Regulatory T Cells in the Pathogenesis of Graves' Disease.

Maintaining a delicate balance between the prompt immune response to pathogens and tolerance towards self-antigens and commensals is crucial for health. T regulatory (Treg) cells are pivotal in preserving self-tolerance, serving as negative regulators of inflammation through the secretion of anti-inflammatory cytokines, interleukin-2 neutralization, and direct suppression of effector T cells. Graves' disease (GD) is a thyroid-specific autoimmune disorder primarily attributed to the breakdown of tolerance to the thyroid-stimulating hormone receptor. Given the limitations of currently available GD treatments, identifying potential pathogenetic factors for pharmacological targeting is of paramount importance. Both functional impairment and frequency reduction of Tregs seem likely in GD pathogenesis. Genome-wide association studies in GD have identified polymorphisms of genes involved in Tregs' functions, such as CD25 (interleukin 2 receptor), and Forkhead box protein P3 (FOXP3). Clinical studies have reported both functional impairment and a reduction in Treg frequency or suppressive actions in GD, although their precise involvement remains a subject of debate. This review begins with an overview of Treg phenotype and functions, subsequently delves into the pathophysiology of GD and into the existing literature concerning the role of Tregs and the balance between Tregs and T helper 17 cells in GD, and finally explores the ongoing studies on target therapies for GD.

Epidemiology, Natural History, Risk Factors, and Prevention of Graves' Orbitopathy.

GO is the most frequent extrathyroidal manifestation of Graves' disease, although it may rarely occur in euthyroid/hypothyroid patients with chronic autoimmune thyroiditis. It is a relatively infrequent disorder, and men tend to have more severe ocular involvement at an older age. The prevalence of GO is lower than in the past among patients with recent onset Graves' hyperthyroidism, and moderate-to-severe forms requiring aggressive treatments are no more than 5-6% of all cases of GO. After an initial inflammatory (active) phase and a phase of stabilization (plateau phase), GO tends to improve and eventually inactivates (inactive or burnt-out phase). Minimal-to-mild GO often remits spontaneously, but complete restitutio ad integrum almost never occurs when GO is more than mild. Several risk factors contribute to its development on a yet undefined genetic background. Cigarette smoking is the most important of them. Early diagnosis, control and removal of modifiable risk factors, early treatment of mild forms of GO may effectively limit the risk of progression to more severe forms, which have a profound and dramatic impact on the quality of life of affected individuals, and remain a therapeutic challenge, often requiring long-lasting and multiple medical and surgical therapies.

Cardiometabolic healthy and unhealthy obesity: does vitamin D play a role?

OBJECTIVE: The aim of this observational study was to clarify the link between vitamin D status and metabolic syndrome (MetS) in people with visceral obesity. DESIGN AND METHODS: One hundred ninety-six consecutive patients (152 women; mean age 51 ± 13 years) with visceral obesity (mean body weight 103 ± 20 kg, mean waist circumference (WC) 119 ± 13 cm) were enrolled at the Obesity Outpatient Clinic of the University of Insubria in Varese. Anthropometric measurements were recorded. Laboratory tests, including vitamin D (25(OH)D)), fasting blood glucose (FBG), lipid profile, liver and kidney function tests were assessed. Vitamin D status was defined according to the European Society of Endocrinology guidelines, MetS to the 2009 harmonized definition. RESULTS: An inverse association emerged among 25(OH)D, body mass index (BMI) (P = 0.001) and WC (all P = 0.003). Serum 25(OH)D levels were inversely related to FBG and systolic blood pressure (SBP) (respectively, P = 0.01 and 0.02). Median serum 25(OH)D levels were 13.3 ng/mL (CI 95% 12; 15) in MetS and 16 ng/mL (CI 95% 14; 18) (P = 0.01) in non-MetS patients. Among patients with MetS, lower 25(OH)D concentrations were related to higher risk of hypertension (HT) (odds ratio (OR) 1.7, CI 95%, 0.7;4) and hyperglycemia (IFG)/type 2 diabetes (OR 5.5, CI 95% 2; 14). CONCLUSION: Vitamin D status and MetS are inversely correlated in visceral obesity, particularly with regard to glucose homeostasis and BP. More extensive studies are required to investigate the potential for causality.

Novel treatment modalities for Graves' orbitopathy.

Non-surgical treatments for moderate to severe and active Graves' orbitopathy (systemic glucocorticoids with or without orbital radiotherapy) have limited effects on the underlying autoimmune process causing the disease. Although the clinical responses to treatment are often good, at least one third of patients with Graves' orbitopathy are eventually dissatisfied with the treatment outcome. Progress in our understanding of the autoimmune basis of Graves' orbitopathy (although still incomplete) made it possible, similar to other autoimmune disorders, to envision the use of novel immunomodulating drugs. Among the currently available biologic agents, the CD20+ B cell-depleting agent, rituximab, and tumor necrosis factor-alpha inhibitors are presently the drugs that have the best chance of being employed in the future for the treatment of Graves' orbitopathy. However, randomized, controlled clinical trials to support their use are warranted.

Lower dose prednisone prevents radioiodine-associated exacerbation of initially mild or absent graves' orbitopathy: a retrospective cohort study.

CONTEXT: Radioiodine (RAI) therapy may cause progression of mild or absent Graves' orbitopathy (GO), preventable by oral prednisone. Optimal doses of prednisone are undefined. OBJECTIVE: The aim of this study was to compare the effectiveness of reported doses [starting dose, >0.3 mg/kg body weight (bw)], and lower (<0.3 mg/kg bw)] doses of prednisone. DESIGN AND SETTING: We conducted a retrospective matched cohort study at a University Center. PATIENTS: Of 111 RAI-treated Graves' patients with mild or no GO, 35 received no steroid prophylaxis (absence of GO and/or risk factors for RAI-associated GO progression); 28 received low-dose prednisone (starting dose, 0.16-0.27 mg/kg bw; mean +/- sd, 0.22 +/- 0.03 mg/kg bw; group 1); and 48 received higher doses (group 2). Among the latter, 28 (starting dose, 0.32-0.56 mg/kg bw; mean +/- sd, 0.36 +/- 0.05 mg/kg bw) were matched with group 1 according to several relevant variables. Prednisone was started 1 d after RAI and withdrawn after 6 wk. MAIN OUTCOME MEASURES: We assessed ocular changes (1, 3, and 6 months after RAI) and side effects of prednisone. RESULTS: Two of 35 patients not receiving steroid prophylaxis (6%) developed mild-to-moderate GO (clinical activity score, 2/7 and 3/7) after RAI. No patients in group 1 or group 2 had GO progression. Side effects were very mild and inconstant, although more frequent in group 2. Both groups showed an increase in bw, an increase that was significantly higher in group 2. CONCLUSION: Lower doses of oral prednisone (about 0.2 mg/kg bw) are as effective as previously reported doses (0.3-0.5 mg/kg bw). A shorter treatment period (6 wk) is probably sufficient. The increase in bw is less using lower doses of prednisone.

Ectopic submandibular thyroid tissue with a coexisting normally located multinodular goitre: case report and review of the literature.

The simultaneous finding of submandibular ectopic thyroid tissue and functional orthotopic thyroid gland is an extremely rare event. The present report describes the case of a woman presenting with a left submandibular mass, distant from a palpable multinodular goitre. Ultrasonography showed an ovoidal solid mass adjacent to the lower margin of the left submandibular gland. Cytological specimens showed colloid material and thyroid follicular cells with no malignant features. A preoperative CT scan demonstrated a very thin connection between the thyroid and the submandibular mass. The patient underwent total thyroidectomy and excision of the submandibular mass. The histopathological diagnosis of the thyroid tissue was multinodular goitre, and the submandibular mass was ectopic thyroid tissue showing a hyperplastic pattern. The main differential diagnosis of the submandibular mass was a metastasis from a well differentiated cancer. This case illustrates that an ectopic thyroid off the midline may not necessarily be a metastasis from a thyroid cancer.

Solitary intrathyroidal metastasis of renal clear cell carcinoma in a toxic substernal multinodular goiter.

INTRODUCTION: Thyroid gland is a rare site of clinically detectable tumor metastasis. CASE REPORT: A 71-year-old woman was referred to our department for an evaluation of toxic multinodular substernal goiter. She had a history of renal clear cell carcinoma of the left kidney, which had been resected 2 years previously. US confirmed the multinodular goiter. Total thyroidectomy with neuromonitoring was performed on March 2008. A histological examination revealed a solitary metastasis of a clear cell renal cancer in a diffuse multinodular goiter. No distant metastases are detected. CONCLUSION: Although uncommon, it is important for the endocrine surgeon and endocrine oncologist to be able to recognize and differentiate intrathyroid metastases from more primary common thyroid neoplasms. The diagnosis can be suspected if the patient has a thyroid tumor and a past history of extrathyroid cancer. These tumors, on the whole, tend to behave more aggressively and, in most cases, the use of multimodality therapy is recommended.

Diagnosis and management of amiodarone-induced thyrotoxicosis: similarities and differences between North American and European thyroidologists.

OBJECTIVE: To investigate how North American thyroidologists assess and treat amiodarone-induced thyrotoxicosis (AIT) and to compare the results with those of the same questionnaire-based survey previously carried out among European thyroidologists. DESIGN: Members of the American Thyroid Association (ATA) with clinical interests were sent by e-mail a questionnaire on the diagnosis and management of AIT, 115 responses were received from the United States and Canada, representing about one-third of ATA members with clinical interests. RESULTS: The majority of respondents (91%vs. 68% in Europe, P < 0.05) see < 10 new cases of AIT per year, and AIT seems less frequent than amiodarone-induced hypothyroidism (AIH) in North America (34% and 66% of amiodarone-induced thyroid dysfunction, respectively, vs. 75% and 25%, respectively, in Europe, P < 0.001). When AIT is suspected, in North America hormonal assessment is mostly based on serum free T4 (FT4) and TSH measurements, while serum free T3 (FT3) determination is requested less frequently than in Europe; thyroid autoimmunity is included in the initial assessment less than in Europe. Most commonly used additional diagnostic procedures include, as in Europe, thyroid colour-flow Doppler sonography, and to a lesser extent, thyroid radioactive iodine uptake and scan, but Europeans tend to request multiple tests more than North Americans. Withdrawal of amiodarone is more often considered unnecessary by North American thyroidologists (21%vs. 10% in Europe in type 1 AIT, P < 0.05, 34%vs. 20% in type 2 AIT, P < 0.05). In type 1 AIT thionamides represent the treatment of choice for North Americans as well as for Europeans, but the former use them as monotherapy in 65%vs. 51% of Europeans (P < 0.05) who more often consider potassium perchlorate as an useful addition (31%vs. 15% of North Americans, P < 0.01). Glucocorticoids are the selected treatment for type 2 AIT, alone (62%vs. 46% in Europe, P < 0.05) or in association with thionamides (16%vs. 25% in Europe, P = NS). After restoration of euthyroidism, thyroid ablation in the absence of recurrent thyrotoxicosis is recommended in type 1 AIT less frequently by North Americans. If amiodarone therapy needs to be reinstituted, prophylactic thyroid ablation is advised by 76% in type 1 AIT, while a 'wait-and-see' strategy is adopted by 61% in type 2 AIT, similar to behaviour of European thyroidologists. CONCLUSION: Similarities and differences exist between expert North American and European thyroidologists concerning the diagnosis and management of AIT. While differences reflect the frequent uncertainty of the underlying mechanism leading to AIT, similarities may represent the basis to refine the diagnostic criteria and to improve the therapeutic outcomes of this challenging clinical situation.

Perspectives in pharmacological management of Graves' hyperthyroidism and orbitopathy.

Drugs currently used for Graves' hyperthyroidism (thionamides) or for the major extrathyroidal expression of Graves' disease, Graves' orbitopathy (systemic glucocorticoids with or without orbital radiotherapy), have limited effects on the autoimmune processes underpinning these disorders. Thionamides show a high rate of treatment failure and at least 30% of patients with Graves' orbitopathy are eventually dissatisfied with treatment outcome. Progress in our understanding of the autoimmune basis of Graves' hyperthyroidism and orbitopathy made it possible, similar to other autoimmune disorders, to envision the use of novel immunomodulating drugs. Among the currently available biologic agents, the CD20(+) B-cell-depleting agent, rituximab, and TNF-alpha inhibitors are the drugs that have the highest chance of finding a place in the treatment of Graves' hyperthyroidism and orbitopathy, although randomized, controlled clinical trials are warranted to support their use.

An update on the pharmacological management of hyperthyroidism due to Graves' disease.

Pharmacological treatment, usually by thionamides (carbimazole, methimazole, propylthiouracil) is, in addition to radioiodine therapy and thyroidectomy, one of the available therapies for Graves' hyperthyroidism. Thionamides represent the treatment of choice in pregnant women, during lactation, in children and adolescents and in preparation for radioiodine therapy or thyroidectomy. Side effects are relatively frequent but are in general mild and transient. Two main regimens are available: titration method (use of the lowest dose maintaining euthyroidism; duration: 12-18 months) and block-and-replace method. Neither one has clear advantages in terms of outcome but the latter method is associated with more frequent side effects. Hyperthyroidism relapses in approximately 50% of patients, to whom ablative therapy should be offered.

Diagnosis and management of amiodarone-induced thyrotoxicosis in Europe: results of an international survey among members of the European Thyroid Association.

OBJECTIVE: To determine how expert European thyroidologists assess and treat amiodarone-induced thyrotoxicosis (AIT). DESIGN: Members of the European Thyroid Association (ETA) with clinical interests were asked to answer a questionnaire on the diagnosis and management of AIT. A total of 124 responses were received: 116 from Europe, seven from USA and one from Brazil. After excluding responses coming from the same centre, 101 responses from 24 European countries were analysed, representing approximately 65% of clinically active European ETA members. RESULTS: The majority of respondents (68%) see 1-10 new cases of AIT/year, and AIT seems to be more frequent than amiodarone-induced hypothyroidism in Europe, where in many instances iodine intake is borderline or moderately deficient. A good collaboration with cardiologists exists in most centres, and patients receiving chronic amiodarone treatment are checked for thyroid function most commonly every 4-6 months. When AIT is suspected, a diffuse or nodular goitre is present or in the absence of apparent abnormalities of the thyroid, free thyroxine (FT4), free triiodothyronine (FT3) and TSH are assayed by almost 90% of respondents. Thyroid autoimmunity is evaluated in the initial assessment by > 80%, while evaluation of urinary iodine excretion is unhelpful for > 60%. Most commonly used additional diagnostic procedures include thyroid ultrasonography, particularly colour flow Doppler sonography, and, to a lesser extent, a thyroid uptake scan. If the thyroid gland is apparently normal, measurement of thyroidal radioactive iodine uptake is considered useful by a large proportion of respondents to establish the destructive nature of the process. Differentiation of type I and type II AIT is difficult and, possibly, not correct for 27% of respondents, who believe that mixed (or indefinite) forms are probably more frequent than previously recognized. Approximately 10-20% do not consider amiodarone withdrawal necessary in the therapeutic strategy of AIT, especially if the thyroid gland is apparently normal. Most respondents (82%) treat type I AIT with thionamides, either alone (51%) or in combination with potassium perchlorate (31%), while the preferred treatment for type II AIT is represented by glucocorticoids (46%). Some respondents, in view of diagnostic difficulties, initially treat all cases of AIT with a combination of thionamides and glucocorticoids. After restoration of euthyroidism, ablative therapy is recommended by 34% in type I and only 8% in type II AIT. If amiodarone therapy needs to be reinstituted, prophylactic thyroid ablation is recommended by 65% in type I AIT, while a wait-and-see strategy is adopted by 70% in type II AIT. CONCLUSION: Areas of certainty and uncertainty concerning AIT are present among expert European thyroidologists, both from a diagnostic and a therapeutic standpoint. Diagnostic criteria need to be refined in order to improve therapeutic outcome.

Oxidative stress and Graves' ophthalmopathy: in vitro studies and therapeutic implications.

Graves' ophthalmopathy (GO) is a disorder of autoimmune origin caused by a complex interplay of endogenous and environmental factors. After recognition of one or more antigens shared by thyroid and orbit, activated T lymphocytes infiltrating the orbit trigger a cascade of events leading to production of cytokines, growth factors and oxygen reactive species. Proliferation of adipocytes and fibroblasts then follows, with an increased synthesis of glycosaminoglycans (GAG), which attract water and cause edema of orbital structures and venous congestion. Proliferation of orbital fibroblasts and adipocytes, both in the retroocular tissue and in the perimysium of extraocular muscles, are among the most important events leading to the increased volume of orbital structures (fibroadipose tissue and extraocular muscles). The contribution of oxygen reactive species to the changes occurring in the orbit is underscored by in vitro studies. Superoxide radical stimulates orbital fibroblasts to proliferate and to produce GAG. Furthermore, hydrogen peroxide induces expression of HLA-DR and heat shock protein-72, involved in antigen recognition and T-lymphocyte recruitment. Cigarette smoking, which is probably the most important environmental factor associated with GO occurrence and maintenance, might also act, among other mechanisms, by enhancing generation of oxygen reactive species and reducing antioxidant production. Substances such as nicotinamide, allopurinol and pentoxifylline reduce superoxide- or hydrogen peroxide-induced proliferation of fibroblasts, GAG production and HLA-DR or HSP-72 expression by GO orbital fibroblasts, possibly through scavenging oxygen free radicals. Two small, non-randomized and/or uncontrolled studies investigated the effects of nicotinamide, allopurinol or pentoxifylline on GO. Favorable results were reported, but data are not fully convincing and the true effectiveness of these agents needs to be verified in randomized, controlled trials enrolling a larger number of patients. It currently seems unlikely that they may find a relevant place in the limited armamentarium available for the management of severe GO.