Thyroid-associated Ophthalmopathy Research Articles

Comprehensive analysis of cytokine gene polymorphisms defines the association of IL-12 gene with ophthalmopthy in Korean children with autoimmune thyroid disease

In early onset autoimmune thyroid disease (AITD) showing a strong genetic tendency, cytokines have been suggested to play a critical role in the development of AITD. To directly compare the influences of several cytokine gene polymorphisms, 25 single nucleotide polymorphisms (SNPs) in 17 cytokine genes were analyzed on 104 Korean children with AITD [Hashimoto's disease (HD) = 44, Graves' disease (GD) = 60 (thyroid-associated ophthalmopathy (TAO) = 29, non-TAO = 31)] and 192 controls. Compared with healthy controls, any significant association with polymorphisms of cytokine genes was not found in HD and GD. Among GD patients, non-TAO group only showed significant associations with IL-12 C allele (rs3212227: A > C) (76.6% vs. 51.6%, OR = 0.3 [0.15–0.71], Pc = 0.007). Particularly, the frequency of IL-12C allele was significantly lower in the non-TAO group than in the TAO group (82.8% vs. 51.6%, Pc = 0.018). Our comprehensive analysis of cytokine gene polymorphisms suggests that IL-12 gene may play impact on specific pathogenesis of ophthalmopathy in Korean children with AITD.

Observation of Corneal Langerhans Cells by In Vivo Confocal Microscopy in Thyroid-Associated Ophthalmopathy

ABSTRACT Purpose: To examine the density and morphology of Langerhans cells (LCs) in the cornea of patients with thyroid-associated ophthalmopathy (TAO). Methods: Forty patients with TAO and 20 healthy volunteers were studied. All subjects underwent a thorough ophthalmic examination of both eyes. The ocular surface status was assessed by Ocular Surface Disease Index (OSDI) symptom questionnaires, tear break-up time (BUT), fluorescein staining and the Schirmer test. Laser scanning in vivo confocal microscopy was applied to evaluate the LC density and morphology in both central and peripheral cornea. The correlations between confocal microscopy data and clinical data were also analyzed. Results: The OSDI and fluorescein staining values were significantly higher, while BUT and Schirmer test scores were lower in both active and inactive TAO patients compared to the controls. Central LC densities of patients with active TAO (76.38 ± 67.77 cell/mm2) and inactive TAO (47.49 ± 38.58 cell/mm2) were both significantly higher than those of the controls (21.46 ± 21.74 cell/mm2). The number of LCs in the peripheral cornea was also significantly increased in the active TAO group (131.53 ± 74.18 cell/mm2) compared to the control group (70.21 ± 37.76 cell/mm2). Central LC morphology (LCM) values were significantly higher in both active (1.77 ± 0.63) and inactive (1.51 ± 0.63) TAO groups compared to the control group (1.01 ± 0.80), whereas peripheral LCM scores of the two TAO groups were increased without statistical significance. There were significant correlations between both central LC density and central LCM scores and clinical data, including clinical activity score, OSDI and Schirmer test scores, and between peripheral LC density and OSDI and Schirmer test scores. No significant correlations were found between peripheral LCM scores and clinical data. Conclusions: The increase of corneal LCs in density and maturation in patients with TAO reflects an activated state of the local immune system, which indicates an inflammatory process in the cornea of TAO.

Clinical Features of Dry Eye in Thyroid-Associated Ophthalmopathy According to Disease Activity

Purpose: To evaluate the clinical features of dry eye in thyroid-associated ophthalmopathy (TAO) according to disease activity and analyze the related factors. Methods: This study included 157 patients diagnosed with TAO and dry eye between March 2009 and March 2015. According to the clinical activity score (CAS), TAO patients were divided into inactive (CAS < 3) and active (CAS ≥ 3) groups. Clinical features included age, sex, visual acuity, proptosis, palpebral fissure width, orbital computed tomography (CT) findings, thyroid hormones, and ocular surface parameters including tear film break-up time (TFBUT), Schirmer tests, keratoepitheliopathy scores, and ocular surface disease index (OSDI) were obtained and compared between the groups. In addition, correlations between clinical features and ocular surface parameters were analyzed in both groups. Results: In the inactive and active TAO groups, CAS was 1.24 ± 0.69 and 4.23 ± 1.13, respectively (p = 0.001). Thyrotropin-binding inhibitory immunoglobulin was significantly higher in the active TAO group than in the inactive TAO group (p = 0.048). On orbital CT, extraocular muscle hypertrophy was more common in the active TAO group than the inactive TAO group (p = 0.020). No significant difference was found in age, sex, visual acuity, free T4, and thyroid-stimulating hormone between the two groups. During analysis of the tear film and ocular surface parameters, TFBUT (p = 0.006) was shorter and OSDI score (p = 0.028) was higher in the active TAO group than the inactive TAO group. TFBUT was negatively correlated with proptosis (r = -0.432, p = 0.001; r = -0.308, p = 0.032) and palpebral fissure width (r = -0.367 p = 0.012; r = -0.312, p = 0.031) in both groups. OSDI was positively correlated with proptosis in the active TAO group (r = 0.301, p = 0.033). Conclusions: TFBUT was shorter and OSDI score higher in dry eye patients with active TAO than in patients with inactive TAO. The TFBUT was negatively correlated with proptosis and palpebral fissure width in both groups. J Korean Ophthalmol Soc 2016;57(7):1037-1043

Optic Disc, Macula, and Retinal Nerve Fiber Layer Measurements Obtained by OCT in Thyroid-Associated Ophthalmopathy.

Aim. To compare the measurements of retinal nerve fiber layer (RNFL), macula and optic disc parameters obtained by optical coherence tomography (OCT), and intraocular pressure (IOP) between the patients with thyroid-associated ophthalmopathy (TAO) and healthy controls. Methods. One hundred and thirty-two eyes of 66 patients with TAO and 72 eyes of 36 healthy controls were included in the study. Proptosis level was determined by Hertel exophthalmometer. Optic disc, peripapillary retinal nerve fiber layer, and macula parameters were measured by OCT. All measurements of the patients were compared with those of age- and sex-matched healthy controls. Results. No statistically significant difference was found between the patients with TAO and control group in terms of demographic characteristics (P > 0.05). Exophthalmometer measurements and IOP were higher in TAO group (P < 0.05). Mean macula thicknesses in TAO and control groups were 239.3 ± 29.8 μm and 246.6 ± 31.8 μm, respectively, and the difference between the groups was statistically significant (P = 0.000). TAO group had thinner inferior RNFL thickness and macular thicknesses (superior, inferior, temporal, and nasal) and higher disc area and C/D ratio when compared with the control group (P < 0.05). Conclusion. IOP, disc area, and C/D area ratio were higher in the patients with TAO and the thicknesses of macula and inferior RNFL were thinner when compared with healthy controls. This trial is registered with registration number at clinicaltrials.gov NCT02766660.

Prevalence and risk factors of thyroid-associated ophthalmopathy among Indians

Background: Thyroid-associated ophthalmopathy (TAO) is a part of an autoimmune process that can affect the orbital and periorbital tissue, the thyroid gland, and, rarely, the pretibial skin or digits. The aim of the present study was to determine the prevalence of TAO among Indian patients with thyroid dysfunction and the risk factors associated with TAO. Methods: A cross-sectional study of thyroid eye disease was conducted on patients with thyroid dysfunction visiting the outpatient department of a tertiary care centre. Demographic data, past medical history, family history, and life-style data were collected from all patients. An ophthalmologist interviewed the patients and noted the presence of symptoms and signs relevant to thyroid eye disease. Results: Out of a total of 100 patients, who were eligible for analysis, 80 were diagnosed with mild to moderate TAO and 20 were diagnosed with severe TAO. There were more male patients in patients with a severe course (50%) compared to those with a mild to moderate course (42.5%). More patients with a severe course were smokers compared to those with a mild to moderate course (chi-square test, p=0.021). More patients with a severe course had a higher clinical activity score (p=0.007). Conclusions: We have confirmed that smoking is the strongest risk factor for development of a severe course of TAO in Indian patients. Thus, it is important for patients with Graves' disease to refrain from smoking.

Outcome of Radioiodine Therapy in a West African Population.

Hyperthyroidism continues to be a pressing public health concern in West Africa. Its prevalence in Africa has been quoted as 1.2%-9.9%, with Graves’ disease as its most common cause. Radioiodine-131 (RAI) therapy of hyperthyroidism recently commenced in two government hospitals in Ghana and Nigeria. This is a retrospective analysis of consecutive patients treated with RAI for primary hyperthyroidism at the National Centre for Radiotherapy and Nuclear Medicine (NCRNM) from 2008-2013, and in the University College Hospital (UCH) from 2006-2013. Cure was defined as euthyroidism or hypothyroidism occurring at 6 months post-RAI. Data were analysed using SPSS version 21 and Epi Info version, categorical data were evaluated with the Chi-square test and Fisher's exact test. 94 patients were studied, aged 20-74 years; 78 were females, and 16 were males. 38 were Ghanaian and 56 Nigerian. The presence of thyroid-associated ophthalmopathy (TAO) made cure less likely (χ2 P = 0.006, odds ratio = 0.118; 95% confidence interval, 0.027-0.518). Other factors assessed proved to be insignificant. Our findings suggest that hyperthyroid patients with TAO will benefit from a higher RAI dose than their counterparts without TAO.

The Change of Lacrimal Gland Volume in Korean Patients with Thyroid-associated Ophthalmopathy

PurposeTo describe the change of lacrimal gland volumes in Korean patients with thyroid-associated ophthalmopathy (TAO) via computed tomography (CT).MethodsA retrospective review of CT images from 217 TAO patients and 135 control subjects was performed. The TAO patients were diagnosed between May 2005 and May 2014 and had a CT performed on initial presentation (330 orbital CT scans). These images were compared with 270 orbital CT scans from the control group, obtained between May 2013 and May 2014. An open source DICOM viewer was used to calculate the volume of the lacrimal gland.ResultsThe mean volume of the lacrimal gland in TAO patients was 0.816 cm3 in the right orbit (standard deviation [SD], 0.048) and 0.811 cm3 in the left orbit (SD, 0.051), with no significant difference between right and left (p = 0.192). However, significant differences were observed between TAO patients and healthy individuals (p < 0.001). There was no significant difference between mean lacrimal gland volumes of males (0.812 cm3; SD, 0.037) and females (0.816 cm3; SD, 0.029) (p = 0.513). There was a negative correlation between gland volume and age in TAO patients (Pearson r = -0.479, p = 0.00). The subjective tearing (right: r = 0.244, p = 0.018; left: r = 0.226, p = 0.024), corneal superficial punctate keratopathy (right: r = 0.192, p = 0.040; left: r = 0.206, p = 0.036), and exophthalmometry (right: r = 0.182, p = 0.032; left: r = 0.180, p = 0.046) correlated with lacrimal gland volume.ConclusionsThis study is the first to use CT images to calculate the lacrimal gland volume of Korean TAO patients. In TAO patients, the lacrimal gland volume was notably increased compared to control subjects. The lacrimal gland volume decreased with age, but there was no difference between gender and no difference between left and right. The lacrimal gland volume correlated with subjective tearing, corneal superficial punctate keratopathy and exophthalmometry.

An update on thyroid-associated ophthalmopathy in children and adolescents.

Risk of developing thyroid-associated ophthalmopathy (TAO) in children and adolescents is similar or may be even slightly higher than in adults. The aim of this article is to review and summarize current knowledge regarding diagnostic and therapeutic measures in pediatric TAO. MEDLINE and EMBASE papers were searched using the terms 'pediatric Graves' ophthalmopathy' 'pediatric Graves' orbitopathy', 'thyroid-associated ophthalmopathy in childhood and adolescence' from the year 1970 to December 2015. TAO usually accompanies hyperthyreosis in Graves' disease, but may also occur in patients with hypothyreosis due to chronic lymphocytic thyroiditis (Hashimoto's disease) or in euthyroid patients. Current information regarding epidemiology, pathogenesis, symptoms and treatment of TAO in children and adolescents is presented. The course of the disease is usually mild, eye disturbances often regress after restoring euthyroidism and a 'wait and see' policy is appropriate in the majority of patients. In rare cases, sight-threatening complications [dysthyroid optic neuropathy (DON) or corneal breakdown] may develop and immediate surgical intervention might become necessary. Close cooperation between pediatric endocrinologists and opthalmologists is extremely important to ensure best care and quality of life in patients with thyroid gland dysfunction. Further investigations on pathogenesis and course of TAO in children and adolescents should be performed for better management of this disease in this group of patients.

Customized Orbital Decompression Surgery Combined with Eyelid Surgery or Strabismus Surgery in Mild to Moderate Thyroid-associated Ophthalmopathy.

PurposeTo evaluate the efficacy and safety of customized orbital decompression surgery combined with eyelid surgery or strabismus surgery for mild to moderate thyroid-associated ophthalmopathy (TAO).MethodsTwenty-seven consecutive subjects who were treated surgically for proptosis with disfigurement or diplopia after medical therapy from September 2009 to July 2012 were included in the analysis. Customized orbital decompression surgery with correction of eyelid retraction and extraocular movement disorders was simultaneously performed. The patients had a minimum preoperative period of 3 months of stable range of ocular motility and eyelid position. All patients had inactive TAO and were euthyroid at the time of operation. Preoperative and postoperative examinations, including vision, margin reflex distance, Hertel exophthalmometry, ocular motility, visual fields, Goldmann perimetry, and subject assessment of the procedure, were performed in all patients. Data were analyzed using paired t-test (PASW Statistics ver. 18.0).ResultsForty-nine decompressions were performed on 27 subjects (16 females, 11 males; mean age, 36.6 ± 11.6 years). Twenty-two patients underwent bilateral operations; five required only unilateral orbital decompression. An average proptosis of 15.6 ± 2.2 mm (p = 0.00) was achieved, with a mean preoperative Hertel measurement of 17.6 ± 2.2 mm. Ocular motility was corrected through recession of the extraocular muscle in three cases, and no new-onset diplopia or aggravated diplopia was noted. The binocular single vision field increased in all patients. Eyelid retraction correction surgery was simultaneously performed in the same surgical session in 10 of 49 cases, and strabismus and eyelid retraction surgery were performed in the same surgical session in two cases. Margin reflex distance decreased from a preoperative average of 4.3 ± 0.8 to 3.8 ± 0.5 mm postoperatively.ConclusionsThe customized orbital decompression procedure decreased proptosis and improved diplopia, in a range comparable to those achieved through more stepwise techniques, and had favorable cosmetic results when combined with eyelid surgery or strabismus surgery for mild to moderate TAO.

The Evolving Functions of Autophagy in Ocular Health: A Double-edged Sword.

Autophagy plays an adaptive role in cell survival, development, differentiation and intracellular homeostasis. Autophagy is recognized as a 'self-cannibalizing' process that is active during stresses such as starvation, chemotherapy, infection, ageing, and oxygen shortage to protect organisms from various irritants and to regenerate materials and energy. However, autophagy can also lead to a form of programmed cell death distinct from apoptosis.Components of the autophagic pathway are constitutively expressed at a high level in the eye, including in the cornea, lens, retina, and orbit. In addition, the activation of autophagy is directly linked to the development of eye diseases such as age-related macular degeneration (ARMD), cataracts, diabetic retinopathy (DR), glaucoma, photoreceptor degeneration, ocular tumours, ocular infections and thyroid-associated ophthalmopathy (TAO). A high level of autophagy defends against external stress; however, excessive autophagy can result in deterioration, as observed in ocular diseases such as ARMD and DR.This review summarizes recent developments elucidating the relationship between autophagy and ocular diseases and the potential roles of autophagy in the pathogenesis and treatment of these diseases.

Clinical factors affecting intraocular pressure change after orbital decompression surgery in thyroid-associated ophthalmopathy.

ObjectiveTo report the physiological monitoring of intraocular pressure (IOP) during the postoperative periods after orbital decompression surgery and ascertain the correlation between the clinical factors and IOP changes.MethodsThe medical records of 113 orbits from 60 patients who underwent orbital decompression surgery were reviewed retrospectively. IOP measurement during the postoperative periods was classified based on the postoperative day: week 1 (1–7 days), month 1 (8–41 days), month 2 (42–70 days), month 3 (71–97 days), month 4 (98–126 days), and final (after 127 days). The mean postoperative follow-up was 286.5 days for orbits with at least 6 months of follow-up. Univariate and multivariate linear regression analyses were performed to assess the correlation between the IOP reduction percentage and clinical factors.ResultsThe mean IOP increased from 16.9 to 18.6 mmHg (10.1%) at postoperative week 1 and decreased to 14.4 mmHg (14.5%) after 2 months. Minimal little changes were observed postoperatively in the IOP after 2 months. Preoperative IOP had a significant positive effect on the reduction percentage both at postoperative week 1 (β=2.51, P=0.001) and after 2 months (β=1.07, P=0.029), and the spherical equivalent showed a positive correlation with the reduction level at postoperative week 1 (β=1.71, P=0.021).ConclusionSurgical decompression caused a significant reduction in the IOP in thyroid-associated orbitopathy, and the amount of reduction was closely related to preoperative IOP; however, it may also cause a transient elevation in the IOP during the early postoperative phase in highly myopic eyes.

Surgical Outcomes of Balanced Deep Lateral and Medial Orbital Wall Decompression in Korean Population: Clinical and Computed Tomography-based Analysis.

PurposeTo evaluate the clinical outcomes of balanced deep lateral and medial orbital wall decompression and to estimate surgical effects using computed tomography (CT) images in Korean patients with thyroid-associated ophthalmopathy (TAO).MethodsRetrospective chart review was conducted in TAO patients with exophthalmos who underwent balanced deep lateral and medial orbital wall decompression. Exophthalmos was measured preoperatively and postoperatively at 1 and 3 months. Postoperative complications were evaluated in all study periods. In addition, decompressed bone volume was estimated using CT images. Thereafter, decompression volume in each decompressed orbital wall was analyzed to evaluate the surgical effect and predictability.ResultsTwenty-four patients (48 orbits) with an average age of 34.08 ± 7.03 years were evaluated. The mean preoperative and postoperative exophthalmos at 1 and 3 months was 18.91 ± 1.43, 15.10 ± 1.53, and 14.91 ± 1.49 mm, respectively. Bony decompression volume was 0.80 ± 0.29 cm3 at the medial wall and 0.68 ± 0.23 cm3 at the deep lateral wall. Postoperative complications included strabismus (one patient, 2.08%), upper eyelid fold change (four patients, 8.33%), and dysesthesia (four patients, 8.33%). Postsurgical exophthalmos reduction was more highly correlated with the deep lateral wall than the medial wall.ConclusionsIn TAO patients with exophthalmos, balanced deep lateral and medial orbital wall decompression is a good surgical method with a low-risk of complications. In addition, deep lateral wall decompression has higher surgical predictability than medial wall decompression, as seen with CT analysis.

Raise awareness of IgG4 relative ocular disease

Purpose IgG4-related ocular disease is a chronic systemic disease with lymphocyte abnormal. The lacrimal glands, extraocular muscles and infraorbital nerve were often involved which was often the first symptom of systemic disease. While ophthalmologists did not know this disease well. They usually misdiagnosed it as idiopathic inflammatory pseudotumor, thyroid-associated ophthalmopathy etc, which resulted in delayed treatments. Here pathogenesis, clinical features and treatment methods of IgG4-relative ocular disease were described in order to improve awareness of this ocular disease, reduce clinical misdiagnosis, improve disease prognosis and standardized treatment. As the incidence of this disease increased in recent years, it is very necessary to improve awareness of the disease for ophthalmologists.

Association of serum IL-2, IL-6, and IL-17 levels with the activity of thyroid-associated ophthalmopathy

Objective To investigate the involvement of interleukin(IL)-2, IL-6, and IL-17 in the disease activity of thyroid-associated ophthalmopathy(TAO). Methods The baseline serum levels of interleukin(IL)-2, IL-6, and IL-17, measured by enzyme-1inked immunosorbent assay, were compared among 80 TAO patients, 30 Graves' disease(GD)patients without ophthalmopathy, and 30 healthy subjects(NC)to determine the TAO-associated changes of cytokines. Based on clinical activity score(CAS), TAO patients were divided into non-active or active groups. Then, a cohort of 45 patients with active moderate-to-severe TAO received iv methylprednisolone therapy for 12 weeks, and changes in serum cytokines were evaluated. Results Serum IL-2 levels were gradually increased in NC, GD, and TAO groups(P 0.05), but higher compared with NC group(P 0.05). The serum levels of IL-17 were positively related with CAS and thyrotropin receptor antibody(P<0.01). After methylprednisolone therapy for 12 weeks, significant decreases of IL-6 and IL-17 levels compared to their baseline levels(P<0.05)were observed while IL-2 showed no significant change. Conclusion The serum level of IL-2 was decreased in TAO patients, while the serum levels of IL-6 and IL-17 were increased. In addition, IL-17 might serve as a useful biomarker for evaluating TAO activity. (Chin J Endocrinol Metab, 2015, 31: 946-950) Key words: Thyroid-associated ophthalmopathy; Clinical activity score; Cytokines; Glucocorticoids

Serum insulin-like growth factor-1 level and its expression in orbital adipose tissue in TAO patients

Background Insulin-like growth factor-1 (IGF-1) participates in the regulation of the biological activity of cells.Researches showed that the serum IGF-1 level is significantly raised in the patients with Graves diseases.Thyroid associated ophthalmopathy (TAO) is one of Graves diseases, and orbital adipose cells are the target cells of thyroid autoantigens.However, whether IGF-1 is associated with TAO is still unclear. Objective This study was to investigate the expressions of IGF-1 in both circulating blood and orbital adipose tissue in TAO patients. Methods A retrospective cohort study was performed.Eighty-six TAO patients were enrolled in West China Hospital of Sichuan University from August 2009 to February 2014.According to the clinical activity score criteria(CAS), the patients were divided into active stage (CAS≥4, 35 patients) and inactive stage (CAS<4, 51 patients). Eighty-six health adult persons were enrolled as the controls.The periphery blood of 3 ml was collected from each subject to detect the serum IGF-1 level by ELISA.Orbital adipose tissues were obtained during the surgery from 35 TAO patients and 35 patients with benign orbital tumor or orbital adipose prolapse from August 2009 to February 2014.The histopathological examination of orbital adipose tissue was carried out to evaluate the pathological characteristics, and the expression of IGF-1 in orbital adipose tissue was assessed by immunochemistry.This study protocol was approved by Ethic Committee of West China Hospital of Sichuan University, and informed consent was obtained from each subject before entering the cohort. Results The mean serum IGF-1 level was (0.862±0.026)ng/ml in the TAO patients, and that in the normal controls was (0.767± 0.480)ng/ml, without significant difference between them (P=0.281). The mean serum IGF-1 level was (0.877±0.355)ng/ml and (0.803±0.031)ng/ml in active stage and inactive stage of patients, respectively, and no significant difference was found between them (P=0.834). IGF-1 expression located in cellular membrane and cytoplasm.The expressing intensity of IGF-1 in orbital adipocytes was significantly enhanced in the TAO patients with the positive rate of 74.29%, and that in the controls was 45.46%, showing a statistical difference between the two groups (χ2=5.289, P=0.021). Conclusions Serum IGF-1 level dose not rise in TAO patients, but the expression of IGF-1 in orbital adipocytes up-regulates, indicating that mature orbital adipocytes of TAO are regulated mainly by IGF-1. Key words: Autoimmune diseases/metabolism; Insulin-like growth factor-1; Humans; Thyroid-associated ophthalmopathy

Construction of murine model of TAO by immunification with recombinant extracellular domain of human thyrotropin receptor in cationic liposomes

Background Thyroid-associated ophthalmopathy (TAO) is a kind of clinically common and incurable ocular disease, and its incidence is at top place.The etiology and pathologic mechanism of TAO are still unknown because of shortness of replicative animal models and difficulty to acquire the ocular tissues in the early stage of the disease.To better understand the pathogenesis of TAO and investigate effective treatable measures, an appropriate animal model should be developed. Objective This study was to immunize female BALB/c mice with the recombinant plasmid of human thyroid-stimulating hormone receptor (TSHR) extracellular domain in cationic liposomes for the establishement of TAO models. Methods Thirty-two 6- to 8-week-old female BALB/c mice were randomly assigned to four groups according to computer random allocation.pcDNA3.1+ /hTSHR289 of 100 μg in an adjuvant cationic liposomes was injected via anterior tibialis muscle and peritoneal cavity separately in the recombinant plasmid injection group in 0, 3, 6 weeks, and pcDNA3.1 or cationic liposomes was injected in the liposomes injection group or the blank plasmid group in the same way, respectively, and normal saline solution was injected in the blank control group.Body weight of the mice was measued before and 1 month, 2, 3 and 4 months after initial injection.The manifestations were observed after modeling.The mice were sacrificed 17 weeks after initial injection, and the histopathology examination was carried out on the thyroid gland and orbital tissue.The heart blood was collected from the mice, and serum contents of total thyroxin 4 (TT4) and thyroid-stimulating hormone (TSH) were assayed by ELISA. Results Protrusion, eyelid swell and keratitis occurred in 12 eyes of 6 mice in the recombinant plasmid injection group after immunization.A significant difference in the body weight of the mice was found among the blank control group, blank plasmid group, liposomes injection group and recombinant plasmid injection group (Fgroup=3.425, P=0.028), and the body weight was considerably reduced in the recombinant plasmid injection group in comparison with the blank control group, blank plasmid group, liposomes injection group (Ftime=0.838, P=0.023). The serum levels of TT4 were (7.75±1.00), (7.96±0.76), (6.76±1.10) and (4.43±2.88)μg/dl in the blank control group, liposomes injection group, blank plasmid group, and recombinant plasmid injection group, and those of TSH were (6.36±2.58), (4.83±3.96), (6.63±1.71) and (1.60±1.76)ng/ml, showing significant differences among the groups (F=7.150, P<0.001; F=5.521, P<0.01), and the serum levels of TT4 and TSH were remarkably lower in the recombinant plasmid injection group than those of the blank control group, liposomes injection group and blank plasmid group (all at P<0.05). Histopathology revealed the lymphocyte infiltration of thyroid gland in 6 mice and proliferation of orbital adipose tissue, infiltration of lymphocytes and mastocytes, deposition of hyaluronic acid as well as swell, breakage and inflammatory cell infiltration of extraocular muscle in 15 eyes of the recombinant plasmid injection group. Conclusions A murine model of TAO can be successfully induced by immunization with recombination plasmid pcDNA3.1+ /hTSHR289 and cationic liposomes.The histopathology characteristics and ocular findings of the animal models are similar to human TAO. Key words: Graves disease; Disease models, animal; Immunization/methods; Mice, inbred BALB/c; Receptors, thyrotropin/blood; Thyroxine/blood; Recombinant plasmid; Thyroid-associated ophthalmopathy

Changes of orbital tissue volumes and proptosis in patients with thyroid extraocular muscle swelling after methylprednisolone pulse therapy.

To evaluate the changes of orbital tissue volumes and proptosis after methylprednisolone pulse therapy in thyroid-associated ophthalmopathy (TAO). The cross-sectional areas of orbital tissues and proptosis were measured with magnetic resonance imaging in 40 orbits of 20 patients with TAO before and after methylprednisolone pulse therapy. The volumes of the whole orbit, orbital fatty tissue, and extraocular muscles were calculated. The volumes and proptosis were compared before and after treatment using a paired t test. Before treatment, the mean volumes were 33.0 ± 4.8 cm(3) in the whole orbit, 19.9 ± 4.1 cm(3) in the orbital fatty tissue, and 4.6 ± 1.2 cm(3) in the total extraocular muscles. After treatment, the mean volumes were 32.5 ± 4.4 cm(3) in the whole orbit, 19.9 ± 3.7 cm(3) in the orbital fatty tissue, and 4.0 ± 1.0 cm(3) in the total extraocular muscles. The mean volumes of the whole orbit (P = 0.17) and orbital fatty tissue (P = 0.82) were not significantly decreased after treatment, while the mean volume of total extraocular muscles was significantly decreased (P < 0.001). The mean proptosis value was 18.9 ± 2.8 mm before treatment and 18.6 ± 3.4 mm after treatment. The mean proptosis value was not significantly decreased after treatment (P = 0.30). The volume of orbital fatty tissue seemed to be unchanged after methylprednisolone pulse therapy while that of total extraocular muscles was decreased. The proptosis value seemed to be unchanged after treatment.

The Role of Iodine and Selenium in Autoimmune Thyroiditis.

Iodine and selenium (Se) are both essential elements to thyroid hormone economy, while they represent key players in the development of autoimmune thyroiditis.Chronic high iodine intake has been associated in various studies with increased frequency of autoimmune thyroiditis. In susceptible individuals, iodine excess increases intra-thyroid infiltrating Th17 cells and inhibits T regulatory (TREG) cells development, while it triggers an abnormal expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in thyrocytes, thus inducing apoptosis and parenchymal destruction. As was shown in a mouse model, high iodine supply leads to changes in the immunogenicity of the thyroglobulin molecule, upregulation of vascular intercellular adhesion molecule-1 (ICAM-1), and reactive oxygen species (ROS) generation in the thyrocytes. Serum Se levels were found decreased in Hashimoto thyroiditis and especially in Graves' disease as well as in thyroid-associated ophthalmopathy patients, the levels being related to the pathogenesis and outcome. Selenium is strongly involved, via the variable selenoproteins, in antioxidant, redox, and anti-inflammatory processes. Selenium enhances CD4+/CD25 FOXP3 and T regulatory cells activity while suppressing cytokine secretion, thus preventing apoptosis of the follicular cells and providing protection from thyroiditis. Selenium supplementation may be useful in autoimmune thyroid diseases, though, while usually well-tolerated, it should not be universally recommended, and it is also likely to be helpful for those with low Se status and autoimmunity. Broadly speaking, the achievement and maintenance of "selenostasis" as well as adequate urinary iodine excretion are mandatory to control disease, while, putatively, they may additionally be critical to preventing disease.

Pentraxin-3 Is a TSH-Inducible Protein in Human Fibrocytes and Orbital Fibroblasts.

CD34(+) fibrocytes are bone marrow-derived monocyte progenitor cells that traffic to sites of tissue injury and repair. They putatively infiltrate the orbit in thyroid-associated ophthalmopathy where they appear to transition into CD34(+) orbital fibroblasts (OFs) that interact with residential CD34(-) fibroblasts. A unique phenotypic attribute of fibrocytes and CD34(+) OFs is their expression of the functional thyrotropin receptor (TSHR) and other "thyroid-specific" proteins. When activated through TSHR, fibrocytes express a number of cytokines and other inflammatory genes. Here we sought to determine whether pentraxin-3 (PTX-3), an acute-phase protein involved in inflammation and autoimmunity, might be induced by TSH in fibrocytes and OFs. These cells were collected from patients with Graves disease and healthy individuals. PTX-3 mRNA levels were determined by real-time PCR, protein was determined by ELISA and Western blot, and PTX-3 gene promoter activity was assessed with reporter assays. PTX-3 expression was induced by TSH in both cell types, regardless of the health status of the donor and was a consequence of increased steady-state PTX-3 mRNA levels. M22, a TSHR-activating monoclonal antibody, also induced PTX-3. The induction could be attenuated by dexamethasone and by IGF-I receptor-blocking antibodies, teprotumumab and 1H7. TSH effects were mediated through phosphatidylinositol 3-kinase/AKT, mammalian target of rapamycin/p70(s6k), Janus tyrosine kinase 2 pathways, and enhanced PTX-3 mRNA stability. These findings indicate that PTX-3 is a TSH target gene, the expression of which can be induced in fibrocytes and OFs. They suggest that PTX-3 might represent a previously unidentified nexus between the thyroid axis and the mechanisms involved in tissue remodeling.

Diagnosis, Follow-Up and Treatment Results in Thyroid Ophthalmopathy.

Objectives:To discuss our follow-up and treatment results in thyroid-associated ophthalmopathy (TAO).Ma­te­ri­als and Met­hods:The records of 168 TAO cases who were followed at our clinic between October 1998 and October 2013 were reviewed retrospectively. The severity and activity of the disease were evaluated according to the criteria of the European Group on Graves’ Ophthalmopathy (EUGOGO) and Clinical Activity Score (CAS).Re­sults:Sixty-three men and 105 women participated in the study. The mean age of the patients was 42.3±12.4 years. Smoking habit was noted in 54.2% of the cases. Graves’ disease was the most common (80.4%) thyroid pathology accompanying TAO. TAO was mild in 64.4%, moderate-to-severe in 33.6% and severe in 2% of the eyes. Male gender was found as an independent risk factor for severity of the disease (p=0.040). TAO was in the active phase in 32.6% of the eyes. Older age and high thyroid receptor antibody titer were correlated with disease activity (P=0.031 and P<0.001, respectively). Thirty-four patients (20%) were treated for ocular findings. The most common treatment was systemic steroid therapy (12%); others included orbital decompression (5%), orbital radiotherapy (2%), and topical application of guanethidine (1%).Conclusion:Non-infiltrative phase and mild ocular findings were generally seen in TAO. Therefore, treatment is not recommended for many cases. Systemic steroid therapy is the most commonly used treatment modality in the active phase. However, orbital decompression surgery is necessary in a small number of cases with sight-threatening ocular findings.