Unusual Clinical Course of Graves’ Thyrotoxicosis and Concomitant Sarcoidosis: Case Report and Review of Literature

ObjectiveTo report a case of Graves’ disease with concomitant sarcoidosis involving the thyroid gland.MethodsWe present the clinical, laboratory, imaging, and pathologic findings and describe the clinical course of a patient with Graves’ disease and sarcoidosis, who was unresponsive to propylthiouracil and radioiodine treatment.ResultsA 23-year-old woman presented with thyrotoxicosis and a large goiter. Laboratory studies and findings on thyroid uptake and scan were consistent with Graves’ disease. She was also found to have hilar lymph-adenopathy and hepatosplenomegaly. Despite treatment with antithyroid drugs and radioiodine therapy, her hyperthyroidism persisted. Surgical resection of the thyroid gland and 2 lymph nodes disclosed noncaseating granulomas, consistent with sarcoid.ConclusionAutoimmune endocrinopathies and, less commonly, thyroid autoimmune disease have been reported in patients with sarcoidosis. Similarities exist in the pathogenesis of these two conditions. Concomitant sarcoidosis in the thyroid gland in patients with Graves’ disease may contribute to the resistance to antithyroid drugs and radioiodine therapy. (Endocr Pract. 2007;13:159-163)     

Serum Thyrotropin in Graves’ Disease: A More Reliable Index of Circulating Thyroid-Stimulating Immunoglobulin Level than Thyroid Function?

ObjectiveTo assess the relationship between serum thyrotropin (thyroid-stimulating hormone or TSH) on one hand and thyroid-stimulating immunoglobulin (TSI), free thyroxine (T₄), and triiodothyronine (T₃) levels on the other in Graves’ disease, inasmuch as TSH may be suppressed in the presence of TSI because TSI may bind to the TSH receptor on the thyroid gland membrane and thus eliminate the need for circulating TSH for stimulating the thyroid gland.MethodsWe determined serum TSI levels in 37 women and 13 men with Graves’ disease, stratified into 4 groups on the basis of serum TSH levels irrespective of serum free T₄ and T₃ levels. Our reference ranges were 0.72 to 1.74 ng/dL for free T₄, 80 to 200 ng/dL for T₃, and to 4.0 μU/mL for TSH.ResultsMean serum TSI concentrations were highest (215% ± 28%) in patients with undetectable TSH levels (< 0.03 μU/mL) and lowest (103% ± 9%) in those with supernormal TSH concentrations (> 4.0 μU/mL). TSI levels were intermediate in the other study groups: 157% ± 16% in patients with subnormal though detectable TSH levels (0.03 to 0.39 μU/mL) and 125% ± 12% in those with normal TSH levels (0.4 to 4.0 μU/mL). Moreover, a progressive decline in TSI levels with increasing serum TSH concentrations was noted, along with a significant negative correlation (r = -0.45; P < 0.01) between serum TSI and TSH concentrations. Finally, relationships between free T₄ and T₃ levels on one hand and TSI or TSH levels on the other were not significant, with a considerable variability in free T₄ and T₃ levels being noted in individual study groups.ConclusionSerum TSH is frequently suppressed after treatment with antithyroid drugs or radioiodine (¹³¹I), irrespective of clinical thyroid function as expressed by increased, normal, or decreased free T₄ and T₃ concentrations. In an individual patient with Graves’ disease, the serum TSH level may be more reflective of the circulating TSI concentration than is thyroid gland function as expressed by free T₄ and T₃ concentrations and therefore may be as reliable a predictor of remission as TSI. (Endocr Pract. 2007;13:615-619)     

Regulation of the phosphatidylinositol 3-kinase,Akt/protein kinase B,FRAP/mammalian target of rapamycin,and ribosomal S6 kinase 1 signaling pathways by thyroid-stimulating hormone (TSH) and stimulating type TSH receptor antibodies in the thyroid gland

Thyroid-stimulating hormone (TSH) regulates the growth and differentiation of thyrocytes by activating the TSH receptor (TSHR). This study investigated the roles of the phosphatidylinositol 3-kinase (PI3K), PDK1, FRAP/mammalian target of rapamycin, and ribosomal S6 kinase 1 (S6K1) signaling mechanism by which TSH and the stimulating type TSHR antibodies regulate thyrocyte proliferation and the follicle activities in vitro and in vivo. The TSHR immunoprecipitates exhibited PI3K activity, which was higher in the cells treated with either TSH or 8-bromo-cAMP. TSH and cAMP increased the tyrosine phosphorylation of TSHR and the association between TSHR and the p85alpha regulatory subunit of PI3K. TSH induced a redistribution of PDK1 from the cytoplasm to the plasma membrane in the cells in a PI3K- and protein kinase A-dependent manner. TSH induced the PDK1-dependent phosphorylation of S6K1 but did not induce Akt/protein kinase B phosphorylation. The TSH-induced S6K1 phosphorylation was inhibited by a dominant negative p85alpha regulatory subunit or by the PI3K inhibitors wortmannin and LY294002. Rapamycin inhibited the phosphorylation of S6K1 in the cells treated with either TSH or 8-bromo-cAMP. The stimulating type TSHR antibodies from patients with Graves disease also induced S6K1 activation, whereas the blocking type TSHR antibodies from patients with primary myxedema inhibited TSH- but not the insulin-induced phosphorylation of S6K1. In addition, rapamycin treatment in vivo inhibited the TSH-stimulated thyroid follicle hyperplasia and follicle activity. These findings suggest an interaction between TSHR and PI3K, which is stimulated by TSH and cAMP and might involve the downstream S6K1 but not Akt/protein kinase B. This pathway may play a role in the TSH/stimulating type TSH receptor antibody-mediated thyrocyte proliferation in vitro and in the response to TSH in vivo.     

Management of hyperthyroid patients following radioactive iodine therapy,with a specific emphasis on Graves’ disease

Radioactive iodine (RAI) therapy is commonly used for hyperthyroid patients. The post-RAI management greatly depends on RAI treatment goal (ablative vs. non ablative) and the underlying thyroid disease (Graves’ disease vs. thyroid functional autonomy). Communication with patients improves quality and safety of RAI. Standardization of follow-up is required for patients with Grave's disease who are exposed to hypothyroidism, thyrotoxic flare and thyroid eye disease (de novo or worsening Graves’ ophthalmopathy).     

Quantitative high-throughput screening using a live-cell cAMP assay identifies small-molecule agonists of the TSH receptor

The thyroid-stimulating hormone (TSH; thyrotropin) receptor belongs to the glycoprotein hormone receptor subfamily of 7-transmembrane spanning receptors. TSH receptor (TSHR) is expressed mainly in thyroid follicular cells and is activated by TSH, which regulates the growth and function of thyroid follicular cells. Recombinant TSH is used in diagnostic screens for thyroid cancer, especially in patients after thyroid cancer surgery. Currently, no selective small-molecule agonists of the TSHR are available. To screen for novel TSHR agonists, the authors miniaturized a commercially available cell-based cyclic adenosine 3',5' monophosphate (cAMP) assay into a 1536-well plate format. This assay uses an HEK293 cell line stably transfected with the TSHR coupled to a cyclic nucleotide gated ion channel as a biosensor. From a quantitative high-throughput screen of 73,180 compounds in parallel with a parental cell line (without the TSHR), 276 primary active compounds were identified. The activities of the selected active compounds were further confirmed in an orthogonal homogeneous time-resolved fluorescence cAMP-based assay. Forty-nine compounds in several structural classes have been confirmed as the small-molecule TSHR agonists that will serve as a starting point for chemical optimization and studies of thyroid physiology in health and disease.     

Thyroid Peroxidase Antibody Positivity is Associated With Relapse-Free Survival Following Antithyroid Drug Treatment for Graves Disease

Objective: Graves’ disease is an autoimmune disease characterized by production of autoantibodies directed against the thyroid gland. Thyrotropin-receptor antibodies (TRAbs) are clearly pathogenic, but the role of thyroidperoxidase antibodies (TPOAbs) in Graves disease is unknown.Methods: We retrospectively studied whether TPOAb positivity reduced risk of relapse following antithyroid drug (ATD) treatment in newly diagnosed Graves disease.Results: During follow-up of 204 patients with TRAb-positive Graves disease, 107 (52%) relapsed following withdrawal of ATD. Mean age was 40.0 years, and 82% were female. The average duration of ATD treatment was 23.5 months and was not different between patients who relapsed and those with sustained remission. Absence of TPOAbs significantly increased risk of Graves relapse (odds ratio, 2.21). Male sex and younger age were other factors significantly associated with increased risk of relapse.Conclusion: TPOAb positivity significantly improves the odds of remission following ATD treatment in newly diagnosed Graves’ disease.     

Successful Treatment of Thyroid Storm with Plasmapheresis in a Patient with Methimazole-Induced Agranulocytosis

ObjectiveTo report a case of a patient with Graves disease presenting with agranulocytosis induced by methimazole, with subsequent thyroid storm and successful therapeutic use of plasmapheresis.MethodsThe clinical features and laboratory findings in a patient with agranulocytosis and thyroid storm are presented, and the available literature on utilization of plasmapheresis in the setting of thyrotoxicosis is reviewed.ResultsA 40-year-old Vietnamese woman with Graves disease was admitted with methimazole-induced agranulocytosis. Treatment with methimazole was discontinued, and therapy with antibiotics, granulocyte colonystimulating factor, and ibuprofen was initiated. During hospitalization of the patient, her clinical status deteriorated, with development of pericarditis, thrombocytopenia, and thyroid storm. Treatment with plasmapheresis yielded near-euthyroidism in 3 days. Subsequently, she underwent successful total thyroidectomy.ConclusionOur case highlights the effectiveness of plasmapheresis when clinical situations prohibit the use of traditional treatment methods for thyrotoxicosis or thyroid storm (or both). (Endocr Pract. 2010;16:673-676)     

初始小剂量甲巯咪唑对Graves病甲亢患者甲状腺功能和Visfatin、TNF-α、IL-6水平的影响

目的:分析初始小剂量甲巯咪唑治疗对Graves病甲状腺功能亢进症(甲亢)患者甲状腺功能和内脂素(Visfatin)、肿瘤坏死因子-α(Tumor necrosis factor-alpha, TNF-α)、白介素-6(Interleukin-6, IL-6)水平的影响。方法:选择我院2017年1月-2018年6月诊治的125例Graves病甲亢患者,根据入院编号随机数字表法分为两组。对照组63例给予甲硫咪唑15 mg/次,2次/d;研究组62例给予甲硫咪唑10 mg/次,2次/d,两组均连续治疗6个月,对比两组治疗总有效率、治疗前后甲状腺功能和血清Visfatin、TNF-α、IL-6水平的变化。结果:治疗后,研究组的治疗总有效率显著高于对照组(90.32%vs. 77.78%,P<0.05);两组患者的甲状腺功能指标血清游离三碘甲状腺原氨酸(Free triiodothyronine, FT3)、血清游离甲状腺素(FT4)水平均显著降低、敏感促甲状腺激素(Sensitive thyroid stimulating hormone, s TSH)水平均显著升高,且研究组以上指标变化较对照组更显著(P<0.05);两组患者的血清Visfatin、TNF-α、IL-6水平均较治疗前显著下降,且研究组以上指标均显著低于对照组(P<0.05)。结论:初始小剂量(10 mg/次)甲巯咪唑治疗Graves病甲亢的疗效显著优于甲硫咪唑15 mg/次治疗,可能与其有效改善患者的甲状腺功能和血清Visfatin、TNF-α、IL-6等炎症因子水平有关。     

Thyroid-Stimulating Antibody/Thyroid-Stimulating Hormone Receptor Antibody Ratio as a Sensitive Screening Test for Active Graves’ Orbitopathy

ObjectiveGraves’ orbitopathy (GO), an extrathyroidal manifestation of Graves’ disease, can seriously threaten a patient's quality of life. Given that immunosuppressive treatment during the early active phase of GO has been found to reduce both disease activity and severity, sensitive screening tests are needed.MethodsThe present study included 86 patients with GO, in whom serum levels of thyroid-stimulating hormone (TSH), free triiodothyronine (T3), free thyroxine, thyroid-stimulating antibody, TSH receptor antibody, thyroid peroxidase antibody, thyroglobulin, and thyroglobulin antibody were measured within 2 months before magnetic resonance imaging (MRI) for orbit assessment.ResultsThe thyroid-stimulating antibody/TSH receptor antibody ratio was able to distinguish MRI results with a correct classification rate of 81%. When focusing on patients without T3 predominant Graves’ diseases, the ratio distinguished MRI results at a rate of 92%. Receiver operating characteristic curve analysis revealed a cutoff antibody ratio of 87, which yielded a sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of 91%, 95%, 18.2, and 0.0957, respectively, for distinguished MRI results.ConclusionsThe thyroid-stimulating antibody/TSH receptor antibody ratio is a highly sensitive and specific indicator for active GO, especially in patients without T3 predominance, and serves as a good screening test for active GO in primary care settings.     

TSH Receptor Antibodies: Relevance & Utility

Objective: Antibodies (Abs) to the thyrotropin (TSH) receptor (TSH-R) play an important role in the pathogenesis of autoimmune thyroid disease (AITD). We define the complex terminology that has arisen to describe TSH-R-Abs, review the mechanisms of action of the various types of TSH-R-Abs, and discuss significant advances that have been made in the development of clinically useful TSH-RAb assays.Methods: Literature review and discussion.Results: TSH-R-Abs may mimic or block the action of TSH or be functionally neutral. Stimulating TSH-R-Abs are specific biomarkers for Graves disease (GD) and responsible for many of its clinical manifestations. TSH-R-Abs may also be found in patients with Hashimoto thyroiditis in whom they may contribute to the hypothyroidism of the disease. Measurement of TSH-R-Abs in general, and functional Abs in particular, is recommended for the rapid diagnosis of GD, differential diagnosis and management of patients with AITD, especially during pregnancy, and in AITD patients with extrathyroidal manifestations such as orbitopathy. Measurement of TSH-R-Abs can be done with either immunoassays that detect specific binding of Abs to the TSH-R or cell-based bioassays that also provide information on their functional activity and potency. Application of molecular cloning techniques has led to significant advances in methodology that have enabled the development of clinically useful bioassays. When ordering TSH-R-Ab, clinicians should be aware of the different tests available and how to interpret results based on which assay is performed. The availability of an international standard and continued improvement in bioassays will help promote their routine performance by clinical laboratories and provide the most clinically useful TSH-R-Ab results.Conclusion: Measurement of TSH-R-Abs in general, and functional (especially stimulating) Abs in particular, is recommended for the rapid diagnosis, differential diagnosis, and management of patients with Graves hyperthyroidism, related thyroid eye disease, during pregnancy, as well as in Hashimoto thyroiditis patients with extra-thyroidal manifestations and/or thyroid-binding inhibiting immunoglobulin positivity.Abbreviations: Ab = antibody; AITD = autoimmune thyroid disease; ATD = antithyroid drug; cAMP = cyclic adenosine 3′,5′-monophosphate; ELISA = enzyme-linked immunosorbent assay; GD = Graves disease; GO = Graves orbitopathy; HT = Hashimoto thyroiditis; MAb = monoclonal antibody; TBAb = thyrotropin receptor blocking antibody; TBII = thyroid-binding inhibiting immunoglobulin; TSAb = thyrotropin receptor–stimulating antibody; TSB-Ab or TRBAb = thyrotropin receptor–stimulating blocking antibody; TSH = thyrotropin; TSH-R = thyrotropin receptor     

Determination of susceptibility to pharmacologic treatment in Graves'-Basedow disease]

The authors present the results of research on the usefulness of clinical data, thyroid hormones, TSH, antithyroid antibody, HLA estimations and a type of behavior, for prognosing the susceptibility to pharmacological therapy in thyrotoxicosis, specially in Graves disease. The highest chance of predictability was found in patients with small goiter, HLA-DR5 positive with onset of the disease at the age before 40. In general it is difficult to predict the reaction to therapy in individual case with high probability.     

Serum Selenium Levels in Patients With Graves Disease With or Without Thyroid Ophthalmopathy

BackgroundGraves disease is one of the most common autoimmune thyroid diseases. Thyroid has the highest concentration of selenium (Se) in the body. Se plays a crucial role in the functioning of some thyroid enzymes; however, there are controversial results regarding the administration of serum Se levels in patients with Graves disease.MethodsIn this study, patients with Graves disease with orbitopathy (GO group) or without orbitopathy (GD group) were recruited. Healthy individuals without a history of any disease were enrolled as the control group. Serum Se and thyroid hormone levels, including T3, T4, and thyroid-stimulating hormone (TSH), were measured using atomic absorption and radioimmunoassay techniques, respectively.ResultsIn this cross-sectional study, 60 and 56 patients and 58 healthy subjects were included in the GO, GD, and control groups. Serum Se levels in the GO, GD, and control groups were 94.53 ± 25.36 μg/dL, 96.82 ± 30.3 μg/dL, and 102.55 ± 16.53 μg/dL, respectively (P = .193). There was a reverse association between the serum Se level and thyroid hormones, including T3, T4, and TSH, in the GO group. However, serum Se levels exhibited a significant reverse association with T4 and TSH hormones but not with T3 in the GD group.ConclusionOur results showed no significant differences in the serum Se levels in the GO and GD groups compared with that in the control group. In addition, we did not detect any significant difference in the serum Se levels between the GO and GD groups.     

Gender Influences the Clinical Presentation and Long-Term Outcome of Graves Disease

Objective: The outcome of antithyroid drug (ATD) treatment for Graves disease (GD) is difficult to predict. In this study, we investigated whether male gender, besides other factors usually associated with a poor outcome of ATD treatment, may affect disease presentation and predict the response to medical treatment in subjects with GD.Methods: We studied 294 patients with a first diagnosis of GD. In all patients, ATD treatment was started. Clinical features, thyroid volume, and eye involvement were recorded at baseline. Serum levels of free thyroxine (FT4), free triiodothyronine (FT3), thyroid-stimulating hormone (TSH), and TSH-receptor antibodies (TRAb) were measured at baseline and during the follow-up. Treatment outcome (FT4, FT3, and TSH serum levels and further treatments for GD after ATD withdrawal) was evaluated.Results: When compared to women, men showed a significantly larger thyroid volume and a higher family positivity for autoimmune diseases. During ATD, the mean serum levels of TSH, FT4, FT3, and TRAb did not differ between groups. Within 1 year after ATD discontinuation, relapse of hyperthyroidism was significantly more frequent in men than in women. Within the 5-year follow-up period, the prevalence of men suffering a late relapse was higher compared with that of women. The outcome at the end of the 5-year follow-up period was significantly associated with gender and TRAb levels at disease onset.Conclusion: Male patients with GD have a poorer prognosis when submitted to medical treatment with ATDs. A larger goiter at presentation and a stronger genetic autoimmune background might explain this gender difference in patients with GD.Abbreviations:ATD = antithyroid drugFT3 = free triiodothyronineFT4 = free thyroxineGD = Graves diseaseGO = Graves orbitopathyRAI = radioiodineTRAb = thyroid-stimulating hormone-receptor antibodyTSH = thyroid-stimulating hormone     

Functional TSH receptor in human abdominal preadipocytes and orbital fibroblasts

Controversy continues about whether, and to whatlevels of abundance, thyroid-stimulating hormone receptors (TSHR) arefound in human tissues other than the thyroid gland. Restrictedexpression to the thyroid and orbit would suggest that TSHR representsthe target autoantigen in thyroid-associated ophthalmopathy. A more generalized pattern of tissue expression would be inconsistent withTSHR acting as the autoantigen that is solely responsible forselectively targeting the immune system to the orbit. We have detectedTSHR mRNA in human abdominal adipose tissue by Northern blot analysis.TSHR protein was also detected, by immunoblotting with two differentantibodies, in preadipocytes isolated from human abdominal subcutaneousand omental adipose tissue and in derivative adipocytes differentiatedin primary culture. Preadipocytes treated with thyroid-stimulatinghormone (TSH) exhibited a sevenfold increase in the activity of p70 S6kinase, a serine/threonine kinase recently recognized as a downstreamtarget of TSHR in thyroid cells. Activation of p70 S6 kinase by TSH wasalso observed in orbital fibroblasts. Thus TSHR protein expression isfound in fibroblasts from several anatomic locations, suggesting thatfactors other than site-limited TSHR expression must be involved inrestricting the distribution of Graves' disease manifestations.Furthermore, the presence of functional TSHR in preadipocytes raisesthe possibility of a novel role for TSHR signaling in adipose tissue development.

     

The posttranslational modification of thyrotropin receptor and thyroid diseases

The thyrotropin receptor (TSHR), lutropin receptor, and follitropin receptor are related members of the superfamily of leucine-rich repeats containing adenylate cyclase stimulating receptors. The unique posttranslational modification of the TSHR leads to the transformation of its monomeric form to the subunit structure where the subunits A and B are connected by disulphide bonds. This natural processing occurs with the release from the receptor of a short peptide C, and is followed by the release of the subunit A. Both monomeric and dimeric forms of the receptor are stimulated by TSH, so no clear functional significance of TSHR modifications have been found. We can speculated that the processing of TSHR with the release of its large fragments contributes to the development of autoimmune diseases and production anti-TSH receptor autoantibodies. The extrathyroidal manifestations of Graves disease may also be related to metastasis of the autoimmune reaction to extrathyroidal sites via the released A subunit. The TSHR processing may, to some extent, be connected to the hyperthyroidism since the release of the subunit A from the receptor augmented the adenylate cyclase activity in the absence of TSH. According to the recent model of receptors action the TSHR is in equilibrium between the inactive (closed) and active (opened) conformations. In opened conformation it can associate with Gs protein and trigger the intracellular signal. TSH and stimulating autoantibodies preferentially bind to opened receptors and stabilizes them.     

Oligomerization of the human thyrotropin receptor: fluorescent protein-tagged hTSHR reveals post-translational complexes

To examine thyrotropin (TSH) receptor homophilic interactions we fused the human TSH receptor (hTSHR) carboxyl terminus to green fluorescent protein (GFP) and the corresponding chimeric cDNA was expressed in Chinese hamster ovary cells. Fluorescent TSH receptors on the plasma membrane were functional as assessed by TSH-induced cAMP synthesis. The binding of TSH, as well as TSHR autoantibodies, induced time- and dose-dependent receptor capping. Fluorescence resonance energy transfer between receptors differentially tagged with GFP variants (RFP and YFP) provided evidence for the close proximity of individual receptor molecules. This was consistent with previous studies demonstrating the presence of TSHR dimers and oligomers in thyroid tissue. Co-immunoprecipitation of GFP-tagged and Myc-tagged receptor complexes was performed using doubly transfected cells with Myc antibody. Western blotting of the immunoprecipitated complex revealed the absence of noncleaved TSH holoreceptors. This further suggested that cleavage of the holoreceptor into its two-subunit structure, comprising disulfide-linked TSHR-alpha and TSHR-beta subunits, was required for the formation of TSHR dimers and higher order complexes.