A cross-sectional study of subclinical and clinical thyroid disorders in women with microscopic colitis compared to controls.

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.

Autoimmunity in sarcoidosis: the tip of the Iceberg.

Sarcoidosis is a mysterious condition with an etiology that has to date eluded explanation. Innumerable clinical and serological organ- and non-organ-specific autoimmune associations have been reported. Many of the associated conditions are life-threatening but easily manageable if diagnosed early. Due to the long latency that precedes the clinical onset of autoimmune diseases, it is prudent to ensure a long follow-up and a broad viewing perspective while maintaining a high index of suspicion when viewing the autoimmunity iceberg in sarcoidosis.

Fracture Incidence in Graves' Disease: A Population-Based Study.

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.

Long-Term Outcome of Graves' Disease: A Gender Perspective.

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.

Long term outcome after toxic nodular goitre.

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.

Treatment of patients with Graves' disease in Sweden compared to international surveys of an 'index patient'.

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 (131I). This preference for ATD is in line with most countries/regions, with the exception of USA and the Middle East/North Africa, where 131I 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 131I 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.

Impaired Quality of Life After Radioiodine Therapy Compared to Antithyroid Drugs or Surgical Treatment for Graves' Hyperthyroidism: A Long-Term Follow-Up with the Thyroid-Related Patient-Reported Outcome Questionnaire and 36-Item Short Form Health Status Survey.

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.

The Long-Term Outcome of Treatment for Graves' Hyperthyroidism.

Background: The treatment efficacy of antithyroid drug (ATD) therapy, radioactive iodine (131I), 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, 131I, 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 131I 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 131I therapy, including 2% (20/1186) who had received both surgery and 131I. 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 131I 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.

Thyrostimulin (a TSH-like Hormone) expression in orbital and thyroid tissue.

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.

COX-2 and SCD, markers of inflammation and adipogenesis, are related to disease activity in Graves' ophthalmopathy.

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.

Adjuvant Treatment of Graves' Disease with Diclofenac: Safety, Effects on Ophthalmopathy and Antibody Concentrations.

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.

Overexpression of immediate early genes in active Graves' ophthalmopathy.

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.

Presence of Thyroid-Stimulating Hormone Receptor Antibodies in a Patient with Subacute Thyroiditis followed by Hypothyroidism and Later Graves' Disease with Ophthalmopathy: A Case Report.

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.

Association of BTG2, CYR61, ZFP36, and SCD gene polymorphisms with Graves' disease and ophthalmopathy.

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.

Smoking induces overexpression of immediate early genes in active Graves' ophthalmopathy.

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.

Gene expression in Graves' ophthalmopathy and arm lymphedema: similarities and differences.

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.

Incidence of hyperthyroidism in Sweden.

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.