrome patients)

Variable	Thyroid function status				P
	Euthyroid (n=78)	Subclinical hypothyroidism (n=16)	Overt hypothyroidism (n=4)	Subclinical hyperthyroidism (n=2)
WC (cm)	105.162±2.189	106.125±1.821	108.00±1.000	105	P1: 0.553 NS
					P2: 0.167 NS
					P3: 0.133 NS
BMI (kg/m2)	30.976±1.175	31.700±1.396	31.066±1.677	29	P1: 0.299 NS
					P2: 0.393 NS
					P3: 0.748 NS
SBP	130.375±2.798	131.687±2.301	134.333±1.154	136	P1: 0.684 NS
					P2: 0.315 NS
					P3: 0.262 NS
DBP	87.825±2.741	89.562±2.827	90.333±1.527	85	P1: 0.656 NS
					P2: 0.130 NS
					P3: 0.317 NS
FBG	117.150±2.942	118.625±3.981	119.333±3.785	118	P1: 0.487 NS
					P2: 0.614 NS
					P3: 0.935 NS
TGs	170.425±13.175	175.000±8.610	179.666±1.527	180	P1: 0.01**
					P2: 0.01**
					P3: 0.04*
HDL-cholesterol	36.387±3.0126	36.750±3.714	37.666±2.081	39	P1: 0.179 NS
					P2: 0.267 NS
					P3: 0.152 NS

*Significant (P<0.05), **Highly significant (P<0.01). TGs: Triglycerides, P1: Between euthyroid and subclinical hypothyroidism,P2: Between euthyroid and overt hypothyroidism, P3: Between subclinical hypothyroidism and overt hypothyroidism, NS: Nonsignificant (P>0.05), WC: Waist circumference, SBP: Systolic blood pressure, DBP: Diastolic blood pressure, FBG: Fasting blood glucose, TGs: Triglycerides, HDL: High-density lipoprotein

Table 3

Correlation components of metabolic syndrome with TSH and FT4 in Group 2

Variable	FT4		TSH
	r	P	r	P
WC	−0.250	0.001**	0.140	0.001**
SBP	0.080	0.315 NS	−0.05	0.315 NS
DBP	0.040	0.620 NS	−0.041	0.620 NS
FBG	−0.066	0.376 NS	0.340	0.376 NS
TG	−0.105	0.299 NS	0.055	0.299 NS
HDL-cholesterol	0.037	0.722 NS	−0.490	0.722 NS

*Significant (P<0.05), **Highly significant (P<0.01). WC: Waist circumference, SBP: Systolic blood pressure, DBP: Diastolic blood pressure, FBG: Fasting blood glucose, TG: Triglyceride, HDL-cholesterol: High-density lipoprotein cholesterol, r: Correlation coefficient, NS: Nonsignificant (P>0.05)

DISCUSSION

The prevalence of MetS is increasing worldwide, with various areas having individual groups of epidemiological hazard factors, and there is clear proof of a higher incidence of MetS in South Asian countries, including Saudi Arabia.[567] Thyroid hormones influence MetS components such as plasma glucose, blood pressure, HDL-C, and TGs and play a significant role in controlling energy balance, lipids, and glucose metabolism. It has been found that hypothyroidism is associated with dyslipidemia, obesity, and an increased hazard of CVD.[23] IR has been suggested as a possible pathophysiological basis for glucose intolerance in hypothyroid patients.[24]

Thyroid malfunction and MetS are the two most frequent endocrine malformations, with a high degree of comorbidity. Both are distinguished by a group of common abnormalities such as abdominal obesity, hyperglycemia, hypertension, reduced HDL-cholesterol, and elevated TG and recognized independent risk factors of atherosclerotic CVD. Both are related to significant morbidity and mortality and thus affect virtually health-care worldwide.[2526] To significantly reduce the impending risk, dyslipidemia and IR should be aggressively controlled.

According to the findings of this study, BMI, WC, SBP, DBP, FBG, fasting insulin, HOMA, TC, TG, LDL cholesterol, and TSH values were substantially higher in the MetS group in relation to the control group.[2728] The results in the present study clearly demonstrate that the prevalence of TD in MetS patients was 22%, with a high predominance of Subclinical Hypothyroidism (SCH) (16%) followed by Overt hypothyroidism (4%) and subclinical hyperthyroidism (2%). Earlier findings have shown a similar association between MetS and TD; however, in the present study, results were more statistically significant.[29303132333435363738]

In an Indian community of MetS patients, Shantha et al., 2009 found a significant incidence of SCH (21.90%) and overt hypothyroidism (7.40%).[39] Similar findings were reported by Meher et al. 2013 who found that the MetS group had a substantial occurrence of overt hypothyroidism (4%) and SCH (22%).[40] Ruhla et al., 2010 described that the euthyroid individuals with a higher plasma TSH level (2.5–4.5mL/L) are characterized as obese, increased TG level, and higher risk of MetS.[41]

Similarly, Wang et al., 2010 reported that 7.21% of Taiwanese MetS patients have TD. The study also found that 4.55% of people had SCH, and 2.64% had subclinical hyperthyroidism.[42] According to Lai et al., 2011 the total prevalence of TD was 7.60%, with 2.10% of patients being subclinical hypothyroid and 5.50% being subclinical hyperthyroid.[43] With a sample size of 220 people, Uzunlulu et al., 2007 found that SCH occurred in 36 (16.4%) of the MetS cases. These studies clearly demonstrate a high prevalence of MetS in the South Asian population, nearly one-sixth of MetS patients associated with SCH. These findings provide a scientific basis for SCH as a clinical parameter in the diagnosis and management of MetS.[44] It is evident that TSH plasma level and MetS component as closely associated; however, risk factor dependency remains a growing concern.[45] The pathophysiological role of thyroxin in MetS is known; however, no association between FT4 and MetS in aged populations with healthy thyroid profiles.[46] TD is associated with higher levels of cholesterol, glucose, insulin, and HOMA-IR levels, according to the findings of Garduno-Garcia et al. in 2010.[29] When determining the link between thyroid function and metabolic variables, the combined use of TSH and FT4 is a better strategy than relying just on FT4. Deshmukh et al., 2018, demonstrated that hypothyroidism is prevailing in the Indian population with MetS. The high rate of TD cases identified throughout the study emphasizes the importance of ongoing thyroid monitoring in MetS patients in a real-world environment.[30]

The findings of current work largely disagree with a study conducted in Turkey concluded that the TSH was not associated with any MetS variants.[31] Furthermore, results from the present study also disagree with a study by Lee et al., 2019 emphasizes a nonassociation between SCH and MetS. However, SCH may be related to abdominal obesity and probably adolescent hypertension.[32] Wang et al., 2012 concluded that no significant relationships were found between MetS predominance and thyrotropin levels, which contradicts the results obtained in the current work. Wang et al., 2012 did not demonstrate clinically pertinent biochemical markers variations in thyrotropin levels, or statistical relationships were shown between subclinical thyroid disease and MetS in healthy persons.[33] Increased WC, decreased HDL-C, increased fasting glucose, HOMA-IR, triglycerides, and SBP were all seen in patients with TD in the current study. There is grown research proof established a correlation between TD and components of MetS. According to Meher et al., 2013, there is a link between subclinical hypothyroidism and MetS and the usefulness of thyroid function screening tests in individuals with MetS.[4034] Obesity, low BMR, and low/impaired energy metabolism still affect a major portion of the hypothyroid population.[35] AbuAlhamael et al., 2018 looked at how hypothyroidism and MetS are linked and how aging plays a role in the progression of the disease.[36] Ding et al., 2021 reported that lower standard FT4 is an independent threat factor for MetS, and lower standard thyroid function is associated with larger MetS hazards.[37]

Overwhelming research evidence clearly demonstrates that MetS is multifactorial in origin, and TD is one of the most critical risk factors. A study in Nigeria[38] examined the link between MetS and high FT4 levels. Schubert et al. demonstrated a close association between FT3 and MetS components. The fact that a lower FT4 is related to MetS in the male population is worth noting.[47] Hemodynamic changes are common in hypothyroidism, and they include a narrowing of the pulse pressure, an extension of the circulatory time, and a decrease in blood circulation to the tissues. These pathophysiological alterations cause an increase in systemic vascular resistance, culminating in hypertension.[48] Rotterdam's study suggested a two-fold rise in the jeopardy of atherosclerosis in patients with hypothyroidism.[49] Hypothyroidism affects lipid metabolism with lipid accumulation, precisely LDL cholesterol, and TG.[50] An increased plasma TG level was also reported in subclinical hypothyroidism with decreased SBP and DBP. There is substantial research evidence that supports a close association between TD and MetS, and hence a rise in TSH alters lipid profile and increases a higher risk of MetS.[51] Thyroid hormones remain in the active interplay between TSH, free T4, and T3, with the risk of MetS during TD.[52]

Tromso and Basel thyroid studies both concluded that substituting L-Thyroxine improves LDL cholesterol levels and clinical symptoms of hypothyroidism in persons with subclinical hypothyroidism. Optimizing plasma LDL cholesterol may reduce the risk of CVD-based mortality by 9%–31%.[53] Lipid profile and physiological outcomes differ in both genders, such as the male population experiences High triglycerides, low HDL cholesterol, and high blood pressure during High triglycerides, low HDL cholesterol, and increased WC in case of females. The scientific basis behind the higher prevalence of MetS in the female population is due high rate of obesity.[54] As found in the present study, the predominance of overt and subclinical hypothyroidism in MetS shows possibilities of detrimental influence on cardiovascular conditions. However, it remains doubtful whether patients with subclinical hypothyroidism should be treated and the definite advantage of prescribing levothyroxine for CVD. TSH levels above normal are associated with central adiposity, hypertension, dyslipidemia, hyperuricemia, inflammation, and hypercoagulability.[55] Van-Tienhoven-Wind et al. 2017 stated that a rise in TSH level inward the euthyroid range allows an increased Leptin/adiponectin ratio in MetS persons, which prospective contributes toward a negative cardiac profile in these patient cohorts.[56]

Although there was adequate research evidence on IR in hyperthyroidism, Singh et al., 2010 stated that patients suffering from hypothyroidism established IR and dyslipidemia as detected by the higher HOMA-IR and cholesterol and triglyceride levels, respectively, as matched to the controls.[57] Hypothyroidism can cause IR, according to studies by Rochon et al. in 2003 and Stanická et al. in 2005.[5859] A study[60] has shown that subclinical hypothyroidism causes IR. These associations with IR may partially account for the increased prevalence of hypothyroidism in patients with MetS, implying that IR plays a significant role in pooling risk factors for CVD.[24]

Limitation of study

The current study, however, has some restrictions. In the first place, the sample size was insufficient, and in the second, the iodine consumption status of the patients was not assessed. It has been realized that both iodine insufficiency and excess can lead to thyroid ailment, especially subclinical hypothyroidism.

CONCLUSION

MetS is a multifactorial disorder that also serves as a risk factor for CVD. Thyroid hormones are a critical risk factor for MetS and TD enhances the risk by several folds. Investigating TD with MetS group is critical for determining the level of overlap between these two clinical disorders and may highlight the significance of thyroid function tests in MetS patients. The results highlight here a close association between TD and MetS with differential contribution from physical, anthropometric, and biochemical parameters. The result also shows a close association of TD and MetS in the rise of risk of CVD due to hemodynamic alterations. The result also demonstrates hypothyroidism as a key risk factor due to TD in MetS. The results obtained from the present study provide a scientific basis for not only diagnosis but also the management of TD, associated MetS, and CVD.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.