Mild Graves Research Articles

Favorable Effect of Bromocriptine and Pentoxifylline in Mild Graves Disease Orbitopathy: A Randomized, Open, Clinical Trial

Favorable Effect of Bromocriptine and Pentoxifylline in Mild Graves Disease Orbitopathy: A Randomized, Open, Clinical Trial

A SURVEY OF CLINICAL PRACTICE PATTERNS IN MANAGEMENT OF GRAVES DISEASE IN THE MIDDLE EAST AND NORTH AFRICA

Graves disease (GD) is commonly seen in endocrine clinical practice. The objective of this study was to evaluate the current diagnosis and management of patients with GD in the Middle East and North Africa (MENA). An electronic survey on GD management was performed using an online questionnaire of a large pool of practicing physicians. Responses from 352 eligible and willing physicians were included in this study. They were mostly endocrinologists (157) and internal medicine physicians (116). In addition to serum thyroid-stimulating hormone (TSH) and free thyroxine assays, most respondents would request serum antithyroid peroxidase antibody and TSH-receptor autoantibody (50% and 46%, respectively), whereas serum antithyroglobulin antibodies would be ordered by fewer respondents (36%). Thyroid ultra-sound would be requested by a high number of respondents (63.7%), while only a small percentage would order isotopic thyroid studies. Antithyroid drug (ATD) therapy was the preferred first-line treatment (52.7%), followed by radio-iodine (RAI) treatment (36.8%), β-blockers alone (6.9%), thyroidectomy (3.2%), and no therapy (1.3%). When RAI treatment was selected in the presence of mild Graves orbitopathy and/or associated risk factors for its occurrence/exacerbation, steroid prophylaxis was frequently used. The preferred ATD in pregnancy was propylthiouracil in the first trimester and carbimazole in the second and third trimesters. On most issues, choices of the MENA physicians fell between European and American practices. Hybrid practices are seen in the MENA region, perhaps reflecting training and affiliations. Management approaches most suitable for patients in this region are needed. ATD = antithyroid drug CBZ = carbimazole FT3 = free T3 FT4 = free T4 GD = Graves disease GO = Graves orbitopathy MENA = Middle East and North Africa MMI = methimazole RAI = radioactive iodine RAIU = RAI uptake T3 = tri-iodothyronine T4 = thyroxine TG Ab = antithyroglobulin antibodies TRAb = TSH-receptor autoantibody TSH = thyroid-stimulating hormone PTU = propylthiouracil TID = thrice daily UAE = United Arab Emirates US = ultrasound.

Natural course of mild Graves' orbitopathy: is it a chronic remitting or a transient disease?

The natural course of Graves' orbitopathy (GO) has been poorly documented. The aim of this review is to provide current knowledge regarding the natural course of mild GO, trying to address the issue of whether and to what extent it constitutes a chronic remitting or transient disease. We systematically searched PubMed for English language publications until August 2016 under the following terms: "Graves' orbitopathy" OR "Graves' ophthalmopathy" OR "thyroid eye disease" AND "natural course" OR "natural history". Few studies have investigated the course of mild orbital disease in patients with GO. Large controlled trials are lacking and data can be extracted mainly from small retrospective and some prospective studies, after excluding patients who had received radioiodine for thyrotoxicosis or surgical treatment for GO. In general, more than half of GO patients may show spontaneous improvement in their clinical features, whereas no safe conclusions can be drawn with regard to complete resolution, with percentages ranging from 6 to 58%. The question whether mild GO is a remitting, albeit chronic disease, or even a transient event in the course of Graves' disease, remains currently unanswered.

CD28/CTLA-4/ICOS haplotypes confers susceptibility to Graves\u2019 disease and modulates clinical phenotype of disease

Graves’ disease, an autoimmune disease with heterogeneous symptoms including Graves’ orbitopathy, has a combined genetic/environmental background, where variations within CD28/CTLA-4/ICOS genes are considered as disease markers.Association of CD28c.17+3T>C(rs3116496), CTLA-4g.319C>T(rs5742909), CTLA-4c.49A>G(rs231775), CTLA-4g.*642AT(8_33), CT60(rs3087243), Jo31(rs11571302), ICOSc.1554+4GT(8_15) polymorphisms with susceptibility to Graves’ disease and clinical outcome was investigated. The study group comprised of 561 Polish Caucasians, including 172 unrelated Graves’ disease patients. CTLA-4c.49A>G, CTLA-4g.319C>T, and CT60 were genotyped by PCR–RFLP; Jo31 and CD28c.17+3C>T by minisequencing; CTLA-4g.*642AT(8_33) and ICOSc.1554+4GT(8_15)—PCR and fluorescence-based technique. CD28c.17+3T>C(rs3116496)T/CTLA-4g.319C>T(rs5742909)C/CTLA-4c.49A>G(rs231775)G/CTLA-4g.*642AT(8_33)(AT16–21)/CT60(rs3087243)G/Jo31(rs11571302)G/ICOSc.1554+4GT(8_15)(m) and TCA(AT<16)GT(m) haplotypes increased risk of Graves’ disease, especially in males, as well as overall Graves’ orbitopathy development with severe outcome. TCG(AT16–21)GG(l) haplotype increased risk of Graves’ disease and reduced the chance of successful medical treatment. Although this haplotype was mainly observed in patients without signs of Graves’ orbitopathy, if Graves’ orbitopathy developed it favored a Graves’ orbitopathy outcome. Haplotype TCA(AT>21)GT(m) increased Graves’ disease risk in women and, in all patients, was linked to Graves’ disease without Graves’ orbitopathy. TCG(AT<16)GG(m) haplotype was predominantly observed in patients without Graves’ orbitopathy, whereas TCA(AT16–21)GG(m) was absent in those patients. TCA(AT16–21)GG(m) occurred in patients with a mild Graves’ orbitopathy outcome. The marker CTLA-4g.*642AT(8_33) was the only independent Graves’ disease risk factor, whereas CT60 was an independent factor for disease progression. Sporadic Graves’ disease was related to presence of CTLA-4c.49A>G[A] and the rare CTLA-4g.319C>T[T] allele variant. Familial background of the disease was exclusively associated with CTLA-4g.*642AT(8_33)[AT>21]/[AT>21] genotype. CD28/CTLA-4/ICOS loci may confer inherited susceptibility to Graves’ disease or may be involved in susceptibility to Graves’ disease and play a pathogenetic role.

Efficacy and safety of radioiodine therapy for mild Graves ophthalmopathy depending on cigarette consumption: a 6‑month follow‑up.

INTRODUCTION Graves ophthalmopathy (GO) is an autoimmune disease associated with Graves disease. Its treatment is largely dependent on the severity and activity of ocular lesions. Particular attention should be given to radioiodine (RAI) therapy. Although its use is a valuable therapeutic option for hyperthyroidism, it may be followed by worsening of GO. OBJECTIVES The aim of the present study was to analyze how the severity of nicotine addiction affects the response to RAI treatment in patients with GO. PATIENTS AND METHODS A total of 106 patients (58 smokers and 48 nonsmokers) with mild GO treated with 800 MBq of RAI were included to the study. We assessed the serum levels of thyroid‑stimulating hormone (TSH), thyroid hormones, autoantibodies against thyroperoxidase, thyroglobulin, and TSH receptor (TSHR‑Abs), as well as urinary cotinine levels and severity of ophthalmopathy. Analyses were conducted at baseline (before RAI treatment) and 2 and 6 months after the therapy. RESULTS Significant differences in serum levels of TSHR‑Abs were found between nonsmokers and smokers at 2 and 6 months after RAI therapy, whereas there were no differences at baseline. In smokers, there were significant differences in the severity of ophthalmopathy and the concentration of serum TSHR‑Abs assessed at baseline and at 6 months of follow‑up. Six months after RAI therapy, 46.2% of smokers and 4.3% of nonsmokers (P <0.001) progressed from mild to moderate GO. CONCLUSIONS High urinary cotinine levels in smokers were associated with the deterioration of ocular lesions after RAI treatment. A high dose of RAI did not induce an exacerbation of GO in nonsmokers who were administered oral steroid prophylaxis.

Choroidal changes observed with enhanced depth imaging optical coherence tomography in patients with mild Graves orbitopathy.

PurposeTo evaluate the choroidal thickness in patients with Graves orbitopathy (GO) using enhanced depth imaging-optical coherence tomography (EDI-OCT).MethodsThirty-one patients with GO were evaluated prospectively. All subjects underwent ophthalmologic examination including best-corrected visual acuity, intraocular pressure measurement, biomicroscopic, and fundus examination. Choroidal thickness was measured at the central fovea. In addition, visual evoked potential measurement and visual field evaluation were performed.ResultsThe mean choroidal thickness was 377.8±7.4 μ in the GO group, and 334±13.7 μ in the control group. (P=0.004). There was a strong correlation between the choridal thickness and the clinical activity scores (CAS) of the patients (r=0.281, P=0.027). Additionally, there was a correlation between the choroidal thickness and the visual-evoked potential (VEP) P100 latency measurements of the patients (r=0.439, P=0.001).ConclusionsThe results of this study demonstrate that choroid is thicker in patients with GO. The choroidal thickness is also correlated with the CAS and VEP P100 latency measurements in these patients.

Efficacy and safety of radioiodine therapy for mild Graves' ophthalmopathy in dependence on nicotine consumption

Efficacy and safety of radioiodine therapy for mild Graves' ophthalmopathy in dependence on nicotine consumption

Lack of Association between Selenium Status and Disease Severity and Activity in Patients with Graves' Ophthalmopathy

Background: Selenium (Se) is of importance for regular functioning of the immune system and thyroid gland, and may have a health effect in mild Graves' ophthalmopathy (GO). Objective: As the Se status declines in inflammation, we analyzed whether GO activity or severity affects the Se status of patients. Methods: Serum Se and selenoprotein P (SePP) concentrations were retrospectively determined in 84 consecutive GO patients before treatment and compared to their clinical activity score (CAS) and severity of eye changes (NOSPECS) status, and to the concentrations of autoantibodies targeting the TSH receptor (TRAK) or the IGF1 receptor (IGF1R-aAB). Results: Serum Se and SePP were linearly associated, indicating a suboptimal Se status of our patients. In comparison to data from other European cohorts, the majority of GO patients had a relatively poor Se status ([Se] ± SD; 70.0 ± 23.8 µg/l), below the threshold needed for full expression of selenoproteins. TRAK were inversely associated with Se concentrations, while IGF1R-aAB titers were not associated with Se. Neither Se nor SePP concentrations differed between GO patients with severe versus mild or active versus inactive disease, or showed significant associations with the CAS or NOSPECS values. Conclusion: GO patients are at risk of a low Se status, yet disease severity or activity does not seem to affect Se or SePP concentrations directly. However, as the retrospective nature of the analysis does not allow conclusions on a potential causative role of Se on Graves' disease or GO risk, these results neither support nor discourage adjuvant Se supplementation attempts.

Selenium and the thyroid.

This article provides an update on the role of the essential trace element selenium and its interaction with the other trace elements iodine and iron that together contribute to adequate thyroid hormone status. Synthesis, secretion, metabolism and action of thyroid hormone in target tissues depend on a balanced nutritional availability or supplementation of these elements. Selenium status is altered in benign and malignant thyroid diseases and various selenium compounds have been used to prevent or treat widespread diseases such as goiter, autoimmune thyroid disease or thyroid cancer. Several studies, most with still too low numbers of cases, indicate that selenium administration in both autoimmune thyroiditis (Hashimoto thyroiditis) and mild Graves' disease improves clinical scores and well-being of patients and reduces thyroperoxidase antibody titers. However, published results are still conflicting depending on basal selenium status, dose, time and form of selenium used for intervention. Evidence for sex-specific selenium action, lack of beneficial effects in pregnancy and contribution of genetic polymorphisms (selenoprotein S) has been presented. Adequate nutritional supply of selenium that saturates expression of circulating selenoprotein P, together with optimal iodine and iron intake, is required for a healthy and functional thyroid during development, adolescence, adulthood and aging.

A 2013 European survey of clinical practice patterns in the management of Graves' disease.

Management of Graves' disease (GD) in Europe was published in 1987. Aim of this survey was to provide an update on clinical practice in Europe, and to compare it with a 2011 American survey. Members of the European Thyroid Association (ETA) were asked to participate in a survey on management of GD, using the same questionnaire of a recent American survey. A total of 147 ETA members participated. In addition to serum TSH and free T4 assays, most respondents would request TSH-receptor autoantibody (TRAb) measurement (85·6%) and thyroid ultrasound (70·6%) to confirm aetiology, while isotopic studies were selected by 37·7%. Antithyroid drug (ATD) therapy was the preferred first-line treatment (83·8%). Compared to the previous European survey, Europeans currently more frequently use TRAb measurement and thyroid ultrasound for diagnosis and evaluation, but first-line treatment remains ATDs in a similar percentage of respondents. Current clinical practice patterns differ from those in North America, where isotopic studies are more frequently used, and radioiodine (RAI) still is first-line treatment. When RAI treatment is selected in the presence of mild Graves' orbitopathy and/or associated risk factors for its occurrence/exacerbation, steroid prophylaxis is frequently used. The preferred ATD in pregnancy is propylthiouracil in the first trimester and methimazole in the second and third trimesters, similar to North America. Significant changes in clinical practice patterns in Europe were noted compared to the previous European survey, as well as persisting differences in diagnosis and therapy between Europe and North America.

FGFβ and TGFβ contribute to tissue remodeling, fibrosis and inflammation in the orbital tissue of severe Grav

AbstractPurpose To assess FGF‐β, TGF‐β, COX2 expression and immunocompetent cells in the orbital fat/connective tissue of patients with severe and mild Graves’ orbitopathy as possible prognosting factors of the course of disease.Methods Orbital tissue from 27 patients with GO undergoing orbital decompression (26 females and 1 male): 1) patients with severe GO (n = 18), the mean clinical activity score (CAS) was 8,5 (SD 2.5); 2) Patients with mild GO (n= 9), CAS was 2.2 (SD 0.8). 10 individuals undergoing blepharoplasty with no history of orbital inflammation served as controls. We evaluated the expression of CD4+, CD8+. CD20+, CD68 and FGF‐β, TGF‐β, COX2 in the orbital tissue by immunohistochemical stainingResults The robust intraorbital CD4 + T cells infiltration in severe GO more than with mild GO with absence of CD20+ B lymphocytes and less CD8 infiltration were seen. CD68 expression (fibroblasts and macrophages staining) observed in the fibrous connective area of the adipose tissue of the mild GO and robust in severe GO. Increased FGFβ expression was observed in the fibroblasts and adipocytes in the connective tissue of the severe GO. The prominent TGFβ expression was observed in the fibrous connective tissue of the severe and mild GO. No expression of COX2 in the orbital tissue specimen was found in patients with GO.Conclusion Macrophages and CD4 T lymphocytes are both engaged in the active/severe and long stage of inflammation in the orbital tissue. FGFβ and TGFβ expression may contribute to tissue remodeling, fibrosis and perpetuation of inflammation in the orbital tissue of GO especially in severe GO. Their high expression may suggest lack of effect of anti‐inflammatory treatment.

Markers of inflammation and fibrosis in the orbital fat/connective tissue of patients with Graves' orbitopathy: clinical implications.

Purpose. To assess FGF-β, TGF-β, and COX2 expression and immunocompetent cells in the orbital tissue of patients with severe and mild Graves' orbitopathy. Patients and Methods. Orbital tissue was taken from 27 patients with GO: (1) severe GO (n = 18), the mean clinical activity score (CAS) being 8.5 (SD 2.5); and (2) mild GO (n = 9), the mean CAS being 2.2 (SD 0.8), and from 10 individuals undergoing blepharoplasty. The expression of CD4+, CD8+, CD20+, and CD68 and FGF-β, TGF-β, and COX2 in the orbital tissue was evaluated by immunohistochemical methods. Results. We demonstrated predominant CD4+ T cells in severe GO. CD68 expression was observed in the fibrous connective area of mild GO and was robust in severe GO, while the prominent TGF-β expression was seen in all GO. Increased FGF-β expression was observed in the fibroblasts and adipocytes of severe GO. No expression of COX2 was found in patients with GO. Conclusions. Macrophages and CD4 T lymphocytes are both engaged in the active/severe and long stage of inflammation in the orbital tissue. FGF-β and TGF-β expression may contribute to tissue remodeling, fibrosis, and perpetuation of inflammation in the orbital tissue of GO especially in severe GO.

Spontaneous Improvement of Untreated Mild Graves' Ophthalmopathy: Rundle's Curve Revisited

According to Rundle's curve, Graves' ophthalmopathy (GO) worsens during an initial phase up to a peak of maximum severity, then improves and reaches a static plateau, with the activity curve preceding the severity curve by a few months. To our knowledge, no studies have tried to replicate Rundle's curve, and very few have investigated the natural history of GO. Here, we studied GO natural history retrospectively and tried to identify factors that may affect it. A total of 65 patients with untreated GO underwent an eye assessment after a median of seven months after the appearance of GO and then after a median of 40 months. The primary endpoints were the variation of the single GO features and of the NOSPECS score, as well as the overall outcome of GO. The secondary endpoint was the influence of several variables (age, sex, smoking, GO and thyroid disease duration, thyroid treatment, thyroid status, thyroid volume, anti-TSH receptor autoantibodies) on the outcome of GO. The majority of patients had mild, minimally active GO, and only five had a Clinical Activity Score (CAS) >3. There was a significant reduction of CAS (p<0.0001) and NOSPECS (p=0.01) between the first and last observation, with a timing pattern resembling Rundle's curve. This difference was confirmed even when patients with a CAS >3 at first observation were excluded. At the last observation, 50.8% of patients had improved, 33.8% had remained stable, and 15.4% had worsened moderately or substantially. The overall outcome of GO was not affected by any of the variables under examination. In confirmation of Rundle's observations, untreated GO improves spontaneously with time in the majority of patients, with an activity peak between 13 and 24 months, which may have implications in determining the proper timing of GO treatments.

Selenium and the Course of Mild Graves' Orbitopathy

Selenium and the Course of Mild Graves' Orbitopathy

CLINICAL ACTIVITY SCORES ARE IMPROVING IN PATIENTS WITH MILD THYROID-ASSOCIATED ORBITOPATHY RECEIVING ADJUVANT SELENIUM SUPPLEMENTATION

The essential trace element selenium (Se) exerts complex effects on the endocrine and immune systems, partly due to its antioxidant capacity. The importance of an optimal Se intake has been established in autoimmune thyreoiditis. A recently published study reported beneficial results in Se supplemented patients with mild Graves’ orbitopathy. Eight female patients with mild Graves’ orbitopathy and three female patients with mild orbitopathy based on Hashimoto thyreoiditis participated in the study. The status of the orbita was registered at the beginning of the study and one-six months thereafter both according to the scores recommended by the American Thyroid Association (ATA) and clinical activity scores (CAS). The patients were treated according to their thyroid hormone status, their antibody results and their CAS. Moreover, they received adjuvant Se as 100 or 200 μg sodium-selenite. Serum Se concentrations were measured before Se supplementation was implemented and 1-6 months after the beginning of treatment. ATA scores improved in 10 patients and worsened slightly in one female patient. CAS improved in all study participants. Mean Se concentrations were 75.08±11.55μg/l before supplementation was started and 91.35±17.37μg/l one-eight months later (p<0.05). At the beginning of the study, the majority of patients exhibited elevated antibody levels. After conventional treatment and adjuvant Se supplementation, antibody levels decreased or reached the normal range (except in the case of one patient).

Advances in Graves' Disease

Advances in Graves' Disease

Selenium and the Course of Mild Graves' Orbitopathy

Selenium and the Course of Mild Graves' Orbitopathy

Selenium and the Course of Mild Graves' Orbitopathy

Selenium and the Course of Mild Graves' Orbitopathy

Selenium, Mild Graves Ophthalmopathy and Current Smoking Status

Selenium, Mild Graves Ophthalmopathy and Current Smoking Status

The Role of Oxidative Stress on the Pathogenesis of Graves' Disease

Graves' disease is a most common cause of hyperthyroidism. It is an autoimmune disease, and autoimmune process induces an inflammatory reaction, and reactive oxygen species (ROSs) are among its products. When balance between oxidants and antioxidants is disturbed, in favour of the oxidants it is termed “oxidative stress” (OS). Increased OS characterizes Graves' disease. It seems that the level of OS is increased in subjects with Graves' ophthalmopathy compared to the other subjects with Graves' disease. Among the other factors, OS is involved in proliferation of orbital fibroblasts. Polymorphism of the 8-oxoG DNA N-glycosylase 1 (hOGG1) involved in repair of the oxidative damaged DNA increases in the risk for developing Grave's disease. Treatment with glucocorticoids reduces levels of OS markers. A recent large clinical trial evaluated effect of selenium on mild Graves' ophthalmopathy. Selenium treatment was associated with an improved quality of life and less eye involvement and slowed the progression of Graves' orbitopathy, compared to placebo.