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Abstrak :
Latar belakang. Graves? Disease (GD) merupakan penyakit autoimun yang paling banyak menyebabkan hipertiroidisme dan ditandai adanya autoantibodi terhadap reseptor hormon tiroid (TSHR). Sel dendritik (DC) berperan penting dalam menentukan jenis respon imun tubuh, berupa aktivasi atau toleransi, salah satunya dengan cara mensekresikan mediator yang dapat mempengaruhi kerja sel-sel lain. Vitamin D merupakan imunoregulator alami yang dalam kondisi normal dapat mempengaruhi DC untuk mensekresikan IDO dan IL-10 serta menekan sekresi IL-12 dari DC. Sekresi IDO dan IL-10 oleh DC dapat mencetuskan respon toleransi dengan meningkatkan aktivitas sel T regulatori (Treg) dalam mencegah dan/atau mengurangi produksi autoantibodi terhadap TSHR. Belum diketahui apakah pemberian vitamin D pada kondisi GD dapat meningkatkan sekresi IDO dan IL-10 serta menekan sekresi IL-12. Tujuan. Melihat pengaruh kadar vitamin D terhadap fungsi DC dan sistem imun pasien GD dalam mensekresikan IL-12, IDO dan IL-10. Metode. Sampel merupakan bahan biologis tersimpan yang berupa supernatan kultur DC dari monosit (kultur MDDC) dan serum dari pasien GD. Kultur MDDC dari pasien GD sebelum perlakuan, diberi pendedahan tanpa atau dengan 1,25(OH)2D3 100 nM, waktu inkubasi 7 hari, dengan penambahan lipopolisakarida (LPS) pada hari ke-5. Kultur MDDC dari pasien GD setelah perlakuan, diinkubasi tanpa 1,25(OH)2D3 selama 7 hari dengan pemberian LPS pada hari ke-5. Serum berasal dari pasien GD sebelum dan sesudah mendapatkan terapi standar PTU 100 mg 3 kali sehari dengan atau tanpa suplementasi 1α(OH)D3. Serum dan supernatan diuji dengan metode ELISA untuk mengukur kadar 25(OH)D3, IL-12, IDO dan IL-10, kemudian diuji secara statistik untuk melihat pola dari tiap parameter. Hasil. Rerata kadar IL-12 lebih rendah secara signifikan pada kultur MDDC dengan pemberian vitamin D 100 nM. Rerata kadar IDO dan IL-10 cenderung tetap pada kultur MDDC dengan pemberian vitamin D 100 nM. Peningkatan kadar vitamin D dalam serum berkorelasi negatif dengan kadar IL-12 dan IDO, baik dalam supernatan kultur MDDC maupun dalam serum pasien GD. Pada kelompok pasien GD dengan peningkatan kadar vitamin D serum tinggi, respon sekresi IL-10 pada MDDC dan sistem imun pasien GD cenderung meningkat. Semakin tinggi rasio kadar IL-12/IL-10 pada supernatan kultur MDDC dan serum pasien GD, maka semakin tinggi juga kadar IDO yang disekresikan. Simpulan. Pemberian vitamin D pada kultur MDDC dari pasien GD dapat menekan respon inflamasi MDDC dengan mengurangi sekresi kadar IL-12 dan mempertahankan kadar IDO dan IL-10. Peningkatan kadar vitamin D serum dapat menekan kadar IL-12 dan IDO, juga berpotensi meningkatkan kadar IL-10, baik pada keadaan in vitro maupun in vivo. ...... Background. Graves' disease (GD) is a type of autoimmune disease that causes hyperthyroidism. GD patients have excess autoantibodies specific for thyroid stimulating hormone receptors (TSHR). Dendritic cells (DCs) play an important role in determining the type of immune response, either activation or tolerance, by secreting mediator molecules that affect other cells. Vitamin D is a natural immunoregulator which in normal condition can affect IDO and IL-10 secretion by DC while suppresing IL-12 secretion by this cell. Secretion of IDO and IL-10 by DC can trigger tolerance by increasing regulatory T cells (Treg) activity in preventing and/or reducing the production of autoantibodies against TSHR. There is still no evidence whether administration of vitamin D at GD conditions can increase the secretion of IDO and IL-10 and suppress the secretion of IL-12. Aim. To identify the effect of vitamin D in vitro and in vivo on IL-12, IDO and IL-10 secretion by DC and on the immune system of GD patients. Method. Samples were stored biological liquid in the form of serum and monocyte derived dendritic cells (MDDC) culture supernatant from GD patients. MDDC cultures of pre-treatment GD patients were incubated for 7 days with or without 1,25(OH)2D3 100 nM, with an addition of LPS on day 5. MDDC cultures of post-treatment GD patients were incubated without 1,25(OH)2D3 for 7 days, with an addition of LPS on day 5. Serum were obtained from GD patients before and after standard therapy of 100mg PTU 3 times a day with or without 1α(OH)D3 supplementation. Levels of 25(OH)D3, IL-12, IDO and IL-10 in the serum and supernatant were measured by ELISA and the results were statistically analyzed to see the pattern of each parameter. Results. The mean levels of IL-12 are significantly lower in MDDC culture with 100 nM vitamin D. The mean levels of IDO and IL-10 in MDDC cultures with 100 nM vitamin D are maintained at the same levels with MDDC without vitamin D. Increased levels of vitamin D in serum is negatively correlated with IL-12 and IDO levels, both in the MDDC supernatant and in the serum of GD patients. In the high-increment-serum-vitamin-D-level group of GD patients, IL-10 secretion in vitro and in vivo tends to increase. Higher ratio of IL-12/IL-10 levels affects an increase in IDO secretion, both in MDDC culture and in patient?s serum. Conclusion. Vitamin D exposure in MDDC culture of GD patients can suppress the inflammatory response by reducing IL-12 secretion and maintaining IDO and IL-10 levels. Increased vitamin D serum level can suppress IL-12 and IDO levels and is also potential in increasing IL-10 level, both in vitro and in vivo.

Abstrak :
Latar Belakang : Mortalitas akibat kondisi hipertiroid sebesar 20% dan peningkatan kematian sebesar 1,13x. Mortalitas akibat penyakit pada kelenjar tiroid dihubungkan dengan kejadian kardiovaskuler, salah satunya infark miokard yang diperantarai oleh mekanisme aterosklerosis. Pemeriksaan ketebalan tunika intima-media arteri karotis (CIMT) direkomendasikan untuk menilai risiko kejadian KV. Penelitian ini bertujuan untuk membandingkan ketebalan tunika intima-media pada pasien Graves kondisi hipertiroid dengan kondisi remisi. Metode : Penelitian ini bersifat cross-sectional dengan populasi terjangkau adalah pasien Graves yang berobat ke poliklinik metabolik endokrinologi RSCM yang dilakukan pada bulan Desember 2019 hingga April 2020. Kondisi overt hipertiroid didefinisikan dengan pasien Graves yang masih memiliki gejala toksik dengan laboratorium TSH rendah dan FT4 tinggi, belum mendapat pengobatan atau belum eutiroid dalam pengobatan minimal 3 bulan. Kondisi remisi didefinisikan dengan kondisi eutiroid setelah berhenti pengobatan selama minimal 6 bulan. Pasien kemudian diambil data dan dilakukan pemeriksaan laboratorium meliputi TSH, fT4, profil lipid, gula darah dan pemeriksaan EKG. Setelahnya dilakukan pemeriksaan CIMT menggunakan USG doppler dengan software yang secara otomatis mengukur CIMT sebanyak 3x pada sisi kanan dan kiri arteri karotis, kemudian diambil nilai rata rata pemeriksaan tersebut. Hasil Penelitian : Didapatkan 32 pasien kondisi overt hipertiroid dan 17 kondisi remisi. Median tebal tunika intima-media arteri karotis (CCA-IMT) pada subjek overt hipertiroid adalah 0,473 mm dengan rentang 0,384-0,639 mm. Median CCA-IMT pada subjek remisi adalah 0,488 mm dengan rentang 0,388-629 mm. Tidak didapatkan perbedaan rerata CIMT pada kondisi hipertiroid dan kondisi remisi (p :0,109). Dalam analisis tambahan didapatkan bahwa didapatkan adanya pengaruh usia dalam ketebalan tunika intima media pada pasien graves baik kondisi overt hipertiroid dan kondisi remisi. Background : Mortality caused by hyperthyroid estimated around 20% and increasing risk of date 1,13 times than all-caused mortalitu. Hyperthyroid associated with cardiovascular event, such as atherosclerosis mediated myocardial infarction. Carotid intima media thickness recommended to evaluate risk of cardiovascular event. Aim of this study to compare CIMT between overt hyperthyroid and remission in Graves disease. Method : This is cross-sectional study with targeted population was Graves patient who came in metabolic endocrinology policlinic in Cipto Mangunkusumo hospital. This study being done within December 2019 until April 2020. Overt hyperthyroid was defined as clinically toxic as well as laboratorium supported for thyrotoxicosis, treatment naïve or havent reached euthyroid within 3 month of treatment. While remission defined as clinical and laboratorium euthyroid after minimal 6 month stopping anti thyroid drugs. History, physical examination, laboratorium examination (included TSH, fT4, lipid profile, fasting blood glucose) as well as electrocardiogram obtained. CIMT evaluated in right and left artery carotid with ultrasonography that automatically count for thickness intima media then calculated means after 3 times examination. Data then collected and being analysed. Result : we collect 32 patient in overt hyperthyroid and 17 in remission state. Median CIMT in overt hyperthyroid and in remission state was 0,473 mm and 0,488 mm, consecutively, p : 0,109. Additional multivariate analysis stated aged had correlation with carotid intima media in Graves disease. Conclusion : there are no significant differences in carotid intima media thickness between overt hyperthyroid and remission state in Graves disease.

Abstrak :
Pendahuluan: Graves' disease merupakan etiologi dari hipertiroidisme yang paling sering ditemukan dan salah satu manifestasi klinis yang sering muncul adalah oftalmopati. Jalur persinyalan CD40-CD40L memiliki peranan yang penting dalam patogenesis penyakit autoimun, salah satunya adalah Graves' disease. Graves' disease melibatkan jalur persinyalan CD40-CD40L yang berperan pada proses diferensiasi, proliferasi, dan aktivasi sel B dewasa sebagai respons dari antigen yang berbeda. Penelitian ini bertujuan menganalisis gen CD40L pada rs3092951, yang terletak pada 5' flanking region bagian promoter. Metode: Sampel berasal dari 60 penderita Graves' disease yang dianalisis dengan metode SSP-PCR untuk mengetahui variasi genetik dan metode ELISA untuk mengetahui kadar sCD40L. Hasil: Variasi genetik CD40L rs3092951 tidak berperan pada risiko kekambuhan dan derajat oftalmopati (p>0,05). Ditemukan perbedaan kadar sCD40L yang signifikan pada pasien kambuh dengan tidak kambuh (p<0,05) dan pada pasien dengan derajat oftalmopati (p<0,05). Kesimpulan: Terdapat hubungan yang signifikan antara kadar sCD40L terhadap risiko kekambuhan dan derajat oftalmopati pada penderita Graves' disease, hubungan yang signifikan tidak ditemukan pada variasi genetik gen CD40L rs3092951. Introduction: Graves disease is the most common etiology of hyperthyroidism. Graves' ophthalmopathy occurs in patients with hyperthyroidism and one of the most common clinical manifestations is ophthalmopathy. The CD40- CD40L signaling pathway play an important role in the pathogenesis of autoimmune diseases, one of them is Graves' Disease. Graves' disease involves the CD40-CD40L signaling pathways which play a role in differentiation, proliferation, and activation of mature B cells in response to different antigen. This study analyzed the CD40L gene at rs3092951 which is located at the promoter of the 5' flanking region. Methods: Samples were taken from 60 Graves' disease patients analyzed by SSP-PCR method to determine the genetic variation and ELISA method to determine the levels of sCD40L. Results: Significant correlation was not found between genetic variation of CD40L rs3092951 with the risk of recurrence and the degree of ophthalmopathy (p>0.05). There is a significant difference in sCD40L levels in patients with recurrence and without recurrence (p <0.05) and in patients with degrees of ophthalmopathy (p<0.05). Conclusion: There was a significant correlation between the sCD40L levels with the risk of recurrence and the degree of ophthalmopathy, no significant correlation was found in genetic variation of CD40L rs3092951.

Abstrak :
Latar Belakang. Kualitas hidup merupakan keluaran klinis yang seringkali terlupakan pada pengkajian pasien penyakit Graves. Saat ini belum ada kuesioner kualitas hidup pasien gangguan tiroid yang tervalidasi dalam Bahasa Indonesia. Penelitian terkait kualitas hidup belum pernah dilakukan pada pasien penyakit Graves di Indonesia. Metode. Penelitian ini menggunakan desain potong lintang yang terbagi ke dalam dua tahap yaitu (1) validasi kuesioner ThyPRO dalam Bahasa Indonesia dan (2) pengambilan data kualitas hidup pasien penyakit Graves dan faktor-faktor yang memengaruhinya. Studi ini dikerjakan pada bulan Maret sampai November 2022 di Poliklinik Endokrin Metabolik RSCM, Jakarta, Indonesia. Hasil. 50 subjek pasien gangguan tiroid dan 150 subjek pasien penyakit Graves berpartisipasi masingmasing pada tahap pertama dan kedua penelitian ini. Tahap pertama studi ini menghasilkan kuesioner ThyPROid (Thyroid-Related Patient-Reported Outcome Indonesian version) atau “Kuesioner Kualitas Hidup Pasien Tiroid Berbahasa Indonesia” yang secara keseluruhan valid dan reliabel. Kualitas hidup pasien penyakit Graves yang diperoleh pada penelitian ini adalah baik (72,7%) dan kurang (27,3%). Faktor-faktor yang memengaruhi kualitas hidup kurang pada penelitian ini adalah Indeks Wayne dengan skor di atas 19 dan oftalmopati derajat sedang-berat dan aktif. Riwayat sudah diobati, baik dengan obat anti-tiroid, pembedahan maupun terapi iodium radioaktif merupakan faktor protektif bagi kualitas hidup kurang. Kesimpulan. Menggunakan kuesioner ThyPROid yang sudah divalidasi dalam Bahasa Indonesia, sebagian besar pasien penyakit Graves memiliki kualitas hidup yang baik. Faktor yang memengaruhi kualitas hidup kurang adalah Indeks Wayne, oftalmopati derajat sedang-berat dan aktif. Riwayat sudah diobati, baik dengan obat anti-tiroid, pembedahan maupun terapi iodium radioaktif, merupakan faktor protektif kualitas hidup kurang. Kata kunci. Penyakit Graves, kualitas hidup, Indonesia, ThyPRO, Indeks Wayne, oftalmopati, pengobatan, obat anti-tiroid, pembedahan, terapi iodium radioaktif. ......Introduction. Quality of life is a clinical outcomes which frequently forgotten in any assessment of patients with Graves’ disease. There is currently no questionnaire for quality of life assessment for patients with thyroid disease which are validated in Bahasa Indonesia. Study about quality of life has never been conducted in patients with Graves’ disease in Indonesia. Methods. This cross-sectional study divided into two phases, that is: (1) ThyPRO questionnaire validation in Bahasa Indonesia, and (2) data collection on quality of life in patients with Graves’ disease and the factors affected it. This study was conducted on March to November 2022 in Endocrine & Metabolic Polyclinic Cipto Mangunkusumo Hospital, Jakarta, Indonesia. Results. 50 subjects of patients with thyroid disease and 150 subjects of patients with Graves’ disease participated each in the first and the second phase of the study. First phase of the study resulted with ThyPROid questionnaire (Thyroid-Related Patient Reported Outcome Indonesian version) which overall is valid and reliable. Quality of life in patients with Graves’ disease that were obtained from this study was good (72,7%) and poor (27,3%). Factors that affected poor quality of life in this study was higher score of Wayne Index (total score > 19) and moderate-to-severe degree and active Graves’ ophthalmopathy. History of treatment, either with anti-thyroid medication, surgery, or radioactive iodine therapy, was protective factor for poor quality of life. Conclusion. Using ThyPROid questionnaire which were validated in Bahasa Indonesia, most of the patients with Graves’ disease in this study has good quality of life. Factors which affected poor quality of life was high Wayne Index and moderate-to-severe degree and active Graves’ ophthalmopathy. History of treatment, either with anti-thyroid medication, surgery, or radioactive iodine therapy, was protective factor for poor quality of life.

Abstrak :
Background: graves disease (GD) is the most common condition of thyrotoxicosis. The management of GD is initiated with the administration of antithyroid drugs; however, it requires a long time to achieve remission. In reality more than 50% of patients who had remission may be at risk for relapse after the drug is stopped. This study aimed to evaluate the role of clinical factors such as smoking habit, degree of ophtalmopathy, degree of thyroid enlargement; genetic factors such as CTLA 4 gene on nucleotide 49 at codon 17 of exon 1, CTLA 4 gene of promotor -318, TSHR gene polymorphism rs2268458 of intron 1; and immunological factors such as regulatory T cells (Treg) and thyroid receptor antibody (TRAb); that affecting the relapse of patients with Graves disease in Indonesia. Methods: this was a case control study, that compared 72 subjects who had relapse and 72 subjects without relapse at 12 months after cessation of antithyroid treatment, who met the inclusion criteria. Genetic polymorphism examination was performed using PCR-RFLP. The number of regulatory T cells was counted using flow cytometry analysis and ELISA was used to measure TRAb. The logistic regression was used since the dependent variables were categorical variables. Results: the analysis of this study demonstrated that there was a correlation between relapse of disease and family factors (p=0.008), age at diagnosis (p=0.021), 2nd degree of Graves ophthalmopathy (p=0.001), enlarged thyroid gland, which exceeded the lateral edge of the sternocleidomastoid muscles (p=0.040), duration of remission period (p=0.029), GG genotype of CTLA 4 gene on the nucleotide 49 at codon 17 of exon 1 (p=0.016), CC genotype of TSHR gene on the rs2268458 of intron 1 (p=0.003), the number of regulatory T cells (p=0.001) and TRAb levels (p=0.002). Conclusion: genetic polymorphisms of CTLA 4 gene on the nucleotide 49 at codon 17 of exon 1, TSHR gene SNP rs2268458 of intron 1, number of regulatory T cells and TRAb levels play a role as risk factors for relapse in patients with Graves disease.