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fact, that the concept, in general, includes also normal blood lipids and optimal blood pressure levels. An assessment of quality of medical and preventive care for patients with diabetes who have concomitant CAD and MI, demonstrates that it does not meet commonly accepted standards [11; 12]: inadequately low percentage of prescribing first-line drugs for the management of these patients — ACE inhibitors, beta-blockers, statins, antiplatelet agents, not to mention about combination therapy.
Conclusions
61 568 register-cards of patients with type 2 diabetes were analyzed for assessment of prevalence of CAD in the given population and for assessment of medical and preventive measures provided to patients with CAD. 10 130 (16.5 %) of all patients were found to have CAD and 949 (1.5 %) ofthem had MI. In general, the number of men with CAD was 5 325 (52.6 %), which was higher than among women — 4 805 (47.4 %). However, concerning particularly MI, the number of women with MI was twice higher than that of men (66.9 % vs. 33.1 %).
Indicators of fasting plasma glucose and postprandial blood glucose in patients with CAD and MI did not range significantly between each other, remaining within high values: 8.5 ± 0.1 and 10.4 ± 0.2 mmol/l, respectively. HbAlc was a common value, registered in all regions, but they were inadmissibly high: 8.5 ± 0.2 %.
Concerning registration ofblood lipids, it can be said that this aspect was also defective, with some regions determining only one part of lipid spectrum and one region completely omitting registrations of lipids. Despite high levels of cholesterol and triglycerides, lipid-lowering therapy in 30 % of cases consisted only of nicotinic acid and statins were administered with unreasonably low frequency — 3.5 %.
Analysis of prescriptions for patients with type 2 diabetes in the presence of CAD and MI showed that drugs of first choice were not used frequently enough: ACE inhibitors — 32.2 %, beta-blockers — 10.3 %, diuretics — 9.2 %. There were no records on usage of antiplatelet agents. Unsatisfactory situation was also with administration of combination therapy with different groups of drugs, which can be concluded from absence of any records about such.
References:
1. Akbarov Z., Rakhimova G., Ismailov S. et al. Register-card of a patient with diabetes and its filling//Learner's guide. - Tashkent, 2006. - 29 p.
2. State Register of patients with diabetes, software "Diabetes Register 2008". - Moscow, 2008.
3. Zhuk E. The experience of usage of all-European program Diabcare in patients with diabetes mellitus in the city of Novosibirsk//The problem of Endocrinology. - 1996. - No. 2. - P. 11-13.
4. Ikramova F., Rakhimova G., Sherov U. The prevalence of cardiovascular disease and diabetic microvascular complications in patients with type 2 diabetes according to the screening in Bukhara region//Biology and Medicine Issues. - 2008. - No. 2/1. - P. 86-88.
5. Suntsov Y., Dedov I., Kudriakov S. State Register of diabetes: epidemiologic characteristics of NIDDM//Diabetes. - M., 1998. - No. 1.
6. Khaydarova F. A. Clinical and epidemiological aspects of late complications of diabetes//Author's abstract on competition for Ph.D (candidate's thesis). - Tashkent, 1998.
7. American Diabetic Association. Screening for type 2 diabetes. American Diabetic Association Position Statement//Diabetes Care. -2004. - 27: 1-14.
8. Beckman J., Creager M. A., Libby P. Diabetes and atherosclerosis. Epidemiology, pathophysiology, and management//Journal of American Medical Association. - 2002. - 287: 2570-2581.
9. Gaede P., Vedel P., Larsen N., Jensen G. V. H., Parving H., Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes//New England Journal of Medicine. - 2003. - 348: 383-393.
Asatova Munira Miryusupovna, MD, Professor, Head of the Department of Obstetrics, Gynecology and Perinatal Medicine of the Tashkent Institute of Postgraduate Medical Education Khegay Olga Aleksandrovna, a senior fellow of the department E-mail: ohegay899@gmail.com Jalalov Uktam Jalilovich, candidate of the department
Estimation of efficiency two protocols of correction of autoimmune thyroiditis in patients with reproductive dysfunction
Abstract: There were held a prospective, parallel-group study of 80 patients at different stages of autoimmune thyroiditis (AIT), before and after the correction of levothyroxine, and the combination levothyroxine with thiamazolum. It is shown that at AIT along with thyroid disbalance, elevated antithyroid antibodies observed elevated levels of proinflammatory cytokines. Correction of AIT combination with levothyroxine thiamazolum led to a significant reduction in levels of pro-inflammatory cytokines, titers of antithyroid antibodies, thyroid imbalance and restoration.
Keywords: autoimmune thyroiditis, antithyroid antibodies, cytokines, infertility, miscarriage.
Thyroid diseases rank first among the causes of endocrine infertility and miscarriage. The close relationship of thyroid and reproductive systems determined the presence of common central regulatory mechanisms, as well as interaction on the peripheral thyroid hormone levels and ovaries [7; 9]. In the structure of thyroid pathology leading place occupies the AIT, which, according to the definition of domestic and foreign authors is an organ multifactorial disease of the thyroid gland and is characterized by lymphocytic infiltration of its tissue, followed by progressive destruction of epithelial cells of the thyroid, leading to a permanent reduction of its function [3; 9] is a major cause of primary hypothyroidism.
Currently there is no evidence for the effectiveness of any methods of influence on the actual autoimmune process in the thyroid gland (immunosuppressants, immunomodulators, corticosteroids, plasmapheresis, drugs of thyroid hormones) [2]. At the same time there is evidence of immunocorrective effect of levothyroxine, is widely used in the treatment of autoimmune thyroiditis [4].
A. M. McGregor with coauthors (1980) showed that acts directly on carbimazole autoantibody synthesis by lymphocytes [18], D. P. Rennie with coauthors (1983) studied the effect of methima-zole, thyroxine and their combined use with rats induced thyroiditis thyroglobulin [20]. According to the authors the use of methima-zole and thyroxine significantly reduced the severity of the disease, the effect of thyroxine on antibody levels was less effective. The use of combination therapy was more effective than monotherapy with methimazole. Meanwhile R. Jansson with coauthors (1985) not indicated statistically significant difference in reducing the level of antibodies to thyroid peroxidase (ATPO) when using a combination of thyroxine and thyroxine with methimazole [15]. The authors suggest that thyroxine, normalizing the concentration of thyroid-stimulating hormone in the blood serum may reduce the autoantigen properties to tireotsitov with subsequent decrease autoantibody titers. According A. P. Weetman with coauthors (1983) and M. L. Chabernaud with coauthors (1996) methimazole inhibits lymphocyte proliferation and inhibits the production of autoantibodies to thyroglobulin [13; 22]. Analysis of the given literature shows a lack of consensus on AIT correction. Of particular relevance given circumstance becomes in women with autoimmune thyroiditis and reproductive dysfunction. According to the local authorities is not advisable to control the level of antithyroid autoantibodies to assess the dynamics of treatment and predicting AIT, as well as to treat the isolated presence of antithyroid antibodies [9]. In accordance with clinical guidelines of the Russian Association ofEndocrinologists, "big" diagnostic features, the combination of which allows to establish the diagnosis ofAIT, are: primary hypothyroidism (overt or subclinical resistant); antibodies to thyroid tissue; ultrasound signs of autoimmune disease (diffuse decrease in echogenicity of the thyroid gland). In the absence of at least one of the "big" diagnostic features diagnosed AIT is merely probabilistic in nature [11]. According Whickam' study, the annual risk of hypothyroidism in women with elevated ATPO and euthyroid is 2.1 % [21]. Non-equity methodological approaches require a woman addressed with reproductive dysfunction, and elevated levels of antithyroid antibodies, when the time allotted for the restoration of reproductive function is limited. Analysis of completed clinical studies examining the relationship of autoimmune diseases of the thyroid gland and the female reproductive system, confirm that the underestimation of the thyroid function and the absence of standards of treatment leads to an increase in women's reproductive disorders [16; 17; 19]. Position gynecologist based on timely diagnosis ofAIT, an autoimmune process refinement phase with the assessment of the functional state of the ovaries.
Objective: Estimation of the effectiveness of levothyroxine monotherapy and combination with levothyroxine thiamazolum in women with autoimmune thyroiditis and reproductive dysfunction.
Materials and methods
The study involved 80 women with reproductive dysfunction and autoimmune thyroiditis, in 41.3 % of women diagnosed with early pregnancy miscarriage, at 58.7 % of infertility. The diagnosis of autoimmune thyroiditis was set on the basis of complaints, typical ultrasound picture of the thyroid gland, and increased content of antithyroid autoantibodies in the blood. The criterion for inclusion of patients was raising ATPO and/or antibodies to thyroglobulin (ATG) more than 5 times with strictly to the parameters specified in the test kit.
All women, together with the physical examination, conducted a study of hormonal, cytokine levels, and ultrasound of the thyroid gland. Determination of blood thyroid stimulating hormone (TSH), free thyroxine (fT4) was performed by immunoenzyme method using a standard set of firms «Human» (Germany). To determine the blood of autoantibodies to thyroglobulin (ATG) and thyroid peroxidase (ATPO) use a standard set of the company "Med-Bio-line" (Russia). Study of cytokines: interleukin-1 (IL-1p), interleu-kin-6 (IL-6), interleukin-18 (IL-18) and tumor necrosis factor-a (TNF-a) was performed on Stat Fax-2100 unit using standard sets of the company «Vector-Best» (Russian).
Depending on the level of TSH and fT4 4 groups of patients were formed: Group 1 — thyrotoxicosis (n = 20), all the patients in this group was lower than normal TSH, fT4 normal or above normal; Group 2 — subclinical hypothyroidism (n = 20), the criterion for inclusion was the content of TSH above normal, normal fT4; Group 3 — overt hypothyroidism (n = 20), patients had high levels of TSH and reduced fT4 respect to the parameters specified in the test kit; Group 4 — euthyroidism (n = 20), all patients TSH level was normal. Depending on the treatment, each group was divided into 2 subgroups of 10 persons. Thus, we investigated the efficacy of the methods of AIT correction differentially depending on the functional state of the thyroid gland on a background of an autoimmune process.
Group of patients with AIT stage of hyperthyroidism monotherapy conducted cardioselective ^-blocker metoprolol in doses of25-50 mg. per day, in groups ofwomen with subclinical hypothyroidism, the manifest hypothyroidism and euthyrosis stage levothyroxine used in individually selected dose of25-100 mkg. depending on the level TSH. In parallel, a combined therapy is similar in all groups of patients, and included 2 drugs: levothyroxine individually selected dose of 25-100 mkg/day depending on the level of TSH and thiamazol individually selected dose of10-20 mg/day depending on the level of anti-thyroid antibodies. Assesment of the effectiveness of the treatment was carried out in 2 months. The average age of patients was 27.3 ± 5.3 years. The control group consisted of 10 women with reproductive dysfunction without AIT. The average age of patients in the control group was 29.2 ± 4.3 years.
Statistical processing of the results was carried out on a Personal Computers using standard packages applied statistical analysis software (SPSS-22, Microsoft Excel). Determination of the distribution type of sampling performed using the Kolmogorov-Smirnov test. To analyze the results of the study nonparametric test (U-test the Mann and Whitney test for independent samples, the Wilcoxon test for dependent samples, Spearman rank correlation) were used. To determine the statistical differences between the study groups, the analysis was carried out with the help of U-test the Mann and Whitney test for independent samples, the results of which showed no
significant difference between the groups prior to the intervention. After the treatment in order to study the effectiveness of the intervention of a comparative analysis using the Wilcoxon test was carried out for dependent samples in each group.
Results and discussions
The results of the study of thyroid status in patients with autoimmune thyroiditis in the stage of leveling hyperthyroidism showed symptoms of hyperthyroidism in all patients receiving combination therapy, baseline TSH was 0.2 ± 0.1 mlU/L after treatment 1.3 ± 0.6 mlU/L (p = 0.005). In the group of patients receiving metoprolol thyrotoxicosis only survived after 3 months, no significant changes were observed in the level of TSH. Against the background of a combination therapy achieved significant reduction ATPO level with 960.1 ± 810.6 IU/mL before treatment to 459.8 ± 514.2 IU/mL after treatment (p = 0.005) and ATG with 413.3 ± 298.7 IU/ml before treatment to 166.6 ± 208.7 IU/ml after treatment (p = 0.005). In the group of patients who received monotherapy observed increase in titer ATPO and ATG, although the changes were not statistically significant.
The results of the study of proinflammatory cytokines in patients with autoimmune thyroiditis hyperthyroidism in a stage shown a significant decrease of IL-1p, IL-6, IL-18 and TNF-a at the significance level of p = 0.005 after combination therapy. As a result, symptomatic therapy with metoprolol, in the absence of pathogenic therapy observed natural course of the disease, which was reflected in statistically significant decrease in the level of IL-1p and IL-6 and increased levels of IL-18 and TNF-a with respect to baseline values before treatment.
The results of the study of thyroid status in patients with AIT in a stage of subclinical hypothyroidism showed similar efficacy in restoring thyroid imbalance: on the background oflevothyroxine monotherapy showed a significant decrease in TSH levels with 8.8 ± 6.5 mIU/l to 3.3 ± 1.8 mIU/l after the treatment (p = 0.005) for the combined therapy has changed from TSH 6.4 ± 2.1 mIU/l to 3.1 ± 1.4 mIU/l after treatment (p = 0.005) and increase in the content fT4 — with 1.2 ± 0.2 ng/dl to 1.6 ± 0.2 ng/dl (p = 0.005) after monotherapy and 1.4 ± 0.2 ng/dl to 1.7 ± 0.2 ng/dl (p = 0.005) after the combination therapy. Level ATPO resulting monotherapy decreased from 1353.1 ± 987.6 IU/ml to 1076.0 ± 724.7 IU/ml (p = 0.013), as a result of combination therapy was able to achieve a significant reduction — from 1311.4 ± 915.7 IU/mL to 660.9 ± 654.4 IU/ml (p = 0.005). A similar pattern was observed in the level of APG, which decreased by monotherapy with 528.8 ± 796.3 IU/mL to 473.9 ± 730.8 IU/ml (p = 0.047), on the background of a combination therapy with 628.2 ± 489.0 IU/ml and 236.7 ± 281.0 IU/ml (p = 0.005). These results confirm the observations of other authors, according to which patients with AIT after treatment with levothyroxine was reduced level of ATG [1, 10]. Burmeister L. A. (1994) thinks that probably this can be explained by the fact that fT4 inhibits production of TSH, resulting in decreased synthesis of thyroglobulin [12] and as a result — is reduced synthesis of autoantibodies directed against him. To date, the actual the question is about mechanisms underlying dysregulation of immune system in autoimmune disease [8]. According to research an important role in apoptosis belong thyroxine, which regulates the functioning of the protein tyrosinekinase, an important element in the implementation of the death signal [14]. With a lack of thyroid hormone suppression of apoptosis occurs [6]. Dynamics of proinflammatory cytokines, depending on the type of correction showed a significant decrease of IL-1p in both groups, with 75.8 ± 49.6 pg/ml to 32.7 pg/ml (p = 0.005) after monotherapy and 74.1 ± 56.5 pg/ml to 24.7 ± 43.4 pg/ml (p = 0.005)
after the combination therapy. IL-6 values decreased with the same level of importance in both groups after treatment with 123.1 ± 67.6 pg/ml to 57.2 ± 43.5 pg/ml (p = 0.007) after monotherapy and 144.7 ± 66.3 pg/ml to 25.2 ± 59.2 pg/ml (p = 0.007) after the combination therapy. Values of IL-18 remained within the regulatory parameters before and after treatment in both groups were not statistically significant deviations. TNF-a was significantly more decreased as a result of monotherapy and amounted to 20.0 ± 29.6 pg/ml vs. 51.4 ± 48.0 pg/mL before treatment (p = 0.005), decreased to as a result of the combination therapy 7.1 ± 9.7 pg/ml vs 38.0 ± 51.6 pg/ml before treatment (p = 0.028).
Against the background of the correction in AIT stage overt hypothyroidism was observed a significantly decrease in TSH and elevated levels fT4 in both groups after treatment. TSH levels decreased as a result of monotherapy to 4.5 ± 2.7 mIU/L versus 14.8 ± 6.8 mIU/L before treatment (p = 0.005) and a result of combination therapy to 2.9 ± 2.1 mIU/l versus 12.9 ± 4.0 mIU/l before treatment (p = 0.005). Content fT4 on monotherapy was 1.3 ± 0.3 ng/dL vs. 0.5 ± 0.1 ng/dL before treatment (p = 0.005), in the combined therapy — 1.4 ± 0.4 ng/dL vs. 0.6 ± 0.1 ng/dL before treatment (p = 0.005). Meaning ATPO decreased in both groups, more significantly after combined therapy — up to 662.3 ± 752.3 IU/ml with respect to 1395.3 ± 1136.6 IU/mL before treatment (p = 0.007) after monotherapy decreased to 844.6 ± 625.5 U/ml relative to 1183.2 ± 943.9 IU/ml before treatment (p = 0.028). Content ATG has hardly changed in the group ofwomen who received monotherapy, whereas in the group ofpatients receiving combination therapy with ATG level significantly decreased to 381.5 ± 333.9 IU/ml with respect to 793.5 ± 478.3 IU/mL before treatment (p = 0.005).
Against the background of the correction in AIT stage overt hypothyroidism significantly decrease in the level of IL-1p was achieved only as a result of combination therapy — with 69.4 ± 48.7 pg/ml to 7.0 ± 2.6 pg/mL after treatment (p = 0.005). Similarly, there was a significant reduction in IL-6 only as a result of the combination therapy — from 111.3 ± 73.4 pg/ml to 16.8 ± 10.9 pg/ml (p = 0.005). The content of IL-18 in both groups before and after treatment remained within standard parameters. With regard to TNF-a, its content is significantly reduced as a result of the combination therapy and has made 4.9 ± 1.9 pg/ml with respect to 66.9 ± 64.7 pg/mL before treatment (p = 0.008). As a result, variables of monotherapy of the parameters of IL-1p, IL-6 and TNF-a was not observed.
The results of the study of thyroid status in patients with autoimmune thyroiditis in euthyrosis stage showed no significant changes in the level of TSH and fT4 before and after treatment in both groups. As for the content ATPO, it was significantly reduced in both groups, with 978.0 ± 873.6 IU/mL to 749.7 ± 689.6 IU/ml after monotherapy (p = 0.007), and 1027.3 ± 535.2 IU/ml and 521.1 ± 396.4 IU/ml after combination therapy (p = 0.005). Contents ATG more significantly decreased as a result of the combination therapy — 173.1 ± 239.2 IU/ml (compared to 375.0 ± 299.6 IU/ml before the treatment, p = 0.005) resulting in monotherapy ATG decreased to 382.3 ± 408.9 U/ml (compared to 477.8 ± 439.0 IU/ml before the treatment, p = 0.037).
Cytokines had a major role in the pathogenesis and development of autoimmune thyroid disease. At AIT characteristic is the activation of the immune system, and increase the level of pro-inflammatory cytokines. It is known that TNF-a, is the most apoptotic cytokine. Patients with AIT sets significantly increase in TNF-a concentration in serum more pronounced at AIT in euthyrosis stage. Our results are consistent with those of other authors. According to O. I. Urazova with coauthors (2008), Production ofthis cytokine is
associated with both the severity of the immune process and the plays an important role in the progression of the disease and its stage
level of thyroid hormones [8]. The results of the study of cytokine of development of the ultimate — hypothyroidism [5].
status in patients with autoimmune thyroiditis in euthyrosis stage Conclusions:
showed a significant decrease in the level of IL-1p, IL-6, IL-18 and 1. Combination Therapy of thymazolum and thyroxine led to TNF-a have received combination therapy patients. However, as the most significant decrease in the level of ATPO, ATG and proina result of monotherapy significantly decrease was noted only in flammatory cytokines IL-1p, IL-6 and TNF-a in patients with au-the level of IL-1p and TNF-a. TNF-a. It has an activating effect on toimmune thyroiditis patients regardless of the stage. Suppression the cytotoxic activity of lymphocytes infiltrating the thyroid gland, of autoimmune aggression will likely contribute to the preservation and is involved in the processes of destruction mediated apopto- and restoration of thyroid cells and thyroid imbalance. sis i. e. It is a component of host defense response, which controls 2. The results of the research make it necessary to continue the «strength» of the autoimmune process [10]. The release of research in assessing the functional status of patients with ovarian TNF-a thyroid stimulated autoimmune thyroiditis lymphocytes AIT patients with regard to the stage and treatment protocol.
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