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1.
Zhonghua Nei Ke Za Zhi ; 58(11): 823-825, 2019 Nov 01.
Artigo em Chinês | MEDLINE | ID: mdl-31665858

RESUMO

This study was aimed to investigate the association between dyslipidemia and thyroid associated ophthalmopathy (TAO). We evaluated the relationship between dyslipidemia and TAO in 218 patients with Graves' disease (GD) and found that the serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) in the GD subjects with TAO (n=110) were significantly increased [(5.32±1.39) mmol/L vs. (3.18±2.12) mmol/L, (2.98±0.75) mmol/L vs. (1.25±0.98) mmol/L] than those in the GD subjects without TAO (n=108). TC and LDL-C were positively correlated with the Clinical disease activity score (CAS) [TC (r=0.7, P=0.03),LDL-C (r=0.82, P=0.03)], and the levels of TC (OR=2.56, P=0.02) and LDL-C(OR=2.01, P=0.015) were positively associated with TAO. These suggested that high serum cholesterol level is a novel risk factor for TAO, and management of blood lipids should be included in the treatment of TAO.


Assuntos
Colesterol/sangue , Oftalmopatia de Graves/diagnóstico , Hipercolesterolemia/diagnóstico , LDL-Colesterol , Oftalmopatia de Graves/sangue , Humanos , Hipercolesterolemia/sangue , Fatores de Risco
2.
J Endocrinol Invest ; 42(2): 217-225, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29949121

RESUMO

PURPOSE: Venous thromboembolic events (VTE), with their life-threatening manifestation as pulmonary embolism, are potential adverse effects of intravenous methylprednisolone (IVMP) pulse therapy, partially due to a hypercoagulable state. The aim of the study was to analyze the influence of IVMP on selected hemostatic parameters in patients with moderate-to-severe Graves' orbitopathy (GO). METHODS: 26 euthyroid patients with GO were treated with 12 pulses of IVMP (6 × 0.5, 6 × 0.25 g every week). Hemostatic variables [factor (F) II, FV, FVII, FVIII, fibrinogen, antithrombin, activated partial thromboplastin time (aPTT), prothrombin time, international normalized ratio of prothrombin time, platelets and D-dimer] were analysed before, 24 and 48 h after 1st, 6th and 12th pulse. RESULTS: A constant, transient trend in changes of some hemostatic variables was observed after all assessed pulses. We discovered an increase in median activity of FVIII 24 and 48 h after pulses, with a shortening of aPTT 24 h after each IVMP pulse (p < 0.00005). FVII decreased 24 h after each pulse (p < 0.0005 after 1st and 12th, p < 0.00005 after 6th). Fibrinogen level decreased 48 h after each pulse (P < 0.00005). We did not observe any statistically significant changes in hemostatic parameters in the long-term evaluation. Therapy was concluded in one patient after the 9th pulse due to pulmonary embolism. CONCLUSIONS: The increase of FVIII activity is a consequence of treatment with IVMP and occurs after each pulse. In patients with additional risk factors of VTE, anticoagulation prophylaxis should be considered.


Assuntos
Anti-Inflamatórios/uso terapêutico , Fator VIII/metabolismo , Oftalmopatia de Graves/tratamento farmacológico , Metilprednisolona/uso terapêutico , Adulto , Idoso , Anti-Inflamatórios/administração & dosagem , Feminino , Oftalmopatia de Graves/sangue , Humanos , Masculino , Metilprednisolona/administração & dosagem , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
3.
J Endocrinol Invest ; 42(4): 471-480, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30132285

RESUMO

BACKGROUND: A role of the insulin-like growth factor-1 receptor (IGF-1R) in the pathogenesis of Graves' orbitopathy (GO) has been proposed, but the existence and function of anti-IGF-1R-antibodies (IGF-1R-Abs) are debated. METHODS: We designed a cross-sectional investigation to measure serum IGF-1R-Abs by a commercial assay in consecutive patients with Graves' disease (GD) compared with healthy subjects and patients with autoimmune thyroiditis (AT). A total of 134 subjects were screened including 27 healthy subjects, 80 GD patients (54 of whom with GO), and 27 AT patients. The main outcome measure was the prevalence of positive serum IGF-1R-Abs in GO, compared with GD without GO and with the other study groups. RESULTS: Having established a cut-off value at 55.2 ng/ml for positive tests, positive IGF-1R-Abs were more frequent in GD (25%), than in AT (3.7%, P = 0.003) and healthy subjects (0%, P = 0.006). Within GD, there was no difference between patients with or without GO. Serum levels of IGF-1R-Abs differed across the study population (P < 0.0001), reflecting their higher concentrations in GD (P < 0.0001 vs both AT and healthy subjects), but with no difference between patients with or without GO. In patients with GO, there was an inverse correlation between serum IGF-1R-Abs and CAS (R = - 0.376, 95% CI: from - 0.373 to - 0.631; P = 0.005), the significance of which remains to be investigated. CONCLUSIONS: Serum autoantibodies against the IFG-1R are present in one-fourth of GD patients, regardless of the presence of GO. Further functional studies are needed to investigate the significance of their inverse correlation with GO activity.


Assuntos
Autoanticorpos/sangue , Biomarcadores/sangue , Doença de Graves/sangue , Oftalmopatia de Graves/sangue , Receptores de Somatomedina/imunologia , Adolescente , Adulto , Idoso , Autoanticorpos/imunologia , Estudos de Casos e Controles , Estudos Transversais , Feminino , Doença de Graves/imunologia , Doença de Graves/patologia , Oftalmopatia de Graves/imunologia , Oftalmopatia de Graves/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
4.
PLoS One ; 13(12): e0209583, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30576385

RESUMO

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), along with its receptor fibroblast growth factor-inducible (Fn)14, is associated with various biological activities including inflammation. However, its role in the pathogenesis of Graves' orbitopathy (GO) is unknown. In this study, we investigated the mechanism by which TWEAK regulates inflammatory signaling in orbital fibroblasts from GO patients. We found that TWEAK and tumor necrosis factor-α (TNFA) mRNA levels were upregulated in GO as compared to non-GO tissue samples. TWEAK, TNF receptor (TNFR)1, TNFR2, and TNFR superfamily member 12A mRNA, and TWEAK and Fn14 protein levels were increased by interleukin (IL)-1ß and TNF-α treatment. Treatment with exogenous recombinant TWEAK increased the transcript and protein expression of the pro-inflammatory cytokines IL-6, IL-8, and monocyte chemoattractant protein-1 to a greater extent in GO than in non-GO cells, while treatment with the anti-Fn14 antibody ITEM4 suppressed TWEAK-induced pro-inflammatory cytokine release and hyaluronan production. Additionally, the serum level of TWEAK was higher in Graves' disease patients with (341.86 ± 86.3 pg/ml) as compared to those without (294.09 ± 41.44 pg/ml) GO and healthy subjects (255.33 ± 39.38 pg/ml), and was positively correlated with clinical activity score (r = 0.629, P < 0.001) and thyroid binding immunoglobulin level (r = 0.659, P < 0.001). These results demonstrate that TWEAK/Fn14 signaling contributes to GO pathogenesis. Moreover, serum TWEAK level is a potential diagnostic biomarker for inflammatory GO, and modulating TWEAK activity may be an effective therapeutic strategy for suppressing inflammation and tissue remodeling in GO.


Assuntos
Citocina TWEAK/genética , Oftalmopatia de Graves/genética , Inflamação/genética , Receptor de TWEAK/genética , Adulto , Apoptose/genética , Quimiocina CCL2/genética , Citocina TWEAK/sangue , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Regulação da Expressão Gênica/genética , Oftalmopatia de Graves/sangue , Oftalmopatia de Graves/patologia , Humanos , Inflamação/sangue , Inflamação/patologia , Interleucina-1beta/genética , Interleucina-6/genética , Interleucina-8/genética , Masculino , Pessoa de Meia-Idade , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo II do Fator de Necrose Tumoral/genética , Transdução de Sinais/genética , Receptor de TWEAK/sangue , Fator de Necrose Tumoral alfa/genética
5.
J Endocrinol Invest ; 41(12): 1457-1468, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30194634

RESUMO

PURPOSE: Over the past several decades, many papers have been published about the usefulness of thyrotropin receptor antibodies (TRAbs) as biomarkers of Graves' ophthalmopathy (GO). However, results have been inconsistent. The purpose of this analysis is to determine a possible cause of these discrepancies and to examine the usefulness of TRAbs as biomarkers for GO, especially 'thyrotropin-binding inhibiting immunoglobulin (TBII)' and 'thyroid-stimulating antibody (TSAb)'. METHOD: 26 articles discussing the association between TRAbs and GO were selected which were then divided into three groups based on the study method and whether or not the patients had been treated for hyperthyroidism. From the results of the papers reviewed, a provisional conclusion was made and a theoretical model on the TBII-TSAb coordinate plane was developed to confirm that conclusion. RESULTS: TSAb is reported to be significantly or strongly associated with GO in the studies of pre- and post-treated patients for hyperthyroidism. TBII is positively correlated, negatively correlated or uncorrelated with GO in studies of pre-treated patients. However, it is generally agreed upon that TBII and GO are closely correlated in studies of post-treated patients. CONCLUSION: We conclude that the level of TBII may not be a reliable indicator of the current state of GO in pre-treated patients. Whereas, in post-treated patients, due to changes in the correlation between TBII and TSAb due to the effect of hyperthyroidism treatment, the level of TBII can be a more reliable indicator of GO. Furthermore, the current level of TBII is closely associated with the onset and severity of GO in the future and it can be a valid predictor of GO. However, the TSAb level appears to be more reliable.


Assuntos
Oftalmopatia de Graves/diagnóstico , Imunoglobulinas Glândula Tireoide-Estimulantes/sangue , Receptores da Tireotropina/imunologia , Biomarcadores/sangue , Oftalmopatia de Graves/sangue , Oftalmopatia de Graves/imunologia , Humanos
6.
Anal Bioanal Chem ; 410(27): 7121-7133, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30135996

RESUMO

Approximately 50% of patients with Graves' disease (GD) develop retracted eyelids with bulging eyes, known as Graves' ophthalmopathy (GO). However, no simple diagnostic blood marker for distinguishing GO from GD has been developed yet. The objective of this study was to conduct comprehensive profiling of lipids using plasma and urine samples from patients with GD and GO undergoing antithyroid therapy using nanoflow ultrahigh performance liquid chromatography electrospray ionization tandem mass spectrometry. Plasma (n = 86) and urine (n = 75) samples were collected from 23 patients with GD without GO, 31 patients with GO, and 32 healthy controls. Among 389 plasma and 273 urinary lipids that were structurally identified, 281 plasma and 191 urinary lipids were quantified in selected reaction monitoring mode. High-abundance lipids were significantly altered, indicating that the development of GD is evidently related to altered lipid metabolism in both plasma and urine. Several urinary lysophosphatidylcholine species were found to be increased (3- to 10-fold) in both GD and GO. While the overall lipid profiles between GD and GO were similar, significant changes (area under receiver operating curve > 0.8) in GO vs. GD were observed in a few lipid profiles: 58:7-TG and (16:1,18:0)-DG from plasma, 16:1-PC and 50:1-TG from urine, and d18:1-S1P from both plasma and urine samples. An altered metabolism of lipids associated with the additional development of ophthalmopathy was confirmed with the discovery of several candidate markers. These can be suggested as candidate markers for differentiating the state of GO and GD patients based on plasma or urinary lipidomic analysis. Graphical abstract.


Assuntos
Oftalmopatia de Graves/sangue , Oftalmopatia de Graves/urina , Lipídeos/sangue , Lipídeos/urina , Cromatografia Líquida de Alta Pressão/métodos , Feminino , Oftalmopatia de Graves/diagnóstico , Oftalmopatia de Graves/metabolismo , Humanos , Metabolismo dos Lipídeos , Masculino , Metabolômica/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos
7.
Sci Rep ; 8(1): 9262, 2018 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-29915201

RESUMO

Graves' disease (GD) is an autoimmune disorder that causes the overproduction of thyroid hormones and consequent cascade of systemic metabolism dysfunction. Moreover, Graves' ophthalmopathy (GO) is the main extrathyroidal manifestation of Graves' disease (GD). The goal of the study was to identify metabolic signatures in association with diagnostic biomarkers of GD without GO and GO, respectively. Ninety metabolites were profiled and analyzed based on a non-targeted primary metabolite profiling from plasma samples of 21 GD patients without GO, 26 subjects with GO, and 32 healthy subjects. Multivariate statistics showed a clear discrimination between healthy controls and disease group (R2Y = 0.518, Q2 = 0.478) and suggested a biomarker panel consisting of 10 metabolites. Among them, most of metabolites showed the positive association with the levels of thyrotropin receptor antibodies. With combination of proline and 1,5-anhydroglucitol, which were identified as GO-specific modulators, the re-constructed biomarker model greatly improved the statistical power and also facilitated simultaneous discrimination among healthy control, GO, and GD without GO groups (AUC = 0.845-0.935). Finally, the comparative analysis of tissue metabolite profiles from GO patients proposed putative metabolic linkage between orbital adipose/connective tissues and the biofluidic consequences, in which fumarate, proline, phenylalanine, and glycerol were coordinately altered with the blood metabolites.


Assuntos
Oftalmopatia de Graves/patologia , Metabolômica , Órbita/patologia , Glândula Tireoide/patologia , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Análise Discriminante , Feminino , Oftalmopatia de Graves/sangue , Oftalmopatia de Graves/metabolismo , Humanos , Análise dos Mínimos Quadrados , Masculino , Redes e Vias Metabólicas , Metaboloma , Análise Multivariada , Curva ROC
8.
J Endocrinol Invest ; 41(12): 1417-1423, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29923059

RESUMO

BACKGROUND: It has been suggested that high cholesterol represents a risk factor for Graves' orbitopathy (GO). In a recent cross-sectional study, a correlation between cholesterol and the presence of GO was found in patients with a Graves' disease (GD) of recent onset. To confirm this observation, we conducted a retrospective investigation in consecutive patients with GD. The primary outcome was the relationship between the presence of GO and low-density lipoprotein (LDL)-cholesterol. METHODS: The design entailed the inclusion of consecutive patients with a GD of recent onset, with or without GO, who came to our observation to receive radioiodine over a period of 6 months, and a stratification aimed at having two homogeneous group of patients in terms of thyroid function. A total of 86 patients fulfilled the inclusion and evaded the exclusion criteria. All patients underwent an ophthalmological assessment and serum lipids were measured. RESULTS: Serum levels of LDL-cholesterol were significantly higher in patients with GO (135.3 ± 41.3 mg/dL) compared with those without GO (106.6 ± 23.9 mg/dL, P = 0.0007). In a similar manner, serum levels of total cholesterol were higher in patients with GO (211.6 ± 44.0 mg/dL) than in those without GO (176.0 ± 27.2 mg/dL, P = 0.0001). There was no relationship between GO severity and activity and cholesterol. There was no relationship between GO and high-density lipoprotein-cholesterol or triglycerides. CONCLUSIONS: Our study confirms a relationship between the presence of GO and cholesterol in patients with GD of recent onset. Whether lowering of cholesterol ameliorates, GO remains to be established.


Assuntos
Colesterol/sangue , Oftalmopatia de Graves/sangue , Oftalmopatia de Graves/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Oftalmopatia de Graves/epidemiologia , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
Dis Markers ; 2018: 7010196, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29736194

RESUMO

Background: Thyroid-associated orbitopathy (TAO) is the most common autoimmune disease of the orbit. It occurs more often in patients presenting with hyperthyroidism, characteristic of Graves' disease, but may be associated with hypothyroidism or euthyroidism. The diagnosis of TAO is based on clinical orbital features, radiological criteria, and the potential association with thyroid disease. To date, there is no specific marker of the orbital disease, making the early diagnosis difficult, especially if the orbital involvement precedes the thyroid dysfunction. Summary: The goal of this review is to present the disease and combine the available data in the literature concerning investigation of TAO biomarkers. Conclusions: Despite the progress done in the understanding of TAO disease, some important pieces are still missing. Typically, for the future, major efforts have to be done in the discovery of new biomarkers, validation of the suspected candidates on multicenter cohorts with standardized methodologies, and establishment of their clinical performances on the specific clinical application fields in order to improve not only the management of the TAO patients but also the therapeutic options and follow-up.


Assuntos
Autoanticorpos/sangue , Citocinas/sangue , Oftalmopatia de Graves/sangue , Biomarcadores/sangue , Desoxiguanosina/análogos & derivados , Desoxiguanosina/urina , Oftalmopatia de Graves/urina , Humanos
10.
Ophthalmic Plast Reconstr Surg ; 34(4S Suppl 1): S13-S19, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29771755

RESUMO

BACKGROUND: Thyroid stimulating hormone receptor antibodies (TSHR-Ab) cause autoimmune hyperthyroidism and are prevalent in patients with related thyroid eye disease (TED). PURPOSE: To provide a historical perspective on TSHR-Ab and to present evidence-based recommendations for clinical contemporary use. METHODS: The authors review the recent literature pertaining to TSHR-Ab in patients with TED and describe the various immunoassays currently used for detecting TSHR-Ab and their clinical applications. RESULTS: We provide a historical summary and description of the various methods used to detect TSHR-Ab, foremost, the functional TSHR-Ab. Increasing experimental and clinical data demonstrate the clinical usefulness of cell-based bioassays for measurements of functional TSHR-Ab in the diagnosis and management of patients with autoimmune TED and in the characterization of patients with autoimmune-induced hyperthyroidism and hypothyroidism. Thyroid stimulating hormone receptor antibodies, especially the functional stimulating antibodies, are sensitive, specific, and reproducible biomarkers for patients with autoimmune TED and correlate well with clinical disease activity and clinical severity. Unlike competitive-binding assays, bioassays have the advantage of indicating not only the presence of antibodies but also their functional activity and potency. CONCLUSIONS: Measurement of TSHR-Ab (especially stimulating antibodies) is a clinically useful tool for the management of patients with TED.


Assuntos
Autoanticorpos/imunologia , Autoimunidade , Oftalmopatia de Graves/imunologia , Receptores da Tireotropina/imunologia , Animais , Oftalmopatia de Graves/sangue , Humanos , Receptores da Tireotropina/sangue
11.
Endocr Res ; 43(4): 264-274, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29787340

RESUMO

Purpose/aim of the study: Graves' ophthalmopathy (GO) is closely related to the thyroid autoimmune disorder Graves' disease. Previous studies have suggested roles for thyroidal CD8+ T cells and autoimmunity against calsequestrin-1 (CASQ)-1 in the link between thyroidal and orbital autoimmune reactions in GO. A role for autoimmunity against CollXIII has also been suggested. In this study, we aimed to investigate correlations between some thyroidal and peripheral blood T-cell subsets and thyroidal T-cell reactivity against CASQ1 and CollXIII in patients with GO. MATERIALS AND METHODS: Fresh thyroid tissues were processed by enzyme digestion and density gradient to isolate mononuclear cells (MNCs). Peripheral blood MNCs were also isolated using density gradient. Flow-cytometric analysis was used to identify the various T-cell subsets. T -cell reactivity to CASQ1 and CollXIII was measured by a 5-day culture of the MNCs and BrdU uptake method. RESULTS: We found a positive correlation between thyroidal CD8+  T cells and CD8+ T-regulatory (T-reg) cells in patients with GO. Thyroidal T cells from two out of the three patients with GO tested (66.7%) showed a positive response to CASQ1, while thyroidal T cells from none of the six Graves' Disease patients without ophthalmopathy (GD) tested showed a positive response to this antigen. Thyroidal T cells from these patient groups however, showed no significant differences in their response to CollXIII. CONCLUSIONS: Our observations provide further evidence for a possible role of thyroidal CD8+ T cells, CD8+ T-reg cells and the autoantigen CASQ1 in the link between thyroidal and orbital autoimmune reactions of GO.


Assuntos
Calsequestrina/farmacologia , Colágeno Tipo XIII/farmacologia , Doença de Graves/metabolismo , Oftalmopatia de Graves/metabolismo , Linfócitos T/efeitos dos fármacos , Glândula Tireoide/efeitos dos fármacos , Adulto , Feminino , Doença de Graves/sangue , Oftalmopatia de Graves/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Linfócitos T/metabolismo , Glândula Tireoide/metabolismo
12.
Biomed Res Int ; 2018: 5961974, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29675428

RESUMO

Background: Thyroid associated ophthalmopathy (TAO) is an autoimmune disease, which involves inflammation and tissue remodeling. Pentraxin-3 (PTX3) is a component of innate immune system and recently implicated in autoimmunity. This observation may indicate that PTX3 participates in the inflammatory process of TAO. Methods: All studies were performed on TAO patients and healthy controls (45: 28 in total). RNA-seq was used to detect differential gene expression of orbital adipose-connective tissue. Quantitative PCR was performed to verify the results. PTX3 protein in orbital adipose-connective tissues was visualized by immunohistochemistry (IHC). PTX3 concentration in serum was determined by enzyme-linked immunosorbent assay (ELISA). Results: RNA-seq showed 1.86-log⁡2FC higher PTX3 expression in the orbital adipose-connective tissues from TAO group than controls (FDR = 0.0059). qPCR confirmed the difference (5.59-fold increase, p = 0.0012). The presence of PTX3 protein was demonstrated. Orbital adipose tissue from healthy controls showed weak staining for PTX3 while tissue from TAO group was strongly positive. Serum PTX3 concentration was significantly elevated in patients when compared to the control group (1.9-fold increase; p < 0.0001). Conclusions: Patients with TAO showed increased presence of PTX3 in orbital tissue and serum, which may suggest a potential relationship of PTX3 and TAO.


Assuntos
Biomarcadores/sangue , Biomarcadores/metabolismo , Proteína C-Reativa/metabolismo , Oftalmopatia de Graves/sangue , Oftalmopatia de Graves/metabolismo , Componente Amiloide P Sérico/metabolismo , Glândula Tireoide/metabolismo , Tecido Adiposo/metabolismo , Adulto , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Expressão Gênica/fisiologia , Humanos , Masculino , Órbita/metabolismo , RNA/metabolismo
13.
Adv Clin Exp Med ; 27(1): 99-103, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29521049

RESUMO

BACKGROUND: Graves' orbitopathy (GO), also known as thyroid-associated ophthalmopathy, is characterized by dramatic tissue reactivity. Both inflammation and tissue remodeling characterize the clinical course of GO. Some data has been found regarding the association of MMPs and TIMPs in GO. MATERIAL AND METHODS: Serum concentrations of MMP-9, MMP-2, TIMP-1, and TIMP-2 were determined by ELISA method. OBJECTIVES: Forty-eight patients (34 females, 14 males, with median age 51.5 years) with GD and hyperthyroidism were enrolled in the study. In 28 patients, active, moderate-to-severe grade orbitopathy was diagnosed. The aim of this study was to assess the serum concentrations of MMP-2, MMP-9, TIMP-1, and TIMP-2 in patients with Graves' disease (GD), with and without GO, and their relationship with disease severity, as well as to evaluate how these concentrations change after successful treatment. RESULTS: Median serum concentrations of MMP-2 and MMP-9 were significantly higher in all patients with GD as well as in the subgroup with GO than in the control group. Median serum concentrations of TIMP-1 and TIMP-2 were significantly higher in all patients with GD than in controls. The same significant differences were observed in the subgroups with and without GO in comparison with controls. The GO subgroup showed a significant positive correlation between the MMP-9 concentration and the serum level of TSHRAb antibodies, and a clinical activity score ≥4 according to EUGOGO. CONCLUSIONS: In our study we found that only MMP-9 differentiates the patients with and without GO, and may be used as a marker of the disease severity in patients with this manifestation of GD.


Assuntos
Doença de Graves/sangue , Oftalmopatia de Graves/sangue , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Inibidor Tecidual de Metaloproteinase-1/sangue , Inibidor Tecidual de Metaloproteinase-2/sangue , Idoso , Ensaio de Imunoadsorção Enzimática , Feminino , Doença de Graves/diagnóstico , Oftalmopatia de Graves/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade
14.
Graefes Arch Clin Exp Ophthalmol ; 256(6): 1195-1201, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29397435

RESUMO

PURPOSE: This study surveyed the novel autoantigens expressed in the orbital fat tissue of patients with Graves' orbitopathy (GO) and explored the possibility of the autoantibodies against novel autoantigens as biomarkers for GO. METHODS: We used immuno-proteomic methods to survey novel autoantigens expressed in the orbit fat tissue of GO patients and confirmed by enzyme-linked immunosorbent assay (ELISA). RESULTS: One protein spot (aldehyde dehydrogenase 2 (ALDH2)) revealed high reactivity with the GO serum than did the healthy control serum and was further verified by ELISA. We found that the plasma anti-ALDH2 antibody level was increased in GO patients compared to healthy control donors. In addition, anti-ALDH2 antibody level was correlated with GO activity classified by clinical activity score(r = 0.588, p < 0.001, using Pearson's correlation). CONCLUSIONS: These increased levels of anti-ALDH2 antibody in GO serum suggested that ALDH2 could attribute target autoantigen in GO, and anti-ALDH2 autoantibody might serve as a biomarker for GO and help to predict disease activity.


Assuntos
Aldeído-Desidrogenase Mitocondrial/imunologia , Autoanticorpos/sangue , Oftalmopatia de Graves/imunologia , Proteômica/métodos , Adulto , Idoso , Aldeído-Desidrogenase Mitocondrial/sangue , Biomarcadores/sangue , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Oftalmopatia de Graves/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
15.
Thyroid ; 28(3): 386-394, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29336220

RESUMO

BACKGROUND: Limited data suggest that treatment with statins is associated with a reduced risk of Graves' orbitopathy (GO) in patients with Graves' disease (GD), attributed to the anti-inflammatory rather than to the hypolipemic effects of these medications. The aim of the present study was to investigate whether there is an association between high cholesterol and GO. The primary outcome was the relation between GO and low-density lipoprotein (LDL)-cholesterol. The secondary outcomes were the relation between severity or activity (the clinical activity score [CAS]) of GO and LDL-cholesterol. METHODS: A cross-sectional investigation was conducted in consecutive patients with GD who came under the authors' observation to undergo radioiodine treatment, a stratification aimed at forming two distinct groups of patients under the same conditions. A total of 250 patients were enrolled, 133 with and 117 without GO. Ophthalmological assessments and serum lipids measurements were performed. RESULTS: In multivariate analyses with correction for the duration of hyperthyroidism, a variable that differed between patients with respect to the presence or absence of GO, a correlation between the presence of GO and both total (p = 0.01) and LDL-cholesterol (p = 0.02) was observed. In patients with hyperthyroidism lasting <44 months, total and LDL-cholesterol were higher (p = 0.01 and p = 0.008, respectively) among GO patients. In this subgroup, based on the presence/absence of GO, cutoff values were established for total (191 mg/dL) and LDL-cholesterol (118.4 mg/dL), above which an increased risk of GO was observed (total cholesterol relative risk: 1.47; p = 0.03; LDL-cholesterol relative risk: 1.28; p = 0.03). GO severity and CAS did not correlate with serum lipids. However, CAS was found to be higher (p = 0.02) in patients with high total cholesterol. When the analysis was restricted to untreated GO patients, a correlation was found between CAS and both total (p = 0.04) and LDL-cholesterol (p = 0.03), after adjustment for GO duration. CONCLUSIONS: In patients with a short duration of hyperthyroidism, total and LDL-cholesterol correlate with the presence of GO, suggesting a role of cholesterol in the development of GO. Depending on GO duration, total and LDL-cholesterol correlate with GO activity, suggesting a role of cholesterol in the clinical expression of GO.


Assuntos
Colesterol/sangue , Oftalmopatia de Graves/diagnóstico , Adolescente , Adulto , Idoso , Estudos Transversais , Feminino , Oftalmopatia de Graves/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
16.
Ocul Immunol Inflamm ; 26(7): 1094-1100, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28548552

RESUMO

PURPOSE: To investigate the clinical implications of cysteine-rich angiogenic inducer 61 (CYR61) in Graves' orbitopathy (GO). METHODS: Sera from 52 GO patients, 23 Graves' disease (GD) patients, and 20 healthy controls, and orbital fat tissue samples from 12 of 52 GO patients and 8 control subjects were included for analysis. Concentrations of CYR61 were measured from sera with an enzyme-linked immunosorbent assay, and CYR61 mRNA expression levels were evaluated from orbital fat tissue with polymerase chain reaction. RESULTS: Serum CYR61 levels were higher in GO patients than in controls (p = 0.001). Patients with active GO showed higher CYR61 levels than those with inactive GO (p < 0.001) or GD (p = 0.004). Expression of CYR61 mRNA was 7.4-fold higher in patients with GO than in healthy controls (p < 0.001). CONCLUSIONS: CYR61 could be an adjuvant biomarker associated with the inflammatory activity of GO.


Assuntos
Biomarcadores/sangue , Proteína Rica em Cisteína 61/sangue , Oftalmopatia de Graves/sangue , Tecido Adiposo/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Proteína Rica em Cisteína 61/genética , Ensaio de Imunoadsorção Enzimática , Feminino , Expressão Gênica/fisiologia , Marcadores Genéticos , Oftalmopatia de Graves/genética , Humanos , Masculino , Pessoa de Meia-Idade , Órbita/metabolismo , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , Adulto Jovem
17.
J Endocrinol Invest ; 41(6): 719-727, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29190000

RESUMO

OBJECTIVE: Graves' orbitopathy (GO) is an inflammatory orbital disease of autoimmune origin with the potential to cause severe functional and psychosocial effects. The pathogenesis has not been fully elucidated. We investigated whether DNA methylation was associated with GO incidence in Chinese patients. MATERIALS AND METHODS: Six GO patients and six age-matched controls were recruited, and genome-wide DNA methylation patterns were analyzed in their peripheral blood. t tests were performed to determine differential methylated sites in genomic regions and the univariable logistic regression analyses was performed to evaluate their risk with GO incidence. Cluster analysis and principal component analysis (PCA) were performed to determine the effects of the extracted differentially methylated sites. RESULTS: One hundred and forty-eight differentially methylated sites were identified, including CD14 (fold change = 4.31, p = 0.005), IL17RE (fold change = 2.128, p = 0.005), and DRD4 (fold change = 0.25, p = 0.004), and were supported by cluster and PCA analyses. Univariable logistic regression analyses showed that the methylation patterns at 12 loci were associated with GO incidence. The relative risk per 1% decrease in methylation at ZCCHC6 and GLI3 was 0.15 (95% CI 0.03-0.91; p = 0.039) and 0.65 (95% CI 0.42-0.98; p = 0.042), respectively. Pearson correlation analyses demonstrated that methylation levels at IL17RE were positively associated with Clinical Activity Score (CAS) (r = 0.967, p < 0.05). CONCLUSIONS: Our results demonstrate that differential methylation levels at analyzed sites (genes) may be risk markers of GO. DNA methylation analysis could provide new insights into understanding the disease and provide new treatment strategies for GO in Chinese patients.


Assuntos
Biomarcadores/análise , Metilação de DNA , Genoma Humano , Oftalmopatia de Graves/sangue , Oftalmopatia de Graves/genética , Sequenciamento Completo do Genoma/métodos , Estudos de Casos e Controles , Seguimentos , Loci Gênicos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
18.
Bratisl Lek Listy ; 118(8): 495-498, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29050489

RESUMO

PURPOSE: To evaluate the neutrophil-to-lymphocyte ratio (NLR) levels to predict the severity of inflammation in thyroid ophthalmopathy (TO). METHODS: Fifty-six patients with TO and 40 healthy subjects were included in this study. TO patients were divided into two groups according to clinical activity score (CAS). Group 1 included 24 active TO patients and Group 2 included 32 inactive TO patients. The thyroid status, white blood cell (WBC), neutrophil, and lymphocyte counts were performed. NLR was calculated by dividing the neutrophil count by the lymphocyte count. RESULTS: The mean age was 53.6 ± 5.4 in active TO group, 54.2 ± 5.6 in inactive TO group, and 52.7 ± 5.2 in the control group. The WBC, neutrophil, lymphocyte and NLR levels were higher in patients with TO than in the control group (p < 0.05). A significant difference in NLR was found between the inactive and active TO groups (p < 0.05). CONCLUSION: NLR values were found to be higher in patients with TO than in controls. NLRvalues were also found higher in active TO patients than in inactive TO patients (Tab. 3, Ref. 26).


Assuntos
Oftalmopatia de Graves/sangue , Linfócitos/citologia , Neutrófilos/citologia , Estudos de Casos e Controles , Feminino , Humanos , Inflamação , Contagem de Leucócitos , Leucócitos/citologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Glândula Tireoide
19.
Thyroid ; 27(9): 1185-1193, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28805160

RESUMO

BACKGROUND: This study aimed to explore the relation of immunoglobulin G4 (IgG4) to clinical and laboratory characteristics of patients newly diagnosed with Graves' disease (GD) without or with Graves' ophthalmopathy (GO) and to analyze association of IgG4 with development and grade of GO in GD patients. METHODS: Sixty-four GD patients and 64 sex- and age-matched euthyroid subjects were enrolled. Serum levels of thyroid hormones, thyroid autoantibodies, immunoglobulin G (IgG), and IgG4 were measured, and ophthalmological and ultrasonographical evaluation was performed. RESULTS: In GD patients compared with euthyroid subjects, levels of thyroid hormones, thyroid autoantibodies and IgG4 as well as the IgG4/IgG ratio were elevated. GD patients having GO in comparison to not having GO were characterized by a female predominance; a high incidence of smoking history; high levels of T3, free T4, TSH receptor autoantibody (TRAb) and IgG4; and a high IgG4/IgG ratio after adjusting for sex. In GD patients, the IgG4 level was the independent factor associated with GO development on multivariate analysis. When severity and activity of GO were classified using the European Group on Graves' Orbitopathy criteria in GD patients with GO, IgG4 levels and IgG4/IgG ratio were elevated in the moderate-to-severe group compared with the mild group and in the active group compared with the inactive group. IgG4 levels and IgG4/IgG ratio became elevated as clinical activity score increased. IgG4 levels were positively correlated with TRAb levels. The high IgG4 group in comparison to the normal IgG4 group had a high incidence of family history of autoimmune thyroid disease, high levels of free T4, TRAb and IgG4, a high IgG4/IgG ratio and extensive hypoechogenicity. CONCLUSIONS: These results suggest that IgG4 levels are elevated in newly diagnosed GD patients compared with euthyroid subjects and in the presence of GO compared with the absence of GO. Moreover, our findings suggest that IgG4 levels are associated with the development and grade of GO in GD patients.


Assuntos
Autoanticorpos/análise , Autoimunidade , Oftalmopatia de Graves/imunologia , Imunoglobulina G/análise , Glândula Tireoide/imunologia , Adulto , Estudos de Casos e Controles , Saúde da Família , Feminino , Oftalmopatia de Graves/sangue , Oftalmopatia de Graves/etiologia , Oftalmopatia de Graves/fisiopatologia , Hospitais Universitários , Humanos , Masculino , Pessoa de Meia-Idade , Ambulatório Hospitalar , Reprodutibilidade dos Testes , República da Coreia , Fatores de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Fumar/efeitos adversos , Adulto Jovem
20.
Endokrynol Pol ; 68(5): 498-504, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28660988

RESUMO

INTRODUCTION: Glucocorticoids represent the therapy of choice for active and moderate-to-severe Graves' orbitopathy (GO). In some patients, rituximab, a monoclonal antibody against the cluster of differentiation (CD) 20 receptor of B-lymphocytes, can serve as a second-line or an alternative treatment. The effect of very low-dose of rituximab on the clinical activity of GO and corresponding clinical or laboratory changes is reported. MATERIAL AND METHODS: Changes of Clinical Activity Score (CAS) for GO, proptosis, levels of thyroid-stimulating hormone receptor antibodies, and depletion of CD19+ and CD20+ B-lymphocytes were determined in ten patients (two men and eight women) with active moderate-to-severe GO treated with a single 100-mg dose of rituximab. Correlations between differences of clinical and laboratory parameters were performed. RESULTS: A significant decrease of CAS was found during subsequent examinations compared to the baseline values. A significant depletion of CD19+ and CD20+ B-lymphocytes was detected after rituximab administration. Differences between follow-up and baseline levels of CD20+ positively correlated with differences in CAS after six (p < 0.05) and 12 months (p < 0.01). Differences in CD19+ levels correlated with differences in CAS after 12 months (p < 0.05) of the treatment. Two patients developed dysthyroid optic neuropathy (DON) requiring orbital decompression. No other rituximab side effects were reported during the whole study duration. CONCLUSIONS: A single very low-dose of rituximab appears to be very well tolerated and effective enough to reduce clinical activity in active moderate-to-severe GO patients without impending DON.


Assuntos
Antígenos CD20/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Oftalmopatia de Graves/tratamento farmacológico , Rituximab/farmacologia , Adulto , Idoso , Antígenos CD19/sangue , Antígenos CD19/efeitos dos fármacos , Antígenos CD20/sangue , Linfócitos B/metabolismo , Feminino , Oftalmopatia de Graves/sangue , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Rituximab/uso terapêutico , Tireotropina/sangue , Tireotropina/efeitos dos fármacos
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