Euthyroid Graves' Disease Research Articles

Cardiac Autonomic Neuropathy in Graves' Disease: Smoking and Age as Predictive Factors

ObjectivesHypermetabolic state in Graves' disease (GD) has a great impact on heart homeostasis, acting directly on the heart muscle and modulating the autonomic nervous system. To characterize cardiac autonomic neuropathy (CAN) as a possible complication in patients with GD. MethodsWe evaluated euthyroid GD patients and a control group of healthy euthyroid people. CAN was assessed using autonomic tests of cardiovascular reflex and heart rate variability: respiratory, Valsalva, orthostatic and orthostatic hypotension tests, high frequency, low frequency, and very low-frequency bands. Transthoracic echocardiography was performed in GD patients. ResultsSixty GD patients and 50 people in control group were assessed. CAN was diagnosed in 20% of GD and 14% in the control group. Among GD, 13.3% presented incipient, and 6.7% established CAN, while in the control group, it was verified incipient in 8% and established in 6% (P = .7479). All GD patients with CAN presented an alteration in the deep breathing test. Age and smoking were evidenced as factors associated with the presence of CAN, while higher TRAb values at diagnosis decreased the chance of CAN. ConclusionsThe prevalence of CAN in euthyroid GD patients was 20%. Changes in the cardiac autonomic nervous system were identified, pointing to the importance of evaluating this complication in these patients. Smoking was a predictive factor for CAN, increasing its relationship with conditions that aggravate GD.

Serum Lipoprotein(a) Is Not Associated with Graves' Ophthalmopathy.

Aim: To investigate the relationship of serum lipoprotein(a) [Lp(a)] and other serum lipids with presence of Graves' ophthalmopathy (GO). Methods: A total of 99 consecutive patients diagnosed with Graves' disease (GD), aged 18-65 years, who had not received prior treatment for GO, thyroid surgery, or radioactive iodine therapy, were recruited between June 2020 and July 2022. In addition, 56 healthy controls (HCs) were included as the control group. All patients underwent an ophthalmological examination, and were classified based on the presence of GO into the GO group (n = 45) and no GO group (n = 54). Fasting blood samples were collected from all participants to analyze serum lipid parameters, including Lp(a), total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. Results: The median serum levels of Lp(a) were 5.7 [4.3-9.2] in the GO group, 6.7 [3.7-9.9] in the no GO group, and 4.7 [3-7.6] in the HC group. The intergroup comparisons of serum Lp(a) levels showed no significant result. The serum levels of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides were also similar between the groups (P > 0.05 for all). However, when analyzing only euthyroid GD patients and the control group, the serum LDL cholesterol levels were found to be significantly higher in the euthyroid GO group [median: 132 interquartile range (IQR) (110-148) mg/dL] than in the HCs [median: 96 IQR (94-118) mg/dL] (P = 0.002). Conclusion: The findings of our study did not support the association between serum Lp(a) levels and GO.

Elevated Levels of Circulating Biomarkers Related to Leaky Gut Syndrome and Bacterial Translocation Are Associated With Graves' Disease.

BackgroundA growing number of studies have found dysbiosis of the intestinal microbiota in patients with Graves’ disease (GD). The intestinal epithelial barrier serves as the first line of defense, protecting the immune system from excessive stimulation of microbiota and toxins. Most autoimmune diseases are associated with a gut barrier dysfunction (leaky gut) which allows bacterial translocation. However, to date, potential correlations between intestinal barrier dysfunction and GD have not been explored.MethodsSerum lipopolysaccharide (LPS), intestinal fatty acid-binding protein (I-FABP), zonulin, D-lactate, and diamine oxidase (DAO) were measured to assess barrier integrity in 91 patients with GD (61 initial GD and 30 euthyroid GD) and 44 healthy controls. The quality of life (QOL) of patients with GD was assessed using the thyroid-specific patient-reported outcome (ThyPRO-39) questionnaire.ResultsThe serum levels of LPS, I-FABP, zonulin, and D-lactate were significantly higher in patients with initial GD than in healthy controls. Logistic regression analysis revealed that zonulin and D-lactate were independently associated with risk for GD and circulating zonulin could effectively distinguish patients with initial GD from healthy controls. Correlation analyses showed that I-FABP, LPS, and D-lactate were positively associated with FT4 and negatively associated with TSH. In addition, circulating LPS, zonulin, and D-lactate levels were all independent predictors of TRAb levels. Moreover, higher circulating LPS levels in patients with GD were associated with more severe hyperthyroidism (higher concentrations of FT3, FT4, and TRAb and lower TSH concentrations) and worse scores of hyperthyroid and eye symptoms.ConclusionPatients with initial GD show a disrupted intestinal barrier, characterized by elevated levels of leaky gut biomarkers. Increased intestinal permeability and bacterial translocation were associated with TRAb levels and hyperthyroidism in GD. Further research is required to elucidate the underlying mechanisms.

A systematic review of euthyroid Graves' disease (Review).

Euthyroid Graves' Disease (EGD) is a challenging pathology, due to its atypical clinical manifestations and the absence of abnormal thyroid function. Typically, thyroid ophthalmopathy is associated with elevated thyroid hormone levels and with the presence of thyrotropin receptor antibodies (TRAb) but a low percentage of patients remain euthyroid without developing hyperthyroidism during long-term follow-up periods. Although it is considered a different pathology, it shares a lot of similarities with Graves' disease, rendering the diagnosis more difficult. It is also important to note that ophthalmopathy may be the first clinical manifestation of Graves' disease and that thyroid function examinations do not present abnormalities over a long period. Treatment choices for euthyroid disease do not differ from those described in Graves' ophthalmopathy. However, it is considered that since euthyroid patients develop milder ophthalmic symptoms and their clinical activity score is lower, they tend to have better responses to treatment. Moreover, atypical sight-threatening cases such as exposure keratopathy and dysthyroid optic neuropathy with variable responses to therapy also exist. Disease management consists of a favorable collaboration between ophthalmologists and endocrinologists because patients with EGD can develop thyroid abnormalities over time. In conclusion, the diagnosis of EGD is difficult, clinical manifestations and evolution are variables depending on several factors, including the heterogeneity of TRAb. This review aimed to identify the characteristics of this disease by reviewing the clinical studies and case reports published in previous years.

LncRNA:mRNA expression profile in CD4+ T cells from patients with Graves' disease.

Graves’ disease (GD) is a common autoimmune disease that affects the thyroid gland. As a new class of modulators of gene expression, long noncoding RNAs (lncRNAs) have been reported to play a vital role in immune functions and in the development of autoimmunity and autoimmune disease. The aim of this study is to identify lncRNAs in CD4+ T cells as potential biomarkers of GD. lncRNA and mRNA microarrays were performed to identify differentially expressed lncRNAs and mRNAs in GD CD4+ T cells compared with healthy control CD4+ T cells. Quantitative PCR (qPCR) was used to validate the results, and correlation analysis was used to analyze the relationship between these aberrantly expressed lncRNAs and clinical parameters. The microarray identified 164 lncRNAs and 93 mRNAs in GD CD4+ T cells differentially expressed compared to healthy control CD4+ T cells (fold change >2.0 and a P < 0.05). Further analysis consistently showed that the expression of HMlincRNA1474 (P < 0.01) and TCONS_00012608 (P < 0.01) was suppressed, while the expression of AK021954 (P < 0.01) and AB075506 (P < 0.01) was upregulated from initial GD patients. In addition, their expression levels were recovered in euthyroid GD patients and GD patients in remission. Moreover, these four aberrantly expressed lncRNAs were correlated with GD clinical parameters. Moreover, the areas under the ROC curve were 0.8046, 0.7579, 0.8115 for AK021954, AB075506, HMlincRNA1474, respectively. The present work revealed that differentially expressed lncRNAs were associated with GD, which might serve as novel biomarkers of GD and potential targets for GD treatment.

High Titers of Thyrotropin Receptor Antibodies Are Associated With Orbitopathy in Patients With Graves Disease.

Serum TSH receptor autoantibody (TSH-R-Ab) is a biomarker of Graves disease (GD). Studies have shown that the levels of this TSH-R-Ab have clinical significance. To differentiate between thyroidal GD only and Graves orbitopathy (GD + GO). Controlled, follow-up study. Academic tertiary referral center for GD + GO. Sixty patients with GD, GD + GO, and controls. Serial serum dilution analyses with six automated, ELISA, and cell-based assays for TSH-R-Ab. Differentiation among GD phenotypes. All undiluted samples of hyperthyroid-untreated GD patients were positive with the six assays but became negative at dilution 1:9 in four of six assays. In contrast, all undiluted samples of hyperthyroid-untreated GD + GO patients remained positive up to dilution 1:81, P < 0.001. At high dilutions 1:243, 1:729, 1:2187, and 1:6561, the rate of stimulating TSH-R-Ab positivity in the bioassay for GD + GO patients was 75%, 35%, 5%, and 0%, respectively (all P < 0.001). The five ELISA and/or automated assays confirmed this marked difference of anti-TSH-R-Ab detection between GD-only and GD + GO. In comparison, the baseline-undiluted samples of GD vs GD + GO showed an overlap in the ranges of TSH-R-Ab levels. Subsequent to 12-month methimazole treatment, samples from euthyroid GD + GO patients were still TSH-R-Ab positive at the high dilution of 1:243. In contrast, all GD samples were negative already at dilution 1:3. A GD patient with TSH-R-Ab positivity at dilution 1:729 developed de novo GO. TSH-R-Ab titers, as determined by dilution analysis, significantly differentiate between GD and GD + GO.

Clinical course of thyroid function and thyroid associated-ophthalmopathy in patients with euthyroid Graves' disease.

BackgroundEuthyroid Graves’ disease (EGD) is a rare condition defined as the presence of thyroid-associated ophthalmopathy (TAO) in patients with normal thyroid function. Due to the rarity of this disease, only a limited number of studies and case reports are available for further evaluation of the characteristics of the disease. The aim of this study was to examine the changes in the thyroid function, thyrotropin receptor antibodies (TRAb) and eye symptoms, and then determine whether TRAb is related to TAO in EGD patients. TRAb in this study was defined as including both thyrotropin-binding inhibitory immunoglobulin (TBII) and thyroid-stimulating immunoglobulin (TSAb).Patients and methodsMedical records of patients diagnosed with EGD were reviewed. Ophthalmologists specializing in TAO examined the eyes of all subjects.ResultsOf the 58 patients diagnosed with EGD, 24.1% developed hyperthyroidism, while 3.4% developed hypothyroidism. A total of 72.4% of the 58 patients remained euthyroid throughout the entire follow-up period. At the initial presentation, TBII and TSAb were positive in 74.5% and 70.5%, respectively. Ophthalmic treatments were administered to 30 (51.7%) out of the 58 patients. A significant spontaneous improvement of the eye symptoms was found in 28 of the EGD patients who did not require eye treatments. EGD patients exhibited positive rates for both TBII and TSAb, with the number of the TRAb-positive patients gradually decreasing while the eye symptoms spontaneously improved over time. There were no correlations found between TRAb at initial presentation and the eye symptoms.ConclusionTBII and TSAb were positive in about 70% of EGD patients at their initial visit. Thyroid functions of EGD patients who have been euthyroid for more than 6.7 years may continue to remain euthyroid in the future.

HLA DQ2 Haplotype, Early Onset of Graves Disease, and Positive Family History of Autoimmune Disorders are Risk Factors for Developing Celiac Disease in Patients with Graves Disease

The diagnosis of celiac disease (CD) in patients with different autoimmune diseases including Graves disease (GD) remains a challenge. The aims of our study were to: (1) assess the prevalence of CD in Polish patients with GD and (2) evaluate the prevalence of CD in the subgroups of patients with GD divided on the basis of clinical and human leukocyte antigen (HLA) typing criteria. The prospective study was conducted at an academic referral center. The study groups consisted of consecutive, euthyroid patients with GD (n = 232) and healthy volunteers without autoimmune thyroid diseases (n = 122). The diagnosis of CD was based on elevated immunoglobulin A autoantibodies to the enzyme tissue transglutaminase (IgA-TTG) and small intestine biopsy findings. CD was diagnosed in 8 patients with GD (3.4%) and 1 healthy volunteer (0.8%). The development of CD in patients with GD was strongly associated with HLA-DQ2 haplotype (as predicted from linkage disequilibria, 14.6% vs. 1.5%, P = .009; odds ratio [OR] = 11.3; 95% confidence interval [CI] 1.3-252.7): 6 patients with CD carried HLA-DRB1(*)03, 1 carried an HLA-DRB1(*)04 allele, and 1 had an HLA-DRB1(*)07/(*)11 genotype. Multivariate analysis showed independent associations between CD and early GD onset (P = .014, OR = 9.6), autoimmunity in family (P = .029, OR = 6.3) and gastroenterologic symptoms (P = .031, OR = 8.1). The results of our study suggest that serologic screening for CD may be considered in GD patients (1) with the HLA alleles typical for CD, (2) with an early onset of GD, or (3) a family history of autoimmunity. Moreover, the diagnosis of CD should be explored in euthyroid GD patients with nonspecific gastrointestinal symptoms.

Increased chemokine (C-C motif) ligand 21 expression and its correlation with osteopontin in Graves' disease.

Graves' disease (GD) is a chronic autoimmune process characterized by the production of auto-antibodies that presumably consequent to the lymphocytic infiltrates in the thyroid. Chemokine (C-C motif) ligand 21 (CCL21) is important for the circulation of CC-chemokine receptor 7 (CCR7)-expressing cells. Meanwhile, osteopontin (OPN) enhances the production of proinflammatory cytokines and chemokines through NF-κB and MAPK signaling pathways in GD. Although CCL21 has been reported to play a vital role in several autoimmune diseases, little is known about the relationship between CCL21 and GD development. This study aimed to detect the CCL21 level in GD and to examine the role of OPN in regulating CCL21 production. 40 initial GD patients, 15 euthyroid GD patients, 12 TRAb-negative GD patients, and 25 healthy control donors were recruited. CCL21 levels in plasma and culture supernatants were quantified by enzyme-linked immunosorbent assay (ELISA). CD4+ T cells were isolated from peripheral blood mononuclear cells using antibody-coated magnetic beads. Quantitative polymerase chain reaction was used to determine CCL21 expression levels in CD4+ T cells. We demonstrated for the first time that plasma CCL21 levels were overexpressed in GD patients and recovered in TRAb-negative GD patients. Moreover, CCL21 levels correlated with TRAb levels and plasma OPN concentrations. Furthermore, we demonstrated that recombinant OPN increased the expression of CCL21 in a dose- and time-dependent manner. These data indicated a clinical correlation between plasma CCL21 levels and GD. CCL21 could serve as a novel biomarker for GD as well as a potential target for TRAb-positive GD treatment.

Increase of Interferon-γ Inducible CXCL9 and CXCL11 Serum Levels in Patients with Active Graves' Disease and Modulation by Methimazole Therapy

Chemokine (C-X-C motif) ligand (CXCL)9 and CXCL11 play an important role in the initial phases of autoimmune thyroiditis (AT); however, their serum levels in patients with Graves' disease (GD) have never been evaluated in relation to thyroid function and treatment. To evaluate CXCL9 and CXCL11 serum levels in GD and to relate these parameters to the clinical phenotype, we measured CXCL9 and CXCL11 serum levels in 91 GD patients; 91 AT, 34 nontoxic multinodular goiters (MNGs), 31 toxic nodular goiters (TNGs), respectively; and 91 healthy controls (age- and sex-matched). Mean CXCL9 and CXCL11 levels were higher in GD in comparison with controls, euthyroid AT, MNG, or TNG (p < 0.05, ANOVA; CXCL9: 274 ± 265, 76 ± 33, 132 ± 78, 87 ± 48, and 112 ± 56 pg/mL; CXCL11: 140 ± 92, 64 ± 20, 108 ± 48, 76 ± 33, 91 ± 41 pg/mL, respectively). Hyperthyroid GD patients had significantly higher CXCL9 or CXCL11 than euthyroid or hypothyroid GD patients. GD patients with untreated hyperthyroidism had higher CXCL9 or CXCL11 than hyperthyroid or euthyroid GD patients under methimazole (MMI) treatment. Comparable CXCL9 and CXCL11 levels were observed in newly diagnosed untreated hyperthyroid GD versus untreated patients with relapse of hyperthyroidism after a previous MMI course. Serum CXCL9 and CXCL11 levels are associated with the active phase of GD both in newly diagnosed and relapsing hyperthyroid patients. The reduction of serum CXCL9 and CXCL11 levels in treated patients with GD may be related to the immunomodulatory effects of MMI.

Chemokine (C-C Motif) Ligand 20, a Potential Biomarker for Graves' Disease, Is Regulated by Osteopontin

ContextGraves’ disease (GD) is a common autoimmune disease involving the thyroid gland. The altered balance of pro- and anti-inflammatory cytokines plays an important role in the pathogenesis of GD. Chemokine (C-C motif) ligand 20 (CCL20) is important for interleukin-17 (IL-17) signal activation and a potent chemoattractant for Th17 cells. Meanwhile, Osteopontin (OPN), a broadly expressed pleiotropic cytokine, has been implicated in GD through inducing Th1-involved response to enhance the production of proinflammatory cytokines and chemokines, but little is known about the role of OPN in regulating CCL20 and IL-17 signaling.ObjectiveThis study sought to explore the possibility of CCL20 level as a biomarker for GD, as well as investigate the role of OPN in regulating CCL20 production.MethodsFifty untreated GD patients, fifteen euthyroid GD patients, twelve TRAb-negative GD patients and thirty-five healthy control donors were recruited. OPN, CCL20 and other clinical GD diagnosis parameters were measured. CD4+T cells were isolated from peripheral blood mononuclear cells (PBMCs) using antibody-coated magnetic beads. Enzyme-linked immune-sorbent assay and quantitative polymerase chain reaction were used to determine CCL20 expression level.ResultsWe found that the plasma CCL20 level was enhanced in GD patients and decreased in euthyroid and TRAb-negative GD patients. In addition, CCL20 level correlated with GD clinical diagnostic parameters and plasma OPN level. Moreover, we demonstrated that recombinant OPN and plasma from untreated GD patients increased the expression of CCL20 in CD4+T cells, which could be blocked by OPN antibody. Furthermore, we found that the effect of OPN on CCL20 expression was mediated by β3 integrin receptor, IL-17, NF-κB and MAPK pathways.ConclusionsThese results demonstrated that CCL20 might serve as a biomarker for GD and suggested the possible role of OPN in induction of CCL20 expression.

Th1/Th2 cytokine production and reception features in Graves' disease

Cytokines and their receptors belong to a significant role in the initiation and the subsequent course and outcome of autoimmune thyroid disease. Interleukin-2 (IL-2), interleukin-4 (IL-4) and tumor necrosis factor-alpha (TNF-α)-cytokines, which have a multifaceted impact on the various stages of the immune response: the development of inflammatory response, cell proliferation, antibody and acute phase proteins synthesis. Pre-existing pattern of development of autoimmune thyroiditis (Hashimoto's thyroiditis) and Graves' disease (GD) as a state with two opposite positions of the predominant profile of Th1/Th2-lymphocyte activation. The study evaluated the cytokine production by Th1- and Th2-lymphocytes in patients with GD, assessment of lymphocyte receptor system and identified lymphocytes subpopulation in patients with BG, and the impact on the functional state of thyroid gland. It was shown that the immunoregulatory cytokines as Th1(IL2)- and Th2(IL-4)-helper lymphocytes are involved in the immune mechanism of BG. The level of IL-2, IL4, and TNF-α, and the number complementary lymphocyte receptors were not significantly changed in euthyroid or hyperthyroid GD patient. Nevertheless, there are strong correla! tions between production of immunoregulatory cytokines (IL-2, IL-4) with the functional state of the thyroid gland and increase of its volume in GD patient, what confirms the “functional synergies” of these cytokines in autoimmune inflammation in the GD.

Long-term follow-up of seven patients with ophthalmopathy not associated with thyroid autoimmunity: heterogeneity of autoimmune ophthalmopathy.

BackgroundOphthalmopathy is the most common extrathyroidal manifestation of Graves’ disease. However, in approximately 5% of cases this autoimmune eye disorder occurs in the apparent absence of Graves’ hyperthyroidism: the so-called euthyroid Graves’ disease (EGD).MethodsSeven patients with EGD were followed for evidence of thyroid and orbital autoimmunity, for up to 10 years. Calsequestrin and collagen XIII antibodies were measured by enzyme linked immunosorbent assay (ELISA), and TSH-receptor (TSH-r) antibodies were measured as TSH-r-binding antibody (TRAb) and thyroid-stimulating immunoglobulin (TSI). Eye signs were characterized and quantified as clinical activity score (CAS), NOSPECS classes, Nunery types 1 and 2, and margin-reflex distance (MRD).ResultsCalsequestrin antibodies were detected on at least one occasion in three of the seven patients and collagen XIII antibodies were detected one or more times in five patients. In one patient with isolated congestive ophthalmopathy who was studied intensely, collagen XIII antibodies were initially positive and then became negative as the eye disease stabilized, while antibodies targeting calsequestrin were always negative. TRAb was not detected in any patient, but TSI was detected in three patients on one occasion each. Ultrasound abnormalities were found in four of the six patients for whom this was carried out, but there was no clear evidence for thyroiditis in any of these patients. For comparison, 13 patients were studied with typical Graves’ ophthalmopathy. There were no significant differences compared to EGD in respect to the prevalence of positive calsequestrin or collagen XIII antibodies, but these patients included more smokers (eight out of 13 versus none out of seven).ConclusionsEarlier studies suggesting that patients with EGD eventually develop thyroid dysfunction have not been confirmed here, although follow-up continues, and the possibility that such patients have had thyroid autoimmunity in the past, or that they will develop it in the future cannot be excluded. Overall, it is likely that the ophthalmopathy associated with Graves’ hyperthyroidism is the same disease as that observed in patients – such as those reported here – in whom thyroid dysfunction and thyroid autoimmunity are not present during the period of follow- up. The role of autoimmunity against the TSH-r in euthyroid patients with ophthalmopathy has not been proven and the significance of the orbital antibodies is unclear.

Isolated lateral rectus muscle involvement as a presenting sign of euthyroid Graves disease

A 27-year-old man who presented with diplopia and proptosis and was diagnosed with euthyroid Graves disease and restrictive strabismus. It was determined that his symptoms were caused by isolated lateral rectus muscle involvement. Diplopia resolved and ocular motility improved substantially following 6 weeks of oral corticosteroid therapy.

Increased percentage of L-selectin+ and ICAM-1+ peripheral blood CD4+/CD8+ T cells in active Graves' ophthalmopathy.

The purpose of the study was to evaluate the percentage of CD4+/CD8+ peripheral T cells expressing CD62L+ and CD54+ in patients with Graves' disease and to assess if these estimations could be helpful as markers of active ophthalmopathy. The study was carried out in 25 patients with Graves' disease (GD) divided into 3 groups: 1/ 8 patients with active Graves' ophthalmopathy (GO) (CAS 3-6, GO complaints pound 1 year), 2/ 9 patients with hyperthyroid GD without symptoms of ophthalmopathy (GDtox) and 3/ 8 patients with euthyroid GD with no GO symptoms (GDeu). The control group consisted of 15 healthy volunteers age and sex matched to groups 1-3. The expression of lymphocyte adhesion molecules was evaluated by using three-color flow cytometry. In GO group the percentage of CD8+CD54+, CD8+CD62L+, CD4+CD54+ and CD4+CD62L+ T cells was significantly higher as compared to controls (p<0.001, p<0.05, p<0.01, p<0.001 respectively). The percentage of CD8+CD54+ T lymphocytes was also elevated in GO group in comparison to hyperthyroid GD patients (p< 0.05). CD4+CD62L+ and CD8+CD54+ percentages were also increased in GDtox and GDeu as compared to controls. We found a positive correlation between the TSHRab concentration and the percentage of CD8+CD62L+ T cells in all studied groups (r= 0.39, p<0.05) and between the TSHRab level and CAS (r= 0.77, p<0.05). The increased percentage of CD8+CD54+ and CD8+CD62L+ T cells in patients with Graves' ophthalmopathy may be used as a marker of immune inflammation activity.

A Case of Euthyroid Graves Disease Which Developed Into Graves Disease With Thyrotoxicosis After Subacute Thyroiditis

The presence of stimulating TSH receptor antibody (TRAb) results in Graves disease with thyrotoxicosis. However, some patients with Graves disease are euthyroid despite the presence of this antibody. Patient: A 42-year-old Japanese woman had suffered from diplopia. Thyroid function, however, was normal. Serum TRAb levels were elevated at 1.7 U/L (normal range: under 1.0 U/L). The working diagnosis was euthyroid Graves disease. Eighteen months later, she noticed pain and tumor in the anterior region of the neck. Physical examination revealed 3.2-cm diameter, firm tumor in the left lobe of thyroid accompanied by exquisite tenderness. The serum free plasma free thyroxin, free triiodethyronine, and TSH was 1.60 ng/dL, 3.62 pg/mL, and below 0.01 mU/L, respectively. The erythrocyte sedimentation rate was 64 mm/h, TRAb values had increased to 3.52 U/L. Three months later, the serum levels of FT4 and TRAb increased and the diagnosis of Graves disease with thyrotoxicosis was made. To our best knowledge, this is the first case report of euthyroid Graves disease being connected to hyperthyroid Graves disease by subacute thyroiditis.

Ratio of Serum IgG3 to Total IgG Concentration and Goiter Size Are Independent Factors in Intractability of Graves' Disease

Peripheral immunoglobulin (Ig) G(3)-secreting cells and serum concentrations of interleukin (IL)-10, a class-switching factor to IgG(3)-secreting cells, increase in patients with intractable Graves' disease (GD). However, they are not practical for laboratory tests. To find more stable and easily detectable markers of disease intractability or disease severity in patients with GD or Hashimoto's disease (HD), we examined the serum concentration of IgG(3) in 58 euthyroid GD patients who had been undergoing antithyroid drug treatment for more than 5 years but still must continue drug treatment to maintain a euthyroid state (intractable GD), 26 GD patients who had maintained a euthyroid state for more than 2 years without any treatment (GD in remission), 20 untreated, thyrotoxic GD patients, 40 euthyroid HD patients treated with thyroxine (5 men and 35 women), 13 untreated, euthyroid HD patients, and 39 healthy volunteers. Serum concentrations of IgG(3 )increased in euthyroid patients with intractable GD and in those with GD in remission, but serum concentrations of IgG were not altered. The ratio of serum concentrations of IgG(3) to total IgG (IgG(3)/IgG ratio) was higher in euthyroid patients with intractable GD than in those with GD in remission. Multiple logistic-regression analysis demonstrated that IgG(3)/IgG ratio and goiter size were independent factors in disease intractability of GD patients. These results suggest that IgG(3)/IgG ratio and goiter size may be used as independent markers associated with GD intractability.

Determination of oxidative stress in thyroid tissue and plasma of patients with Graves' disease

Background The aim of our study was to evaluate the oxidant/antioxidant status of thyroid tissue in Graves' disease (GD) patients and to compare the results of GD thyroid tissue with plasma of patients and healthy controls. Methods We studied 25 consecutive patients with GD hyperthyroidism who underwent surgical treatment. The patients were divided into groups according to the duration of antithyroid drug treatment, the type of antithyroid drugs used, the presence of ophthalmopathy, and recurrence after a complete course of antithyroid drugs. Thiobarbituric acid-reacting substances (TBARS), glutathione peroxidase (GPx) activity, superoxide dismutase (SOD) activity, and total thiol (t-SH) content of tissue and plasma samples were determined. Results TBARS concentrations were found to be significantly increased in GD patients' plasma compared with controls' plasma (0.1 ±0.02 nmol/mg protein vs. 0.062 ± 0.01 nmol/mg protein). Significantly decreased t-SH concentrations were measured in GD patients' plasma compared with controls (8.26 ± 1.9 nmol/mg protein vs. 13.03 ± 3.3 nmol/mg protein). Tissue TBARS, t-SH, GPx, and SOD measurements in GD patients indicated significantly increased concentrations compared with the plasma levels of patients. Patients with shorter treatment duration before the operation had significantly increased plasma and tissue TBARS and decreased plasma and tissue t-SH concentrations. Patients on propylthiouracil treatment had significantly lower plasma and tissue concentrations of TBARS than patients on methimazole. Patients with recurrence had significantly higher plasma and tissue TBARS and lower plasma and tissue t-SH concentrations than patients treated for the first time. Conclusions In euthyroid GD patients on antithyroid drugs, increased oxidative stress and a compensatory increase in the antioxidant defense system are more prominent in thyroid tissue than in plasma. Patients who relapsed had markers indicating increased oxidative stress. Thus, ongoing autoimmunity may contribute to increased oxidative stress in GD patients, even in the euthyroid state.

Influence of methimazole treatment on parameters of oxidative stress in patients with Graves’ disease

It is known that hyperthyroidism is associated with oxidative stress. Graves’ disease (GD) is an autoimmune thyroid disorder responsible for 70–80% of all cases of hyperthyroidism. The aim of this study was to examine the change of oxidative stress and antioxidant enzyme activities in 23 patients with Graves’ disease before and after treatment with methimazole and in 31 healthy controls. The level of malondialdehyde (MDA) in the plasma, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities in erythrocytes were measured. Serum levels of TSH and free thyroxin (FT4) were also estimated. We observed increased concentrations of FT4 and suppressed TSH levels before treatment. The concentrations of thyroid hormones and of TSH normalized after the methimazole treatment. Significantly higher MDA concentrations were found in hyperthyroid GD patients in comparison to controls (1.96±0.10 vs 1.71±0.05 μmol/l, p<0.05). After a long-term drug treatment, the plasma levels of MDA decreased and reached values close to the controls (mean 1.73 μmol/l). Activity of GPX in erythrocytes in hyperthyroidism was higher compared to controls (9.3±1.2 vs 6.6±0.5 U/gHb, p<0.05). After thyrostatic treatment in euthyroidism, the activity of GPX was found to decrease in euthyroid GD patients in comparison to hyperthyroid patients, compared to controls (3.9±0.5 vs 9.3±1.2 U/gHb and 3.9±0.5 vs 6.6±0.5 U/gHb; p<0.001, p<0.001, respectively). Our data confirm the presence of increase in lipid peroxidation in hyperthyroid patients, which is corrected in euthyroidism. We hypothesize that in hyperthyroidism, the enhanced activity of GPX was induced by oxidative stress and was connected with TSH receptor hyperstimulation. After treatment with methimazole, GPX activity was lowered. Observed alterations of GPX activity after Graves’ disease treatment may be related to the deficiency of cellular antioxidative defense that persists during the course of disease. The disturbed antioxidative defense in patients with Graves’ disease indicates the possible usefulness of supplementation with antioxidants in particular with selenium as an important component of selenoenzymes such as GPX.

Increase of interferon‐γ‐inducible CXC chemokine CXCL10 serum levels in patients with active Graves’ disease, and modulation by methimazole therapy

CXCL10 plays an important role in the initial phases of Graves' disease (GD) and autoimmune thyroiditis (AT); however, until now, CXCL10 serum levels (sCXCL10) in patients with GD have never been evaluated in relation to thyroid function and treatment. To evaluate sCXCL10 in GD. Cross-sectional. One hundred and three GD, 164 AT, 20 nontoxic multinodular goitre (NTMNG), 16 toxic nodular goitre (TNG) patients and 70 healthy controls (age- and sex-matched). We measured sCXCL10 in patients and controls, to relate this parameter to the clinical phenotype. Mean sCXCL10 in GD and AT patients were comparable (122+/-81 and 133+/-102 pg/ml) and significantly higher (P<0.01) than in controls or NTMNG patients (73+/- 32 and 76+/- 25 pg/ml, respectively). Hyperthyroid GD had significantly higher sCXCL10 than euthyroid or hypothyroid GD (145+/- 92, 107+/- 56 and 105+/- 46 pg/ml, respectively; P=0.01). GD patients with untreated hyperthyroidism had higher sCXCL10 than hyperthyroid or euthyroid GD patients under methimazole (MMI) treatment (166+/-125, 124+/- 41 and 94+/- 35 pg/ml, respectively; P=0.006). Comparable sCXCL10 levels were observed in newly diagnosed untreated hyperthyroid GD patients with respect to untreated patients with relapse of hyperthyroidism after a previous MMI course (176+/-125, 155+/- 97 pg/ml, respectively). GD had similar sCXCL10 to AT and higher than TNG patients or controls (all age- and sex-matched) (144+/- 81, 149+/- 114, 101+/- 27 and 86+/- 44 pg/ml, respectively; P=0.02). sCXCL10 is associated with the active phase of GD in both newly diagnosed and relapsing hyperthyroid patients. The reduction in sCXCL10 in treated patients with GD may be related to the immunomodulatory effects of MMI.