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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: In gender-skewed conditions such as Graves' disease (GD), the outcome naturally becomes dominated by the majority. This may lead to gender-biased misunderstandings regarding treatment outcomes. This especially holds true when complications, such as depression, are unevenly distributed. We have, therefore, studied the long-term outcome of GD from a gender perspective., Materials and Methods: A cohort of 1186 patients with GD was included in a follow-up 6-10 years after inclusion. Choice of treatment, the feeling of recovery, long-term treatment, comorbidity, and quality of life were investigated with questionnaires. All results were studied sex-divided., Results: We included 973 women and 213 men. There was no difference between men and women in the choice of treatment. At follow-up, women scored significantly worse in the general questionnaire 36-item Short-Form Health Status (SF-36) domain bodily pain and in the thyroid-specific Thyroid-Related Patient-Reported Outcome (ThyPRO) domains depression, impaired sex life, and cosmetic complaints, all p  < 0.05. Women were twice as likely (29.5%) to be treated with levothyroxine after successful treatment with antithyroid drugs (ATD) compared with men (14.9%, p  < 0.05)., Conclusion: After treatment for GD, women were more affected by depression, impaired sex life, cosmetic issues, and bodily pain despite successful cure of hyperthyroidism. The prevalence of hypothyroidism was also doubled in women. Whether these observed gender differences reflect a worse outcome of GD in women or a natural consequence of a higher prevalence of these symptoms and autoimmunity in the female population is difficult to disentangle. Nevertheless, several years after GD, women reveal more persistent symptoms., Competing Interests: The authors declare no competing financial interests., (© Jan Calissendorff et al., 2023; Published by Mary Ann Liebert, Inc.)

Background: The purpose of treating toxic nodular goitre (TNG) is to reverse hyperthyroidism, prevent recurrent disease, relieve symptoms and preserve thyroid function. Treatment efficacies and long-term outcomes of antithyroid drugs (ATD), radioactive iodine (RAI) or surgery vary in the literature. Symptoms often persist for a long time following euthyroidism, and previous studies have demonstrated long-term cognitive and quality of life (QoL) impairments. We report the outcome of treatment, rate of cure (euthyroidism and hypothyroidism), and QoL in an unselected TNG cohort., Methods: TNG patients (n = 638) de novo diagnosed between 2003-2005 were invited to engage in a 6-10-year follow-up study. 237 patients responded to questionnaires about therapies, demographics, comorbidities, and quality of life (ThyPRO). Patients received ATD, RAI, or surgery according clinical guidelines., Results: The fraction of patients cured with one RAI treatment was 89%, and 93% in patients treated with surgery. The rate of levothyroxine supplementation for RAI and surgery, at the end of the study period, was 58% respectively 64%. Approximately 5% of the patients needed three or more RAI treatments to be cured. The patients had worse thyroid-related QoL scores, in a broad spectrum, than the general population., Conclusion: One advantage of treating TNG with RAI over surgery might be lost due to the seemingly similar incidence of hypothyroidism. The need for up to five treatments is rarely described and indicates that the treatment of TNG can be more complex than expected. This circumstance and the long-term QoL impairments are reminders of the chronic nature of hyperthyroidism from TNG., (© 2022. The Author(s).)

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: Orbital morphological changes are often present in patients with Graves' disease (GD) already at diagnosis, and cyclooxygenase type 2 (COX-2) is overexpressed in active Graves' ophthalmopathy (GO)., Objective: To investigate if adjuvant treatment of GD with the COX inhibitor and peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist diclofenac decreases the development of ophthalmopathy and if laboratory parameters are affected., Methods: This is a multicenter trial where 61 subjects were randomized to methimazole (block and replace with l-thyroxine) either with or without diclofenac 50 mg 1 × 2 for 12 months. The primary end point development of GO after 24 months was evaluated. Smoking habits were registered and the thyroid parameters TSH, free T4, free T3, TSH receptor antibodies (TRAb) and anti-TPO were followed. Safety parameters (kidney, liver and blood) and adverse events were regularly registered., Results: GO developed in 11% (n = 3) of the patients treated with diclofenac and in 21% (n = 6) of the controls (p = 0.273). The adverse event profile was acceptable without any severe events related to diclofenac. Both TRAb and anti-TPO concentrations decreased during treatment with methimazole, but the anti-TPO concentrations were lower in patients treated with diclofenac after 15 months (p = 0.031). The TRAb concentrations were not significantly changed between groups. Smokers had higher concentrations of TRAb than nonsmokers both at diagnosis of GD (p = 0.048) and after 15 months (p = 0.042)., Conclusions: Treatment with diclofenac had no significant influence on development of GO. Diclofenac reduces anti-TPO concentrations and seems to be safe to use in GD patients.

Background: The development of Graves' disease (GD) after subacute thyroiditis (SAT) is very rare and only a limited number of cases have been reported., Objectives: Here, we report a patient with SAT followed by hypothyroidism and later GD, with ophthalmopathy, occurring 11 years after SAT., Conclusion: This case illustrates the appearance of thyroid-stimulating hormone (TSH) receptor antibodies in a female 1 year after SAT, the development of hypothyroidism requiring thyroxine, and later the occurrence of GD with severe ophthalmopathy, 11 years after SAT. The occurrence of SAT and GD may be coincidental but SAT may have induced the appearance of TSH-receptor antibodies, with the bioactivity changing from blocking, leading to hypothyroidism, and later to a stimulating activity that led to GD in a genetically susceptible patient.

Background: Cigarette smoking is a risk factor for the development of Graves' ophthalmopathy (GO). In a previous study of gene expression in intraorbital fat, adipocyte-related immediate early genes (IEGs) were overexpressed in patients with GO compared to controls. We investigated whether IEGs are upregulated by smoking, and examined other pathways that may be affected by smoking., Methods: Gene expression in intraorbital fat was studied in smokers (n=8) and nonsmokers (n=8) with severe active GO, as well as in subcutaneous fat in thyroid-healthy smokers (n=5) and nonsmokers (n=5) using microarray and real-time polymerase chain reaction (PCR)., Results: With microarray, eight IEGs were upregulated more than 1.5-fold in smokers compared to nonsmokers with GO. Five were chosen for confirmation and were also overexpressed with real-time PCR. Interleukin-1 beta/IL-1B/(2.3-fold) and interleukin-6/IL-6/(2.4-fold) were upregulated both with microarray and with real-time PCR in smokers with GO compared to nonsmokers. Major histocompatibility complex, class II, DR beta 1/HLA-DRB1/was upregulated with microarray (2.1-fold) and with borderline significance with real-time PCR. None of these genes were upregulated in smokers compared to nonsmokers in subcutaneous fat., Conclusions: IEGs, IL-1B, and IL-6 were overexpressed in smokers with severe active GO compared to nonsmokers, suggesting that smoking activates pathways associated with adipogenesis and inflammation. This study underlines the importance of IEGs in the pathogenesis of GO, and provides evidence for possible novel therapeutic interventions in GO. The mechanisms activated by smoking may be shared with other conditions such as rheumatoid arthritis.

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.

Patients with low thyroid peroxidase antibodies (anti-TPO) and increased TSH-receptor antibodies (TRAb) at diagnosis of Graves' disease (GD) have been suggested to have an increased risk to develop Graves' ophthalmopathy (GO). The aim was to evaluate if GO development can be predicted.This is an observational study with registration of possible GD and GO risk factors.399 patients with GD were registered 2003-2008 in Malmö, Sweden and out of these 310 were retrospectively followed up to 6 years. The main outcome measures were anti-TPO titer, TRAb titer, smoking habits, radioiodine treatment and GO development.TRAb was assessed with a third generation assay at GD diagnosis in 231 patients. The proportion of patients with GO increased above the median 6.3 IU/L both at diagnosis of GD (p=0.001) and at follow-up (p=0.0001).The distribution of GO patients anti-TPO above or below 20 kIU/L at diagnosis of GD was similar between groups (p=0.239). However at follow-up anti-TPO<20 kIU/L was associated with an increased proportion of newly developed GO as compared to the cohort with anti-TPO>20 kIU/L (p=0.018).87% of patients who developed GO after GD diagnosis had TRAb above 6.3 IU/L and/or anti-TPO below 20 kIU/L. The proportion of GO was doubled in GD patients treated with radioiodine but could not explain the described findingsAnti-TPO<20 kIU/L and/or TRAb>6.3 IE/L at the time of GD diagnosis were associated with an increased risk to develop GO after diagnosis of GD., (© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.)

BACKGROUND AND AIMS. Microscopic colitis (MC), predominantly affecting women, is associated with thyroid disorders, although purely defined of which type, or compared with controls. Its association with subclinical thyroid disorders, and related increased risk of cardiovascular diseases, has never been examined. The aim was to examine the prevalence of autoantibodies and subclinical and clinical thyroid dysfunction in female patients with MC compared with controls. METHODS. Women younger than 73 years old with biopsy-verified MC from the Department of Gastroenterology in Skåne, during 2002-2010, were invited. Out of 240 identified, 133 were finally included. A questionnaire about medical history was completed and blood samples were collected. Serum was analyzed for free thyroxin and triiodothyronine, thyroid-stimulating hormone and anti-thyroid peroxidase (anti-TPO) antibodies. A population-based group of 737 women served as controls. RESULT. The prevalence of thyroid disorders in patients was higher compared to controls [odds ratio (OR) = 2.98, 95% confidence interval (CI) = 1.78-4.99], but the prevalence of subclinical disorders was not different (OR = 1.18, 95% CI = 0.48-2.85). Anti-TPO antibodies were present in 10.6% of MC patients and 18.6% of controls. Twenty-five MC patients had hypothyroidism: 15 with Hashimoto's hypothyroidism, 6 with completed treatment of thyrotoxicosis and 4 with completed surgery after nontoxic goiter. CONCLUSION. Thyroid disorders, autoimmune hypothyroidism being most frequent, are more prevalent in patients with MC than in controls, whereas the prevalence of subclinical thyroid disorders in MC patients does not differ significantly from controls.

Introduction: The incidence of hyperthyroidism has been reported in various countries to be 23-93/100,000 inhabitants per year. This extended study has evaluated the incidence for ~40% of the Swedish population of 9 million inhabitants. Sweden is considered to be iodine sufficient country., Methods: All patients including children, who were newly diagnosed with overt hyperthyroidism in the years 2003-2005, were prospectively registered in a multicenter study. The inclusion criteria are as follows: clinical symptoms and/or signs of hyperthyroidism with plasma TSH concentration below 0.2 mIE/l and increased plasma levels of free/total triiodothyronine and/or free/total thyroxine. Patients with relapse of hyperthyroidism or thyroiditis were not included. The diagnosis of Graves' disease (GD), toxic multinodular goiter (TMNG) and solitary toxic adenoma (STA), smoking, initial treatment, occurrence of thyroid-associated eye symptoms/signs, and demographic data were registered., Results: A total of 2916 patients were diagnosed with de novo hyperthyroidism showing the total incidence of 27.6/100,000 inhabitants per year. The incidence of GD was 21.0/100,000 and toxic nodular goiter (TNG=STA+TMNG) occurred in 692 patients, corresponding to an annual incidence of 6.5/100,000. The incidence was higher in women compared with men (4.2:1). Seventy-five percent of the patients were diagnosed with GD, in whom thyroid-associated eye symptoms/signs occurred during diagnosis in every fifth patient. Geographical differences were observed., Conclusion: The incidence of hyperthyroidism in Sweden is in a lower range compared with international reports. Seventy-five percent of patients with hyperthyroidism had GD and 20% of them had thyroid-associated eye symptoms/signs during diagnosis. The observed geographical differences require further studies.

Objective: Several studies indicate that in utero exposure to maternal autoimmune diseases and transplacental passage of autoantibodies affect the risk of autoimmunity in the offspring, e. g., maternally derived GAD65 autoantibody correlates with decreased risk of type 1 diabetes, whereas thyroid peroxidase autoantibody (TPOAb) positivity at birth is associated with increased incidence of autoimmune thyroid disease later in life. The aim of this study was to identify immunological changes in children born to mothers with thyroid autoimmunity that may be related to in utero exposure to autoantibodies., Design and Method: Open label prospective analysis of cord blood lymphocytes and serum cytokines by Flow Cytometry in children born to mothers with autoimmune thyroiditis (AIT) (n=31) and to healthy mothers (n=76) and titers of thyroid autoantibodies were determined in cord blood and in maternal peripheral blood at delivery., Results: We found an increase (almost 30%) in the frequency of cord blood natural killer (NK) cells (p=0.0016) and a minor increase in the subset of T cells expressing NK markers (p=0.028), in children born to AIT mothers. There were no detectable differences in the phenotype or frequency of cord blood memory/activated T cells, including CD4 (+)CD25 (+) T cells, between the 2 groups. The levels of pro-inflammatory cytokines TNF-α, IL-10, IL-12p70, IFN-γ and IL-1β were significantly decreased in offspring of AIT mothers as compared to healthy controls., Conclusions: Maternal thyroid autoimmunity and transplacental passage of autoantibodies against thyroid antigens may affect the generation or expansion of cells with NK activity and the secretion of inflammatory cytokines., (© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.)

Background: Graves' ophthalmopathy (GO) and lymphedema share some pathogenetic mechanisms, such as edema, inflammation, and adipogenesis. The aim of this study was to examine similarities and differences between chronic GO and chronic lymphedema., Methods: Intraorbital adipose tissue was collected from patients with active (n = 10) or chronic GO (n = 10) and thyroid-healthy controls (n = 10). Arm subcutaneous adipose tissue was obtained from patients with chronic arm lymphedema (n = 10), where the unaffected arm served as a control. Gene expression was studied using microarray and real-time polymerase chain reaction., Results: The following genes were significantly upregulated (p < 0.05) in lymphedema but not in GO and have functions in wound healing, fibrosis, fat metabolism, inflammation, differentiation, development, adhesion, and the cytoskeleton: ATP-binding cassette, sub-family G (WHITE), member 1 (ABCG1), actin, alpha 2, smooth muscle, aorta (ACTA2), secreted frizzled-related protein 2 (SFRP2), tenascin C (TNC), pentraxin-related gene, rapidly induced by IL-1 beta (PTX3), and carboxypeptidase X (M14 family), member 1 (CPMX1). In chronic GO, but not in lymphedema, adipocyte-related immediate early genes known to be overexpressed in patients with active GO were upregulated but at a lower level than previously shown for the active phase. Genes of the Wnt pathway, such as secreted frizzled-related protein 1, 2, and 3, were up- and downregulated in both chronic GO and lymphedema. Parathyroid hormone-like hormone (PTHLH) was downregulated (p = 0.01) and apolipoprotein L domain containing 1 (APOLD1) was upregulated (p = 0.05) in both active and chronic GO., Conclusions: There are more differences than similarities between chronic ophthalmopathy and chronic lymphedema, but both conditions exhibit less inflammation and adipogenesis compared to the active phases. In lymphedema, fibrosis dominates. PTHLH, which can inhibit adipogenesis, is downregulated both in active and chronic ophthalmopathy, indicating the possibility of an increased risk of adipogenesis.

Objective: The objective of this study was to investigate quality of life (QoL) in patients with Graves' disease treated with radioiodine or antithyroid drugs., Design and Methods: The design of the study consists of an open, prospective, randomized multicenter trial between radioiodine and medical treatment. A total of 308 patients were included in the study group: 145 patients in the medical group and 163 patients in the radioiodine group. QoL was measured with a 36-item Short Form Health Status Survey questionnaire (SF-36) at six time points during the 48-month study period., Results: Patient who developed or got worse of thyroid-associated ophthalmopathy (TAO) at any time point during the 4-year study period (TAO group) had lower QoL when no respect was paid to the mode of treatment. TAO occurred in 75 patients who had radioiodine treatment at some time point during the study period as compared with TAO in 40 medically treated patients (P<0.0009). Comparisons between the group of patients who have had TAO versus the group without TAO, in relation to treatments and time, showed significantly decreased QoL scores for the TAO groups at several time points during the study. In patients without TAO, there were no differences in QoL related to mode of treatment., Conclusions: The QoL in patients with Graves' ophthalmopathy was similar in radioiodine and medically treated patients, but patients who developed or had worsening of TAO had decreased QoL independent of mode of treatment. Furthermore, patients with TAO recovered physically within 1 year but it took twice as long for them to recover mentally.

Context: Previous randomized trials have suggested an association between radioiodine treatment for Graves' hyperthyroidism and thyroid-associated ophthalmopathy (TAO)., Objectives: The aim of the study was to compare the occurrence of worsening or development of TAO in patients who were treated with radioiodine or antithyroid drugs., Design: We conducted a randomized trial (TT 96) with a follow-up of 4 yr. PATIENTS, SETTING, AND INTERVENTION: Patients with a recent diagnosis of Graves' hyperthyroidism were randomized to treatment with iodine-131 (163 patients) or 18 months of medical treatment (150 patients). Early substitution with T(4) was given in both groups., Main Outcome Measure: Worsening or development of TAO was significantly more common in the iodine-131 treatment group (63 patients; 38.7%) compared with the medical treatment group (32 patients; 21.3%) (P < 0.001)., Results: The risk for de novo development of TAO was greater in patients treated with iodine-131 (53 patients) than with medical treatment (23 patients). However, worsening of TAO in the 41 patients who had ophthalmopathy already before the start of treatment was not more common in the radioiodine group (10 patients) than in the medical group (nine patients). Smoking was shown to influence the risk of worsening or development of TAO, and smokers treated with radioiodine had the overall highest risk for TAO. However, in the group of smokers, worsening or development of TAO was not significantly associated with the choice of treatment for hyperthyroidism., Conclusions: Radioiodine treatment is a significant risk factor for development of TAO in Graves' hyperthyroidism. Smokers run the highest risk for worsening or development of TAO irrespective of treatment modality.

Background: Thyroid hormones are important for normal fetal development. Maternal hypothyroidism during early pregnancy is associated with impaired neuropsychological development of children and other adverse outcomes. The primary aim of this prospective study was to determine whether thyroxine-treated pregnant women with hypothyroidism are adequately thyroxine substituted in early pregnancy. A secondary aim was to determine if fetal loss differed between females with thyrotropin (TSH) values within and outside the reference range at their first TSH test, scheduled for 1-2 weeks after verification of pregnancy., Methods: This was a prospective open-labeled study. During the years 1997-2002, 119 consecutive pregnancies in 101 females with thyroid diseases were followed at the Department of Endocrinology, Malmö University Hospital. At the first visit, 63 patients, median age 30 years (range 17-45 years), were on thyroxine substitution therapy for hypothyroidism. In these patients 83% were in their first trimester at the time of the initial test., Results: Of the 63 patients on thyroxine substitution for hypothyroidism 32 (51%; Group A) patients had serum TSH values within the reference range at their initial test and 31 (49%; Group B) had serum TSH values outside the reference range. Twelve (19%) had TSH values of <0.40 mIU=L and 19 (30%) had TSH values of >4.0 mIU=l. The fetal loss was 2 of 32 (6%) in Group A compared to 9 of 31 (29%) in Group B ( p < 0.05)., Conclusions: In 49% of pregnant women on thyroxine substitution, serum TSH values were outside the reference range when first tested, generally in the first trimester. Fetal loss was significantly greater in pregnant women with abnormal TSH values compared to those with normal TSH values. Thyroid function in pregnant women on thyroxine substitution should be monitored early in pregnancy and carefully followed during pregnancy. The thyroxine dose should be increased as needed early in pregnancy to avoid hypothyroidism.

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.

Objectives: To investigate the incidence of hyperthyroidism in Stockholm County, in those patients who were diagnosed with hyperthyroidism for the first time during the years 2003-2005., Design: All new cases of hyperthyroidism > or = 18 years of age were prospectively registered to calculate the total incidence of hyperthyroidism, as well as the incidence of the subgroups: Graves' disease (GD), toxic multinodular goitre and solitary toxic adenoma (STA). Eight specialized units/hospitals in Stockholm County participated in the registration. The participating physicians were all specialists in medical endocrinology, oncology, nuclear medicine or surgery., Results: During a 3-year period, 1431 new patients of hyperthyroidism were diagnosed in a well-defined adult population (> 18 years of age) of in average 1,457,036 inhabitants. This corresponds to a mean annual incidence of hyperthyroidism of 32.7/100,000. The incidence of GD was 24.5/100,000 per year, toxic nodular goitre was 3.3/100,000 per year and STA was 4.9/100,000 per year., Conclusions: The total incidence of hyperthyroidism in Stockholm County was found to be 32.7/100,000 per year, of which 75% had GD. There were a higher percentage of smokers among the patients with hyperthyroidism compared with the overall population in Stockholm, but no difference in the frequency of smoking between patients with GD and toxic nodular goitre.

Context: Inflammation and adipogenesis are two parallel processes with increased activity in severe Graves' ophthalmopathy., Objective: The aim of this work was to define target genes for therapeutic intervention in adipogenesis and inflammation in Graves' ophthalmopathy., Design: Orbital tissue was obtained from patients with ophthalmopathy in acute or chronic phase undergoing orbital surgery to study gene expression followed by the study of potential intervention mechanisms in preadipocytes., Setting: Clinic of Endocrinology, University Hospital, Malmö, Sweden., Participants: Patients in acute severe or in chronic phase of ophthalmopathy., Interventions: Lateral orbital decompression in acute phase and restorative surgery in chronic phase. In vitro treatment of preadipocytes with rosiglitazone and diclofenac., Main Outcome Measure: Gene expression in intraorbital tissue or preadipocytes and differentiation of preadipocytes., Results: A marker of adipose tissue, stearoyl-coenzyme A desaturase (SCD), and the proinflammatory gene, cyclooxygenase-2 (COX-2), were overexpressed in patients in active phase compared to the chronic phase of ophthalmopathy. In growth-arrested preadipocytes stimulated with rosiglitazone, COX-2 expression increased temporarily within 1 hour and decreased to undetectable levels after 48 hours. In contrast, SCD and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) expression increased continuously from day 2 to day 7 during adipogenesis. Diclofenac, an inhibitor of cyclooxygenases with antagonistic effects on PPAR-gamma, reduced the number of mature adipocytes by approximately 50%., Conclusion: We conclude that inflammation and adipogenesis decrease with a decrease in activity of ophthalmopathy and that the nonsteroidal antiinflammatory drug diclofenac inhibits adipogenesis. This may represent a putative future treatment of endocrine ophthalmopathy.

Objective: To investigate gene expression of thyrostimulin in orbital and thyroid tissue from patients with and without Graves' disease., Design: Real-time reverse transcriptase polymerase chain reaction (RT-PCR) was used for detection of thyrostimulin gene expression in intraorbital adipose tissue from patients with severe ophthalmopathy and thyroid healthy controls in addition to thyrostimulin expression in normal thyroid tissue, multinodular goiter tissue, and Graves' thyroid tissue., Main Outcome: In intraorbital tissue, thyrostimulin expression was identified in both patients and controls with fluorescence intensities varying between 0.23 and 0.88 in patients and 0.29 and 8.9 in controls before treatment with DNase. The signal of thyrostimulin was weak or absent in intraorbital adipose tissue from patients with ophthalmopathy and thyroid healthy controls after treatment of samples with DNase. This was in contrast to the expression of the thyroid-stimulating hormone (TSH) receptor and the housekeeping gene cyclophilin A that were detected both before and after DNase treatment. Similar results were found when analyzing human and rat thyroid tissue., Conclusions: Neither did we demonstrate gene expression of thyrostimulin in intraorbital adipose tissue or in thyroid tissue, nor could we confirm earlier findings in rat thyroid tissue. Whether thyrostimulin is a regulator of thyroid function has to be further investigated in future studies.

Objective: Changes in eye protrusion in patients treated with pioglitazone., Design: Open-label prospective., Patients: Thirty-six patients with type 2 diabetes and HbA1c >or= 6.5% were included in a study where pioglitazone was added to current therapy with metformin and sulphonylurea., Measurements: The degree of eye protrusion before and 26 weeks after treatment with pioglitazone was measured using Krahn's exophthalmometer., Results: Thirteen patients (group A) exhibited an increase of >or= 2 mm and 23 patients (group B) exhibited an increase of < 2 mm (P (between groups) = 0.036). Patients of group A vs. group B had the same BMI, HbA1c and mean doses of pioglitazone, but had lower levels (mean +/- SD) of adiponectin in microg/ml at the start (4.9 +/- 2.1) vs. (7.1 +/- 2.5), P = 0.017 and at the end of study (10.2 +/- 4) vs. (14.9 +/- 5), P = 0.007. Patients with thyroid disturbance were more frequent in group A (five vs. one), P = 0.02. In a logistic regression analysis, thyroid disturbance, low adiponectin levels and pioglitazone dose predicted a significant change in eye protrusion., Conclusions: A subgroup of patients with type 2 diabetes treated with pioglitazone responded with increased eye protrusion. This subgroup showed decreased plasma concentration of adiponectin and more frequent thyroid disturbance, and was treated with higher doses of pioglitazone. The relationship between insulin resistance, thyroid disturbance and thiazolidinedione-induced eye protrusion should be further studied.

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.

Background: Females have an increased incidence of autoimmune diseases. However, no gender difference in the incidence of type 1 diabetes is found. The frequency of antibodies against glutamic acid decarboxylase (GADA) in diabetes mellitus depends on age at diagnosis and also gender. Several studies have shown that high GADA levels can predict future beta-cell failure and need for insulin treatment. The aim of this study was to investigate possible gender differences in relation to GADA levels, fasting plasma C-peptide levels and frequency of other autoimmune endocrine diseases in GADA-positive patients with different age at diabetes diagnosis., Methods: GADA were screened in 4974 patients from a local diabetes registry, and plasma C-peptide was measured and a history of other autoimmune endocrine diseases was recorded. Of these patients, 822 were GADA positive and were further divided into four groups depending on the age at diagnosis of diabetes; Group 1: <20 years, Group 2: 20-39 years, Group 3: 40-59 years and Group 4: > or =60 years., Results: Female patients in Group 3 had lower fasting plasma C-peptide levels (median 0.21[0.00-0-56] vs. 0.41[0.00-0.73] nmol/L, p=0.02), higher GADA levels (median 7 [4-9] vs. 5 [2-7] Arbitrary Unit (AU), p=0.0003) and higher frequency of other autoimmune endocrine diseases (22.4 vs. 5.3%, p=0.0001) than male patients. In a stepwise logistic regression analysis, diabetes duration (p<0.000001), high GADA levels (Exp (B) 3.68 CI 1.69-7.98, p=0.001) and low BMI (p=0.00002) were associated with total beta-cell failure in Group 3., Conclusions: GADA-positive female diabetic patients with an age at diagnosis between 40 and 59 years have higher GADA levels and a more severe loss of beta-cell function than male patients with the same age at diagnosis. This could be due to the effect of sex steroids and/or GnRH on the regulation of the immune system. Female patients with high GADA levels also had a high prevalence of other autoimmune endocrine diseases, especially autoimmune thyroid disease, which further emphasises the need for screening of thyroid function in female patients with high GADA levels., (Copyright 2004 John Wiley & Sons, Ltd.)

To study whether antibodies to glutamic acid decarboxylase (GADab) are associated with subclinical beta-cell damage and impaired insulin secretion, we screened 441 nondiabetic patients with autoimmune thyroiditis (AT) for GADab, and 15 (3.4%) were found positive. Antibodies to IA-2 were found in two GADab+ and one GADab- patients. We matched 11 GADab+ and 13 GADab- AT patients who were euthyroid on thyroxin supplementation, and 13 control subjects for sex, age, and body mass index and measured insulin, C-peptide, and glucagon response to glucose and arginine at three blood glucose concentrations (fasting, 14 mmol/liter, >25 mmol/liter). In the fasting state, all groups had similar blood glucose concentration and HbA1c level, but the serum insulin concentration was higher in the AT patients compared with the control subjects (P < 0.04). The acute insulin response to arginine was lower in GADab+ than in GADab- thyroiditis subjects at glucose concentration of 14 and >25 mmol/liter (AIR(14): 76.8 +/- 52.0 vs. 158.2 +/- 118.2 mU/liter, P = 0.040; AIR(>25): 84.3 +/- 64.4 vs. 167.9 +/- 101.5 mU/liter, P = 0.035). In conclusion, GADab were associated with a decreased insulin secretion capacity in nondiabetic subjects with thyroiditis, which suggests that GADab positivity could be a marker of subclinical insulitis.

Objective: To study the effects and serum levels of glibenclamide (Gb) and its active metabolites in patients on chronic Gb medication on different daily doses., Material and Methods: Fifty patients with type 2 diabetes on regular Gb therapy (1.75-14.0 mg daily). Blood samples were taken immediately before and 90 min after regular Gb intake. A standardized breakfast was served 30 min after drug intake. Serum insulin and proinsulin levels were determined by ELISA methods without cross-reactivities. Serum drug levels were determined by HPLC. Fischer's R to Z-test (correlation coefficients) and paired Student t-tests were used when comparing values within the entire group and unpaired non-parametric Mann-Whitney tests were used when comparing high and low dose levels. A p-value < 0.05 was considered significant., Results: There were significant correlations between daily Gb dose, on the one hand, and, on the other, HbAlc (r = 0.55), Delta-insulin (r = - 0.59) and Delta-proinsulin (r = - 0.52) levels. Significant correlations between Gb therapy duration and insulin (r = - 0.40) and proinsulin (r = - 0.34) secretion and between Gb dose and ratio proinsulin/insulin (RPI) at both time points (r = 0.32 and 0.30) were also found. The RPI was lower after Gb intake. In patients on > or = 10.5 mg steady state serum metabolite levels (Ml and Ml + M2) were higher (29(0-120) and 33 (0-120) ng/ml) than those of Gb itself (18(0-64) ng/ml). A great inter-subject variability in Gb levels at both time points was seen., Conclusions: Our results indicate that, in patients on chronic medication, Gb is capable of stimulating both insulin and proinsulin secretion; the effect on insulin release is relatively greater. The effect was more pronounced in patients on a low Gb dose, either because of less impaired beta-cells in those receiving low doses, or due to reduced sulphonylurea sensitivity in those on high dosage (down-regulation). In patients on a daily dose of 10.5 mg or more, serum metabolite levels of clinical relevance were demonstrated; the metabolites may contribute to hypoglycaemic events.

Multiple endocrine neoplasia type 2 (MEN 2) is a rare syndrome in which the consequences for the patient and family members are considerable. Mutation analysis of the RET proto-oncogene is crucial for decision-making regarding each patient. Today, carriers of MEN 2 mutations should be offered prophylactic thyroidectomy with the potential to eliminate the risk for potentially lethal medullary thyroid carcinoma (MTC). Here, we present the first Swedish experience of such operations performed mainly on the basis of genetic analysis. Twenty patients underwent total thyroidectomy at a mean age of 13.5 (6-43) years. In all cases, either manifest MTC (n = 11) or C-cell hyperplasia was found. So far, no patient has any sign of recurrence or developmental insufficiency at 1-5 years follow-up. As the medical and ethical problems in this group of patients are substantial, and as the operations are performed in otherwise healthy children, they should be treated at centers with adequate multidisciplinary expertise and competence.

The effects and kinetics of oral glibenclamide (Gb) and glipizide (Gz) were studied in Caucasian and Chinese patients (ten in each group) with type-2 diabetes. In randomised order, 2.5 mg Gb, 2.5 mg Gz or placebo was given orally before the administration of 75 g oral glucose. Concentrations of insulin and proinsulin were determined using radioimmunoassay (RIA) without cross-reactivities, and sulphonylurea concentrations were determined using high-performance liquid chromatography (HPLC). There were no significant interethnic differences in Gb or Gz effects whether on glucose, insulin or proinsulin/insulin ratio at any time point. Following Gz, however, Chinese patients had greater increments of serum proinsulin at 10-30 min compared with Caucasians. Apart from the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of Gz being higher among the Chinese, no significant interethnic differences in pharmacokinetics were found. It appears that the same dosage principles could be used for Caucasian and Chinese patients with type-2 diabetes when Gb or Gz are prescribed.

Objectives: To investigate the significance of ACE gene insertion/deletion (I/D) polymorphism in the frequency of autoimmune manifestations in sarcoidosis., Design: In patients with sarcoidosis the ACE gene I/D polymorphism was detected with PCR on genomic DNA. The patients with sarcoidosis were divided according to the presence (n = 30) or absence (n = 32) of autoimmune manifestations. The former group was subdivided into thyroid autoimmunity (n = 10), gluten immune reactivity (n = 10) and gastric autoimmunity (n = 17)., Settings: The patients were recruited at the Department of Pulmonary Medicine, and the study was conducted at the Department of Endocrinology, University of Lund, Malmö University Hospital, Malmö, Sweden., Subjects: Sixty-two patients with documented sarcoidosis (30 females, 32 males, median age/range at diagnosis of sarcoidosis 31.5/19-75 years, median age/range at study 47.5/22-81 years) were examined. A total of 107 healthy unrelated subjects without sarcoidosis (60 females, 47 males, median age/range at study 58/40-82 years) served as controls., Results: S-ACE values were significantly increased in patients compared to controls (P = 0.00001). The same was true in the subgroup of sarcoidosis patients with associated autoimmunity compared with those with isolated sarcoidosis (P = 0.0328). A significant association was seen between ACE gene polymorphism (II, ID, DD genotypes) and S-ACE levels in both patients and controls according to the order II < ID < DD. The observed genotype frequency distributions in the different study groups agreed the Hardy-Weinberg equilibrium without significant differences between the patients and the controls. Within the group with autoimmune manifestations the DD genotype was significantly over-represented in X-ray stage III compared to the other X-ray stages (P = 0.0181) and a significant increase in the DD genotype in X-ray stage III (P = 0.035) in the group with autoimmune manifestations compared to isolated sarcoidosis was detected., Conclusion: We confirmed that the S-ACE levels corresponded to the order II < ID < DD in patients with sarcoidosis as well as in healthy controls. S-ACE levels were significantly higher in sarcoidosis patients with autoimmune manifestations. The frequency of the DD genotype was significantly increased in patients with autoimmune manifestations and major granuloma mass (X-ray stage III). The ACE D allele in its homozygous form may confer susceptibility for autoimmune manifestations in sarcoidosis, possibly via the high levels of S-ACE it encodes.

Objective: We analysed the kinetics and effects of glibenclamide (Gb) on glucose, insulin and proinsulin secretion in two ethnic groups (10 in each) of type-2 diabetic patients, one of Caucasian, the other of Chinese origin., Background: Diabetes mellitus type 2 is a global disease affecting all ethnic groups. There are ethnic differences in both the prevalence and metabolic characteristics of the disease. Important interethnic pharmacodynamic and pharmacokinetic differences have been reported for several drugs. With few exceptions, detailed studies on sulphonylurea are lacking., Material and Methods: The patients were studied on two occasions when either no Gb (control) or 1.25 mg Gb was administered i.v., immediately before the administration of a 75-g oral glucose tolerance test. Concentrations of insulin and proinsulin were determined by means of radioimmunoassay without cross-reactivities. Gb concentration was determined using high-performance liquid chromatography. Pharmacodynamic results were calculated using net areas under the curves, with basal values set as zero. A P value less than 0.05 was considered significant., Results: When glucose was administered orally without Gb, Chinese patients had higher plasma glucose increases at 10 min (7.6 mmol/l x min vs 2.6 mmol/l x min) and higher increases of plasma insulin levels than Caucasians at both 10 min (198 pmol/l x min vs 54 pmol/l x min) and 30 min (2286 pmol/l x min vs 1198 pmol/l x min). When Gb was administered, the plasma glucose increases were reduced, and the increases of serum insulin and proinsulin levels were greater in both ethnic groups. Compared with the basal values (-1 min), proinsulin/insulin ratios (RPI) were lowest at 10-30 min, followed by an increase. Chinese patients had higher increases of serum insulin levels at 10 min (1109 pmol/l x min vs 550 pmol/l x min) and a lower RPI at 30 min (6. 0% vs 7.6%) and 240 min (15.0% vs 21.0%) relative to Caucasians. Serum Gb data were best fitted to a biexponential i.v. model. There were no interethnic differences in any of the pharmacokinetic parameters., Conclusion: In summary, following oral glucose administration without Gb, Chinese type-2 diabetic patients had higher plasma insulin levels but also higher plasma glucose levels during the first 10 min, which might reflect reduced insulin sensitivity or more rapid glucose absorption. Gb augmented glucose-induced release of both insulin and proinsulin in both ethnic groups; the effect on insulin secretion was more pronounced. In conclusion, minor pharmacodynamic but no pharmacokinetic differences were found between the two groups. It seems appropriate to employ the same dosage principles when using Gb in Caucasians and Chinese.

Objectives: To study whether there is an increased fracture incidence following thyrotoxicosis., Design: A case-control study., Setting: Malmö University Hospital, Malmö, Sweden., Subjects: All patients (n = 333) from the population of Malmö who were treated for thyrotoxicosis for the first time during the 5-year period 1970-74. A total of 618 controls were selected from the local municipality registry in Malmö. For each case the aim was to randomly select two age- and gender-specific controls, alive in 1993 and born the same year and month as the case., Main Outcome Measures: Fracture incidence, Results: Comparing survivors, there were no differences in the percentage of individuals with fractures (all, fragility, non-fragility) between the patients and the controls. Comparing all individuals and including all fractures, the percentage of individuals with fractures in the entire female patient group (24.6%) was lower (P < 0.05) than in female controls (33.1%). There was a similar but non-significant pattern between male patients and controls. The mean number of all fractures was lower in male patients than in controls (P < 0.05), but no significant difference was noted between female patients and controls. For fragility fractures, there were no significant differences in the percentage of individuals with fractures or in the mean number of fractures between female or male patients and controls., Conclusion: In conclusion we found no increased incidence of fragility fractures in patients with previous thyrotoxicosis as compared with controls. Our results do not support the suggestion that screening for osteoporosis should be performed in patients with previous thyrotoxicosis.

Objectives: The aim of the present study was to explore the frequency of clinical and serological manifestations of gastrointestinal immune reactivity in a large group of Swedish patients with sarcoidosis., Design: In patients with documented sarcoidosis, the presence of pernicious anaemia and coeliac disease was examined. Antibodies to H+/K+ ATPase, gliadin (AGA-IgA/IgG) and endomysium (IgA-EMA) were analysed. In H+/K+ ATPase antibody-positive patients, serum gastrin levels were measured and, when elevated, gastrointestinal biopsy was offered (biopsy performed in 6/9 patients): biopsy was also offered to those with positive EMA or AGA of either class (biopsy performed in 8/12 patients). Subjects from national and local studies were used as controls., Setting: The patients were recruited at the Department of Pulmonary Medicine, and the study was conducted at the Department of Endocrinology, University of Lund, Malmö University Hospital, Malmö, Sweden., Subjects: Of all patients (n = 89) with documented sarcoidosis attending the Department of Pulmonary Medicine between January 1980 and December 1991, 78 [34 females and 44 males; median age at the time of the study, 48 (range 22-81) years; median observation time since the diagnosis of sarcoidosis, 120 (range 1-468) months] were examined., Results: Twenty-nine patients (37.2%) had signs of gastrointestinal immune reactivity. H+/K+ ATPase antibodies were detected in 19 patients (24.4 vs. 4% in controls, P = 0.00015). Serum gastrin levels (median 45, range 22-720 pmol L(-1)) in those patients correlated with antibody titre (r2 = 0.882). Gliadin antibodies were detected in 12 patients (15.4 vs. 8.1% in controls, P = 0.042), of whom 11 (14.1 vs. 4.5% in controls, P = 0.00114) had AGA-IgA alone. One patient had pernicious anaemia and another coeliac disease (EMA-positive)., Conclusion: We have demonstrated a high frequency of gastric autoimmunity and gluten-associated immune reactivity in patients with sarcoidosis, occurring in almost 40% of the cases, the former being the most frequent gastrointestinal immune manifestation. Despite a high frequency of humoral autoimmunity, the frequencies of clinical disease, pernicious anaemia and coeliac disease were not increased as compared with the control population.