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Аутоиммунный полигландулярный синдром взрослых: молекулярно-генетические и клинические характеристики (лекция)
Трошина Е.А., Ларина А.А., Терехова М.А. Аутоиммунный полигландулярный синдром взрослых: молекулярно-генетические и клинические характеристики (лекция). Consilium Medicum. 2019; 21 (4): 91–96. DOI: 10.26442/20751753.2019.4.190361
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Troshina E.A., Larina A.A., Terekhova M.A. Polyglandular autoimmune syndrome in adults: molecular genetic and clinical characteristics (lecture). Consilium Medicum. 2019; 21 (4): 91–96. DOI: 10.26442/20751753.2019.4.190361
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Аннотация
Заболевания эндокринной системы (сахарный диабет, тиреопатии, аутоиммунные полигландулярные синдромы, надпочечниковая недостаточность, аутоиммунная офтальмопатия и т.д.), в развитии которых важную роль играют нарушения иммунного ответа, относятся к числу наиболее тяжелых хронических болезней человека, профилактика и ранняя диагностика которых нередко затруднены из-за наличия латентных фаз течения болезни. Аутоиммунные полигландулярные синдромы (АПС) представляют собой поражение двух и более эндокринных желез, характеризующееся полиорганной недостаточностью. В российской классификации синдром подразделяется на 2 основных подтипа: АПС 1-го типа (распространенность варьирует от 1:9 тыс. до 1 на 200 тыс. населения) и АПС 2-го типа (распространенность составляет 1,4–4,5 случая на 100 тыс. населения). Другие классификации предусматривают выделение скрытых (латентных и потенциальных форм заболевания). Пациенты, страдающие АПС, – особая когорта лиц, требующая тщательного наблюдения и проведения регулярного скрининга на предмет прогнозирования или выявления вновь возникших компонентов в составе АПС. Широкая распространенность и высокая заболеваемость, инвалидизирующие осложнения, репродуктивные потери – все это характерно для аутоиммунных эндокринопатий и является важнейшим вызовом сегодняшнего дня. В лекции суммированы ключевые клинико-диагностические характеристики АПС, предложены практические подходы к терапии данных синдромов, обозначены ключевые лабораторные маркеры для динамического мониторинга заболевания.
Ключевые слова: аутоиммунный полигландулярный синдром, хроническая надпочечниковая недостаточность, аутоиммунный тиреоидит, сахарный диабет 1-го типа, гипопаратиреоз, гипотиреоз, главный комплекс гистосовместимости человека.
Ключевые слова: аутоиммунный полигландулярный синдром, хроническая надпочечниковая недостаточность, аутоиммунный тиреоидит, сахарный диабет 1-го типа, гипопаратиреоз, гипотиреоз, главный комплекс гистосовместимости человека.
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Endocrine system disorders (diabetes mellitus, thyroid gland pathologies, polyglandular autoimmune syndromes, adrenal insufficiency, autoimmune ophthalmopathy and others) in development of which immune response disorders play an important role are among the most severe chronic human diseases prevention and early diagnostics of which are often hampered by disease clinical course latent phases. Polyglandular autoimmune syndromes (PAS) comprise damage of two or more endocrine glands characterized with multiple organ failure. In Russian classification the syndrome is divided into 2 main subtypes: PAS type 1 (the prevalence varies from 1:9 thousands to 1 per 200 thousands population) and PAS type 2 (the prevalence is 1.4–4.5 cases per 100 thousands population). Other classifications comprise hidden (latent and potential) forms of the disorder. Patients with PAS are a special cohort that requires careful monitoring and regular screening for prognosis and detection of new components of PAS. High prevalence and incidence rates, disabling complications, and reproductive losses – all of these are common in autoimmune endocrinopathies and are an important challenge at present. The lecture summarizes key clinical and diagnostic characteristics of PAS, proposes practical approach to these syndromes treatment, and specifies key laboratory markers for the disorder dynamics monitoring.
Key words: polyglandular autoimmune syndrome, chronic adrenal insufficiency, autoimmune thyroiditis, diabetes mellitus type 1, hypoparathyroidism, hypothyroidism, human leukocyte antigens.
Key words: polyglandular autoimmune syndrome, chronic adrenal insufficiency, autoimmune thyroiditis, diabetes mellitus type 1, hypoparathyroidism, hypothyroidism, human leukocyte antigens.
Полный текст
Список литературы
1. Neufeld M, Blizzard RM. Polyglandular autoimmune diseases. In: Pinchera A, Doniach D, Fenzi GF, Baschieri L, ed. Symposium on Autoimmune Aspects of Endocrine Disorders. New York: Academic Press, 1980; p. 357–65.
2. Gombos Z, Hermann R, Kiviniemi M et al. Analysis of extended human leukocyte antigen haplotype association with Addison's disease in three populations. Eur J Endocrinol 2007; 157: 757–61.
3. Hansen MP, Kahaly GJ. Autoimmune polyglandular syndromes Dtsch Med Wochenschr 2013; 138 (7): 319-26; quiz 327-8. DOI: 10.1055/s-0032-1327355
4. Kahaly GJ. Polyglandular autoimmune syndromes. Eur J Endocrinol 2009; 161 (1): 11–20.
5. Betterle C, Lazzarotto F, Presotto F. Autoimmune polyglandular syndrome Type 2: the tip of an iceberg? Clin Exp Immunol 2004; 137 (2): 225–33.
6. Diagnostic criteria in autoimmune diseases. Y Shoenfeld, R Cervera, ME Gershwin, eds. Humana Press, Totowa, NJ. 2008.
7. Betterle C, Dal Pra C, Mantero F, Zanchetta R. Autoimmune Adrenal Insufficiency and Autoimmune Polyendocrine Syndromes: Autoantibodies, Autoantigens, and Their Applicability in Diagnosis and Disease Prediction. Endocr Rev 2002; 23 (3): 327–64. https://doi.org/10.1210/edrv.23.3.0466
8. Betterle C, Volpato M, Greggio AN, Presotto F. Type 2 polyglandular autoimmune disease (Schmidt's syndrome). J Pediatr Endocrinol Metab 1996; 9 (1): 113–23.
9. Albergoni P, Gazzola MV, Slanzi E et al. HLA–DR and DQ associations with autoimmune Addison's disease in Italian patients. Genes Immunity 2003; 4 (1): S35.
10. Betterle C, Zanchetta R. Update on autoimmune polyendocrine syndromes (APS). Clinical Immunology and Allergology. Acta Bio Medica 2003; 74: 9–33.
11. Golden B, Levin L, Ban Y et al. Genetic analysis of families with autoimmune diabetes and thyroiditis: evidence for common and unique genes. J Clin Endocrinol Metab 2005; 90 (8): 4904–11.
12. Kahaly GJ, Frommer L, Schuppan D. Celiac Disease and Glandular Autoimmunity. Nutrients 2018; 10 (7): 814. DOI: 10.3390/nu10070814
13. Fan KC, Yang TH, Huang YC. Vitiligo and thyroid disease: a systematic review and meta-analysis. Eur J Dermatol 2018; 28 (6): 750–63. DOI: 10.1684/ejd.2018.3449.
14. Vrijman C, Kroon MW, Limpens J et al. The prevalence of thyroid disease in patients with vitiligo: a systematic review. Br J Dermatol 2012; 167 (6): 1224–35. DOI: 10.1111/j.1365-2133
15. Klein J, Stato A. The HLA System. First of two Parts. N Engl J Med 2000; 343: 702–9.
16. Klein J, Stato A. The HLA System. Second of two Parts. N Engl J Med 2000; 343: 782–6.
17. Huang W, Connor E, Dela Rosa T et al. Although DR3-DQB1*0201 may be associated with multiple component diseases of the Autoimmune Polyglandular Syndrome, the Human Leukocyte Antigen DR4-DQB1*0302 haplotype is implicated only in beta-cells autoimmunity. J Clin Endocrinol Metab 1996; 81: 2259–63.
18. Erichsen M, Løvås K, Skinningsrud B et al. Clinical, Immunological, and Genetic Features of Autoimmune Primary Adrenal Insufficiency: Observations from a Norwegian Registry. J Clin Endocrinol Metab 2009; 94 (12): 4882–90.
19. Flesch BK, Matheis N, Alt T et al. HLA class II haplotypes differentiate between the adult autoimmune polyglandular syndrome types II and III. J Clin Endocrinol Metab 2014; 99 (1): E177-82. DOI: 10.1210/jc.2013-2852
20. Triolo TM, Baschal EE, Armstrong TK et al. Homozygosity of the Polymorphism MICA5.1 Identifies Extreme Risk of Progression to Overt Adrenal Insufficiency among 21-Hydroxylase Antibody-Positive Patients with Type 1 Diabetes. J Clin Endocrinol Metab 2009; 94 (11): 4517–23.
21. Huber A, Menconi F, Corathers S et al. Joint genetic susceptibility to type 1 diabetes and autoimmune thyroiditis: from epidemiology to mechanisms. Endocr Rev 2008; 29: 697–725.
22. Villano MJB, Huber AK, Greenberg DA et al. Autoimmune thyroiditis and diabetes: dissecting the joint genetic susceptibility in a large cohort of multiplex families. J Clin Endocrinol Metab 2009; 94: 1458–66.
23. Houcken J, Degenhart C, Bender K et al. PTPN22 and CTLA-4 Polymorphisms Are Associated With Polyglandular Autoimmunity. J Clin Endocrinol Metab 2018; 103 (5): 1977–84. DOI: 10.1210/jc.2017-02577
24. Dultz G, Matheis N, Dittmar M et al. CTLA-4 CT60 polymorphism in thyroid and polyglandular autoimmunity. Horm Metab Res 2009; 41 (6): 426–9.
25. Skinningsrud B, Husebye ES, Gervin K et al. Mutation screening of PTPN22: association of the 1858T-allele with Addison's disease. Eur J Human Genetics 2008; 16: 977–82.
26. Никонова Т.В. Сахарный диабет 1 типа и латентный аутоиммунный диабет взрослых (LADA): клинические, иммуно-генетические и гормонально-метаболические аспекты. Автореф. дис. ... д-ра мед. наук. М., 2011.
[Nikonova T.V. Sakharnyi diabet 1 tipa i latentnyi autoimmunnyi diabet vzroslykh (LADA): klinicheskie, immuno-geneticheskie i gormonal'no-metabolicheskie aspekty. Avtoref. dis. ... d-ra med. nauk. Moscow, 2011 (in Russian).]
27. Owen CJ, Eden JA, Jennings CE et al. Genetic association studies of the FOXP3 gene in Graves' disease and autoimmune Addison's disease in the United Kingdom population. J Mol Endocrinol 2006; 37 (1): 97–104.
28. Lopez ER, Lange B, Kahles H et al. Insulin gene polymorphisms in type 1 diabetes, Addison's disease and the polyglandular autoimmune syndrome type II. BMC Med Genet
2008; 9: 65.
29. Lopez ER, Zwermann O, Segni M et al. A promoter polymorphism of the CYP27B1 gene is associated with Addison's disease, Hashimoto's thyroiditis, Graves' disease and type 1 diabetes mellitus in Germans. Eur J Endocrinol 2004; 151 (2): 193–7.
2. Gombos Z, Hermann R, Kiviniemi M et al. Analysis of extended human leukocyte antigen haplotype association with Addison's disease in three populations. Eur J Endocrinol 2007; 157: 757–61.
3. Hansen MP, Kahaly GJ. Autoimmune polyglandular syndromes Dtsch Med Wochenschr 2013; 138 (7): 319-26; quiz 327-8. DOI: 10.1055/s-0032-1327355
4. Kahaly GJ. Polyglandular autoimmune syndromes. Eur J Endocrinol 2009; 161 (1): 11–20.
5. Betterle C, Lazzarotto F, Presotto F. Autoimmune polyglandular syndrome Type 2: the tip of an iceberg? Clin Exp Immunol 2004; 137 (2): 225–33.
6. Diagnostic criteria in autoimmune diseases. Y Shoenfeld, R Cervera, ME Gershwin, eds. Humana Press, Totowa, NJ. 2008.
7. Betterle C, Dal Pra C, Mantero F, Zanchetta R. Autoimmune Adrenal Insufficiency and Autoimmune Polyendocrine Syndromes: Autoantibodies, Autoantigens, and Their Applicability in Diagnosis and Disease Prediction. Endocr Rev 2002; 23 (3): 327–64. https://doi.org/10.1210/edrv.23.3.0466
8. Betterle C, Volpato M, Greggio AN, Presotto F. Type 2 polyglandular autoimmune disease (Schmidt's syndrome). J Pediatr Endocrinol Metab 1996; 9 (1): 113–23.
9. Albergoni P, Gazzola MV, Slanzi E et al. HLA–DR and DQ associations with autoimmune Addison's disease in Italian patients. Genes Immunity 2003; 4 (1): S35.
10. Betterle C, Zanchetta R. Update on autoimmune polyendocrine syndromes (APS). Clinical Immunology and Allergology. Acta Bio Medica 2003; 74: 9–33.
11. Golden B, Levin L, Ban Y et al. Genetic analysis of families with autoimmune diabetes and thyroiditis: evidence for common and unique genes. J Clin Endocrinol Metab 2005; 90 (8): 4904–11.
12. Kahaly GJ, Frommer L, Schuppan D. Celiac Disease and Glandular Autoimmunity. Nutrients 2018; 10 (7): 814. DOI: 10.3390/nu10070814
13. Fan KC, Yang TH, Huang YC. Vitiligo and thyroid disease: a systematic review and meta-analysis. Eur J Dermatol 2018; 28 (6): 750–63. DOI: 10.1684/ejd.2018.3449.
14. Vrijman C, Kroon MW, Limpens J et al. The prevalence of thyroid disease in patients with vitiligo: a systematic review. Br J Dermatol 2012; 167 (6): 1224–35. DOI: 10.1111/j.1365-2133
15. Klein J, Stato A. The HLA System. First of two Parts. N Engl J Med 2000; 343: 702–9.
16. Klein J, Stato A. The HLA System. Second of two Parts. N Engl J Med 2000; 343: 782–6.
17. Huang W, Connor E, Dela Rosa T et al. Although DR3-DQB1*0201 may be associated with multiple component diseases of the Autoimmune Polyglandular Syndrome, the Human Leukocyte Antigen DR4-DQB1*0302 haplotype is implicated only in beta-cells autoimmunity. J Clin Endocrinol Metab 1996; 81: 2259–63.
18. Erichsen M, Løvås K, Skinningsrud B et al. Clinical, Immunological, and Genetic Features of Autoimmune Primary Adrenal Insufficiency: Observations from a Norwegian Registry. J Clin Endocrinol Metab 2009; 94 (12): 4882–90.
19. Flesch BK, Matheis N, Alt T et al. HLA class II haplotypes differentiate between the adult autoimmune polyglandular syndrome types II and III. J Clin Endocrinol Metab 2014; 99 (1): E177-82. DOI: 10.1210/jc.2013-2852
20. Triolo TM, Baschal EE, Armstrong TK et al. Homozygosity of the Polymorphism MICA5.1 Identifies Extreme Risk of Progression to Overt Adrenal Insufficiency among 21-Hydroxylase Antibody-Positive Patients with Type 1 Diabetes. J Clin Endocrinol Metab 2009; 94 (11): 4517–23.
21. Huber A, Menconi F, Corathers S et al. Joint genetic susceptibility to type 1 diabetes and autoimmune thyroiditis: from epidemiology to mechanisms. Endocr Rev 2008; 29: 697–725.
22. Villano MJB, Huber AK, Greenberg DA et al. Autoimmune thyroiditis and diabetes: dissecting the joint genetic susceptibility in a large cohort of multiplex families. J Clin Endocrinol Metab 2009; 94: 1458–66.
23. Houcken J, Degenhart C, Bender K et al. PTPN22 and CTLA-4 Polymorphisms Are Associated With Polyglandular Autoimmunity. J Clin Endocrinol Metab 2018; 103 (5): 1977–84. DOI: 10.1210/jc.2017-02577
24. Dultz G, Matheis N, Dittmar M et al. CTLA-4 CT60 polymorphism in thyroid and polyglandular autoimmunity. Horm Metab Res 2009; 41 (6): 426–9.
25. Skinningsrud B, Husebye ES, Gervin K et al. Mutation screening of PTPN22: association of the 1858T-allele with Addison's disease. Eur J Human Genetics 2008; 16: 977–82.
26. Никонова Т.В. Сахарный диабет 1 типа и латентный аутоиммунный диабет взрослых (LADA): клинические, иммуно-генетические и гормонально-метаболические аспекты. Автореф. дис. ... д-ра мед. наук. М., 2011.
[Nikonova T.V. Sakharnyi diabet 1 tipa i latentnyi autoimmunnyi diabet vzroslykh (LADA): klinicheskie, immuno-geneticheskie i gormonal'no-metabolicheskie aspekty. Avtoref. dis. ... d-ra med. nauk. Moscow, 2011 (in Russian).]
27. Owen CJ, Eden JA, Jennings CE et al. Genetic association studies of the FOXP3 gene in Graves' disease and autoimmune Addison's disease in the United Kingdom population. J Mol Endocrinol 2006; 37 (1): 97–104.
28. Lopez ER, Lange B, Kahles H et al. Insulin gene polymorphisms in type 1 diabetes, Addison's disease and the polyglandular autoimmune syndrome type II. BMC Med Genet
2008; 9: 65.
29. Lopez ER, Zwermann O, Segni M et al. A promoter polymorphism of the CYP27B1 gene is associated with Addison's disease, Hashimoto's thyroiditis, Graves' disease and type 1 diabetes mellitus in Germans. Eur J Endocrinol 2004; 151 (2): 193–7.
________________________________________________
1. Neufeld M, Blizzard RM. Polyglandular autoimmune diseases. In: Pinchera A, Doniach D, Fenzi GF, Baschieri L, ed. Symposium on Autoimmune Aspects of Endocrine Disorders. New York: Academic Press, 1980; p. 357–65.
2. Gombos Z, Hermann R, Kiviniemi M et al. Analysis of extended human leukocyte antigen haplotype association with Addison's disease in three populations. Eur J Endocrinol 2007; 157: 757–61.
3. Hansen MP, Kahaly GJ. Autoimmune polyglandular syndromes Dtsch Med Wochenschr 2013; 138 (7): 319-26; quiz 327-8. DOI: 10.1055/s-0032-1327355
4. Kahaly GJ. Polyglandular autoimmune syndromes. Eur J Endocrinol 2009; 161 (1): 11–20.
5. Betterle C, Lazzarotto F, Presotto F. Autoimmune polyglandular syndrome Type 2: the tip of an iceberg? Clin Exp Immunol 2004; 137 (2): 225–33.
6. Diagnostic criteria in autoimmune diseases. Y Shoenfeld, R Cervera, ME Gershwin, eds. Humana Press, Totowa, NJ. 2008.
7. Betterle C, Dal Pra C, Mantero F, Zanchetta R. Autoimmune Adrenal Insufficiency and Autoimmune Polyendocrine Syndromes: Autoantibodies, Autoantigens, and Their Applicability in Diagnosis and Disease Prediction. Endocr Rev 2002; 23 (3): 327–64. https://doi.org/10.1210/edrv.23.3.0466
8. Betterle C, Volpato M, Greggio AN, Presotto F. Type 2 polyglandular autoimmune disease (Schmidt's syndrome). J Pediatr Endocrinol Metab 1996; 9 (1): 113–23.
9. Albergoni P, Gazzola MV, Slanzi E et al. HLA–DR and DQ associations with autoimmune Addison's disease in Italian patients. Genes Immunity 2003; 4 (1): S35.
10. Betterle C, Zanchetta R. Update on autoimmune polyendocrine syndromes (APS). Clinical Immunology and Allergology. Acta Bio Medica 2003; 74: 9–33.
11. Golden B, Levin L, Ban Y et al. Genetic analysis of families with autoimmune diabetes and thyroiditis: evidence for common and unique genes. J Clin Endocrinol Metab 2005; 90 (8): 4904–11.
12. Kahaly GJ, Frommer L, Schuppan D. Celiac Disease and Glandular Autoimmunity. Nutrients 2018; 10 (7): 814. DOI: 10.3390/nu10070814
13. Fan KC, Yang TH, Huang YC. Vitiligo and thyroid disease: a systematic review and meta-analysis. Eur J Dermatol 2018; 28 (6): 750–63. DOI: 10.1684/ejd.2018.3449.
14. Vrijman C, Kroon MW, Limpens J et al. The prevalence of thyroid disease in patients with vitiligo: a systematic review. Br J Dermatol 2012; 167 (6): 1224–35. DOI: 10.1111/j.1365-2133
15. Klein J, Stato A. The HLA System. First of two Parts. N Engl J Med 2000; 343: 702–9.
16. Klein J, Stato A. The HLA System. Second of two Parts. N Engl J Med 2000; 343: 782–6.
17. Huang W, Connor E, Dela Rosa T et al. Although DR3-DQB1*0201 may be associated with multiple component diseases of the Autoimmune Polyglandular Syndrome, the Human Leukocyte Antigen DR4-DQB1*0302 haplotype is implicated only in beta-cells autoimmunity. J Clin Endocrinol Metab 1996; 81: 2259–63.
18. Erichsen M, Løvås K, Skinningsrud B et al. Clinical, Immunological, and Genetic Features of Autoimmune Primary Adrenal Insufficiency: Observations from a Norwegian Registry. J Clin Endocrinol Metab 2009; 94 (12): 4882–90.
19. Flesch BK, Matheis N, Alt T et al. HLA class II haplotypes differentiate between the adult autoimmune polyglandular syndrome types II and III. J Clin Endocrinol Metab 2014; 99 (1): E177-82. DOI: 10.1210/jc.2013-2852
20. Triolo TM, Baschal EE, Armstrong TK et al. Homozygosity of the Polymorphism MICA5.1 Identifies Extreme Risk of Progression to Overt Adrenal Insufficiency among 21-Hydroxylase Antibody-Positive Patients with Type 1 Diabetes. J Clin Endocrinol Metab 2009; 94 (11): 4517–23.
21. Huber A, Menconi F, Corathers S et al. Joint genetic susceptibility to type 1 diabetes and autoimmune thyroiditis: from epidemiology to mechanisms. Endocr Rev 2008; 29: 697–725.
22. Villano MJB, Huber AK, Greenberg DA et al. Autoimmune thyroiditis and diabetes: dissecting the joint genetic susceptibility in a large cohort of multiplex families. J Clin Endocrinol Metab 2009; 94: 1458–66.
23. Houcken J, Degenhart C, Bender K et al. PTPN22 and CTLA-4 Polymorphisms Are Associated With Polyglandular Autoimmunity. J Clin Endocrinol Metab 2018; 103 (5): 1977–84. DOI: 10.1210/jc.2017-02577
24. Dultz G, Matheis N, Dittmar M et al. CTLA-4 CT60 polymorphism in thyroid and polyglandular autoimmunity. Horm Metab Res 2009; 41 (6): 426–9.
25. Skinningsrud B, Husebye ES, Gervin K et al. Mutation screening of PTPN22: association of the 1858T-allele with Addison's disease. Eur J Human Genetics 2008; 16: 977–82.
26. Nikonova T.V. Sakharnyi diabet 1 tipa i latentnyi autoimmunnyi diabet vzroslykh (LADA): klinicheskie, immuno-geneticheskie i gormonal'no-metabolicheskie aspekty. Avtoref. dis. ... d-ra med. nauk. Moscow, 2011 (in Russian).
27. Owen CJ, Eden JA, Jennings CE et al. Genetic association studies of the FOXP3 gene in Graves' disease and autoimmune Addison's disease in the United Kingdom population. J Mol Endocrinol 2006; 37 (1): 97–104.
28. Lopez ER, Lange B, Kahles H et al. Insulin gene polymorphisms in type 1 diabetes, Addison's disease and the polyglandular autoimmune syndrome type II. BMC Med Genet
2008; 9: 65.
29. Lopez ER, Zwermann O, Segni M et al. A promoter polymorphism of the CYP27B1 gene is associated with Addison's disease, Hashimoto's thyroiditis, Graves' disease and type 1 diabetes mellitus in Germans. Eur J Endocrinol 2004; 151 (2): 193–7.
Авторы
Е.А.Трошина*1, А.А.Ларина1, М.А.Терехова2
1 ФГБУ «Национальный медицинский исследовательский центр эндокринологии», Москва, Россия;
1 ФГБУ «Национальный медицинский исследовательский центр эндокринологии», Москва, Россия;
2 ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет), Москва, Россия
*troshina@inbox.ru
*troshina@inbox.ru
________________________________________________
Ekaterina A. Troshina*1, Anna A. Larina1, Maria A. Terekhova2
1 Endocrinology Research Centre, Moscow, Russia;
1 Endocrinology Research Centre, Moscow, Russia;
2 I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
*troshina@inbox.ru
*troshina@inbox.ru
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