Serum CYR61 Levels are Associated with Graves' Ophthalmopathy and Smoking in Patients with Graves' Disease.

Smoking is a well-known risk factor for Graves' ophthalmopathy (GO) in patients suffering from Graves' disease (GD). Cysteine-rich angiogenic inducer 61 (CYR61), which has multiple physiological functions, has been shown to be associated with GD and GO. In this study, we aimed to investigate the association between smoking and CYR61 concentrations in GD patients with and without GO. Serum CYR61 was measured by ELISA. The association between CYR61 concentration and GO was assessed with binary logistic regression in all patients and in subgroups of smokers and nonsmokers. The Spearman correlation coefficient was used to determine the correlations between CYR61 concentration and clinical parameters. CYR61 levels were significantly higher in GD patients with GO than in patients without GO, in smokers than in nonsmokers and in individuals older than 50 years than in those younger than 50 years. The subgroup of "GO smokers" had the highest CYR61 levels [median (IQR), 119 pg/ml (129.8)], compared with "GO nonsmokers" [84.2 pg/ml (90.8), p=0.04], "no GO smokers" [88.9 pg/ml (109.8), p=0.01] and "no GO nonsmokers" [79.4 pg/ml (129.89), p=0.003]. For each unit increase in CYR61 concentration, the odds of having GO in smokers significantly and independently increased by 1% (OR=1.010; 95% CI: 1.002-1.018, p=0.012). In conclusion, our results indicate that smoking and age increase serum CYR61 levels in patients with GD and GO. The role of CYR61 as a predictor of GO in patients with GD should be evaluated in prospective studies.

Smoking enhances proliferation, inflammatory markers, and immunoglobulins in peripheral blood mononuclear cells from Graves' patients.

Graves' disease (GD) and Graves' ophthalmopathy (GO) are complex autoimmune diseases. This study delved into the impact of cigarette smoke extract (CSE), simvastatin, and/or diclofenac on peripheral blood mononuclear cells (PBMCs). Specifically, we explored alterations in IL-1B, IL-6, PTGS2 expression, B- and T-lymphocyte proliferation, and Immunoglobulin G (IgG) production. We also assessed IGF1's influence on B- and T-lymphocyte proliferation. PBMCs from Graves' patients were exposed to CSE with/without simvastatin and/or diclofenac. Gene and protein expression was compared with untreated PBMCs. B- and T-lymphocyte proliferation was assessed following IGF1 treatment. PBMCs exposed to CSE exhibited increased expression of IL-1B (6-fold), IL-6 (10-fold), and PTGS2 (5.6-fold), and protein levels of IL-1B (4-fold), IL-6 (16-fold) and PGE2 (3.7-fold) compared with untreated PBMCs. Simvastatin and/or diclofenac downregulated the expression of PTGS2 (0.5-fold), IL-6 (0.4-fold), and IL-1B (0.6-fold), and the protein levels of IL-1B (0.6-fold), IL-6 (0.6-fold), and PGE2 (0.6-fold) compared with untreated PBMCs. CSE exposure in PBMCs increased the proliferation of B and T lymphocytes by 1.3-fold and 1.4-fold, respectively, compared with untreated. CSE exposure increased IgG (1.5-fold) in supernatant from PBMCs isolated from Graves' patients. IGF1 treatment increased the proliferation of B and T lymphocytes by 1.6-fold. Simvastatin downregulated the proliferation of B and T lymphocytes by 0.7-fold. Our study shows that CSE significantly upregulated the expression and release of the inflammatory markers PTGS2, IL-6 and IL-1B,the IgG levels, and the proliferation of B and T lymphocytes. Additionally, IGF1 increased the proliferation of B and T lymphocytes. Finally, these effects were decreased by diclofenac and/or simvastatin treatment.

Patients' Persistent Symptoms, Clinician Demographics, and Geo-Economic Factors Are Associated with Choice of Therapy for Hypothyroidism by European Thyroid Specialists: The "THESIS" Collaboration.

Background: Hypothyroidism is common, however, aspects of its treatment remain controversial. Our survey aimed at documenting treatment choices of European thyroid specialists and exploring how patients' persistent symptoms, clinician demographics, and geo-economic factors relate to treatment choices. Methods: Seventeen thousand two hundred forty-seven thyroid specialists from 28 countries were invited to participate in an online questionnaire survey. The survey included respondent demographic data and treatment choices for hypothyroid patients with persistent symptoms. Geo-economic data for each country were included in the analyses. Results: The response rate was 32.9% (6058 respondents out of 17,247 invitees). Levothyroxine (LT4) was the initial treatment preferred by the majority (98.3%). Persistent symptoms despite normal serum thyrotropin (TSH) while receiving LT4 treatment were reported to affect up to 10.0% of patients by 75.4% of respondents, while 28.4% reported an increasing such trend in the past 5 years. The principal explanations offered for patients' persistent symptoms were psychosocial factors (77.1%), comorbidities (69.2%), and unrealistic patient expectations (61.0%). Combination treatment with LT4+liothyronine (LT3) was chosen by 40.0% of respondents for patients who complained of persistent symptoms despite a normal TSH. This option was selected more frequently by female thyroid specialists, with high-volume practice, working in countries with high gross national income per capita. Conclusions: The perception of patients' dissatisfaction reported by physicians seems lower than that described by hypothyroid patients in previous surveys. LT4+LT3 treatment is used frequently by thyroid specialists in Europe for persistent hypothyroid-like symptoms even if they generally attribute such symptoms to nonendocrine causes and despite the evidence of nonsuperiority of the combined over the LT4 therapy. Pressure by dissatisfied patients on their physicians for LT3-containing treatments is a likely explanation. The association of the therapeutic choices with the clinician demographic characteristics and geo-economic factors in Europe is a novel information and requires further investigation.

Thyroid hormones for euthyroid patients with simple goiter growing over time: a survey of European thyroid specialists.

BACKGROUND: Treatment of simple goiter (SG) growing over time with thyroid hormone (TH) therapy is discouraged by international guidelines. PURPOSE: To ascertain views of European thyroid specialists about TH treatment for euthyroid patients with growing SG and explore associations with management choice. METHODS: Online survey on the use of TH for growing SG among thyroid experts from 28 European countries. RESULTS: The response rate was 31.5% (5430/17,247). Most respondents were endocrinologists. Twenty-eight percent asserted that TH therapy may be indicated in euthyroid patients with a growing SG. National and regional differences were noted, from 7% of positive responses in The Netherlands to 78% in Czech Republic (p < 0.0001). TH was more frequently prescribed by respondents over 40 years old (OR 1.77, 2.13, 2.41 if 41-50, 51-60, >60, respectively), and working in areas of former iodine insufficiency (OR 1.24, 95% CI 1.03-1.50). TH was less frequently prescribed by endocrinologists (OR 0.77, 95% CI 0.62-0.94) and respondents working in Southern Europe (OR 0.40, 95% CI 0.33-0.48), Northern Europe (OR 0.28, 95% CI 0.22-0.36) and Western Asia (OR 0.16, 95% CI 0.11-0.24) compared to Western Europe. Associations with respondents' sex, country, availability of national thyroid guidelines, and gross national income per capita were absent or weak. CONCLUSIONS: Almost a third of European thyroid specialists support treating SG with TH, contrary to current guidelines and recommendations. This calls for urgent attention.

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.

Prevalence of Thyroid Peroxidase and Thyroglobulin Autoantibodies in the Swedish Population.

Autoimmune thyroid disease (AITD) may be detected prior to clinical symptoms through the presence of autoantibodies against thyroid peroxidase (TPOab), thyroglobulin (TGab), or both.The present study aimed to develop a novel radiobinding assay (RBA) for TPOab and to determine the prevalence of TPOab and TGab in the Swedish population.Patient samples from 27 newly diagnosed Graves' disease patients in longitudinal follow-up and 124 AITD autoantibody-positive children in prospective follow-up for increased risk of type 1 diabetes were included to validate the novel RBA for TPO. The results of RBA were compared with those obtained by commercial radioimmunoassay (RIA) and electrochemiluminescence (ECL). Furthermore, 476 serum samples from adult blood donors and 297 from 13-year-old school children were analyzed for the presence of TPOab and TGab.Receiver operating characteristics analysis for the novel TPOab resulted in an area under curve (AUC) value of 0.82 (p<0.0001), a sensitivity of 77.8%, and a specificity of 91.9% in adult blood donors, and an AUC value of 0.70 (p<0.0001), a sensitivity of 53.2% and a specificity of 95.3% in the 13-year-old school children, respectively. TPOab levels in RBA correlated with both ECL (r=0.8950, p<0.0001) and RIA (r=0.9295, p<0.0001). The prevalence of TPOab and TGab was 6.3% and 7.6% in adult blood donors and 2.9 and 3.7% in 13-year-old school children.In conclusion, a novel RBA for the determination of TPOab was developed and validated with current methodologies. This study also reports an increasing prevalence of thyroid autoantibodies from adolescence to adulthood.

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.

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.

Characteristics of specialists treating hypothyroid patients: the "THESIS" collaborative.

Introduction: Thyroid specialists influence how hypothyroid patients are treated, including patients managed in primary care. Given that physician characteristics influence patient care, this study aimed to explore thyroid specialist profiles and associations with geo-economic factors. Methods: Thyroid specialists from 28 countries were invited to respond to a questionnaire, Treatment of Hypothyroidism in Europe by Specialists: an International Survey (THESIS). Geographic regions were defined according to the United Nations Statistics Division. The national economic status was estimated using World Bank data on the gross national income per capita (GNI per capita). Results: 5,695 valid responses were received (response rate 33·0%). The mean age was 49 years, and 65·0% were female. The proportion of female respondents was lowest in Northern (45·6%) and highest in Eastern Europe (77·2%) (p <0·001). Respondent work volume, university affiliation and private practice differed significantly between countries (p<0·001). Age and GNI per capita were correlated inversely with the proportion of female respondents (p<0·01). GNI per capita was inversely related to the proportion of respondents working exclusively in private practice (p<0·011) and the proportion of respondents who treated >100 patients annually (p<0·01). Discussion: THESIS has demonstrated differences in characteristics of thyroid specialists at national and regional levels, strongly associated with GNI per capita. Hypothyroid patients in middle-income countries are more likely to encounter female thyroid specialists working in private practice, with a high workload, compared to high-income countries. Whether these differences influence the quality of care and patient satisfaction is unknown, but merits further study.

[Thyroid ultrasound and its role in the investigation of thyroid disease]. / Ultraljud värdefullt komplement i utredning av tyreoideasjukdom.

In Europe thyroid ultrasound has been used at outpatient endocrine clinics since many years, and in southern Sweden only during the last years. Ultrasound has a role in the investigation of Graves' disease, subacute thyroiditis, gestational thyrotoxicosis, postpartum thyroiditis, amiodarone thyrotoxicosis and goiter with or without adenoma, but adenomas are usually investigated by endocrine surgeons in Sweden. If widely used the risk for detection of incidentaloma increases. Indications have to be strictly used to avoid further investigations. If an adenoma is localized, the risk for malignancy and requirement of aspiration is estimated by use of the EU-TIRADS classification based on morphology and size. The aspirate is judged by the Bethesda classification, which determines if further investigation is needed. The use of ultrasound at the outpatient clinic has improved the diagnostic quality and follow-up of thyroid patients.

Increased risk of Graves´ophthalmopathy in patients with increasing TRAb after radioiodine treatment and the impact of CTLA4 on TRAb titres.

INTRODUCTION: Treatment of Graves´ disease (GD) with radioiodine increases the risk of developing Graves´ ophthalmopathy (GO), and the link between thyroid and orbital tissue may be the presence of TSH-receptors. Radioiodine increases the titers of TRAb and the aim was to investigate the relationship between GO and TRAb titers after treatment with radioiodine and to define the impact of risk genes. METHODS: GD patients without ophthalmopathy or previous treatment with radioiodine were prospectively included at treatment with radioiodine for hyperthyroidism. A follow-up was performed 1 year later for the registration of GO development. The study was performed at a University Hospital Clinic; a referral center of all patients treated with radioiodine in the south of Sweden. The main outcome measures were the development of TRAb, anti-TPO, and anti-TG after 3 months and GO after 12 months and relationship to the genetic background (HLA, CTLA-4, and CYR61). RESULTS: Three months of radioiodine TRAb titers increased in two thirds of patients (p < 0.0005) but not in the other third. Anti-TPO titers were associated with TRAb (R = 0.362, p < 0.0001) but not anti-TG. At follow-up 1 year later (n = 204) 32 patients developed GO with a proportion of 70% in the group increasing in TRAb titers and 30% in the group with unchanged or lower TRAb titers (p-value < 0.0005). Patients with GO had higher titers of TRAb than patients without GO. CTLA-4 (rs231775 SNP) was significantly (p < 0.005) associated with TRAb titers above the median three months after radioiodine. CONCLUSIONS: The increase in TRAb titers after treatment with radioiodine is associated with GO and a genetic variation in CTLA-4 is associated with higher titers of TRAb.

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.

Use of Thyroid Hormones in Hypothyroid and Euthyroid Patients: A 2020 THESIS Questionnaire Survey of Members of the Swedish Endocrine Society.

Background: The standard treatment of hypothyroidism is levothyroxine (LT-4). However, there are several controversies regarding treatment of hypothyroid patients. Aim: To investigate the Swedish endocrinologists' use of thyroid hormones in hypothyroid and euthyroid individuals. Methods: Physician members of the Swedish Endocrine Society (SEF) were invited by e-mail to participate in an online survey investigating this topic. Results: Out of the eligible 411 members, 116 (28.2%) responded. The majority (98.9%) stated that L-T4 is the treatment of choice. However, around 50% also prescribed liothyronine (L-T3) or a combination of L-T4+L-T3 in their practice. Combination therapy was mostly (78.5%) used in patients with persistent hypothyroid symptoms despite biochemical euthyroidism on L-T4 treatment. Most respondents prescribed L-T4 tablets and did not expect any major changes with alternative formulations such as soft-gel capsules or liquid formulations in situations influencing the bioavailability of L-T4. In euthyroid patients, 49.5% replied that treatment with thyroid hormones was never indicated, while 47.3% would consider L-T4 for euthyroid infertile women with high thyroid peroxidase (TPO) antibody levels. Conclusion: The treatment of choice for hypothyroidism in Sweden is L-T4 tablets. Combination therapy with L-T4+L-T3 tablets was considered for patients with persistent symptoms despite biochemical euthyroidism. Soft-gel capsules and liquid solutions of L-T4 were infrequently prescribed. Swedish endocrinologists' deviation from endocrine society guidelines merits further study.

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.

Prevalence of diabetes and presence of autoantibodies against zinc transporter 8 and glutamic decarboxylase at diagnosis and at follow up of Graves' disease.

PURPOSE: The aim of this work was to investigate, in patients with newly diagnosed Graves' disease (GD), the frequency of islet autoantibodies including autoantibodies against Zink transporter 8 (ZnT8A), as well as to investigate the relation between thyroid autoantibodies, islet autoantibodies and diabetes both before GD diagnosis and at follow-up. METHODS: Blood samples from 278 patients with newly diagnosed GD were analyzed for autoantibodies against glutamic acid decarboxylase (GADA), insulinoma-associated protein-2 (IA2-A), three variants of zinc transporter 8 (ZnT8A), thyroid peroxidase (TPOA) and the TSH receptor (TRAb). Information on other autoimmune diseases, as well as development of diabetes during follow up was gathered from patient's medical journal. RESULTS: At GD diagnosis, 13.7% were positive for islet autoantibodies, with the majority being positive for GADA (8.7%) and ZnT8A (7.6%). TPOA were found positive in 71% and TRAb in 83%. No association was found between islet autoantibodies and thyroid autoantibodies or diabetes diagnosis during follow up. Positive association was found between islet autoantibodies and all forms of diabetes, diagnosed both before and after GD (OR: 2.5, CI: 1.1-6.8, p = 0.03) but not to other autoimmune diseases at GD diagnosis. CONCLUSIONS: The incidence of GADA and ZnT8A in patients with GD is high and might indicate wide range endocrine autoimmunity, as well as risk for non-autoimmune diabetes rather than exclusively mark beta cell autoimmunity and type 1 diabetes.

The Effect of Radioiodine Treatment on TRAb, Anti-TPO, and Anti-TG in Graves' Disease.

BACKGROUND: In Graves' disease (GD), immunocompetent cells infiltrate thyroid tissue with release of TSH-receptor antibodies (TRAb), and radioiodine treatment is known to elicit an immune response with an increase in TRAb. OBJECTIVES: The aim was to study if all patients treated with radioiodine respond with a release of TRAb, anti-thyroperoxidase (anti-TPO), and anti-thyroglobulin (anti-TG). METHODS: This is a prospective observational study. GD patients (n = 131) were admitted for treatment with radioiodine. Thyroid antibodies were measured before and 3 months after iodine-131 treatment. RESULTS: After 3 months, a fold change > 1.1 was found in 66% of the GD patients, while the remaining 34% did not have a change or decrease in in TRAb. Anti-TPO and anti-TG also increased; the former showed an increase in 73% and the latter of 52%, while 27 and 48% decreased/were unchanged. A significant positive correlation was found between TRAb and anti-TPO, but not between TRAb and anti-TG. In the group with an increase in TRAb, the median fold change was 5.1, but there were no additional effects of tobacco smoking. The proportion of females below the median age (51.5 years) was significantly higher in the group that increased in TRAb compared to the one that decreased/was unchanged (66 vs. 34%). CONCLUSIONS: Treatment with radioiodine elicits an increase in thyroid antibodies, but not in all GD patients. The proportion of responders varied and was affected by age, resulting in a stronger immune response at younger age. However, there were no additional effects of smoking.

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.

Study of Deiodinase Type 2 Polymorphisms in Graves' Disease and Ophthalmopathy in a Swedish Population.

BACKGROUND: Deiodinase type 2 (DIO2) is an enzyme that catalyzes the production of the active form of thyroid -hormone triiodothyronine (T3) from thyroxine (T4) and is important for maintaining intracellular T3 levels. Single nucleotide polymorphisms (SNPs) in DIO2 were associated with several diseases. The association of SNPs in DIO2 with Graves' disease (GD) was suggested in 2 Russian studies. OBJECTIVES: The aim of the study was to examine whether SNPs in DIO2 are associated with GD or Graves' ophthalmopathy (GO). METHODS: Seven SNPs in the DIO2 gene - rs225014 (Thr92Ala), rs12885300, rs2267872, rs225011, rs224995, rs225015, and rs2267873 - were studied to assess their association with GD and GO. In total, 712 patients with GD with (n = 311) or without (n = 399) ophthalmopathy and 1,183 sex-matched controls from Malmö, Sweden were analyzed. In GD patients with available data, the SNPs were examined for association with the levels of free T3, free T4, thyroid-stimulating hormone receptor antibodies (TRAb), and thyroid-peroxidase antibodies (TPOAb). RESULTS: Rs225011 was nominally associated with GD (OR 1.18, CI 1.01-1.37, p = 0.036). None of the SNPs were associated with GO. In GD patients, none of the SNPs were associated with the free-T4 (fT4), TRAb, or TPOAb levels. A weak, nonsignificant association was observed between free-T3 (fT3) levels and rs225014 and rs12885300, separately. CONCLUSIONS: Rs225011 in DIO2 was weakly associated with GD. The mechanism behind this association requires further study. None of the investigated common SNPs in DIO2 was significantly associated with GO, fT3, fT4, TRAb, or TPOAb in GD patients.