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To investigate the long-term outcomes and prognosis of thyrotoxicosis in a large number of patients in a single UK county (Leicestershire).Retrospective cohort analysis of 56,741 thyroid function test (TFT) results, treatment modalities and outcomes in a well-established virtual thyrotoxicosis clinic database.One thousand four hundred and eighty-nine patients were included with a median length of follow-up of 10.9 years. The aetiology of thyrotoxicosis was autoimmune (85.9%), nodular (9.1%) and mixed (5.0%). Treatment modalities included antithyroid drugs (ATDs), radioiodine (RAI; 555 MBq fixed dose) and thyroidectomy.We analysed both individual TFTs and groups of sequential TFTs on or after the same thyroid treatment(s), which we describe as 'phase of thyroid care' (POTC). Patients studied entered the virtual clinic between 1 January 1995 and 1 January 2010; we exported data on every TFT sample up to April 2020.ATD had been used in 99.2% (median 2, maximum seven courses) with long-term ATD (gt;2 years) in 48%. RAI and thyroidectomy were used more commonly with nodular and mixed aetiology. Overall, T4 was more often controlled than thyroid-stimulating hormone (TSH), and at the latest follow-up, T4 was normal ingt;96%, TSH ingt;79% and both ingt;76% of different aetiologies. The mean percentage control of T4 was 85% and TSH 50%; in long-term ATD courses, this improved to 89% and 62%, respectively. In the latest POTC, control of T4 and TSH was best in cases off treatment (95%/87%) and on T4 without ablative therapy (94%/72%), but was broadly similar in patients on long-term ATD (90%/68%), after RAI (92%/60%) or after thyroidectomy (91%/58%). After the first course of ATD, remission or hypothyroidism was seen in 47.3% autoimmune, 20.9% nodular and 32.5% mixed, with 90% relapses seen within 4 years. Relapse was more common in patients with ophthalmopathy, but there was no difference between the sexes.Thyrotoxicosis can be well controlled with minimal specialist clinic attendance using a software-supported virtual shared-care scheme. Long-term ATD appears to be a valid patient choice achieving TFT control comparable to that seen after RAI or surgery. In patients with autoimmune disease, relapse is more common in patients with ophthalmopathy, and hypothyroidism is common after RAI. In nodular disease, we found that spontaneous remission may occur.

To evaluate the prevalence and clinical significance of nonuniform technetium (Patients with GD, referred between July 2005 and March 2018, had TcOf the 276 GD patients (mean age, 49.8 years; 84% female), 25 (9.0%) had nonuniform TcNonuniform radio-isotope uptake is seen in 1 in 11 patients with GD which could be misdiagnosed as toxic multinodular goitre if TRAb levels are not measured. Treatment of GD patients with nonuniform radio-isotope uptake with ATD therapy as first-line appears to be equally effective as compared with those with uniform uptake. TRAb testing should be the main diagnostic test for patients with suspected GD with radio-labelled uptake scans being reserved for those who are TRAb negative.

OBJECTIVE A suboptimal quality of life (QoL) has been reported in patients with Graves' disease treated in adult life, but long-term QoL in those treated in childhood and adolescence is unclear. We wanted to understand how Graves' disease and its management impact on the physical, psychological and social well-being of young people and their longer-term QoL. DESIGN, PATIENTS AND MEASUREMENTS Two questionnaires were used to assess QoL and patient experience of Graves' disease; PedsQL™ Generic Core Scales and a Graves' disease questionnaire devised for this project. The anonymized questionnaires were sent to young people (

In Graves' disease (GD), autoantibodies to the thyroid stimulating hormone receptor (TSHR) cause hyperthyroidism. The condition is often associated with eye signs including proptosis, oedema, and diplopia (collectively termed Graves' orbitopathy [GO]). The safety profile of K1-70Eighteen GD patients stable on antithyroid drug medication received a single intramuscular (IM) or intravenous (IV) dose of K1-70K1-70K1-70

Background Thyrotoxicosis, most often caused by Graves' disease (GD), when treated inadequately may result in premature mortality. There is little consensus as to which of the 3 treatment options available - antithyroid drugs (ATD), radioactive iodine (RAI) and surgery, is better. Aims (i) To assess factors involved in treatment choice and treatment satisfaction in patients treated for Graves' disease; (ii) To assess quality of life (QoL) following treatment of Graves' disease. Method Participants were selected from a prospective study cohort assessing thyrotoxicosis incidence and severity. Of the 172 eligible patients with Graves' disease, 123 treated patients participated (64% had received ATD only, 11% RAI and 25% total thyroidectomy, the latter 2 usually after a period of ATD), along with 18 untreated patients with newly diagnosed Graves' disease (overall participation rate, 73%). Consented patients completed a questionnaire detailing factors involved in treatment choice, QoL and satisfaction with treatment. Results Participants reported that the most important factors in choosing a treatment were the following: the effects on activities of daily living, concern about use of radioiodine, possibility of depression or anxiety, and doctor's recommendations. Satisfaction levels were high across all 3 treatment types. QoL 1-year following treatment was higher than in untreated patients, and comparable with other international studies. Conclusions Patient satisfaction with therapy and QoL does not differ by treatment type. Therefore, clinical and social factors, in combination with patient choice and resource availability, should determine which treatment modality patients with Graves' disease should receive.

Antithyroid drugs (ATDs) are widely used for the treatment of Graves' disease (GD) in the general population. Over the past decade, there has been an increasing awareness that several disturbances of thyroid function may occur in mothers after delivery which may be more prevalent than previously appreciated. Exacerbation of immune reactions occurs 3-12 month following delivery. Management of hyperthyroidism during lactation requires special considerations and should be implemented to prevent any adverse outcomes in mother and neonate. Continuation of breastfeeding is safe and should be encouraged in hyperthyroid mothers taking ATDs, whether these are ATDs being continued after gestation or indeed ATD treatment initiated in the postpartum period. Given PTU hepatotoxicity concerns, experts currently recommend using low-to-moderate MMI doses as a first-line therapy in lactating mothers. PTU should be reserved only as a second-line agent for cases of severe hyperthyroidism (thyroid storm) and allergic reactions to previous MMI treatment. ATD should be administered in divided doses immediately following each feeding. Evaluation of thyroid function tests is advisable at least 3-4 weeks after the initiation of breastfeeding.

Background and objectives Management options are limited for the treatment of Graves' disease, and there is controversy regarding optimal treatment. We describe the demographic and biochemical characteristics of children with Graves' disease and the outcomes of its management. Methods This is a retrospective study reviewing medical records from 2001 to 2011 at a tertiary-care paediatric hospital. Diagnostic criteria included elevated free T4 and total T3, suppressed TSH, and either positive thyroid-stimulating immunoglobulin or thyroid receptor antibodies or clinical signs suggestive of Graves' disease, for example exophthalmos. Patients were treated with antithyroid drugs (ATD), radioactive iodine, or thyroidectomy. The main outcome measures were remission after medical therapy for at least 6 months and subsequent relapse. Results A total of 291 children met diagnostic criteria. A total of 62 were male (21%); 117 (40%) were Hispanic, 90 (31%) Caucasian, and 59 (20%) African American. Mean age (±standard deviation) at diagnosis was 12·3 ± 3·8 (range 3-18·5) years. At diagnosis, 268 patients were started on an antithyroid drug and 23 underwent thyroid ablation or thyroidectomy. Fifty-seven (21%) children achieved remission and 16 (28%) of these patients relapsed, almost all within 16 months. Gender and ethnicity did not affect rates of remission or relapse. Of 251 patients treated with methimazole, 53 (21%) had an adverse reaction, including rash, arthralgias, elevated transaminases, or neutropenia. Conclusions Most children with Graves' disease treated with ATD do not experience remission, but most remissions do not end in relapse. Adverse reactions to methimazole are common but generally mild.

SummaryObjective Thyroid storm (TS) is a life-threatening endocrine emergency. This study aimed to achieve a better understanding of the management of TS by analyzing therapeutic modalities and prognoses reported by nationwide surveys performed in Japan. Design, patients and measurements Retrospective analyses were performed on clinical parameters, outcomes, and treatments in 356 TS patients. Results Patient disease severities assessed via Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores significantly correlated with mortality. Free triiodothyronine (FT3) and the FT3/free thyroxine (FT4) ratio inversely correlated with disease severity. Methimazole (MMI) was used in the majority of patients (78·1%), and there were no significant differences in mortality or disease severity between those treated with MMI and those receiving propylthiouracil (PTU). Patients who received inorganic iodide (KI) demonstrated higher disease severity but no change in mortality compared to those who did not. Patients treated with corticosteroids (CSs) demonstrated significantly higher disease severity and mortality than those who were not. Disease severity in patients treated with intravenous administration of beta-adrenergic antagonists (AAs) was significantly higher than those treated with oral preparations, although no significant difference in mortality was observed between these groups. In addition, mortality was significantly higher in patients treated with non-selective beta-AAs as compared with other types of beta-AAs. Conclusion In Japan, MMI was preferentially used in TS and showed no disadvantages compared to PTU. In severe TS, multimodal treatment, including administration of antithyroid drugs, KI, CSs and selective beta1-AAs may be preferable to improve outcomes.

The treatment options in the young patient with Graves' disease are the same as in adults, namely antithyroid drug (ATD), surgery (partial or total thyroidectomy) and radioiodine. However, the emphasis and expectation is different in the young person, reflecting a range of considerations including age, pubertal status, disease natural history, likely impact of ATD on disease course and the implications of radiation exposure. New therapeutic strategies that could increase the likelihood of long-term remission are being explored.

SummaryObjective 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. Design 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. Results 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. Conclusions 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.

Objective A relationship between iodine intake and the effectiveness of antithyroid drug (ATD) therapy for Graves' disease (GD) has been suggested, and strict restriction of iodine intake has been tried in the treatment of GD in some studies. However, it is unclear whether dietary iodine supplementation improves the prognosis of ATD therapy for GD. This study aimed to clarify whether optimal iodine supplementation during antithyroid drug therapy for GD is associated with lower recurrence rates than iodine restriction. Methods This was a prospective randomized trial of newly diagnosed patients with GD. Patients with newly diagnosed GD were recruited. After ATD therapy and strict dietary iodine restriction for 1 month, patients (n = 459) were randomly assigned to iodine-supplemented and iodine-restricted groups. After exclusion, 405 patients finally completed the study. The iodine-supplemented group included 203 patients (61 males and 142 females) with an average age of 32.2 ± 10.5 years (17-65 years), and the iodine-restricted group included 202 patients (61 males and 141 females) with an average age of 31.9 ± 11.8 years (16-64 years). Patients in the iodine-supplemented group were given about 10 grams of iodized salt every day, while the iodine-restricted group received noniodized salt with low-iodine or noniodine diet. The dietary iodine intervention lasted for 24 months. Urinary iodine concentration (UIC), thyrotropin receptor antibody (TRAb), free T3 (FT3), free T4 (FT4) and thyrotropin (TSH) of 2 groups were measured every 3 months. The recurrence rates within 12 months after withdrawal of ATD were evaluated. Results UIC in the iodine-supplemented group was within the recommended range for optimal iodine intake (135-162 μg/L) and was significantly higher than that in iodine-restricted group (30-58 μg/L). Within 12 months of withdrawal of ATD, the total recurrence rate in the iodine-supplemented group was 35.5%, significantly lower than in the iodine-restricted group, which was 45.5%. Conclusion Optimal dietary iodine supplementation during antithyroid drug therapy for GD is associated with lower recurrence rates than iodine restriction, and therefore, diet control with strict iodine restriction might be an adverse factor in the management of GD.

TSH receptor antibody (TRAb) plays a key role in the pathogenesis of Graves' disease (GD), and its levels correlate with the clinical course. The second- and third-generation TRAb assays have >95% sensitivity and specificity for the diagnosis of GD and have improved the utility of TRAb to predict relapse. TRAb levels decline with antithyroid drug (ATD) therapy and after thyroidectomy. Its level increases for a year following radioactive iodine (RAI) therapy, with a gradual fall thereafter. TRAb level >12 IU/l at diagnosis of GD is associated with 60% risk of relapse at 2 years and 84% at 4 years. The prediction of risk of relapse improves further to >90% with TRAb >7·5 IU/l at 12 months or >3·85 IU/l at cessation of ATD therapy. TRAb tests are not expensive, and hence, TRAb measurements at presentation, after 12 months and/or 18 months (at cessation) of ATD therapy, could potentially guide treatment choices in GD. Elevated TRAb favours definitive treatment in the form of RAI or thyroidectomy, depending on the presence or absence of moderate-to-severe Graves' ophthalmopathy (GO) and the ability to comply with radiation protection requirements. Use of ATDs in early pregnancy is associated with increased risk of congenital anomalies; early ablative treatment (RAI/surgery) should be considered in women of childbearing age at higher risk of relapse of GD. TRAb ≥5 IU/l in pregnant women with current or previously treated GD is associated with increased risk of foetal and neonatal thyrotoxicosis, and hence needs close monitoring. TRAb levels parallel the course of GO, and elevated TRAb is an indication for steroid prophylaxis to prevent progression of GO with RAI therapy.

SummaryContext Neutropenia secondary to antithyroid drug (ATD) therapy in Graves' disease (GD) is well recognized. However, the effect of hyperthyroidism, prior to and after ATD therapy, on neutrophil counts in patients with GD is unclear. Objective To study the prevalence of neutropenia in newly diagnosed untreated GD and the effect of ATD on the neutrophil count. Design Prospective study from August 2010 to December 2014. Setting Endocrinology outpatient clinic in a single centre. Patients Consecutive patients (n = 206) with newly diagnosed GD. Intervention ATD therapy. Main outcome measures Prevalence and factors predicting neutropenia (

Summary Background Thyroid disorders are frequent in patients with Down syndrome (DS). It is well-known that the prevalence of hypo- thyroidism is high but data on hyperthyroidism are scarce. Objectives To assess the prevalence, aetiology, clinical characteristics, evolution and treatment of hyperthyroidism in a population with DS attending a specialized medical centre. Methods Data were gathered by systematic review of 1832 medical records from the Catalan DS Foundation, in Spain, registered between January 1991 and February 2006. Patients with the diagnosis of hyperthyroidism were identified and data on clinical features, physical examination, laboratory and imaging tests, treatment and evolution were collected. Results Twelve patients with hyperthyroidism were recorded (6·5 cases/1000 patients with DS). There were 5 males and 7 females, with a mean age at diagnosis of 16·8 years. The most common presenting symptoms were decreased heat tolerance, sweating, increased irritability and weight loss. All patients had diffuse goitre at physical examination and two patients presented with exophthalmia. Clinical diagnosis was confirmed biochemically. Thyroid-stimulating immunoglobulin levels were raised (mean 128·1 U/l) and imaging tests confirmed the diagnosis of Graves' disease in all cases. Patients started treatment with carbimazole at diagnosis and after a mean period of 40 months without clinical remission, they required definitive therapy with radioactive iodine. Subjects developed hypothyroidism after radio-iodine therapy and replacement therapy with levothyroxine was necessary. Conclusions Hyperthyroidism is more prevalent in patients with DS than in the general population and has no gender predominance. It is caused mainly by Graves' disease. Anti-thyroid drugs were not effective in achieving remission and radioactive iodine as a definitive treatment was required in all cases.

Summary Background An association between radioiodine therapy (RAI) for Graves’ disease (GD) and the development or worsening of Graves’ ophthalmopathy (GO) is widely quoted but there has been no systematic review of the evidence. Aims We undertook a systematic review of randomized controlled trials (RCTs) to assess whether RAI for GD is associated with increased risk of ophthalmopathy compared with antithyroid drugs (ATDs) or surgery. We also assessed the efficacy of glucocorticoid prophylaxis in the prevention of occurrence or progression of ophthalmopathy, when used with RAI. Methods We identified RCTs regardless of language or publication status by searching six databases and trial registries. Dual, blinded data abstraction and quality assessment were undertaken. Random effects meta-analyses were used to combine the study data. Ten RCTs involving 1136 patients permitted 13 comparisons. Two RCTs compared RAI with ATD. Two RCTs compared RAI with thyroidectomy. Four RCTs compared the use of adjunctive ATD with RAI vs. RAI. Five RCTs examined the use of glucocorticoid prophylaxis with RAI. Results RAI was associated with an increased risk of ophthalmopathy compared with ATD [relative risk (RR) 4·23; 95% confidence interval (CI): 2·04 ‐8 ·77] but compared with thyroidectomy, there was no statistically significant increased risk (RR 1·59, 95% CI 0·89‐2·81). The risk of severe GO was also increased with RAI compared with ATD (RR 4·35; 95% CI 1·28‐14·73). Prednisolone prophylaxis for RAI was highly effective in preventing the progression of GO in patients with pre-existing GO (RR 0·03; 95% CI 0·00‐0·24). The use of adjunctive ATD with RAI was not associated with any significant benefit on the course of GO. Conclusion RAI for GD is associated with a small but definite increased risk of development or worsening of Graves’ ophthalmopathy compared with ATDs. Steroid prophylaxis is beneficial for patients with pre-existing GO.

Summary Context Management of Graves’ orbitopathy (GO) and dysthyroid optic neuropathy (DON) continues to be challenging. Other surveys have been successful in elucidating trends in GO management. Knowledge of current practice by members of the Latin American Thyroid Society (LATS) who manage patients with GO was targeted by distribution of a questionnaire. We compared our results with a previously reported European Thyroid Association (ETA) survey. Objectives To determine how endocrinologists in Latin America access and treat patients with GO and compare the results with the same European survey. Results One hundred and two responders representing endocrinologists from 10 countries participated in the survey. Most (57%) participate in a multidisciplinary setting for GO management. Access to a surgeon for orbital decompression was available only ‘within months’ according to 48·3% of responders. Despite suspected DON, 32·4% were reluctant to recommend urgent referral to an eyecare physician. Steroids were preferred as the first-option therapy by 88·2% of responders (by intravenous route by 57·8% of these). The presence of diabetes reduced the use of steroids to 64·7% (P

Thyroid hormones exert multiple effects on the neuromuscular system and the brain, with the most important being their role in stimulating the development and differentiation of the neuromuscular system and brain in foetal and neonatal life. In the presence of hyperthyroidism, muscular and neurological symptoms may be the presenting clinical features of the disease. The frequency and severity of neuromuscular complications vary considerably and are probably related to the degree of hyperthyroidism, although in some patients the neuromuscular dysfunction is caused by associated disorders rather than by hyperthyroidism per se. This update focuses on the most common neurological and muscular disorders that occur in patients with thyrotoxicosis. It is beyond the scope of this paper to discuss thyroid eye disease and cardiac complications, in themselves separate complications of specific myocytes.

SummaryBackground and Objectives Signal peptide-CUB-EGF domain-containing protein 1 (SCUBE1) has been shown to increase in parallel with platelet activation in acute ischaemic and thrombotic diseases. There has been no study evaluating SCUBE1 levels in patients with overt hyperthyroidism (OHyper) and subclinical hyperthyroidism (SHyper), conditions which are known to show impairment of both endothelial and platelet function. This study sought to evaluate SCUBE1 concentrations in patients with SHyper and OHyper, and assessed the effects of antithyroid drug (ATD) therapy on circulating SCUBE1 levels. Design and Methods Forty-five untreated patients with OHyper, 20 untreated patients with SHyper and 30 age- and sex-matched healthy controls were prospectively included in the study. Biochemical and hormonal parameters were evaluated in all patients before and after treatment. Results Compared with the control subjects, SCUBE1 levels were significantly increased in patients with SHyper and OHyper (P < 0·0001 and P = 0·002, respectively). SCUBE1 levels were not significantly different in patients with OHyper compared with patients with SHyper. There was no significant correlation between serum thyroid hormones and SCUBE1 levels. Plasma SCUBE1 levels decreased significantly in both OHyper and SHyper after ATD treatment (P < 0·05). Conclusions Increased SCUBE1 levels in both SHyper and OHyper patients may reflect increased platelet activation and possible endothelial dysfunction, which might augment the risk for atherosclerotic and atherothrombotic complications. SCUBE1 may be used as a reliable marker of endothelial damage in hyperthyroidism, especially in the subclinical period.

OBJECTIVE Graves' disease (GD) is an autoimmune disease characterized by the presence of circulating autoantibodies against thyroid-stimulating hormone (TSH) receptor. Despite extensive research, the pathogenic mechanisms remain unclear. Immune responses associated with the disease may lead to cell activation/apoptosis and the release of microvesicles (MVs) into the circulation. MVs can display biological activities which may aggravate GD further. We studied immune mechanisms in GD by investigating the numbers and phenotype of circulating MVs in patients before and after antithyroid therapy with thiamazole. PATIENTS AND MEASUREMENTS Samples were obtained from 15 patients with GD in the acute phase of hyperthyroidism and following 17-26 months treatment and 14 healthy controls. MVs from platelets, endothelial cells and monocytes exposing inflammation/activation markers (P-selectin, CD40 ligand, E-selectin and HMGB1) and MVs containing nuclear molecules were measured with flow cytometry. RESULTS Patients had elevated baseline values of MVs (P < 0·001 for all types of MVs), while the levels decreased during thiamazole treatment (P < 0·05 for all types of MVs). The majority of MV populations remained, however, significantly higher in patients after treatment compared to levels in controls. CONCLUSIONS GD patients have elevated levels of MVs that carry molecules with potential biological activities. MVs are significantly reduced after antithyroid treatment with thiamazole but still higher compared to levels in healthy controls. Assessment of MV levels and pattern may therefore provide additional information on underlying immune disturbances not obtained by measurements of hormone levels alone.

Summary Objective The clinical manifestations of hyperthyroidism resemble those of the hyperadrenergic state. This study was designed to evaluate the impact of hyperthyroidism on the autonomic nervous system (ANS) and to investigate the relationship between serum thyroid hormone concentrations and parameters of spectral heart rate variability (HRV) analysis in hyperthyroidism. Design and patients Thirty-two hyperthyroid Graves’ disease patients (mean age 31 years) and 32 sex-, age-, and body mass index (BMI)-matched normal control subjects were recruited to receive one-channel electrocardiogram (ECG) recording. Measurements The cardiac autonomic nervous function was evaluated by the spectral analysis of HRV, which indicates the autonomic modulation of the sinus node. The correlation coefficients between serum thyroid hormone concentrations and parameters of the spectral HRV analysis were also computed. Results The hyperthyroid patients revealed significant differences (P

Summary Objective Lithium has been reported to increase radioactive iodine (RaI) doses in benign thyroid disease and in differentiated thyroid carcinoma (DTC). It is not known whether lithium influences the outcome of RaI therapy in DTC. We therefore studied the clinical effects of RaI without and with lithium carbonate in patients with proven metastatic DTC. Controversy also exists on the mechanism by which lithium increases RaI dose in DTC. We performed an in vitro study specifically aimed at examining the effects of lithium on the sodium iodide symporter (NIS). Design In a clinical study, 12 patients were selected with metastases of DTC who had received previous RaI therapy without lithium (control) that had not influenced tumour progression, despite RaI accumulation in metastases. The patients received 1200 mg lithium carbonate/day followed by 6000 MBq RaI. Outcome parameters were RaI uptake, serum thyroglobulin (Tg) levels and radiological dimensions of metastases compared between RaI with lithium and control. In an in vitro study, iodide uptake was studied in the benign rat thyroid cell line FRTL-5, in the polarized non-thyroid MDCK cell line, stably transfected with human sodium iodide symporter (hNIS) to study the effects of lithium on NIS in a non-thyroid background, and the human follicular thyroid carcinoma cell line FTC133-hNIS to study lithium effects in a background of DTC. Lithium chloride (LiCl) was added in concentrations up to 2 mm for 0–48 h. Both steady-state iodide uptake (30 min) and initial rate (2 min) were studied using a specific activity of 100 mCi/mmol I, the latter experiment to determine lithium effects on substrate dependency. Iodide efflux studies were performed as well. Results Despite an increased uptake of RaI in seven patients, no beneficial effect of RaI with lithium was observed on the clinical course as assessed by serum Tg measurements and radiographically. In the in vitro studies, no effects of LiCl on iodide uptake or efflux were observed. Conclusions The addition of lithium to RaI did not have any beneficial effects on the clinical course in 12 patients with metastatic DTC. No beneficial effects of lithium on iodide uptake were observed in vitro. Therefore, the clinical value of lithium in DTC remains subject to debate.

CXCL10 plays an important role in the initial phases of Graves' disease (GD) and autoimmune thyroiditis (AT); however, until now, CXCL10 serum levels (sCXCL10) in patients with GD have never been evaluated in relation to thyroid function and treatment.To evaluate sCXCL10 in GD.Cross-sectional.One hundred and three GD, 164 AT, 20 nontoxic multinodular goitre (NTMNG), 16 toxic nodular goitre (TNG) patients and 70 healthy controls (age- and sex-matched).We measured sCXCL10 in patients and controls, to relate this parameter to the clinical phenotype.Mean sCXCL10 in GD and AT patients were comparable (122+/-81 and 133+/-102 pg/ml) and significantly higher (P0.01) than in controls or NTMNG patients (73+/- 32 and 76+/- 25 pg/ml, respectively). Hyperthyroid GD had significantly higher sCXCL10 than euthyroid or hypothyroid GD (145+/- 92, 107+/- 56 and 105+/- 46 pg/ml, respectively; P=0.01). GD patients with untreated hyperthyroidism had higher sCXCL10 than hyperthyroid or euthyroid GD patients under methimazole (MMI) treatment (166+/-125, 124+/- 41 and 94+/- 35 pg/ml, respectively; P=0.006). Comparable sCXCL10 levels were observed in newly diagnosed untreated hyperthyroid GD patients with respect to untreated patients with relapse of hyperthyroidism after a previous MMI course (176+/-125, 155+/- 97 pg/ml, respectively). GD had similar sCXCL10 to AT and higher than TNG patients or controls (all age- and sex-matched) (144+/- 81, 149+/- 114, 101+/- 27 and 86+/- 44 pg/ml, respectively; P=0.02).sCXCL10 is associated with the active phase of GD in both newly diagnosed and relapsing hyperthyroid patients. The reduction in sCXCL10 in treated patients with GD may be related to the immunomodulatory effects of MMI.

Summary Background and Objective Thyroid hormones have pronounced effects on the cardiovascular system. Thyrotoxicosis affects blood pressure (BP), modifying both diastolic (DBP) and systolic (SBP) pressures. There are no studies examining BP with ambulatory blood pressure monitoring (ABPM) in hyperthyroidism before and after control of thyroid function. Our aims were (1) to analyse ABPM in a group of normotensive hyperthyroid patients before and after normalizing circulating thyroid hormones and (2) to compare these results with those obtained in a group of euthyroid subjects. Patients and Measurements We studied 20 normotensive hyperthyroid subjects [18 women; age (mean ± SEM) 49·0 ± 3·0 years] and 15 healthy subjects. Patients were evaluated by ABPM over 24 h, at diagnosis and after therapy (n = 18). Results The average 24-h, daytime and night-time SBP was significantly greater in hyperthyroid patients than in controls with no significant differences in DBP. Circadian BP rhythm, estimated by the difference between mean values of SBP, DBP and mean BP during daytime and night-time, was unchanged. The average 24-h and daytime SBP significantly decreased after normalizing thyroid function in the 18 hyperthyroid evaluated patients. Daytime SBP and DBP were higher than night-time values both before and after control of thyroid function. However, no differences in circadian BP rhythm were observed. Conclusions Normotensive hyperthyroid patients exhibit higher ambulatory SBP throughout 24 h than normotensive euthyroid subjects. Control of hyperthyroidism decreases ambulatory SBP values. Mean nocturnal fall in BP is comparable in normotensive hyperthyroid patients and control subjects.

Summary Objective The study aims to evaluate the efficacy of combination therapy with propylthiouracil (PTU) and cholestyramine in the treatment of Graves’ hyperthyroidism. Background Thyroxine (T4) is metabolized mainly in the liver by conjugation to glucuronides and sulphates that enter the enterohepatic circulation. Thyrotoxic patients have an abnormal increase in thyroid hormone in their enterohepatic circulation. Previous studies on combination therapy with methimazole and cholestyramine for Graves’ hyperthyroidism have shown it to be an effective adjunctive treatment. In this study, we examined the efficacy of combination therapy with PTU and cholestyramine in the treatment of Graves’ hyperthyroidism. Methods Thirty patients with newly diagnosed Graves’ hyperthyroidism were randomly divided into two groups: group I (n = 15) received PTU 100 mg twice a day, propranolol 40 mg twice a day and cholestyramine 4 g twice a day for 4 weeks; group II (n = 15) received PTU 100 mg twice a day and propranolol 40 mg twice a day for 4 weeks. The therapeutic efficacy was determined by serum total triiodothyronine (TT3), free thyroxine (FT4) and TRAb levels at baseline, and at the end of 2 and 4 weeks during the study period. Results There was no significant difference in baseline thyroid function parameters. At the end of 2 and 4 weeks of the study period, serum TT3 and FT4 levels of group I were significantly lower than those of group II. No significant differences in the TRAb level were found between the two groups. Conclusion Cholestyramine contributed to a more rapid and complete decline in thyroid hormone levels in patients with Graves’ hyperthyroidism. It was thus proved to be an effective and well-tolerated adjunctive therapy.

Summary Objective Renal function is profoundly influenced by thyroid status; however, this has not been studied in detail in human subjects. The purpose of the present study was to determine the relationship between renal function and thyroid status before and after treatment for hypothyroidism and hyperthyroidism, respectively. Design and patients In 37 consecutive hypothyroid and 14 hyperthyroid patients renal function as measured by plasma creatinine and glomerular filtration rate (GFR) [based on the modification of diet in renal disease (MDRD) formula] was determined before treatment and after regaining euthyroidism. Results Renal function improved significantly during treatment of hypothyroidism and decreased during treatment of hyperthyroidism. There was a strong correlation between the change in thyroid status determined as the ratio log10(fT4 post-treatment/fT4 pretreatment) and the change in renal function as a result of therapy expressed as serum creatinine (r2 = 0·81, P

Summary Objective To investigate the risk of hypothyroidism after radioiodine (131I) treatment for hyperfunctioning thyroid nodules. Design Retrospective analysis of patients treated with 131I for hyperfunctioning thyroid nodules and followed up for a maximum of 20 years. Patients A total of 346 patients treated with 131I in the years 1975–95, for a single hyperfunctioning nodule. Measurements Hypothyroidism was defined as TSH levels > 3·7 mU/l. Kaplan–Meier survival analysis was used to analyse permanence of euthyroidism after 131I. A stepwise Cox proportional hazard model was used to identify factors influencing the progression to hypothyroidism. Results The cumulative incidence of hypothyroidism was 7·6% at 1 year, 28% at 5 years, 46% at 10 years and 60% at 20 years. Age (P

Objective The present study was to compare the efficacy of a single daily dose of methimazole (MMI) and propylthiouracil (PTU) in the treatment of Graves' hyperthyroidism. Background Antithyroid drugs, MMI and PTU, are widely used in the treatment of hyperthyroidism. Previous studies in the treatment of hyperthyroidism with a single daily dose of antithyroid drugs have demonstrated a more favourable result with MMI. However, the efficacy of a single daily dose of PTU was inconsistent. In this study, we examined the therapeutic efficacy of single daily doses of MMI and PTU on the change of thyroid hormones and thyrotropin receptor antibodies (TRAb) levels. Methods Thirty patients with newly diagnosed Graves' hyperthyroidism were randomly divided into two groups, each receiving a single dose of either 15 mg MMI or 150 mg PTU daily for 12 weeks. The therapeutic efficacy was determined by serum total triiodothyronine (TT3), total thyroxine (TT4), thyrotropin (TSH), free thyroxine (FT4), and TRAb levels at baseline and at the end of 4, 8 and 12 weeks during the study period. Results There was no significant difference in baseline thyroid function parameters. Serum TT3, TT4 and FT4 levels in the MMI-treated group were significantly lower than those of the PTU-treated group after 4 weeks and through the end of the study. MMI also has superior effect on reducing serum TRAb levels than PTU after 8 weeks and at the end of the study. Conclusion During the 12-week treatment of Graves' hyperthyroidism, a single daily dose of 15 mg MMI was much more effective in the induction of euthyroidism than a single daily dose of 150 mg PTU. In the doses used in this study, MMI is preferable to PTU when a once-daily regimen of antithyroid drug is considered for the treatment of Graves' hyperthyroidism.

Summary objective Antioxidant effects of paraoxonase, a high density lipoprotein (HDL)-associated enzyme that inhibits low density lipoprotein cholesterol (LDL-C) oxidation in human serum, have been reported. Patients with thyroid dysfunction are more susceptible to oxidative stress, and may show enhanced LDL-C oxidation. The purpose of this study was to evaluate serum paraoxonase activity in patients with hyperthyroidism before and after treatment with methimazole (MMI). design and patients Twenty-four hyperthyroid patients (15 women and nine men, aged 43·0 ± 12·9 years) and 23 age- and sex-matched healthy controls were studied. Serum paraoxonase activity, lipid, lipoprotein and apolipoprotein levels were measured in fasting samples. Patients were treated with MMI 20–30 mg daily for the first month, and 5–10 mg daily thereafter, and re-evaluated after 6–9 months of treatment. results Significantly lower serum paraoxonase activity was present in hyperthyroid patients before treatment compared with the controls (43·4 ± 21·9 vs. 72·6 ± 41·2 U/ml, P

Summary objective N-terminal B-type natriuretic peptide (NT-pro-BNP) is secreted from the cardiac ventricles in response to volume expansion and pressure overload, and serum levels are elevated in systolic heart failure. The aim of this study was to evaluate the influence of thyroid function on NT-pro-BNP. design Patients with overt or subclinical thyroid disease were evaluated before and after treatment for their dysthyroid state. patients Seventeen overt and 21 subclinical hypothyroid patients together with six subclinical and 13 overt hyperthyroid patients without cardiac disease were included. Subclinical states had, by definition, free T4 and free T3 estimates within reference ranges. measurements Serum levels of NT-pro-BNP and thyroid hormones were measured, and in 31 patients resting cardiac output was measured by impedance cardiography in the untreated state. results NT-pro-BNP levels were more than four times higher in hyperthyroid than hypothyroid patients, with mean values of 30 and 7 pmol/l, respectively (P

Uncontrolled hyperthyroidism in pregnancy poses a risk to both mother and foetus, and the optimal treatment strategy in this setting remains elusive. Instigation of pharmacological therapy or an alternative intervention during pregnancy requires careful consideration, and the evidence that has underpinned our choice of antithyroid drug has not been robust. Recent research developments have prompted us to question our practice, and reconsider our approach to managing this patient group.

Two widely used antithyroid drug (ATD) regimes for Graves' disease (GD) include the 'blockreplace' (BR) regime (a fixed high-dose of ATD combined with levothyroxine) and the 'titration' regime (a titrating dose of ATD). Anecdotally, it is believed that BR is less prone to fluctuating thyroid function.To study whether, in routine clinical practice, the BR regime, compared with the titration regime, is associated with more stable thyroid function.We retrospectively analysed case-records for 450 patients treated with ATDs for GD at a secondary care hospital. Exclusion criteria included treatment with ATDs for6 months, thyrotoxicosis due to other causes, treatment with radioiodine or thyroidectomy and pregnancy.Two hundred and twenty three patients were treated with the BR regime ('BR group'), 149 with the titration regime ('titration group') and 78 with both regimes. The number of thyroid function tests (TFTs) performed per year (mean(SD): 3·2(1·2) vs 3·4(1·5); adjusted mean difference = -0·4; 95% CI: -0·7 to -0·1; and P = 0·008) and the number of hospital clinic visits per year (mean (SD): 2·9 (1·0) vs 3·2 (1·3); adjusted mean difference = -0·4; 95% CI: -0·7 to -0·2; and P = 0·002) were lower in the BR group than the titration group. The number of abnormal TFT results per year was similar in the two groups (mean(SD): 1·8(1·3) vs 1·8(1·4); adjusted mean difference = 0·05; 95%CI: -0·3 to 0·4; and P = 0·74).In this retrospective study, there was little evidence that patients under BR have more stable thyroid function. Further data from prospective studies, however, are needed to confirm this finding.

Objective Antithyroidal drugs (ATD) are used in the management of Graves' disease either as primary therapy for several months while awaiting remission of the disease or as pretreatment for several weeks prior to definitive radioactive iodine therapy (RAI). We have reported previously that pretreatment with propylthiouracil (PTU) before definitive RAI therapy is associated with a higher RAI treatment failure rate than RAI therapy alone. The objectives of the current study were 2-fold. First, to verify the results of our prior study regarding the effect of PTU used as pretreatment before RAI in a cohort of patients from a different institution and, secondly, to better define the relationship between the number of days off PTU before RAI therapy and therapeutic efficacy of RAI dosing. Design A retrospective review of Graves' disease patients treated from 1980 to 1994. Patients Study patients had to meet the following inclusion criteria: radionuclide studies and thyroid hormone values consistent with Graves' disease, at least 1 year of follow-up data available and discontinuation of the ATD at least 4 days before RAI administration. Exclusion criteria included therapy with any ATD other than PTU or ATD therapy during or following RAI dosing. Measurements Effectiveness of RAI therapy, days on PTU, days off PTU and calculated RAI dose to the thyroid were recorded for each subject. We compared the efficacy of RAI therapy in patients treated with PTU (used either as pretreatment in preparation for RAI therapy or as primary long-term therapy) before RAI administrations to those treated with RAI alone with special attention to the number of days on and off PTU before RAI dosing. Patients were considered RAI treatment failures if a second dose of RAI was required to achieve a euthyroid or hypothyroid state. Results One hundred and sixteen patients met our study criteria. Forty patients received PTU therapy for a mean of 221 +/- 59 days. The PTU was discontinued for a mean of 60 +/- 25 days before RAI dosing. Persistent hyperthyroidism was seen in 9% (7/76) of patients treated with RAI alone. The failure rate of a single dose of radioactive iodine was significantly increased when PTU was discontinued between 4 and 7 days before the administration of RAI (29% vs 9% for RAI alone, P = 0.039). PTU discontinued for at least 1 week before RAI dosing was associated with a nearly 2-fold increase in failure rate, but this difference did not achieve significance (17% vs 9% for RAI alone, P = 0.24). Examining only those patients receiving PTU, patients who had successful single dose RAI therapy tended to receive a higher dose of RAI than patients failing RAI therapy (480 +/- 30 vs 410 +/- 40 MBq administered dose, P = 0.18; and 8.0 +/- 0.9 vs 5.5 +/- 1.1 MBq/g thyroid tissue calculated dose, P = 0.21). Furthermore, total serum thyroxine at diagnosis was significantly higher in patients failing RAI therapy after PTU administration than in patients successfully treated with RAI after receiving PTU (316 +/- 40 vs 225 +/- 13 nmol/L, P = 0.03). Conclusions Propylthiouracil discontinued 4-7 days before radioiodine dosing is associated with a significant increase in the failure rate of a single dose of radioiodine. Discontinuation of the propylthiouracil for at least a week before radioiodine administration is associated with a higher, although not statistically significant, radioiodine failure rate. In patients that require treatment with propylthiouracil before radioiodine therapy, a higher total serum thyroxine level at diagnosis is associated with an increased rate of radioiodine failure. Consideration should be given to increasing empirically the dose of radioiodine administered to Graves' disease patients that have received propylthiouracil within a week of radioiodine administration in an effort to decrease the radioiodine failure rate to an acceptable level.

We report a case of amiodarone-induced thyrotoxicosis of protracted duration, unresponsive to conventional thionamide therapy, with therapy limited by severe adverse drug reactions. Other treatment modalities included high dose corticosteroids, plasmapheresis, lithium and perchlorate. Temporary amelioration was achieved following plasmapheresis; however, this and other measures were unsuccessful in controlling the thyrotoxicosis, which deteriorated to thyroid storm. Histopathologically, a degenerative, inflammatory thyroiditis was evident. We discuss the limitations of conventional drug therapy and the lack of a sustained response to plasmapheresis. The failure of high doses steroids to alter the course of illness and to completely suppress the thyroidal inflammatory process is highlighted. A potential role for renal and hepatic impairment in the observed protracted course of amiodarone-induced thyrotoxicosis is suggested.

OBJECTIVE: Accelerated metabolism is a hallmark of thyrotoxicosis, but the underlying biochemical mechanisms are incompletely understood and the majority of studies have investigated normal subjects rendered only modestly hyperthyroid for a brief period of time. We have therefore studied a group of thyrotoxic patients using several different techniques. DESIGN: Twelve patients with newly diagnosed diffuse (10 patients) or nodular (2 patients) toxic goitre (10 women, 2 men; age 42.8 +/- 3.2 years; BMI 21.6 +/- 0.7 kg/m2) before ('pretreatment') and after ('treated') 11.2 +/- 1.0 weeks treatment with methimazole and compared these patients to a control group ('control') of 11 subjects (9 women, 2 men; age 40.5 +/- 3.9 years; BMI 22.5 +/- 1.0 kg/m2). All were studied for 3 hours in the basal state, using indirect calorimetry, isotope dilution for the measurement of glucose turnover and the forearm technique for assessment of muscle metabolism. RESULTS: Prior to treatment patients with thyrotoxicosis were characterized by increased (P < 0.05) levels of T3 (3.75 +/- 0.23 nmol/l (pretreatment), 1.89 +/- 0.08 (treated) and 1.75 +/- 0.11 (control)), resting energy expenditure (130.5 +/- 3.5 (pretreatment), 107.7 +/- 2.7 (treated) and 106.3 +/- 3.1 (control), % of predicted), protein oxidation (0.67 +/- 0.03 (pretreatment), 0.54 +/- 0.06 (treated) and 0.46 +/- 0.05 (control), mg/kg/min), lipid oxidation (1.34 +/- 0.08 (pretreatment), 1.00 +/- 0.06 (treated) and 1.02 +/- 0.04 (control), mg/kg/min), endogenous glucose production (2.51 +/- 0.13 (pretreatment), 1.86 +/- 0.12 (treated) and 1.85 +/- 0.12 (control), mg/kg/min), non-oxidative glucose turnover (1.28 +/- 0.16 (pretreatment), 0.75 +/- 0.18 (treated) and 0.71 +/- 0.11 (control), mg/kg/min) and a 50% increase in total forearm blood flow. Glucose oxidation (1.23 +/- 0.09 (pretreatment), 1.13 +/- 0.10 (treated) and 1.21 +/- 0.11 (control) mg/kg/min), exchange of substrates in the muscles of the forearm and circulating levels of insulin, C-peptide, growth hormone or glucagon were not influenced by hyperthyroidism. Propranolol (20 mg thrice daily) given to 7 of the patients for 2 days did not affect circulating levels of thyroid hormones, energy expenditure or glucose turnover rates. CONCLUSIONS: These results suggest that all major fuel sources contribute to the hypermetabolism of thyrotoxicosis and that augmented non-oxidative glucose metabolism may further aggravate the condition. All abnormalities diminish with medical treatment of the disease.

Summary OBJECTIVE We previously reported the clinical characteristics of Graves' disease with undetectable TSH binding inhibitor immunoglobulins (TBII) at first visit, but a study of the prognosis of untreated TBII negative patients with anti-thyroid drug medication has never been undertaken. The aim of this paper is to study the difference between negative and positive TBll Graves' disease in relation to the effect of anti-thyroid drug treatment. PATIENTS From January 1986 to April 1991,1545 patients with untreated Graves' disease were referred to Kuma Hospital, Kobe, Japan. Of these, 94 TRAb negative patients were identified. Another 83 TRAb positive patients were randomly selected from the other Graves' disease patients and served as a comparison group. Fifty-six of the 94 patients in the TBII negative group and 52 of the 83 patients in the TBII positive group completed treatment with methimazole only. MEASUREMENTS The trial was conducted as a retrospective study with a maximum treatment period of 36 months and a follow-up period of a further 12 months. From the original pool of patients, we classified 56 TBII negative patients into two groups according to the clinical course taken; Group A in whom TBII remained undetectable throughout methimazole treatment (9 men and 34 women, age 37.2 ± 2.2 years), and Group B who became TBII positive (4 men and 9 women, 31.2 ± 44 years). Fifty-two TBII positive patients served as the comparison Group C (8 men and 44 women, age 38.1 ± 2.0 years). RESULTS Serum free T4 and free T3 levels in groups A and B were significantly lower before treatment than those of Group C (P < 0.001). The thyroid volumes of Group A and B patients were significantly smaller than those of Group C (P < 0.01). The level of TBII in Groups A and B was significantly lower than that in Group C (8.3 ± 0.7 and 8.8·1.1 vs 57.0 ± 28%, respectively, P < 0.001). The level of thyroid stimulating antibody (TSAb) in Groups A and B was significantly lower than that in Group C (478 ± 71.0 and 761 ± 140.3 vs 2143 ± 280%, respectively, P < 0.01), and there were no significant differences in TSAb activities between Groups A and B. The remission rates in Groups A, B and C were 77.4, 36.4 and 36.5%, respectively. These data Indicate that Group A has a good prognosis, but Group B has the same prognosis as Group C. CONCLUSION We conclude that patients In whom TSH binding inhibitor Immunoglobulins remained negative have a much better prognosis than TSH binding inhibitor immunoglobulins positive patients or those who become TSH binding inhibitor immunoglobulins positive, having been initially negative.

SummaryObjective Use of the antithyroid drugs (ATDs) thiamazole (MMI) and propylthiouracil (PTU) is associated with a high frequency of side effects. When patients experience side effects with one (the 1st) ATD, it is usually discontinued and another is administered (the 2nd ATD). We investigated side effects associated with the 1st and 2nd ATDs. Design and Patients Four hundred forty-nine patients with untreated Graves' disease (GD) were randomly assigned to three groups according to ATD type and/or dosage: 15 mg/day MMI, 30 mg/day MMI and 300 mg/day PTU. The type, frequency and onset of side effects were assessed. We also studied the side effects associated with the 2nd ATD after cessation of the 1st ATD. Measurements Cutaneous reactions, liver dysfunction and other side effects were examined every 2 weeks after starting ATD administration. Results The overall frequency of side effects in patients taking 15 mg/day MMI was low. The frequencies of cutaneous reactions in patients taking 30 mg/day MMI and hepatotoxicity in those taking 300 mg/day PTU were high. Hepatotoxicity developed later than cutaneous reactions with PTU. Hepatotoxicity developed earlier in the 30 mg/day MMI group than in the other two groups. The frequency of side effects did not differ between the 2nd and 1st ATDs. Hepatotoxicity occurred at a higher frequency in patients who were switched from MMI to PTU because of hepatotoxicity of the former. Conclusion Attention to the onset times of side effects and cross-reactivity of ATDs can lead to safer treatment of GD.

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.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.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, P0.001); 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).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.

Summary Objective Cigarette smoking is a well-recognized risk factor of Graves’ disease and, particularly, Graves’ ophthalmopathy. Hence, germline polymorphisms of detoxification genes and genes belonging to the major DNA repair‐apoptosis pathways might have an important role in disease susceptibility. In addition, as some of these genes are regulated by thyroid hormones, they may affect the patients’ outcomes. We aimed to assess the influence of the GST , CYP and TP53 gene polymorphisms in the risk of Graves’ disease and its outcome. Design Prospective case-control study. Patients A PCR-based strategy was used for GSTT1, GSTM1 , GSTP1 , CYP1A1 and TP53 codon 72 genotypes in a group of 400 Graves’ disease patients, and to compare them to 574 control individuals with similar environmental exposure features. Results GSTM1 and GSTT1 genotypes were equally distributed in cases and controls, repectively. However, GSTP1 ( P < 0·0001), CYP1A1 ( P < 0·0033) and Pro/ProTP53 ( P < 0·0035) variants appeared more frequently in Graves’ disease patients than in controls. A multivariate analysis indicated that cigarette smoking and inheritance of GSTP1 , CYP1A1 and Pro/ProTP53 variants were important risk factors for Graves’ disease, but only smoking appeared as an independent risk factor for Graves’ ophthalmopathy. There was no association between clinical features, including ophthalmopathy or treatment outcome, and the studied genotypes. Conclusion We concluded that GSTP1 , CYP1A1 and TP53 , but not GSTT1 and GSTM1 germline polymorphisms, may be associated with smoking-related Graves’ disease susceptibility and configure a risk profile for the disease. However, these polymorphisms do not influence the patients’ response to treatment.

Radioiodine has been in use for over 60 years as a treatment for hyperthyroidism. Major changes in clinical practice have occurred with the realization that accurate dosimetry is incapable of avoiding the risks of hypothyroidism, while more accurate assessment of the risks of other adverse effects of radioiodine such as ophthalmopathy and carcinogenesis have become available. More is also known of the potential for pretreatment with an antithyroid drug to affect the outcome of radioiodine treatment. However, we are still uncertain of the benefits of radioiodine treatment in subclinical hyperthyroidism. During the last two decades there has been wider acceptance of radioiodine as a safe and effective therapy for benign, nontoxic goitre, coupled with waning enthusiasm for the use of levothyroxine, as the risks and benefits of this option have become more apparent. The use of recombinant TSH offers the prospect that radioiodine treatment of nontoxic goitre can be simplified and improved, although more studies of this strategy are urgently required.

Objective To determine the frequency and spectrum of serious adverse drug reactions (ADRs) to thionamide antithyroid drugs. Design and methods Data spontaneously reported to the UK-wide pharmacovigilance agency, The Committee on Safety of Medicines (Yellow Card Scheme), between 1963 and 2003 were analysed to determine the spectrum and relative frequency of ADRs to carbimazole and propylthiouracil. Representative data on the number of dispensed prescriptions were available from 1981, and were used as a denominator to estimate relative reporting rates of ADRs attributed to the drugs. Results Between 1981 and 2003 there were 5.23 million prescriptions for thionamide drugs in England and Scotland, 94% of which were for carbimazole. Neutrophil dyscrasia (agranulocytosis and neutropenia) accounted for 49% of all fatalities attributed to these medications. The median time reported for the appearance of neutrophil dyscrasia was 30 days of treatment, but there was a wide range (7-875 days). Neutrophil dyscrasia was more frequently fatal in subjects over 65 years of age; 13.8%vs. 1.2% of fatal reports in younger subjects [odds ratio (OR) 12.90; 5-95% confidence intervals (CI) 1.45-114.92]. Since 1981, reports of most ADRs, including neutrophil dyscrasia, were made significantly more frequently per propylthiouracil prescription dispensed than per carbimazole prescription. Conclusion Detailed data about ADRs to these compounds, and their patient demography, based on a large number of reports are described. Neutrophil dyscrasia is the commonest life-threatening ADR to thionamides. The excess of ADR reports for propylthiouracil compared to carbimazole could reflect genuine differences in toxicity between the compounds, the relative unfamiliarity of UK physicians with propylthiouracil, or the higher use of propylthiouracil in certain patient groups.

Increased oxidative stress, with elevated levels of free radicals, together with diminished antioxidation have been described previously in models of hyperthyroidism and in patients with Graves' disease. However, controversial results have been found about the antioxidant status and its response to treatment.To evaluate the antioxidant/oxidant balance in active Graves' disease and the effects of treatment with methimazole (MMI) and 131 iodine (131I).We studied 69 hyperthyroid (H) patients, 58 female and 11 male, 16-50 years old; total T3: 8 +/- 2 nmol/l, total T4: 264 +/- 65 nmol/l (all mean +/- SD), TSH: 0.1 +/- 0.1 mIU/l, TSH receptor antibody 41 +/- 21%, highest 131Iodine uptake: 67 +/- 16%. As a control group (C), 19 normal adults were studied.Parameters evaluated were: tert-butyl hydroperoxide initiated chemiluminiscence (CL), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx) and total reactive antioxidant potential (TRAP).In patients vs. controls there was an increase in CL levels (6207 +/- 1434 vs. 3000 +/- 851 cpm/mg of haemoglobin, P0.001), decrease in SOD (0.4 +/- 0.1 vs. 0.7 +/- 0.2 U/mg prot, P0.05; corresponding to 0.15 micro g/ml), CAT (2.8 +/- 0.6 vs. 3.8 +/- 0.7 pmol/mg prot, P0.001) and GSH (1.2 +/- 0.4 vs. 2 +/- 0.7 mmol/l erythrocytes, P0.05). The decrease in GPx and TRAP did not show significant differences. The parameters were also recorded in 30 patients who became euthyroid after treatment: 20 of them under MMI therapy (2-12 months) and the rest 3-6 months after 131Iodine administration. All the parameters evaluated were normalized after MMI; however, CL levels stayed high after 131I and only CAT and GSH levels returned to normal values.Our results confirm the imbalance of the antioxidant/oxidant status in hyperthyroid patients. MMI treatment was more effective than 131I therapy to improve that balance. We speculate on the benefits of antioxidant therapy administrated together with the habitual treatment of hyperthyroidism, especially in patients after 131I therapy.

The relationship between emotional stress and the onset of hyperthyroidism has been well investigated, but the relationship between psychological factors and prognosis of antithyroid drug-treated hyperthyroidism is not well known. This study has examined not only emotional stresses but also patients' personality traits using specific tests.A prospective cohort study.Sixty-nine patients with hyperthyroid Graves' disease in the euthyroid state after 2-5 years of antithyroid drug therapy and 32 healthy subjects as the control group.Patients responded to three types of questionnaires, including the Minnesota Multiphasic Personality Inventory for personality traits, the Natsume's Stress Inventory for major life events, and the Hayashi's Daily Life Stress Inventory for daily life stresses.In the Graves' disease patients, stress scores of life events correlated significantly with serum TSH receptor antibody activity (r = 0.424, P0.001) and thyroid volume (r = 0.480, P0.001). When the patients were divided according to prognosis (41 with relapse and 28 with remission), four personality traits including hypochondriasis, depression, paranoia and psychasthenia (mental fatigue) were significantly (P = 0.0146, 0.0052, 0.0125, and 0.0186, respectively) more common in the relapsed Graves' disease group than those of the remitted group. Six personality traits of conversion hysteria, psychopathic deviation, masculinity and feminity, schizophrenia, hypomania, and social introversion were not significantly different between the two groups. The scores of daily hassles (problems of daily life) were also significantly (P = 0.0124) greater in the relapsed Graves' disease group than in the remitted group. The scale scores of depression and psychasthenia showed a positive correlation with scores of daily hassles (r = 0.535, P0.0001; r = 0.580, P0.0001, respectively), while an inverse correlation with scores of daily uplifts (r = -0.373, P = 0.0332; r = -0.322, P = -0.0120, respectively).The results suggest that major life events, personality traits of hypochondriasis and depression, paranoia, mental fatigue, and daily problems aggravate the prognosis of antithyroid drug-treated hyperthyroidism. Escape from life events is virtually impossible; thus coping strategies suggested by the physician may be useful in improving prognosis in Graves' disease.

Previous studies recommend the discontinuation of antithyroid drug (ATD) therapy during pregnancy in women with well-controlled Graves' hyperthyroidism (GH). In this study, we investigated whether this termination of ATD therapy during pregnancy is beneficial in terms of postpartum GH recurrence.A nonrandomized, retrospective study.Sixty-five pregnant GH patients treated with maintenance doses of ATDs were assigned into two groups: ATD therapy was discontinued before delivery in Group 1, but continued during pregnancy and after delivery in Group 2.The prevalence of postpartum recurrence or exacerbation of GH within 1 year after delivery was examined. Serum T4, T3 TSH, and TSH receptor antibody levels were measured.In Group 1, 70.8% (17/24) of patients suffered a recurrence of GH within 1 year after delivery. In contrast, a postpartum exacerbation of GH was observed in only 29% (12/41) of patients in Group 2 (P0.01). Both exacerbations and recurrences of GH appeared primarily within 4-6 months after delivery. Apparent neonatal hypothyroidism and malformations were not observed in the offspring of either group.Continuing antithyroid drug therapy throughout pregnancy prevents postpartum recurrence of Graves' hyperthyroidism without resulting in neonatal hypothyroidism or malformations.

We evaluated thyrotropin-binding inhibitor immunoglobulin (TBII) in sera from patients with Graves' disease (GD) by using the new human recombinant TSH receptor (TSH-R) assay to determine if it is useful for the diagnosis and follow-up of GD.Serum samples from 25 patients with untreated GD, 24 with relapsing GD, 15 with GD in remission and 197 treated GD patients were examined. TBII was also measured in sera from healthy individuals (n = 69).TBII was retrospectively measured by using the conventional porcine TBII assay (pTBII) and the human recombinant TBII assay (hTBII). Specificity was adjusted at 97.5% for both assays by receiver-operating characteristic (ROC) plot analysis, resulting in cut-offs at 10.5% inhibition (hTBII) and 9.9% (pTBII). Sensitivity was 87% for hTBII compared to 52% for pTBII (P0.0001).Even in pTBII-positive patients, hTBII values (57.6 +/- 26.1%) were significantly (P0.0001) higher than pTBII values (34.2 +/- 27.6%). When 139 pTBII-negative serum samples from patients with treated GD were examined, 97 samples (69.8%) were positive for hTBII. hTBII values (23.9 +/- 17.0%) were significantly (P0.0001) higher than pTBII values (4.1 +/- 3.3%). hTBII was positive in 13 of 13 patients who were taking antithyroid drugs but had normal serum TSH levels. When 19 serum samples from pTBII-negative untreated patients with GD were examined, 15 out of 19 (79%) were positive for hTBII. We also examined 24 patients with relapsing GD. hTBII was positive in 16 (64%) patients, whereas seven (16%) were positive for pTBII (P0.01). Positivity of hTBII in these untreated or relapsing GD patients was significantly higher than that of thyroid stimulating antibodies. We then examined TBII levels in 15 patients with GD in remission who had normal serum TSH values. hTBII was positive in seven patients at the time of blood withdrawal, and GD subsequently relapsed in three hTBII-positive patients in 6 months.Low TBII titres can now be followed more accurately during the course of treatment, which will also allow better longitudinal studies on the importance of TBII for the diagnosis as well as the prognosis of GD with respect to remission or relapse.

Dehydroepiandrosterone (DHEA) and DHEA-sulphate (S) have been suggested to play protective roles in many pathological states, some of which are observed in hyperthyroidism. If DHEA and DHEA-S levels change in hyperthyroidism, they might participate as a possible causative link with such pathophysiological changes in hyperthyroidism. However, the CRH-ACTH-DHEA system in hyperthyroidism has not been clearly defined. We examined plasma levels of DHEA and DHEA-S together with ACTH and cortisol in both hyperthyroid (Hyper) and euthyroid states (Eu).Eighteen patients (5 men and 13 women, aged 46.9 +/- 2.8 years) with Graves' disease were studied before treatment and again in the euthyroid state following treatment with methimazole. A 100 microg hCRH stimulation test and a low-dose (0.5 microg) 1-24 ACTH stimulation test were performed on separate days. Basal levels and A area under the response curve (AUC) were compared between Hyper and Eu.DHEA-S was higher in Hyper than in Eu. However, basal DHEA did not differ between Hyper and Eu. The ratio of DHEA to DHEA-S was lower in Hyper than in Eu. AAUC of DHEA during a CRH test was lower in Hyper than in Eu. However, AAUC of DHEA during an ACTH test was similar in both Hyper and Eu. Basal ACTH was higher in Hyper than in Eu. In both CRH and ACTH tests, AAUC of cortisol response was lower in Hyper than in Eu, although the basal cortisol level was not different.The balance of the conversion between DHEA-S and DHEA in the hyperthyroid state favoured DHEA-S. Similar to cortisol, the DHEA response in the CRH test in hyperthyroidism seemed to be insufficiently compensated for by increased ACTH, although the DHEA response to low-dose ACTH was similar in the hyperthyroid and euthyroid states. Increased DHEA-S might play some role in the pathological states in many organs in hyperthyroidism.