PECULIARITIES OF INDICES OF THYROID HOMEOSTASIS IN PATIENTS WITH METABOLIC SYNDROME DEPENDING ON BODY MASS INDEX

Introduction. Nonthyroidal illness syndrome develops in patients against the background of chronic comorbidity as a result of impaired peripheral conversion of thyroid hormones and is characterized by low levels of triiodothyronine (T 3 ). Objective of the study: to find out the features of thyroid homeostasis in patients with metabolic syndrome (MS). Materials and methods. 64 patients with MS and 20 healthy individuals were involved in the investigation. We determined the level of thyroid stimulating hormone (TSH), free thyroxine (fT 4 ) and free triiodothyronine (fT 3 ). To study the functional status of the pituitary-thyroid axis, we calculated fT 3 /fT 4 ratio and thyroid index (TI). Peripheral activity of thyroid hormones was estimated by total thyroid index (TTI). Results. In the course of our study, lower fT 3 levels and increased levels of TSH and fT4 was revealed in patients with MS compared with the group of healthy subjects (p < 0.05). We found a reduction of fT 3 /fT 4 ratio (p < 0.05) compared to the control group (p< 0.05). TTI was lower in the examined patients compared with the group of healthy individuals (p < 0.05). As a result of correlation analysis, it was established that body mass index negatively correlated with the level of fT 3 (r = –0.341, p < 0.05), fT 3 /fT 4 index (r = –0.458, p < 0.05), TI (r = –0.415, p < 0.05) and TTI (r = –0.335, p < 0.05) and positively — with levels of fT 4 (r = 0.405, p < 0.05) and TSH (r = 0.327, p < 0.05). Conclusion. The obtained data suggests the development of nonthyroidal illness syndrome in patients with metabolic syndrome as a result of impaired peripheral conversion of thyroid hormones, which deepens with body mass index growth, i.e. the class of obesity.

Nonthyroidal illness syndrome (NTI), also known as syndrome of low triiodothyronine (T 3 ), occurs against a background of chronic concomitant diseases and is characterized by reduction of triiodothyronine due to inhibition of deiodinases -enzymes which catalyze peripheral conversion of thyroxine (T 4 ) to its active metabolite (T 3 ).These changes are typical for 75 % of hospitalized patients [10,11].About 80 % of thyroid hormones are produced in peripheral tissues through the activity of deiodinases [5,13].
Three types of deiodinases have been identified: deiodinase I-type (D1) was found in the liver and kidneys; type II deyodynase (D2) -in heart, coronary arteries, smooth muscles of arteries, skeletal muscles, nervous system, adipose tissue and thyroid gland; type III deiodinase (D3)in embryonic tissues, placenta, liver and skin [6].D1 and D2 are involved in the conversion of T 4 to T 3 (its active metabolite) by deiodination in following positions: 5-D1, and 5'-D1 and D2.D2 regulates local T 3 activity and its accessibility to nuclear receptors [13].
D3 inactivates thyroid hormones by formation of reverse triiodothyronine (rT 3 ) from T 4 and diiodothyronine from T 3 and rT 3 [9].Changes in the organs in which they function (damage of liver, kidney, brain) cause reduction of these enzymes production and development of NTI.
It is known that the highest level of D2 and the lowest levels of D1 and D3 was revealed in the pituitary gland [7].Under conditions such as stress, obesity, insulin resistance, liver diseases, kidney diseases and other comorbidities the activity of D1 decreases whilst that of D2 and D3 activity increases [7,10].These changes help to Оригинальные исследования /Original Researches/ maintain T 3 levels in the pituitary gland within the normal ranges thanks to its D2-mediated conversion from T 4 , which is why thyroid-stimulating hormone (TSH) level is also within normal limits.Thus, TSH is an unreliable indicator of thyroid hormones metabolism in peripheral tissues against the background of diseases that cause NTI development.
Despite the existence of preconditions for the development of NTI in patients with metabolic syndrome (MS), there exists only sporadic and somewhat conflicting data regarding the development of thyreopathies in these patients.It was found that the incidence of hypothyroidism and nodular goiter significantly increased in patients with MS [7,8,10,12].However, features of peripheral metabolism of thyroid hormones against the background of MS require further research.
The aim of the study: to find out the features of thyroid homeostasis in patients with metabolic syndrome.

Material and methods
The study involved 64 patients with MS who were hospitalized in the Chernivtsi regional endocrinology center and 20 healthy people.
Patients were divided into groups as follows: Group I -20 patients with MS and a body mass index (BMI) within 25-29.9 kg/m 2 (overweight); Group II -15 patient with MS and a body mass index within 30-34.9 kg/m 2 (class I obesity); Group III -9 patients with MS and a body mass index within 35-39.9 kg/m2 (obesity class II and class III); Group IV -20 patients with MS and a body mass index within 18-25 kg/m 2 (normal weight).
The diagnosis of MS was established according to the International Diabetes Federation (IDF) criteria on the basis of anthropometric, clinical and laboratory data [1].The levels of thyroid stimulating hormone (TSH), free thyroxine (fT 4 ) and free triiodothyronine (fT 3 ) were determined.To study the functional state of the pituitary-thyroid axis, fT 3 / fT 4 ratio and thyroid index (TI) were calculated [2].
Peripheral activity of thyroid hormones was assessed using total thyroid index (TTI) [3].
Statistical analysis of the obtained data was carried out using the Student's t-test and Pearson's rank correlation coefficient by means of the software package Statistica 6.0 for Windows.The result was considered reliable at p < 0.05.

Results
Investigation of thyroid homeostasis established significant reduction of fT 3 in all groups of patients with MS compared to the group of healthy individuals (table 1).The lowest level of fT 3 was determined in groups II and III -it was respectively 80.2 and 76,8 % lower than in the group of healthy individuals (p < 0.05).Also fT 3 level was respectively 55.8 and 34.7 % lower in groups I and IV compared with the healthy individuals (p < 0.05).The level of fT 3 in group I was respectively 13.5 and 17.7 % higher when compared with groups II and III (p < 0.05) and was 19.8 % lower than in group IV (p < 0.05).
FT3 level was significantly 31.3 and 33.8 % lower in groups II and III compared to group IV (p < 0.05).
Against this background, a significant elevation of fT 4 levels by 22.9 and 30.1 % in groups II and III respectively has been found compared to the group of healthy individuals and group IV respectively (p < 0.05).
FT 3 /fT 4 ratio underwent the most significant changes and was respectively 2,27 and 2.5 times lower in groups II and III compared with the control group (p < 0.05) and respectively 45.5 and 60.0 % lower -compared with group IV (p < 0.05).
FT 3 /fT 4 ratio in group I was respectively 18.2 and 30.0 % higher compared to groups II and III (p < 0.05) and 23.07 and 92.3 % lower in relation to groups IV and the group of healthy individuals respectively (p < 0.05).
Reduction of fT 3 and elevation of fT 4 proportional to the growth of BMI may indicate a violation of peripheral conversion as a result of inhibition of D1 and activation of D3 which is in turn due to increased leptin content in blood that is typical for people with MS on the background of resistance to leptin.
Patients from groups I and II had respectively 80.3 and 51.9 % (p < 0.05) higher TSH content compared with the group of healthy individuals.Also in group I TSH level was 51.2 % higher than that in group IV (p < 0.05).The highest TSH content in blood serum was revealed in group I.
Noteworthy is the fact that this index had a tendency to decrease in groups with elevated BMI.This gives a line of empirical evidence that increased leptin level, which is typical for obese patients on a background of MS, leads to stimulation of D2 activity in pituitary tissue, accompanied by local formation of a sufficient amount of T 3 and due to this an inhibition of TSH production by the pituitary gland occurs despite the peripheral deficiency of T 3 [4].

Discussion
TI was 1.89, 2.49, 1.96 and 2.67 times higher in groups I, II, III and IV respectively compared with the group of healthy subjects (p < 0.05).TI in group IV exceeded the corresponding figure in group I by 40.8 % (p < 0.05).
TTI in groups I, II, III and IV was respectively 62.6, 83.5, 85.5 and 40.7 %, lower compared with the control group (p < 0.05).TTI was respectively 20.6, 30.5 and 31.9 % lower in groups I, II, III in relation to group IV (p < 0.05).TTI decreased in patients with the highest BMI values, testifying thе violation of peripheral conversion of thyroid hormones which leads to NTI development.
Data, obtained as a result of correlation analysis, indicate the dependence of thyroid supply of organism on components of MS, in particular the degree of obesity.
It is known that patients with MS have resistance to leptin which is accompanied by its increased production by adipose tissue.Revealed changes may be caused by a depression of D1 activity by leptin and as a result, decreased fT 3 levels.Mechanism of negative feedback is impaired in patients with MS (i.e.TSH is not produced in necessary amount because of sufficient formation of T 3 in pituitary tissue due to the activation of D2 in the pituitary gland).This makes TSH an unreliable indicator of disorders of thyroid homeostasis in patients with MS [4].In healthy individuals, leptin stimulates production of TSH by the pituitary gland, but against the background of resistance of receptors to leptin, this process is inhibited [6].
Author declares that there are no conflicts of interest.

Conclusions
1. Impairment of peripheral conversion of thyroid hormones has been revealed in patients with metabolic syndrome which manifests itself by the reduction of free triiodothyronine content, free thyroxine level elevation, lower free triiodothyronine/free thyroxine ratio and lower total thyroid index.
2. Level of thyroid stimulating hormone increased in patients with metabolic syndrome compared with the group of healthy individuals, but in groups with increased BMI more than 35 kg/m 2 its level was reduced, so this index may not be reliable indicator of thyroid hormones metabolism against the background of obesity.