Graves' orbitopathy as a rare disease in Europe: a European Group on Graves' Orbitopathy (EUGOGO) position statement.

BACKGROUND: Graves' orbitopathy (GO) is an autoimmune condition, which is associated with poor clinical outcomes including impaired quality of life and socio-economic status. Current evidence suggests that the incidence of GO in Europe may be declining, however data on the prevalence of this disease are sparse. Several clinical variants of GO exist, including euthyroid GO, recently listed as a rare disease in Europe (ORPHA466682). The objective was to estimate the prevalence of GO and its clinical variants in Europe, based on available literature, and to consider whether they may potentially qualify as rare. Recent published data on the incidence of GO and Graves' hyperthyroidism in Europe were used to estimate the prevalence of GO. The position statement was developed by a series of reviews of drafts and electronic discussions by members of the European Group on Graves' Orbitopathy. The prevalence of GO in Europe is about 10/10,000 persons. The prevalence of other clinical variants is also low: hypothyroid GO 0.02-1.10/10,000; GO associated with dermopathy 0.15/10,000; GO associated with acropachy 0.03/10,000; asymmetrical GO 1.00-5.00/10,000; unilateral GO 0.50-1.50/10,000. CONCLUSION: GO has a prevalence that is clearly above the threshold for rarity in Europe. However, each of its clinical variants have a low prevalence and could potentially qualify for being considered as a rare condition, providing that future research establishes that they have a distinct pathophysiology. EUGOGO considers this area of academic activity a priority.

Management of thyroid eye disease in the United Kingdom: A multi-centre thyroid eye disease audit.

This article aims to provide baseline data and highlight any major deficiencies in the current level of care provided for adult patients with thyroid eye disease (TED). We undertook a prospective, nonrandomized cross-sectional multicenter observational study. During a 3-month period June-August 2014, consecutive adult patients with TED who presented to nominated specialist eye clinics in the United Kingdom, completed a standardized questionnaire. Main outcome measures were: demographics, time from diagnosis to referral to tertiary centre, time from referral to review in specialist eye clinic, management of thyroid dysfunction, radioiodine and provision of steroid prophylaxis, smoking, and TED classification. 91 patients (mean age 47.88 years) were included. Female-to-male ratio was 6:1. Mean time since first symptoms of TED = 27.92 (73.71) months; from first visit to any doctor with symptoms to diagnosis = 9.37 (26.03) months; from hyperthyroidism diagnosis to euthyroidism 12.45 (16.81) months. First, 13% had received radioiodine. All those with active TED received prophylactic steroids. Seven patients who received radioiodine and did not have TED at the time went on to develop it. Then, 60% patients were current or ex-smokers. 63% current smokers had been offered smoking cessation advice. 65% patients had active TED; 4% had sight-threatening TED. A large proportion of patients (54%) were unaware of their thyroid status. Not enough patients are being provided with smoking cessation advice and information on the impact of smoking on TED and control of thyroid function.

Current challenges in the pharmacological management of thyroid dysfunction in pregnancy.

INTRODUCTION: Thyroid dysfunction is common in pregnancy and has adverse fetal and maternal health consequences. A number of challenges in the management of gestational thyroid dysfunction remain unresolved including uncertainties in optimal thresholds for correction of hypothyroidism and strategies for pharmacological management of hyperthyroidism. Areas covered: We addressed key challenges and areas of uncertainty in the management of thyroid dysfunction in pregnancy. Expert commentary: Gestational thyroid hormone reference intervals vary according to population ethnicity, iodine nutrition, and assay method and each population should derive trimester specific reference intervals for use in pregnancy. Subclinical hypothyroidism and isolated hypothyroxinaemia are common in pregnancy but there is no consensus on the benefits of correcting these conditions. Although observational studies show potential benefits of levothyroxine on child neurocognitive function these benefits are have not been supported by two controlled trials. Carbimazole should be avoided in the first trimester of pregnancy due to risk of congenital anomalies but recent studies would suggest that this risk is present to a lesser magnitude with propylthiouracil. Current international guidelines recommend the use of propylthiouracil in the first trimester and switching to carbimazole for the remainder of pregnancy but the benefits and practicalities of this approach is unproven.

HYPOTHYROXINAEMIA AND BRAIN DEVELOPMENT.

The aim of this review is to indicate the current position on the role of thyroxine (T4) and fetal brain development with particular relevance to the human situation. Adequate maternal iodine nutrition and maternal circulating thyroxine (T4) concentrations are essential to ensure optimum T4 placental passage which in turn will ensure transport of T4 into fetal brain cells. These processes are discussed and the role of thyroid hormone transporters is considered. The emphasis on isolated maternal hypothyroxinaemia (IH) as an important factor affecting brain development is discussed from the animal experimental point of view as well as in the clinical setting. There is evidence of neurocognitive impairment as assessed by different modalities in children up to the age of 8 years and some suggestion of increased psychiatric disorder in older persons whose mothers had IH during gestation. Although international guidelines have not in general recommended thyroxine therapy for IH the recent demonstration of adverse obstetric outcomes in women with isolated maternal hypothyroxinaemia may warrant a revision of this strategy.

Prognostic significance of thyroglobulin antibody epitopes in differentiated thyroid cancer.

CONTEXT: Thyroglobulin antibodies (TgAbs) are surrogate markers of disease recurrence or persistence in differentiated thyroid cancer (DTC). However, the prognostic significance of TgAb heterogeneity in DTC has not been investigated. OBJECTIVE: To evaluate the relationship between TgAb epitope specificities and clinical outcomes in DTC patients. DESIGN: We studied 61 TgAb-positive patients with DTC, post-thyroidectomy and remnant ablation (7 males, 54 females; age-range 16-80 years, median follow-up duration 8.9 years). TgAb epitope reactivities were mapped using a panel of 10 thyroglobulin (Tg) monoclonal antibodies delineating six antigenic Tg clusters in competitive ELISA studies. Sera from 45 patients with Hashimoto's thyroiditis (HT) and 22 TgAb-positive healthy subjects served as autoimmune and healthy controls. Tg was measured by immunoradiometric assay (IRMA), electrochemiluminescence immunoassay (ECLIA), and RIA, while TgAbs was measured by ELISA and ECLIA methods. RESULTS: Samples from 26 DTC patients showed TgAb epitope restriction similar to HT patients, while 35 patients exhibited nonspecific reactivity comparable to healthy controls. DTC patients with epitope restriction had higher rates of recurrent/persistent disease (81% vs 17%, P < .001), higher median TgAb concentration (887.0 vs 82.0 kIU/L; P < .001), and a higher prevalence of thyroid lymphocytic infiltration (71.4% vs 26.8%; P < .001) compared to patients with nonspecific reactivity. Samples with epitope restriction also had a lower median Tg-IRMA/RIA ratio (3.0% vs 36.0%; P < .001) denoting greater degrees of Tg assay interference. CONCLUSIONS: TgAb epitope restriction is associated with a less favorable prognosis than nonspecific reactivity in DTC patients. TgAb epitope specificities may have prognostic value in DTC.

Update on a new controversy in endocrinology: isolated maternal hypothyroxinemia.

Isolated hypothyroxinemia (IH) is defined as a thyroxine level in the lower 5th (severe IH) or 10th percentile (mild IH) of the pregnancy-related reference range and a normal TSH. The etiology of IH remains unknown. This review aims to evaluate the biochemical criteria used to define IH in different published studies and to discuss potential maternal as well as fetal outcomes and whether treatment during early pregnancy can prevent the eventual adverse effects. For the current literature a better standardization of free thyroxine assays is needed, as well as the use of appropriated trimester-specific reference intervals for thyroid function tests. Today no study demonstrates a benefit from treating early pregnant IH women on perinatal and fetal outcomes.

Orbital decompression for Graves' orbitopathy in England.

AIMS: The purpose of this study was to obtain data on orbital decompression procedures performed in England, classed by hospital and locality, to evaluate regional variation in care. METHODS: Data on orbital decompression taking place in England over a 2-year period between 2007 and 2009 were derived from CHKS Ltd and analysed by the hospital and primary care trust. RESULTS AND CONCLUSIONS: In all, 44% of these operations took place in hospitals with an annual workload of 10 or fewer procedures. Analysis of the same data by primary care trust suggests an almost 30-fold variance in the rates of decompression performed per unit population. Expertise available to patients with Graves' orbitopathy and rates of referral for specialist care in England appears to vary significantly by geographic location. These data, along with other outcome measures, will provide a baseline by which progress can be judged.

Glucocorticoid administration for Graves' hyperthyroidism treated by radioiodine. A questionnaire survey among members of the European Thyroid Association.

BACKGROUND: Glucocorticoid prophylaxis is required in some instances after radioiodine (RAI) treatment for Graves' hyperthyroidism to prevent progression of Graves' orbitopathy (GO). However, no randomized clinical trial has been performed to ascertain the optimum glucocorticoid therapy. AIM AND METHODS: Aim of this study was to perform a questionnaire-based survey of glucocorticoid prophylaxis among European thyroidologist members of the European Thyroid Association. RESULTS: Eighty-two responses from 25 European Countries were received. Two respondents did not prescribe steroids in any clinical scenario, while 8 gave the drug to all patients receiving RAI therapy. The majority of respondents only gave glucocorticoids to patients showing some degree of ocular involvement or if risk factors for the progression of GO after RAI were present (e.g., cigarette smoking); 24% of responses indicated that clinicians would not give glucocorticoids if patients were thought to have no GO or inactive GO. Ninety-one percent of clinicians used prednisone (53%) or prednisolone (38%). The mean starting dose [given for 16 days (range 2-60 days)] was 37.6 mg prednisone or prednisone-equivalent (range 15-80 mg). Overall, the results of this survey showed a wide diversity in the regimens used, in terms of timing of initiation of treatment, duration of treatment, cumulative doses of administered glucocorticoids and monitoring of side-effects of glucocorticoid treatment. CONCLUSIONS: The results of this study underscore the need for randomized clinical trials to ascertain the optimum regimen of prophylactic glucocorticoid therapy.

The utility of radioiodine uptake and thyroid scintigraphy in the diagnosis and management of hyperthyroidism.

BACKGROUND AND OBJECTIVES: The value and practice of thyroid radionuclide imaging in the diagnosis and management of hyperthyroidism is unsettled. Our objectives were to determine the influence of thyroid uptake and scintigraphy on the diagnosis of hyperthyroidism and the prediction of outcome following radioiodine therapy. PATIENTS AND DESIGN: We reviewed records and scintigraphic studies on 881 hyperthyroid patients carried out between 2000 and 2007. The agreement between the clinical and scintigraphic diagnosis was evaluated by kappa statistics. We determined the relationship between 4-h (123)I uptake and the outcome of (131)I treatment in 626 patients. A multiple logistic regression model was used to determine variables influencing treatment outcome in 1 year. RESULTS: The diagnostic categories were Graves' disease (GD, n = 383), toxic multinodular goitre (n = 253), solitary toxic nodule (n = 164) and Graves' disease coexisting with nodules (n = 81). The mean age of the patients was 58 +/- 17, (M:F 160:721). There was good agreement between clinical and scintigraph diagnosis (K = 0.60, 95% CI 0.57-0.64, P < 0.001); and they were correctly matched in 74%; mismatched in 6% and indeterminate in 20% of patients. Treatment outcome was not associated with scintigraph diagnosis (P = 0.98) or radioiodine uptake at 4 h (P = 0.2). The use of antithyroid medications before treatment predicted treatment failure (odds ratio 2.0, 95% CI 1.2-3.6, P = 0.01). CONCLUSION: Thyroid scintigraphy and uptake studies did not influence diagnosis or treatment outcomes in most cases of hyperthyroidism. Our findings in this retrospective study do not justify their routine use. Selective scanning will reduce cost and exposure to radioisotopes without compromising diagnostic accuracy or treatment outcomes.

Restricted thyroglobulin antibody epitope specificities in subjects with type 1 diabetes mellitus.

OBJECTIVES: Following iodisation in Sri Lanka we observed a high prevalence of thyroglobulin antibodies (TgAbs) in type 1 diabetic (T1DM) patients. The clinical significance of these TgAbs is uncertain. We sought to obtain a detailed epitope analysis of TgAbs in T1DM patients recruited from diabetes clinics and to compare these with TgAb epitope specificities in patients with autoimmune thyroid disease (AITD) and healthy individuals in that country. DESIGN AND METHODS: We used a panel of 10 Tg-MAbs in competitive ELISA reactions in a prospective study of subjects recruited from Colombo, to determine the epitopes recognised by TgAb-positive patients with T1DM (n=58, 34F:24M, median age 16 years), AITD patients (n=42, 33F:9M, median age 37 years) and healthy subjects (n=50, 39F:11M, median age 27 years). The outcomes were a comparison of reactivity with six Tg clusters (I-VI) in these subjects, and the relation of epitope specificity patterns with free thyroxine and TSH. RESULTS: Patients with T1DM and AITD but not healthy control subjects preferentially recognised the immunodominant clusters, I, III and IV. Patients with these narrow epitope specificities had higher median TSH levels (1.60 vs 1.06; P=0.01), and were more frequently positive for antibodies to thyroid peroxidase than those with broad specificities (52.3 vs 7.1%; P=0.004). CONCLUSIONS: The TgAb epitope specificities in euthyroid Sri Lankans with T1DM are similar to AITD patients. TgAb epitope studies may potentially identify T1DM patients at risk of thyroid dysfunction.

Augmentation index in resistance to thyroid hormone (RTH).

OBJECTIVE: Resistance to thyroid hormone (RTH) is associated with a varied clinical presentation. The cardiac effects of RTH have been described but vascular function has yet to be fully evaluated in this condition. We have measured the arterial function of those with RTH to assess any vascular changes. DESIGN: An observational study. PATIENTS: Twelve RTH patients were recruited from the thyroid clinic (mean value +/- SD), age 40.8 +/- 18.7 years; BMI 27.2 +/- 4.2 kg/m(2) and compared with 12 healthy, euthyroid, age-matched controls (age 41.4 +/- 19.3; BMI 24.8 +/- 4.4 kg/m(2)) with no history of cardiovascular disease. No interventional measures were instituted. MEASUREMENTS: Arterial stiffness was measured using pulse wave analysis at the radial artery. Thyroid function, fasting lipids and glucose were also measured on the same occasion in both patients and controls. Results The corrected augmentation index, a surrogate marker of arterial stiffness was significantly higher in patients compared with controls (21.0% +/- 14.1%vs. 5.4% +/- 18.2%, P < 0.03). Low density lipoprotein cholesterol (LDL-cholesterol) levels were also significantly elevated in patients compared with controls (3.0 +/- 0.6 vs. 2.1 +/- 0.5 mmol/l; P < 0.002). CONCLUSION: RTH patients show evidence in this study of increased augmentation index consistent with an increase in arterial stiffness compared with euthyroid controls. They also demonstrate elevated LDL-cholesterol levels. Both these measures may lead to increased cardiovascular risk.

Endothelial dysfunction in a murine model of thyroid hormone resistance.

BACKGROUND: The development of a knockin mouse model of resistance to thyroid hormone (RTH) has led to a greater understanding of both the molecular and clinical behaviour of this syndrome. We have investigated the vascular response in RTH using a specific (TRbeta PV) knockin mouse model targeting the PV mutation to the thyroid hormone receptor beta gene locus. MATERIALS AND METHODS: Ring segments of the thoracic aorta were used to assess the response of homozygous, heterozygous and wild-type controls to contractile agents, potassium chloride and phenylephrine. Each genotype after maximal contraction was exposed to increasing concentrations of relaxing agents, acetylcholine (ACh) and sodium nitroprusside (SNP). RESULTS: The response of these aortic ring segments to ACh and SNP demonstrates that endothelium-dependent relaxation to ACh was significantly impaired in both heterozygous and homozygous mice compared to controls (69.8 +/- 2.0%, 59.7 +/- 1.4% and 75.0 +/- 1.7%, respectively; P < 0.001). However, endothelium independent responses to SNP showed no difference between genotypes (114.4 +/- 3.2%, 116.8 +/- 2.6% and 106.9 +/- 4.9%; P = NS). CONCLUSION: These data suggest that endothelial function is impaired in the RTH mouse aorta. The respective roles of elevated thyroid stimulating hormone (TSH), elevated thyroid hormone concentrations and the mutated thyroid hormone beta receptor require further elucidation.

Prevalence of thyroid antibodies in Nigerian patients.

BACKGROUND: Thyroid antibody testing is not routinely available in developing countries, and few studies have measured thyroid antibodies in Africans. The significance of thyroid autoimmunity in an African setting is thus unclear. AIM: To determine the prevalence of thyroid antibodies in patients attending a Nigerian teaching hospital. DESIGN: Prospective survey. METHODS: We measured antibodies to thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) using an ELISA technique in 104 patients with various thyroid pathologies attending an endocrine referral centre in Lagos, Nigeria. Patients were clinically grouped into Graves' disease (GD) (n = 69), simple non-toxic goitre (SNTG) (n = 21), toxic nodular goitre (TNG) (n = 8) and suspected Hashimoto's thyroiditis (HT) (n = 6). Blood donors without thyroid disease (n = 100) acted as controls. RESULTS: TgAb and TPOAb were found in 4% and 7%, respectively, of healthy adult controls, 11.6 and 76.8% of patients with GD, 25% and 12.5% of patients with TNG and 9.52% and 14.29% of patients with SNTG. TPOAb testing confirmed HT in six patients, and identified two further cases that would have been misdiagnosed without antibody testing. DISCUSSION: Thyroid autoimmunity appears more common in these Nigerian patients than in previous reports from Africa, and TPOAb was significantly associated with auto-immune thyroid disease. The clinical utility of these antibody measurements requires further evaluation in a wider African population.

Peripheral cytokine expression in autoimmune thyroiditis: effects of in vitro modulation by rosiglitazone and dexamethasone.

BACKGROUND: In Hashimoto's thyroiditis (HT), there is evidence for activation of peripheral T-lymphocytes that predominantly express a T helper 1 (T(H)1) cytokine bias. However, the immunomodulatory factors involved in regulating this response have so far received scant attention. In this study, we examine the effects of the glucocorticoid, dexamethasone, and the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligand, rosiglitazone on the expression of interferon (IFN)-gamma (T(H)1) and interleukin (IL)-4 (T(H)2) by activated peripheral CD4(+) and CD8(+) lymphocytes in patients with HT (n = 10) and healthy control subjects (n = 12). METHODS: Peripheral blood mononuclear cells (PBMC) were stimulated in vitro with phorbolmyristate acetate (PMA) and ionomycin in the presence or absence of varying doses of dexamethasone and rosiglitazone (0.01 microM, 1.0 microM, and 100 microM). Cytokine expression was determined by flow cytometry. RESULTS: CD4(+) and CD8(+) IFN-gamma expression was greater in HT than controls (14.87 versus 9.25; p < 0.05 and 21.34 versus 10.16; p < 0.01, respectively). A dose-dependent inhibition of IFN-gamma expression was seen with dexamethasone and rosiglitazone. Inhibition of CD4(+) and CD8(+) IFN-gamma expression with both dexamethasone and rosiglitazone was greater in control subjects than in patients (p < 0.05). There was no significant difference in IL-4 expression between patients and control groups and its expression remained unaffected by either compound. CONCLUSIONS: We show that CD4(+) and CD8(+) T lymphocytes from HT patients express a type 1 cytokine bias that is significantly more resistant to in vitro modulation by rosiglitazone and dexamethasone. Further studies are needed to clarify if this resistance plays a role in the pathogenesis of autoimmune thyroid disease (AITD).

Management of thyroid disorders.

Autoimmune thyroid disease is the predominant form of thyroid dysfunction in the developed world. Although its precise cause is currently unclear, principles of management have been established. There is a vigorous debate about the management of the increasingly commonly recognised subclinical forms of thyroid dysfunction despite recent recommendations. Nodular thyroid disease and thyroid carcinoma have received wide attention. The effects of drugs and pregnancy on thyroid function have also been investigated widely. This short review attempts to give an overview and clarify the current management of common thyroid disorders.

Influences of age, gender, smoking, and family history on autoimmune thyroid disease phenotype.

CONTEXT: Both genetic and environmental factors contribute to susceptibility to Graves' disease (GD) and Hashimoto's thyroiditis (HT), as well as disease manifestations. OBJECTIVE: The objective of the study was to define how endogenous/environmental factors contribute to variation in phenotype. DESIGN/SETTING: This was a multicenter cohort study. PATIENTS/OUTCOME MEASURES: We prospectively collected clinical/biochemical data as part of the protocol for a United Kingdom DNA collection for GD and HT. We investigated, in 2805 Caucasian subjects, whether age at diagnosis, gender, family history (FH), smoking history, and presence of goiter influenced disease manifestations. RESULTS: For 2405 subjects with GD, the presence of goiter was independently associated with disease severity (serum free T4 at diagnosis) (P < 0.001). Free T4 (P < 0.05) and current smoking (P < 0.001) were both independent predictors of the presence of ophthalmopathy. Approximately half of those with GD (47.4% of females, 40.0% of males) and HT (n = 400) (56.4% of females, 51.7% of males) reported a FH of thyroid dysfunction. In GD, a FH of hyperthyroidism in any relative was more frequent than hypothyroidism (30.1 vs. 24.4% in affected females, P < 0.001). In HT, a FH of hypothyroidism was more common than hyperthyroidism (42.1 vs. 22.8% in affected females, P < 0.001). For GD (P < 0.001) and HT (P < 0.05), a FH was more common in maternal than paternal relatives. The reporting of a parent with thyroid dysfunction (hyper or hypo) was associated with lower median age at diagnosis of both GD (mother with hyperthyroidism, P < 0.001) and HT (father with hypothyroidism, P < 0.05). In GD and HT, there was an inverse relationship between the number of relatives with thyroid dysfunction and age at diagnosis (P < 0.01). CONCLUSIONS: Marked associations among age at diagnosis, disease severity, goiter, ophthalmopathy, smoking, and FH provide evidence for interactions between genetic and environmental/endogenous factors; understanding these may allow preventive measures or better tailoring of therapies.

A questionnaire survey on the management of Graves' orbitopathy in Europe.

OBJECTIVE: To determine management patterns among clinicians who treat patients with Graves' orbitopathy (GO) in Europe. DESIGN AND METHODS: Questionnaire survey including a case scenario of members of professional organisations representing endocrinologists, ophthalmologists and nuclear medicine physicians. RESULTS: A multidisciplinary approach to manage GO was valued by 96.3% of responders, although 31.5% did not participate or refer to a multidisciplinary team and 21.5% of patients with GO treated by responders were not managed in a multidisciplinary setting. Access to surgery for sight-threatening GO was available only within weeks or months according to 59.5% of responders. Reluctance to refer urgently to an ophthalmologist was noted by 32.7% of responders despite the presence of suspected optic neuropathy. The use of steroids was not influenced by the age of the patient, but fewer responders chose to use steroids in a diabetic patient (72.1 vs 90.5%, P<0.001). Development of cushingoid features resulted in a reduction in steroid use (90.5 vs 36.5%, P<0.001) and increase in the use of orbital irradiation (from 23.8% to 40.4%, P<0.05) and surgical decompression (from 20.9 to 52.9%, P<0.001). More ophthalmologists chose surgical decompression for patients with threatened vision due to optic neuropathy, who were intolerant to steroids than other specialists (70.3 vs 41.8%, P<0.01). CONCLUSION: Deficiencies in the management of patients with GO in Europe were identified by this survey. Further training of clinicians, easier access of patients to specialist multidisciplinary centres and the publication of practice guidelines may help improve the management of this condition in Europe.