| 1. |
- Calissendorff, Jan, et al.
(författare)
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Long-Term Outcome of Graves' Disease : A Gender Perspective
- 2023
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Ingår i: Women's Health Reports. - : Mary Ann Liebert. - 2688-4844. ; 4:1, s. 487-496
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Cerri, Perparim, et al.
(författare)
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Serum CYR61 Levels are Associated with Graves' Ophthalmopathy and Smoking in Patients with Graves' Disease
- 2021
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Ingår i: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 54:3, s. 168-174
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
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| 4. |
- Khamisi, Selwan, et al.
(författare)
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Fracture Incidence in Graves' Disease: A Population-Based Study.
- 2023
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Ingår i: Thyroid : official journal of the American Thyroid Association. - : Mary Ann Liebert. - 1557-9077 .- 1050-7256. ; 33:11, s. 1349-1357
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 5. |
- Lantz, Mikael, et al.
(författare)
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Adjuvant Treatment of Graves' Disease with Diclofenac : Safety, Effects on Ophthalmopathy and Antibody Concentrations
- 2016
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Ingår i: European Thyroid Journal. - : Bioscientifica. - 2235-0640 .- 2235-0802. ; 5:1, s. 6-50
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 6. |
- Lantz, Mikael, et al.
(författare)
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Increased TRAb and/or Low Anti-TPO Titers at Diagnosis of Graves' Disease are Associated with an Increased Risk of Developing Ophthalmopathy after Onset.
- 2014
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Ingår i: Experimental and Clinical Endocrinology & Diabetes. - : Georg Thieme Verlag KG. - 1439-3646 .- 0947-7349. ; 122:2, s. 113-117
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 7. |
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| 8. |
- Lantz, Mikael, et al.
(författare)
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Thyrostimulin (a TSH-like Hormone) Expression in Orbital and Thyroid Tissue.
- 2007
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Ingår i: Thyroid. - : Mary Ann Liebert Inc. - 1557-9077 .- 1050-7256. ; 17:2, s. 113-118
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 9. |
- Lindgren, Ola, et al.
(författare)
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The Effect of Radioiodine Treatment on TRAb, Anti-TPO, and Anti-TG in Graves' Disease
- 2019
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Ingår i: European Thyroid Journal. - : Bioscientifica. - 2235-0640 .- 2235-0802. ; 8:2, s. 64-69
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 10. |
- Matheis, N, et al.
(författare)
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PROTEOMICS OF ORBITAL TISSUE IN THYROID-ASSOCIATED ORBITOPATHY.
- 2015
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 100:12, s. 1523-1530
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Tidskriftsartikel (refereegranskat)abstract
- A potentially altered protein expression profile in orbital tissue from patients with thyroid-associated orbitopathy (TAO) is suspected.
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| 11. |
- Nilsson, Anton, et al.
(författare)
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Statins Decrease the Risk of Orbitopathy in Newly Diagnosed Patients with Graves Disease
- 2021
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 106:5, s. 1325-1332
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT/OBJECTIVE: The aim of this study was to examine the effect of statins and other lipid-lowering agents on the development of Graves orbitopathy (GO) in patients with newly diagnosed Graves disease (GD). METHODS: Our sample included the full adult population of individuals living in Sweden with newly diagnosed GD between 2005 and 2018 (n = 34 894). We compared the GO incidence in statin users (n = 5574) and nonusers (n = 34 409) by applying Cox regression with a time-varying exposure variable. We adjusted for age, sex, and treatment for hyperthyroidism in the multivariate analyses. RESULTS: Periods of nonusage lasted for a median of 4.3 years (interquartile range [IQR] 1.2-8.4), whereas periods of usage lasted for a median of 4.7 years (IQR 2.0-8.1). Among statin users, 77.1% had used simvastatin, 28.9% atorvastatin, and 8.2% had used other statins. Statin users were found to be significantly less likely to develop GO. In the main analysis based on the full cohort, the unadjusted hazard ratio (HR) was 0.74 (CI 0.65-0.84, P < .001), whereas full adjustment altered the effect to 0.87 (CI 0.76-1.00, P = .04). The main results were largely driven by men; the fully adjusted HR was 0.78 (CI 0.58-1.04, P = .09) for men and 0.91 (CI 0.79-1.06, P = .24) for women. Lipid-lowering agents other than statins did not exhibit a similar protective effect. CONCLUSION: In newly diagnosed patients with GD, treatment with statins may protect against the development of GO. Statins should be investigated in a clinical trial as a preventive treatment for GO in newly diagnosed patients with GD.
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| 12. |
- Planck, Tereza, et al.
(författare)
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ASSOCIATION OF BTG2, CYR61, ZFP36, AND SCD GENE POLYMORPHISMS WITH GRAVES' DISEASE AND OPHTHALMOPATHY.
- 2014
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Ingår i: Thyroid. - : Mary Ann Liebert Inc. - 1557-9077 .- 1050-7256. ; 24:7, s. 1156-1161
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Tidskriftsartikel (refereegranskat)abstract
- 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 twelve 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 (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.
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| 13. |
- Planck, Tereza, et al.
(författare)
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COX-2 and SCD, markers of inflammation and adipogenesis, are related to disease activity in Graves' ophthalmopathy
- 2007
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Ingår i: Thyroid. - : Mary Ann Liebert Inc. - 1557-9077 .- 1050-7256. ; 17:6, s. 511-517
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Tidskriftsartikel (refereegranskat)abstract
- 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, Malmo, 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.
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| 14. |
- Planck, Tereza, et al.
(författare)
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Gene Expression in Graves' Ophthalmopathy and Arm Lymphedema: Similarities and Differences.
- 2011
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Ingår i: Thyroid. - : Mary Ann Liebert Inc. - 1557-9077 .- 1050-7256. ; 21, s. 663-674
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 15. |
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| 16. |
- Planck, Tereza, et al.
(författare)
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Liothyronine Use in Hypothyroidism and its Effects on Cancer and Mortality
- 2021
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Ingår i: Thyroid. - : Mary Ann Liebert Inc. - 1050-7256 .- 1557-9077. ; 31:5, s. 732-739
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Tidskriftsartikel (refereegranskat)abstract
- Background: The prescription of liothyronine (LT3) to treat hypothyroidism is increasing worldwide; however, the long-term safety of LT3 use has yet to be determined. Previous studies have suggested a possible association between LT3 use and breast cancer. The aim of this study was to examine the effects of LT3 use on cancer incidence and mortality. Methods: Our sample included the full adult population of individuals living in Sweden with at least three purchases of thyroid hormone therapy between July 2005 and December 2017. Individual-level data on drug purchases were linked to registry data on cancer incidence and mortality. There were 575,461 individuals with at least three purchases, of which 11,147 had made at least three purchases of LT3, including combinations of levothyroxine (LT4) and LT3. Individuals were followed for a median follow-up time of 8.1 years. We applied Cox regression with a time-varying exposure variable, comparing LT3 users (individuals with at least three cumulative purchases of LT3) with LT4-only users (the rest). Outcomes included breast cancer incidence, any cancer incidence, all-cause mortality, any cancer mortality, and breast cancer mortality. We adjusted for age, sex, previous thyroid cancer, previous other cancer, use of antithyroid preparations, use of sex hormones, and dose in multivariate analyses. Results: Multivariate analyses produced a hazard ratio of 0.93 (95% confidence interval [0.75-1.15]) for breast cancer incidence (only females), 0.97 (0.87-1.08) for any cancer incidence, 0.69 (0.61-0.77) for all-cause mortality, 0.78 (0.62-0.98) for any cancer mortality, and 0.91 (0.50-1.66) for breast cancer mortality (only females). Conclusions: In this large, Swedish, long-term registry-based study, the use of LT3 did not lead to increased breast cancer incidence, any cancer incidence, all-cause mortality, any cancer mortality, or breast cancer mortality compared with LT4 use. Somewhat surprisingly, there was evidence of lower mortality in LT3 users in models adjusting for dose, potentially an artifact of underlying associations between dose and health status/diagnosis.
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| 17. |
- Planck, Tereza
(författare)
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Molecular Etiology of Graves’ Disease and Associated Ophthalmopathy
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Graves' disease (GD) is a complex autoimmune disorder characterized by hyperthyroidism and diffuse goitre. 25-50% of the patients with GD develop eye symptoms, Graves' ophthalmopathy (GO). The overall aim of this thesis was to explore the molecular etiology of GD and GO. By studying gene expression in Studies I, III, and IV, we demonstrated that adipocyte-related immediate early genes (IEGs) including CYR61, COX2, BTG2, and ZFP36 were overexpressed in active GO and to a lesser degree in chronic GO, but not in chronic lymphedema. CYR61-responsive genes were also upregulated in active GO. In Study V, associations were found between SNPs in CYR61, BTG2, and ZFP36 and GD and/or GO. These findings support a role for the IEGs in the pathogenesis of GO. Inflammation and adipogenesis decreased with decreased disease activity in GO, as demonstrated in Studies I and III by the expression pattern of COX2 and SCD in active and chronic GO. In Study III, we showed that the anti-inflammatory drug diclofenac could inhibit adipogenesis in differentiating 3T3-L1 preadipocytes, decreasing the number of mature adipocytes by approximately 50%.These results suggest that diclofenac may be a therapeutic alternative for GO. In Study II, we investigated a potential role of the recently discovered hormone thyrostimulin, in GD and GO. We were not able to detect the expression of the beta subunit of thyrostimulin in human healthy and diseased orbital or thyroid tissues. These findings argue against the role of thyrostimulin in human thyroid physiology or disease. In Study IV, we compared gene expression in chronic arm lymphedema and chronic GO. The expression pattern in lymphedema involved upregulation of genes with roles in wound healing, formation of extracellular matrix and fibrosis, but not upregulation of genes with functions in early adipogenesis. This finding was in contrast to GO, where genes related to adipogenesis, but not fibrosis, were upregulated. To summarize, more differences than similarities exist between chronic arm lymphedema and chronic GO. In Study V, we investigated whether genetic variation in genes with high expression in GO is associated with GD and/or GO in a Swedish and Polish case/control material. The results of the Swedish study showed associations of SNPs in BTG2, CYR61, ZFP36, and SCD with GD and/or GO; however, rs12136280 in BTG2 and rs3753793 in CYR61 were not associated with GD or GO in the Polish material and the meta-analysis was not significant. The shown associations have to be replicated before they can be considered to be true.
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| 18. |
- Planck, Tereza, et al.
(författare)
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Smoking induces overexpression of immediate early genes in active Graves' ophthalmopathy.
- 2014
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Ingår i: Thyroid. - : Mary Ann Liebert Inc. - 1557-9077 .- 1050-7256. ; 24:10, s. 1524-1532
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Tidskriftsartikel (refereegranskat)abstract
- 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 non-smokers (n=8) with severe active GO as well as in subcutaneous fat in thyroid-healthy smokers (n=5) and non-smokers (n=5) using microarray and real-time PCR. Results: With microarray, eight IEGs were upregulated more than 1.5-fold in smokers compared to non-smokers 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 non-smokers. 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 non-smokers in subcutaneous fat. Conclusions: IEGs, IL-1B, and IL-6 were overexpressed in smokers with severe active GO compared to non-smokers 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.
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| 19. |
- Planck, Tereza, et al.
(författare)
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Use of Thyroid Hormones in Hypothyroid and Euthyroid Patients : A 2020 THESIS Questionnaire Survey of Members of the Swedish Endocrine Society
- 2021
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media SA. - 1664-2392. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 20. |
- Planck, Tereza, et al.
(författare)
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Vitamin D in Graves Disease : Levels, Correlation with Laboratory and Clinical Parameters, and Genetics
- 2018
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Ingår i: European Thyroid Journal. - : Bioscientifica. - 2235-0640 .- 2235-0802. ; 7:1, s. 27-33
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim was to compare the vitamin D levels in patients with Graves disease (GD) with the general population and to correlate the vitamin D levels with laboratory and clinical parameters in GD. Moreover, we examined the genetic variation in genes involved in the vitamin D metabolism and their association with GD.Methods: The levels of vitamin D were compared in 292 patients with newly diagnosed GD and 2,305 controls. Single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR), vitamin D binding protein (DBP), and 1-α-hydroxylase (CYP27B1) were examined for association with GD and/or Graves ophthalmopathy (GO) in 708 patients and 1,178 controls.Results: Patients with GD had significantly lower vitamin D levels compared to controls (55.0 ± 23.2 vs. 87.2 ± 27.6 nmol/L, p < 0.001). In patients with GD (n = 219), there was no association between the levels of vitamin D at diagnosis and free thyroxine (fT4), free triiodothyronine (fT3), thyrotropin receptor antibodies (TRAb), GO at diagnosis, or relapse after terminating treatment with antithyroid drugs. Two SNPs in VDR were associated with GD: rs10735810 (OR = 1.36, 95% CI: 1.02-1.36, p = 0.02) and rs1544410 (OR = 1.47, 95% CI: 1.03-1.47, p = 0.02). There was no difference in the mean vitamin D level between genotypes in either rs10735810 or rs154410.Conclusions: Patients with GD had lower vitamin D levels compared to the general population; however, the vitamin D levels did not affect the laboratory or clinical parameters of GD. SNPs in the VDR influenced the risk of GD through mechanisms other than reducing the vitamin D levels.
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| 21. |
- Shaat, Nael, et al.
(författare)
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Association between the rs1544410 polymorphism in the vitamin D receptor (VDR) gene and insulin secretion after gestational diabetes mellitus
- 2020
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:5
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Genetic variants involved in vitamin D metabolism have been associated with diabetes and related syndromes/diseases. We wanted to investigate possible associations of polymorphisms in genes involved in vitamin D metabolism with indices of insulin resistance and insulin secretion, and also with development of diabetes after gestational diabetes mellitus (GDM).MATERIALS AND METHODS: We have studied 376 women with previous GDM. Eight single nucleotide polymorphisms (SNPs) in the genes for vitamin D receptor (VDR) [rs731236, rs7975232, rs10735810, and rs1544410], vitamin D binding protein (DBP) [rs7041 and rs4588], and cytochrome P450 family 27 subfamily B member 1 (CYP27B1) [rs10877012 and rs4646536] were genotyped by TaqMan Allelic Discrimination Assay using the Quantstudio 7 Flex system. A 75-g oral glucose tolerance test (OGTT) was performed 1-2 years postpartum. The homeostasis model assessment of insulin resistance (HOMA-IR) and the disposition index [(insulinogenic index: I30/G30)/HOMA-IR] were used to calculate insulin resistance and insulin secretion, respectively. Serum samples for determination of 25(OH)D3 were collected at the time of the OGTT. Manifestation of diabetes was followed up to five years postpartum.RESULTS: After adjustment for BMI, age, and ethnicity, the A-allele of the VDR rs1544410 polymorphism was found to be associated with increased disposition index (difference per allele = 3.56, 95% CI: 0.4567-6.674; p = 0.03). The A-allele of the DBP rs7041 polymorphism was found to be associated with 25(OH)D3 levels (difference [in nmol/L] per allele = -5.478, 95% CI: -8.315 to -2.641; p = 0.0002), as was the T-allele of the DBP rs4588 polymorphism (OR = -6.319, 95% CI: -9.466 to -3.171; p = 0.0001). None of the SNPs were significantly associated with HOMA-IR or postpartum diabetes.CONCLUSIONS: This study provides evidence that the rs1544410 polymorphism of the VDR gene may be associated with increased insulin secretion in women after pregnancy complicated by GDM. Further studies in other populations are needed to confirm the results.
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| 22. |
- Shahida, Bushra, et al.
(författare)
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Increased risk of Graves´ophthalmopathy in patients with increasing TRAb after radioiodine treatment and the impact of CTLA4 on TRAb titres
- 2022
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Ingår i: Endocrine. - : Springer Science and Business Media LLC. - 1355-008X .- 1559-0100. ; 75:3, s. 856-864
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 23. |
- Shahida, Bushra, et al.
(författare)
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Smoking enhances proliferation, inflammatory markers, and immunoglobulins in peripheral blood mononuclear cells from Graves’ patients
- 2024
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Ingår i: Endocrine Connections. - 2049-3614. ; 13:6
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 24. |
- Shahida, Bushra, et al.
(författare)
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Study of Deiodinase Type 2 Polymorphisms in Graves' Disease and Ophthalmopathy in a Swedish Population
- 2018
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Ingår i: European Thyroid Journal. - : Bioscientifica. - 2235-0640 .- 2235-0802. ; 7:6, s. 289-293
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 25. |
- Sjölin, Gabriel, 1979-, et al.
(författare)
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Long term outcome after toxic nodular goitre
- 2022
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Ingår i: Thyroid Research. - : Springer Science and Business Media LLC. - 1756-6614. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 26. |
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| 27. |
- Sjölin, Gabriel, 1979-, et al.
(författare)
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Treatment of patients with Graves' disease in Sweden compared to international surveys of an 'index patient'
- 2021
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Ingår i: Endocrinology, Diabetes & Metabolism. - : Wiley. - 2398-9238. ; 4:3
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Tidskriftsartikel (refereegranskat)abstract
- 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 (I-131). This preference for ATD is in line with most countries/regions, with the exception of USA and the Middle East/North Africa, where I-131 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 I-131 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.
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