Hipotiroidi Tedavisine Deneysel Alternatif Yöntem: Tiroid Dokusunun Kapsüle Edilmesi

Öz

Amaç: Hipotiroidi tüm yaş gruplarında görülebilen, bireylerin sağlıklarının genel olarak bozulmasına neden olan klinik bir tablodur. Tedavisi genellikle yaşam boyu ilaç kullanımıdır. Bu tedaviye rağmen hormon yetmezliğine bağlı semptomlar görülmekte ve uzun dönem ilaç kullanımına bağlı yan etkiler ortaya çıkmaktadır. Hastalardaki yetersiz tiroid hormon miktarını optimum sınırlara çekmek ve hastaların yaşam kalitesini yükseltmek için tiroid dokusu transplantasyonu alternatif bir yöntem olarak önem taşımaktadır. Sunulan çalışmada, transplantasyonda immün redden etkilenmemek için hem doku kültürü hem de biyouyumlu polimerle kapsüle edilmiş tiroit dokusunun in vitro optimizasyonu amaçlanmıştır. Gereç ve Yöntemler: Mekanik yollarla kültüre edilen tiroid dokusu 2 grupta takip edilmiştir; doku kültürü ve kapsülasyon kültürü. In vitro ortamda 60 gün boyunca takip edilen kapsüllerin morfolojileri ışık mikroskopu ile birlikte T3 ve T4 hormon değerleri ise biyokimyasal olarak değerlendirilmiştir. Bulgular: 3., 9., 12., 15., 30., 45., 60. günlerde toplanan medyum örneklerinden T3 ve T4 seviyeleri gözlemlendi. Kapsüle edilen dokularda, kapsüle edilmeyenlere ve negatif kontrol dokularına göre 15. gün itibariyle T3 değerleri daha yüksek bulundu. Buna rağmen T4 seviyeleri 60 gün boyunca sabit kaldı. Sonuç: Hipotiroidinin kalıcı tedavisi için kapsüle edilen tiroid dokularının in vitro ortamda verimliliği incelenmiştir. Öncül sonuçlarımız umut vaat etmesine rağmen bu optimizasyonun in vivo hayvan çalışmalarında da doğrulandıktan sonra insan çalışmalarına geçilmesi düşünülmelidir

Anahtar Kelimeler

• Hipotiroidi, Aljinat tabanlı kapsülasyon, Tiroid hiperplazi, Hürthle hücreli karsinom

Experimental Alternative Method for the Treatment of Hypothyroidism: Capsulation of the Thyroid Tissue

Abstract

Objective: Hypothyroidism is a clinical condition that affects all age groups. Generally, lifelong medication is required for the treatment. Despite treatment, symptoms that are related to hormone insufficiency and side effects due to long-term medication can be seen. As an alternative approach, thyroid tissue transplantation may be useful, because of its potential to elevate the thyroid hormone levels and thus increase daily quality of life for the patients. Our aim in this study was to detect the in vitro optimal microencapsulation conditions for thyroid tissues with a biocompatible polymer to avoid immune rejection following transplantation.Material and Methods: Thyroid tissues were isolated mechanically, and followed-up in two groups; tissue and capsulated tissue culture. In-vitro capsule formation and morphology were screened using brightfield microscopy and T3 and T4 levels were evaluated biochemically throughout 60 days. Results: T3 and T4 levels were screened from collected medium samples at day 3., 9., 12., 15., 30., 45., 60.. In capsuled tissues T3 level was detected higher than the non-capsuled and negative control tissues from day 15. However, T4 level was stable for 60 days. Conclusion: Efficacy of capsulated thyroid tissues for permanent treatment of hypothyroidism to avoid the immune system was evaluated in vitro. Preliminary results were promising but this optimization requires in vivo confirmation and future human studies should be considered

Keywords

• Hypothyroidism, Alginate based capsulation, Thyroid hyperplasia, Hurthle cell carcinoma

Kaynakça

1. 1. Faggiano A, Del Prete M, Marciello F, Marotta V, Ramundo V, Colao A. Thyroid diseases in elderly. Minerva Endocrinol 2011;36(3):211-31.
2. 2. Salvatore D, Simonides WS, Dentice M, Zavacki AM, Larsen PR. Thyroid hormones and skeletal muscle new insights and potential implications. Nat Rev Endocrinol 2014;10(4):206-14.
3. 3. Vargas-Uricoechea H, Sierra-Torres CH. Thyroid hormones and the heart. Horm Mol Biol Clin Investig 2014;18(1):15-26.
4. 4. Corona G, Wu FC, Forti G, Lee DM, O'Connor DB, O'Neill TW, et al. Thyroid hormones and male sexual function. Int J Androl 2012;35(5):668-79.
5. 5. Di Liegro I. Thyroid hormones and the central nervous system of mammals (Review). Mol Med Rep 2008;1(3):279-95.
6. 6. Daher R, Yazbeck T, Jaoude JB, Abboud B. Consequences of dysthyroidism on the digestive tract and viscera. World J Gastroenterol 2009;15(23):2834-8.
7. 7. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87(2):489-99.
8. 8. Santini F, Marzullo P, Rotondi M, Ceccarini G, Pagano L, Ippolito S, et al. Mechanisms in endocrinology: The crosstalk between thyroid gland and adipose tissue: Signal integration in health and disease. Eur J Endocrinol 2014;171(4):R137-52.

9. 9. Limonard EJ, Bisschop PH, Fliers E, Nieveen van Dijkum EJ. Thyroid function after subtotal thyroidectomy in patients with Graves' hyperthyroidism. Scientific World Journal 2012;2012:548796.
10. 10. Escobar-Morreale HF, Botella-Carretero JI, Morreale de Escobar G. Treatment of hypothyroidism with levothyroxine or a combination of levothyroxine plus L-triiodothyronine. Best Pract Res Clin Endocrinol Metab 2015;29(1):57-75.
11. 11. Siegmund W, Spieker K, Weike AI, Giessmann T, Modess C, Dabers T, et al. Replacement therapy with levothyroxine plus triiodothyronine (bioavailable molar ratio 14 : 1) is not superior to thyroxine alone to improve well-being and cognitive performance in hypothyroidism. Clin Endocrinol (Oxf) 2004;60(6):750-7.
12. 12. Clarke N, Kabadi UM. Optimizing treatment of hypothyroidism. Treat Endocrinol 2004;3(4):217-21.
13. 13. LaRosa DF, Rahman AH, Turka LA. The innate immune system in allograft rejection and tolerance. J Immunol 2007;178(12):7503-9.
14. 14. Wang H, Yang YG. Innate cellular immunity and xenotransplantation. Curr Opin Organ Transplant 2012;17(2):162-7.
15. 15. Fort A, Fort N, Ricordi C, Stabler CL. Biohybrid devices and encapsulation technologies for engineering a bioartificial pancreas. Cell Transplant 2008;17(9):997- 1003.
16. 16. Yang Y, Opara EC, Liu Y, Atala A, Zhao W. Microencapsulation of porcine thyroid cell organoids within a polymer microcapsule construct. Exp Biol Med (Maywood) 2017;242(3):286-96.
17. 17. de Vos P, Bucko M, Gemeiner P, Navratil M, Svitel J, Faas M, et al. Multiscale requirements for bioencapsulation in medicine and biotechnology. Biomaterials 2009; 30(13):2559-70.
18. 18. Pareta R, McQuilling JP, Sittadjody S, Jenkins R, Bowden S, Orlando G, et al. Long-term function of islets encapsulated in a redesigned alginate microcapsule construct in omentum pouches of immune-competent diabetic rats. Pancreas 2014;43(4):605-13.
19. 19. Machluf M, Orsola A, Boorjian S, Kershen R, Atala A. Microencapsulation of Leydig cells: A system for testosterone supplementation. Endocrinology 2003;144(11):4975-9.
20. 20. Mei J, Sgroi A, Mai G, Baertschiger R, Gonelle-Gispert C, Serre-Beinier V, et al. Improved survival of fulminant liver failure by transplantation of microencapsulated cryopreserved porcine hepatocytes in mice. Cell Transplant 2009;18(1):101-10.
21. 21. Moskalenko V, Ulrichs K, Kerscher A, Blind E, Otto C, Hamelmann W, et al. Preoperative evaluation of microencapsulated human parathyroid tissue aids selection of the optimal bioartificial graft for human parathyroid allotransplantation. Transpl Int 2007;20(8):688-96.
22. 22. Sittadjody S, Saul JM, Joo S, Yoo JJ, Atala A, Opara EC. Engineered multilayer ovarian tissue that secretes sex steroids and peptide hormones in response to gonadotropins. Biomaterials 2013;34(10):2412-20.
23. 23. Diaz A, Lipman Diaz EG. Hypothyroidism. Pediatr Rev 2014;35(8):336-47; quiz 48-9.
24. 24. Laurberg P, Andersen S, Bulow Pedersen I, Carle A. Hypothyroidism in the elderly: Pathophysiology, diagnosis and treatment. Drugs Aging 2005;22(1):23-38.
25. 25. Hennessey JV. The emergence of levothyroxine as a treatment for hypothyroidism. Endocrine 2017;55(1):6- 18.
26. 26. Grozinsky-Glasberg S, Fraser A, Nahshoni E, Weizman A, Leibovici L. Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: Meta-analysis of randomized controlled trials. J Clin Endocrinol Metab 2006;91(7):2592-9.
27. 27. Ma C, Xie J, Huang X, Wang G, Wang Y, Wang X, et al. Thyroxine alone or thyroxine plus triiodothyronine replacement therapy for hypothyroidism. Nucl Med Commun 2009;30(8):586-93.
28. 28. Ruggeri RM, Trimarchi F, Biondi B. Management of endocrine disease: l-Thyroxine replacement therapy in the frail elderly: A challenge in clinical practice. Eur J Endocrinol 2017;177(4):R199-R217.
29. 29. Lin RY, Kubo A, Keller GM, Davies TF. Committing embryonic stem cells to differentiate into thyrocyte-like cells in vitro. Endocrinology 2003;144(6):2644-9.
30. 30. Arufe MC, Lu M, Kubo A, Keller G, Davies TF, Lin RY. Directed differentiation of mouse embryonic stem cells into thyroid follicular cells. Endocrinology 2006;147(6):3007-15.
31. 31. Antonica F, Kasprzyk DF, Opitz R, Iacovino M, Liao XH, Dumitrescu AM, et al. Generation of functional thyroid from embryonic stem cells. Nature 2012;491(7422):66-71. 32. Chambers I, Smith A. Self-renewal of teratocarcinoma and embryonic stem cells. Oncogene 2004;23(43):7150- 60.
32. 33. Ghosh Z, Huang M, Hu S, Wilson KD, Dey D, Wu JC. Dissecting the oncogenic and tumorigenic potential of differentiated human induced pluripotent stem cells and human embryonic stem cells. Cancer Res 2011;71(14):5030-9.
33. 34. Toda S, Koike N, Sugihara H. Thyrocyte integration, and thyroid folliculogenesis and tissue regeneration: Perspective for thyroid tissue engineering. Pathol Int 2001;51(6):403-17.
34. 35. Okamoto T, Fujimoto Y, Obara T, Ito Y, Kodama T, Kusakabe K. Trial of thyroid autotransplantation in patients with Graves' disease whose remnant thyroid has unintentionally been made too small at subtotal thyroidectomy. Endocrinol Jpn 1990;37(1):95-101.
35. 36. Shimizu K, Kumita S, Kitamura Y, Nagahama M, Kitagawa W, Akasu H, et al. Trial of autotransplantation of cryopreserved thyroid tissue for postoperative hypothyroidism in patients with Graves' disease. J Am Coll Surg 2002;194(1):14-22.
36. 37. Roy PG, Saund MS, Thusoo TK, Roy D, Sankar R. Fate of human thyroid tissue autotransplants. Surg Today 2003;33(8):571-6.
37. 38. Toledo PC, Rossi RL, Caviedes P. Microencapsulation of Parathyroid Cells for the Treatment of Hypoparathyroidism. Methods Mol Biol 2017;1479:357- 63.
38. 39. Long R, Liu Y, Wang S, Ye L, He P. Co-microencapsulation of BMSCs and mouse pancreatic β cells for improving the efficacy of type I diabetes therapy. Int J Artif Organs 2017;40(4):169-75.
39. 40. Singh MN, Hemant KS, Ram M, Shivakumar HG. Microencapsulation: A promising technique for controlled drug delivery. Res Pharm Sci 2010;5(2):65-77.
40. 41. Del Piano M, Carmagnola S, Ballare M, Sartori M, Orsello M, Balzarini M, et al. Is microencapsulation the future of probiotic preparations? The increased efficacy of gastro-protected probiotics. Gut Microbes 2011;2(2):120- 3.
41. 42. Nakai S, Nakai A, Michida T. Microencapsulation of ascorbic acid for cosmetic by utilizing self-assembly of phase separated polymer. Chem Pharm Bull (Tokyo) 2016;64(10):1514-8.
42. 43. Lam PL, Gambari R. Advanced progress of microencapsulation technologies: In vivo and in vitro models for studying oral and transdermal drug deliveries. J Control Release 2014;178:25-45.
43. 44. Paredes Juarez GA, Spasojevic M, Faas MM, de Vos P. Immunological and technical considerations in application of alginate-based microencapsulation systems. Front Bioeng Biotechnol 2014;2:26.
44. 45. Lu B, Gao Q, Liu R, Ren M, Wu Y, Jiang Z, et al. Effect of a new drug releasing system on microencapsulated islet transplantation. Int J Clin Exp Pathol 2015;8(10):12390- 9.
45. 46. Calafiore R, Basta G, Montanucci P. Microencapsulation of islets for the treatment of type 1 diabetes mellitus (T1D). Methods Mol Biol 2017;1479:283-304.
46. 47. Hwang SR, Seo DH, Byun Y, Park JW. Preparation and in vivo evaluation of an orally available entericmicroencapsulated parathyroid hormone (1-34)- deoxycholic acid nanocomplex. Int J Nanomedicine 2016;11:4231-46.
47. 48. Lin L, Song Y, Song C, Xu P, Song C. Successful xenotransplantation of microencapsulated newborn pig parathyroid cells in the treatment of hypoparathyroidism in rats. Chin Med J (Engl) 2003;116(8):1161-5.
48. 49. Lee CH, Wang YJ, Kuo SM, Chang SJ. Microencapsulation of parathyroid tissue with photosensitive poly(L-lysine) and short chain alginate-co-MPEG. Artif Organs 2004;28(6):537-42.
49. 50. Hasse C, Zielke A, Klock G, Schlosser A, Zimmermann U, Rothmund M. Isotransplantation of microencapsulated parathyroid tissue in rats. Exp Clin Endocrinol Diabetes 1997;105(1):53-6.