Search

Background: Population-based studies have indicated an increase in bone turnover in hyperthyroidism with a subsequent decrease in bone mineral density and an increased risk of fractures, especially in postmenopausal women. However, heterogeneity between studies prevents a definitive conclusion. Graves' disease (GD) is an autoimmune disease, and it is the most common cause of hyperthyroidism. The aim of this study was to investigate fracture risk in patients with GD. Methods: A total of 2134 patients with incident GD and 21,261 age, sex- and county-matched controls were included 16-18 years after diagnosis in a retrospective cohort study. Drug and patient national registries in Sweden were used to assess the risk of developing skeletal complications. Up to 10 years of age, sex- and county-matched controls per patient were selected from databases from the National Board of Health and Welfare and Statistics Sweden. Cox proportional hazards models were fitted to estimate hazard ratios (HR) and confidence intervals [CI]. Results: There were no significant differences in fracture rates between GD and controls but after adjustment for comorbidities, the data showed higher vertebral fracture rates in male GD patients aged >52 years compared to male controls, HR = 2.83 [CI 1.05-7.64]. The rates of osteoporosis treatments as well as treatment with corticosteroids were higher in patients with GD. However, HR for the association between GD and fractures remained largely unchanged after adjustment for osteoporosis treatments and treatments with corticosteroids. Conclusions: There were no significant differences in total fracture rate between GD and the general population. However, men older than 52 years had a higher vertebral fracture rate. This study also shows that patients with treated GD receive more osteoporosis treatments compared to the general population.

Introduction: The treatment strategies for a 42-year-old female index patient with moderate Graves' disease (GD) vary according to several international surveys. The important question whether surveys of treatment preferences in theoretical patient cases also match how real patients are treated has not yet been addressed., Materials and Methods: From a Swedish cohort of 1186 GD patients (TT-12 cohort), 27 women were identified using the same criteria as from the index patient surveys from the European and American Thyroid Associations. This 'index patient cohort' was age 40-45, otherwise healthy female, with two children and uncomplicated GD. The applied first-line treatment of the patients in the index cohort, together with its variations, was compared with the treatment preferences according to international surveys. A comparison with the TT-12 cohort was also performed., Results: In the 'Index cohort', 77.8% were treated with antithyroid drugs (ATD), and 22.2% were treated with radioiodine ( 131 I). This preference for ATD is in line with most countries/regions, with the exception of USA and the Middle East/North Africa, where 131 I was preferred. The distribution of treatment in the TT-12 cohort did not significantly differ from the index cohort. ATD was the preferred treatment in male and young (age 19-22) patients, as was RAI in old (age 69-73) patients. The age-related, but not the gender-related, cases differed significantly from the entire TT-12 cohort., Conclusion: The treatment choice in an index patient in Sweden seems in line with European practice, where ATD is the preferred first choice. This differs compared to US and North African survey intentions, where 131 I is more often used. Age more than gender influences the treatment choice of GD patients. This is, to our best knowledge, the first time an index patient from 'real life' has been presented and compared to treatment preferences of international thyroid association surveys., Competing Interests: Gabriel Sjölin, Kristina Byström, Mats Holmberg, Ove Törring, Selwan Khamisi, Jan Calissendorff, Mikael Lantz, Bengt Hallengren, Helena Filipsson Nyström, Tereza Planck, Göran Wallin: none of the authors have competing financial interests., (© 2021 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

Background: The treatment efficacy of antithyroid drug (ATD) therapy, radioactive iodine ( 131 I), or surgery for Graves' hyperthyroidism is well described. However, there are a few reports on the long-term total outcome of each treatment modality regarding how many require levothyroxine supplementation, the need of thyroid ablation, or the individual patient's estimation of their recovery. Methods: We conducted a pragmatic trial to determine the effectiveness and adverse outcome in a patient cohort newly diagnosed with Graves' hyperthyroidism between 2003 and 2005 ( n  = 2430). The patients were invited to participate in a longitudinal study spanning 8 ± 0.9 years (mean ± standard deviation) after diagnosis. We were able to follow 1186 (60%) patients who had been treated with ATD, 131 I, or surgery. We determined the mode of treatment, remission rate, recurrence, quality of life, demographic data, comorbidities, and lifestyle factors through questionnaires and a review of the individual's medical history records. Results: At follow-up, the remission rate after first-line treatment choice with ATD was 45.3% (351/774), with 131 I therapy 81.5% (324/264), and with surgery 96.3% (52/54). Among those patients who had a second course of ATD, 29.4% achieved remission (vs. the 45.3% after the first course of ATD). The total number of patients who had undergone ablative treatment was 64.3% (763/1186), of whom 23% (278/1186) had received surgery, 43% (505/1186) had received 131 I therapy, including 2% (20/1186) who had received both surgery and 131 I. Patients who received ATD as first-line treatment and possibly additional ATD had 49.7% risk (385/774) of having undergone ablative treatment at follow-up. Levothyroxine replacement was needed in 23% (81/351) of the initially ATD treated in remission, in 77.3% (204/264) of the 131 I treated, and in 96.2% (50/52) of the surgically treated patients. Taken together after 6-10 years, and all treatment considered, normal thyroid hormone status without thyroxine supplementation was only achieved in 35.7% (423/1186) of all patients and in only 40.3% of those initially treated with ATD. The proportion of patients that did not feel fully recovered at follow-up was 25.3%. Conclusion: A patient selecting ATD therapy as the initial approach in the treatment of Graves' hyperthyroidism should be informed that they have only a 50.3% chance of ultimately avoiding ablative treatment and only a 40% chance of eventually being euthyroid without thyroid medication. Surprisingly, 1 in 4 patients did not feel fully recovered after 6-10 years. The treatment for Graves' hyperthyroidism, thus, has unexpected long-term consequences for many patients.

Background: Hyperthyroidism is known to have a significant impact on quality of life (QoL), at least in the short term. The purpose of the present study was to assess QoL in patients 6-10 years after treatment for Graves' disease (GD) with radioiodine (RAI) compared to those treated with thyroidectomy or antithyroid drugs (ATD) as assessed with both thyroid-specific Thyroid-Related Patient-Reported Outcome (ThyPRO) questionnaire and general (36-item Short Form Health Status) QoL survey., Methods: The study evaluated 1186 GD patients in a sub-cohort from an incidence study 2003-2005 who had been treated according to routine clinical practice at seven participating centers. Patients were included if they had returned the ThyPRO (n = 975) and/or the 36-item Short Form Health Status survey questionnaire (n = 964) and informed consent at follow-up. Scores from ThyPRO were compared to scores from a general population sample (n = 712) using multiple linear regression adjusting for age and sex as well as multiple testing. Treatment-related QoL outcome for ATD, RAI, and surgery were compared, including adjustment for the number of treatments received, sex, age, and comorbidity., Results: Regardless of treatment modality, patients with GD had worse thyroid-related QoL 6-10 years after diagnosis compared to the general population. Patients treated with RAI had worse thyroid-related and general QoL than patients treated with ATD or thyroidectomy on the majority of QoL scales. Sensitivity analyses supported the relative negative comparative effects of RAI treatment on QoL in patients with hyperthyroidism., Conclusions: GD is associated with a lower QoL many years after treatment compared to the general population. In a previous small randomized controlled trial, no difference was found in patient satisfaction years after ATD, RAI, or surgery. Now, it is reported that in a large non-randomized cohort, patients who received RAI had adverse scores on ThyPRO and 36-item Short Form Health Status survey. These findings in a Swedish population are limited by comparison to normative data from Denmark, older age, and possibly a more prolonged course in those patients who received RAI, and a lack of information regarding thyroid status at the time of evaluation. The way RAI may adversely affect QoL is unknown, but since the results may be important for future considerations regarding treatment options for GD, they need to be substantiated in further studies.

Background: Environmental and genetic factors predispose an individual to the development of Graves' disease (GD). In an expression study of intraorbital tissue, adipocyte-related immediate early genes (IEGs) and immunomodulatory genes were found to be overexpressed in patients with Graves' ophthalmopathy (GO). We hypothesized that genetic variations in these genes could be associated with GD and/or GO., Methods: A total of 98 single nucleotide polymorphisms (SNPs) in 12 genes were genotyped in 594 GD patients with (n=267) or without (n=327) GO and 1147 sex- and ethnicity-matched controls from Malmö, Sweden., Results: Ten SNPs in four genes (BTG family, member 2 [BTG2], cysteine-rich, angiogenic inducer 61 [CYR61], zinc finger protein 36, C3H type, homolog mouse [ZFP36], and stearoyl-coenzyme A desaturase [SCD]) showed an association with GD and/or GO. SNPs rs12136280 (odds ratio [OR] 1.29, p=0.002), rs6663606 (OR 1.26, p=0.004), and rs17534202 (OR 1.21, p=0.02) in BTG2 and rs3753793 (OR 1.21, p=0.03) in CYR61 were associated with GD. An association with GO was shown for SNPs rs3753793 (OR 1.45, p=0.008), rs6682848 (OR 1.55, p=0.03), rs12756618 (OR 1.77, p=0.049), and rs1378228 (OR 1.29, p=0.049) in CYR61, rs1057745 (OR 1.56, p=0.03) and rs11083522 (OR 1.32, p=0.04) in ZFP36, and rs1393491 (OR 1.38, p=0,048) in SCD. Smoking and CYR61 rs12756618 interacted to increase the risk of GO., Conclusions: We found associations of SNPs in IEGs and SCD with GD and/or GO; however, confirmation in a different population is required.

Objective: Environmental and genetic factors influence thyrotoxicosis, but how population migration affects the disease panorama is not known. In an urban area in southern Sweden, during the years 1990 until 2003, the population increased from 232 000 to 267 000. In parallel, the proportion of inhabitants born outside Sweden increased. The aim was to investigate whether the incidence of Graves' thyrotoxicosis (GD), toxic multinodular goiter (TMNG), and solitary toxic adenoma (STA) has changed in Malmö since 1990 and to study the influence of geographic origin., Design and Method: An open label prospective registration of thyrotoxicosis, gender, age, smoking habits, and ethnic background during 2003-2005 in an urban area in southern Sweden (Malmö) was undertaken., Results: The total incidence of thyrotoxicosis has changed from 43 to 41.6 cases/100,000/year from the years 1988-1990 to 2003-2005 (p-value 0.72). GD increased from 22 to 29.6 (p-value 0.0051), TMNG decreased from 16 to 9.9 (p-value 0.0011) and STA from 4.8 to 2.1 (p-value 0.0054)/100,000/year. The total incidence of GD was higher in inhabitants born outside Sweden up to the age of 69 years and age-specific incidence showed a peak in women aged 50-59 years old in both groups. The greatest difference between immigrants and Swedes up to the age of 69 years was observed in women aged 20-29 years old., Conclusion: The incidence of GD has increased and of TMNG has decreased in Malmö since 1990. Geographic origin seems to affect the incidence of GD. Whether the observed peak in age-related incidence in women 50-59 years is explained by menopausal changes has to be further investigated.

Context: In Graves' ophthalmopathy a major problem is an increase in the intraorbital adipose tissue volume., Objective: The aim of this work was to define mechanisms of orbital adipogenesis., Design: This was an open-label prospective study., Setting: The study was conducted at the Clinic of Endocrinology, University Hospital., Participants: The study consisted of patients (n = 5) with severe ophthalmopathy with affection of the optic nerve and thyroid healthy controls (n = 5)., Interventions: We performed lateral decompression of orbital tissue in patients unresponsive to corticosteroids and restorative surgery of the upper eyelid in thyroid healthy controls., Main Outcome Measure: We made large-scale measurements of gene expression, with microarray technique based on determination of fluorescence intensities in cases and controls., Results: A marker of adipose tissue, stearoyl-coenzyme A desaturase, was overexpressed in ophthalmopathy, and selection criteria were set to favor identification of genes known to be expressed in normal adipogenesis. The immediate early gene, cysteine-rich, angiogenic inducer, 61 (CYR61), was overexpressed in addition to 15 other immediate early genes (IEGs), and the expression of selected IEGs was confirmed with RT-PCR: CYR61, cyclooxygenase-2, dual-specificity phosphatase 1, B cell translocation gene 2, and early growth response 1. CYR61-responsive genes, known to participate in inflammation, IL-1beta, matrix metalloproteinase-3, and vascular endothelial growth factor were also overexpressed. Patients showed greater expression of CYR61 in the active than the chronic phase of ophthalmopathy, indicating that CYR61 is a marker of disease activity. Cyclooxygenase-2, the target gene of IL-1beta, was also overexpressed, although all patients had been treated with corticosteroids., Conclusion: Adipocyte-related IEGs are overexpressed in active ophthalmopathy, and CYR61 may have a role in both orbital inflammation and adipogenesis and serve as a marker of disease activity.

Objectives: To study the frequency of islet cell (ICA) and glutamic acid decarboxylase (GAD-Ab) antibodies in patients with hyperthyroidism of different types at diagnosis before treatment and in the euthyroid state following treatment., Setting: Department of Endocrinology, Malmö University Hospital, Malmö, Sweden., Subjects and Design: Blood samples were collected at diagnosis from 129 hyperthyroid patients, and about 6 months later, from 78 of the patients (euthyroid state). Ninety-two patients had Graves' disease (69 females and 23 males, median age 49 years, range 17-85 years), and 37 patients had toxic nodular goitre/solitary toxic adenoma (34 females and three males, median age 69 years, range 24-86 years)., Interventions: Most patients were treated by radioactive iodine following the first blood sample., Main Outcome Measures: ICA and GAD-Ab in serum., Results: At diagnosis of Graves' disease, ICA were detected in two out of 92 (2.2%) patients, two out of 85 (2.4%) without diabetes mellitus and in the euthyroid state in one patient. None of the patients with toxic nodular goitre/solitary toxic adenoma had detectable ICA. At diagnosis of Graves' disease, GAD65-Ab as well as GAD67-Ab were detected in 11 out of 85 (13%) patients without diabetes. As many as six out of 11 GAD67-Ab-positive patients were GAD65-Ab negative. In the euthyroid state, GAD65-Ab were found in six out of 51 (12%) and GAD67-Ab in eight out of 51 (16%) of the non-diabetic Graves' disease patients. The frequencies of GAD65-Ab and GAD67-Ab in toxic nodular goitre/solitary toxic adenoma, diabetes excluded, were 3 and 0%, respectively, in the hyperthyroid state., Conclusion: The frequency of ICA in patients with hyperthyroidism is not increased as compared to the background population. GAD-Ab seems to be associated with Graves' disease and not with hyperthyroidism. The presence of GAD67-Ab in GAD65-Ab negative sera from patients with Graves' disease indicates autoreactivity against a specific GAD67 epitope.

To explore suppressor T lymphocyte function in Graves' disease, studies were performed in one group of patients in the hyperthyroid state and in another group in the euthyroid state after treatment. Peripheral blood lymphocytes were cultured for 1-7 days. Pokeweed mitogen (PWM; 1.25 micrograms/ml) was added at the initiation of the cultures or after 24 h. The degree of lymphocyte activation was assessed by measurements of the cellular uptake of [3H]thymidine and expressed in counts per minute (CPM). The suppressor lymphocyte function was estimated by a quotient between the maximum CPM values from cultures with and without preincubation. For the hyperthyroid group (n = 15) the quotient was 1.00 +/- 0.07 (mean +/- SEM), for the euthyroid patient group (n = 21) 1.12 +/- 0.05 and for the healthy control group (n = 21) 1.37 +/- 0.08. There was a significant difference between the quotients for the control group and the hyperthyroid (P less than 0.01) as well as the euthyroid (P less than 0.05) patient group. The quotients for the two groups of patients did not differ significantly. In conclusion, the present study supports the view of a defect in suppressor T lymphocyte function in patients with Graves' disease in the hyperthyroid state and indicates that this defect can persist in the euthyroid state after treatment.