Interaction of MMP-9 in the active phase of Graves' disease with and without ophthalmopathy.

Thyroid eye disease (TED) is expressed as orbital inflammation, and serum levels of several proinflammatory cytokines have been studied among patients with Graves' disease (GD) with and without TED; however, a more sensitive and specific marker for the different phases of GD and TED is still lacking. Seventeen active TED, 16 inactive TED, 16 GD without TED, and 16 healthy controls were recruited. Serum IL-17A, MMP-2, MMP-3, and MMP-9 were measured by multiplex bead assay. TED hormone and eye parameters were evaluated, and their relationship with cytokine levels was analyzed. Serum MMP-9 was higher in active TED than healthy controls, whereas IL-17A was lower among these patients than in GD without TED and healthy controls. No differences were found in MMP-3 and MMP-2 concentrations. MMP-9 levels were lower in patients with inactive TED who underwent radioactive iodine (RAI) therapy and those on levothyroxine replacement. MMP-9 levels were elevated in patients on methimazole. A negative correlation was found between age at assessment and time of follow-up with MMP-9 levels in inactive TED. Free T3 and ophthalmometry values were positively correlated with MMP-9 in the GD without TED and inactive TED groups, respectively. In conclusion, serum MMP-9 was increased in patients with active TED and was related to the RAI treatment, longer follow-up time, and higher ophthalmometry in patients with inactive TED, as well as thyroid function in GD without TED. MMP-9 may be involved in both the active phase of TED and the active phase of inflammation related to GD.NEW & NOTEWORTHY Our study addresses clinical aspects of specific ophthalmological examination and serum cytokine concentrations of patients with Graves' disease (GD) with and without ophthalmopathy. Our findings suggest that MMP-9 may be involved in the active phase of ophthalmopathy and in the active phase of GD. The central question is whether MMP-9 is a potential target for future treatments.

Identification and functionalization of thyrotropin receptor antibodies with different antigenic epitopes.

One of the sensitive markers for autoimmune thyroid disease (AITD) clinical identification is thyroid-stimulating hormone receptor antibodies (TRAbs). To quickly distinguish TRAb with distinct antigenic epitopes, a straightforward and uncomplicated technique has not yet been created. The objective of this study is to search for molecular diagnostic targets for different types of AITD {Graves' disease (GD), Graves' orbitopathy (GO), GD with third-degree goiter [GD(3)], hypothyroidism combined with positive TRAb [HT(TRAb+)]} as molecular diagnostic targets. Following action on thyroid cells, differential genes (DEGs) generated by TRAb with distinct antigenic epitopes were detected and identified by RNA sequencing (RNA-Seq), bioinformatics analysis, and quantitative reverse transcription-polymerase chain reaction (RT-qPCR) in the serum of patients with AITD. Using the 5-ethynyl-2'-deoxyuridine (EdU) assay, the effect of coculturing thyroid cells with different antigenic TRAb epitopes on the cells' capacity to proliferate was investigated. Bioinformatics analysis and RT-qPCR validation identified one GD key gene alpha 2-HS glycoprotein (AHSG), two GO key genes [adrenoceptor alpha 1D (ADRA1D) and H2B clustered histone 18 (H2BC18)], two GD(3) key genes [suppressor of cytokine signaling 1 (SOCS1) and cytochrome b-245 beta (CYBB)], and one HT(TRAb+) key gene (MASP2). Correlation analysis and ROC curves showed that the abovementioned genes could be used as molecular diagnostic targets for different types of AITD. Finally, EdU results showed that TRAb inhibited thyroid cell proliferation in the HT(TRAb+) group compared with the normal control group, whereas the remaining three groups promoted thyroid cell proliferation, with a statistically significant difference (P < 0.05). We identified six key genes for different types of AITD, which have diagnostic value for different types of AITD. Meanwhile, we found that TRAbs with different antigenic epitopes in AITD have different biological functions.NEW & NOTEWORTHY We identified six molecular targets of different types of AITD [GD, GO, GD(3), and HT(TRAb+)], which have diagnostic value for different types of AITD. Meanwhile, we found that TRAb with different antigenic epitopes extracted from the sera of patients with AITD had different biological functions, which also provided a new idea for further research on the mechanism of action of TRAb with different antigenic epitopes in AITD.

Methylation levels of the IL10 gene in peripheral blood are related to the intractability of Graves' disease.

The prognosis of autoimmune thyroid diseases (AITDs), including Hashimoto's disease (HD) and Graves' disease (GD), is difficult to predict. DNA methylation regulates gene expression of immune mediating factors. Interleukin (IL)-10 is a Th2 cytokine that downregulates inflammatory cytokines produced by Th1 cells. To clarify the role of methylation of the IL10 gene in the prognosis of AITD, we evaluated the methylation levels of two CpG sites in the IL10 promoter using pyrosequencing. The methylation levels of the -185 CpG site of the IL10 gene were related to age and GD intractability in GD patients. Furthermore, the C carrier of the IL10-592 A/C polymorphism was related to low methylation levels of the -185 CpG site. The methylation levels of the IL10-185 CpG site of the IL10 gene were related to the intractability of GD and were lower in individuals with the C allele of the IL10-592 A/C polymorphism.

Lipid Profile Evolution in Graves' Disease Treated with Titration Regimen of Anti-Thyroid Drugs Versus Block and Replace Regimen.

The aim was to compare the lipid profile of patients with GD treated with anti-thyroid drugs (ATDs) using a titration regimen versus a block and replace regimen. This is an 18-month prospective observational study. In this study were included 149 medically treated GD patients, aged+>+18 years. Pregnant women and patients treated with radioactive iodine therapy or partial/total thyroidectomy were excluded. Patients were divided into 2 subgroups: titration (A) and block and replace (B) therapy, according to the ATD regimen used. Thyroid and metabolic profile was measured at baseline and at least one visit during medical treatment. The whole group included 122 (81.87%) females (F) and 27 (18.12%) males (M), ratio F:M=4.5:1. As expected, at the time of diagnosis, thyrotoxic patients were with normal lipid profile. During medical treatment, in patients who achieved euthyroidism, the cholesterol levels increased as follows: in subgroup A: by 52.9 mg/dl (95% CI: 26.4-79.3), p<0.001 for total cholesterol (T-C), by 33.3 mg/dl (95% CI: 10.3-56.3), p=0.007 for low-density lipoprotein cholesterol (LDL-C) and by 11.44 mg/dl (95% CI: 3.08-19.79), p=0.009 for high-density lipoprotein cholesterol (HDL-C); in subgroup B T-C increased by 45.1 mg/dl (95% CI: 22.2-68), p<0.001 and for LDL-C by 33.57 mg/dl (95% CI: 12.72-54.42), p=0.003. No statistically significant increase in triglyceride levels was determined. Medical treatment of hyperthyroidism due to Graves' disease increased cholesterol levels regardless of the ATD regimen used.

Stimulating thyrotropin receptor antibodies in early pregnancy.

OBJECTIVES: Thyrotropin-receptor antibodies (TRAb) are used to diagnose Graves' hyperthyroidism in pregnant women. Bioassays provide a measure of thyrotropin-receptor stimulatory antibodies (TSI) specifically. The objective was to measure TSI in pregnant women for establishment of a pregnancy-specific cut-off and comparison with immunoassay measurements of TRAb. METHODS: The retrospective Danish study was performed within the North Denmark Region Pregnancy Cohort (2011-2015) that includes stored biobank samples from early pregnancy (median week 10) with immunoassay measurements of thyroid function parameters and TRAb. TSI were measured in the same samples using the Turbo TSI bioassay (Quidel/Ortho-Clinical Diagnostics) with a recommended cut-off of 0.0241 IU/L in non-pregnant adults. A pregnancy-specific TSI cut-off (95-percentile) was established using Regression on Order Statistics. RESULTS: The established TSI cut-off was 0.0418 IU/L (95 % CI: 0.0417-0.0419). Among women with early pregnancy hyperthyroidism (n=438), 43 women (9.8 %) were TSI positive using the established cut-off, and these women had lower TSH (median 0.008 mIU/L) compared to women with TSI levels below 0.0241 (median TSH 0.040 mIU/L) or in the range from 0.0241 to 0.0418 (median TSH 0.033 mIU/L). Among the 438 women with early pregnancy hyperthyroidism, 22 women were positive for TSI and TRAb, 388 were negative for both, and 28 women were positive for either TSI or TRAb. CONCLUSIONS: This is the first study on TSI measurements in a large cohort of early pregnant women. A pregnancy-specific cut-off for TSI was established and agreement in the classification with immunoassay measurements of TRAb was seen in 94 % of cases.

Association between serum vitamin D level and Graves' disease: a systematic review and meta-analysis.

OBJECTIVE: This meta-analysis aims to analyze the relationship between serum vitamin D (VD) levels and Graves' disease (GD). METHODS: We conducted a search for publications on VD and GD in the English language. Our search encompassed databases such as PubMed, Embase, Web of Science, and the Cochrane Library, covering publications available through August 2023. A meta-analysis was performed using Cochrane RevMan 5.4 software. The standardized mean difference (SMD) and 95% confidence interval (CI) were used for outcome calculation. We used R software to test for publication bias. RESULTS: Twelve studies were selected, comprising 937 (22.4%) cases with GD and 3254 (77.6%) controls. The overall meta-analysis revealed that patients with GD are significantly more likely to have low VD levels (SMD = - 0.66; 95% CI: -1.05, - 0.27; p = 0.001) than those in the control group. Egger's test results indicated no publication bias (p = 0.0791). These studies exhibited a high degree of heterogeneity (chi-square = 205.86, p < 0.00001; I2 = 95%). Subgroup analysis was conducted based on assay method, geographic location, and mean age of the case group to explore the heterogeneity sources. Assay methods and geographic locations were identified as potential heterogeneity sources. Based on the mean age, there were no statistically significant differences found in the subgroup analysis of the included studies. CONCLUSION: There is promising evidence that low serum VD levels may increase the risk of GD. Further rigorous and long-term trials are needed to explore the role of VD in the onset and treatment of GD.

Graves' Disease: Acquired Cause of a Moderate Increase in Hemoglobin A2 Level.

BACKGROUND: Hyperthyroidism can lead to diverse hematological disorders, such as microcytosis and a mild increase in hemoglobin A2 fraction. METHODS: This study reported a 31-year-old woman of Moroccan origin recently diagnosed with Graves' disease. Her blood tests revealed microcytosis, hypochromia, and a normal ferritin level. A phenotypic analysis of hemo-globin was performed using two techniques: capillary electrophoresis and reversed-phase high performance liquid chromatography. RESULTS: Both techniques indicated a slight increase in hemoglobin A2 level. These results initially suggested het-erozygous beta-thalassemia, eventually correlating with the concurrent presence of Graves' disease, as evidenced by the normalization of hemoglobin A2 level following treatment. CONCLUSIONS: This case highlights the importance of having clinical, biological, and therapeutic data for a relevant interpretation of a phenotypic hemoglobin study.

IgG4 serum levels in Graves' orbitopathy.

OBJECTIVE: IgG4-related disease (IgG4-RD) can involve many organs, including thyroid and orbital tissues. A link between IgG4, Graves' disease (GD) and Graves' orbitopathy (GO) has been proposed, but results are conflicting. Here we investigated the possible association between IgG4 and GO. METHODS: Retrospective investigation in 297 patients with Graves' disease (GD), 152 with GO. PRIMARY OUTCOME: prevalence of IgG4 ≥ 135 mg/dL (cut-off for IgG4-RD). SECONDARY OBJECTIVES: (1) serum IgG4 concentrations; (2) IgG4/IgG ratio; (3) prevalence of IgG4/IgG ratio ≥ 8.0%; (4) relationship between IgG4 and eye features; (5) relationship between IgG4 and anti-TSH receptor antibodies (TRAbs). RESULTS: Because GO patients had lower FT3 concentrations, we evaluated the main objectives in the second and third FT3 quartiles subpopulation, in which there were no relevant differences between patients with (n = 81) or without GO (n = 67) for baseline parameters. Within this population, the prevalence of IgG4 levels ≥ 135 mg/dL did not differ between patients without and with GO (17.9% vs 17.3%). No difference was observed concerning IgG4 concentrations, prevalence of IgG4/IgG ≥ 8.0%, and IgG4/IgG ratio. There was no relationship between IgG4 and eye features and no correlation between IgG4 levels and TRAb was found. CONCLUSIONS: Our results suggest that, within GD, there is no relationship between serum IgG4 and GO.

Pre- and Post-treatment Serum BAFF Levels and BAFF Gene Polymorphisms in Patients with Graves' Disease.

BACKGROUND: B cell activating factor (BAFF), a crucial factor for B cell survival and differentiation, has been linked to several autoimmune conditions. The aim of this study was to evaluate the association of BAFF gene's polymorphisms with its serum levels and to assess their effect on Graves' disease (GD) susceptibility and presentation. METHODS: Sixty-two GD patients and 152 healthy controls have been enrolled to investigate BAFF rs9514827 (-2841 T/C), rs1041569 (-2701 T/A) and rs9514828 (-871 C/T) gene's polymorphism by PCR-RFLP and serum BAFF level's kinetics under medical treatment by ELISA. RESULTS: Median serum BAFF level at baseline was significantly higher in GD patients (841.7 pg/ml [685.23-1058.32]) comparatively to controls (495.75 pg/ml [383.17-595.7]), p = 7.29 E-25. A ROC curve was used to assess BAFF performances in GD diagnosis and revealed an AUC of 94.9% [0.919-0.979], p = 7.29 E-25. At a cutoff value of 654.9 pg/ml of BAFF at baseline, the sensitivity and the specificity were, respectively, 83.9% and 90.8%. BAFF level was significantly increased in smoking patients (1079.55 pg/ml [875.35-1203]) comparatively to nonsmokers (746.95 pg/ml [643.2-915.7]), p = 3.1 E-5. While -2841 T/C and -2701 T/A genotypes and alleles frequencies were similar between patients and controls, the -871*T allele was significantly more prevalent in patients (0.613) than in controls (0.477); p = .01, OR [95% CI] = 1.73 [1.13-2.65]. The three studied polymorphisms were not associated with serum BAFF level at baseline. CONCLUSION: Serum BAFF level is significantly increased in GD especially in smoking patients. rs9514828 - 871*T allele might be a susceptibility variant for GD.

Alteration of the Intestinal Microbial Flora and the Serum IL-17 Level in Patients with Graves' Disease Complicated with Vitamin D Deficiency.

BACKGROUND: Intestinal flora is associated with Graves' disease (GD). This study explored the association of serum 25(OH)D with the diversity of the intestinal flora and serum IL-17 in GD patients. METHODS: Patients newly diagnosed with GD at 2 centers between 2018 and 2021 were consecutively included. According to their 25(OH)D levels, they were divided into the deficiency group, the insufficiency group, and the sufficiency group. Some patients with vitamin D deficiency or insufficiency were randomly selected and were matched with healthy volunteers (normal control [NC]) in terms of sex, age, and case number. The diversity and differential species of the intestinal flora and serum IL-17 levels were compared. RESULTS: Serum 25(OH)D negatively correlated with serum IL-17, the platelet/lymphocyte ratio, and TSH receptor antibody. The diversity of the intestinal flora decreased in the GD group, with noticeable differences in the composition of the intestinal flora when compared with the NC group. At the phylum level, the GD group exhibited a significantly lower abundance of Firmicutes but a higher abundance of Actinobacteria. At the genus level, the GD group exhibited higher relative abundances of Bifidobacterium, Collinsella, and Pediococcus but lower abundances of Roseburia and Dialister. CONCLUSIONS: The changes in the vitamin D level and the composition of the intestinal flora may partially contribute to the development of GD.

Low levels of serum IL-39 are associated with autoimmune thyroid disease.

BACKGROUND: Interleukin (IL)-39 is a novel member of IL-12 cytokine family, but its role in autoimmune thyroid diseases (AITD) is unclear. The aim of the present study was to determine serum levels of IL-39 in Hashimoto's thyroiditis (HT) and Graves' disease (GD) patients. METHODS: A total of 48 patients with HT, 50 patients with GD, and 45 healthy controls (HCs) were recruited for this study. Levels of serum IL-39 were determined by ELISA. RESULTS: Compared with HC group, levels of serum IL-39 in patients with HT (p < 0.05) and GD (p < 0.01) were drastically reduced. Among patients with HT, serum IL-39 levels had a positive correlation with white blood cell count (WBC) count and free triiodothyronine level. Among patients with GD, the levels of IL-39 in serum were positively correlated with WBC count and C-reactive protein levels. CONCLUSIONS: IL-39 may be a new potential predictor for patients with HT and GD.

Low serum interleukin-38 levels in patients with Graves' disease and Hashimoto's thyroiditis.

BACKGROUND: Autoimmune thyroid disease (AITD) mainly includes Graves' disease (GD) and Hashimoto's thyroiditis (HT), which is caused by individual genetics, autoimmune dysfunction, and a variety of external environmental factors. Interleukin (IL)-38 is involved in a wide range of autoimmune diseases, but little is known about IL-38 expression in AITD. METHODS: Fifty patients with GD, 50 with HT, and 50 healthy controls (HC) were enrolled in this study. Basic information of the participants was obtained through a physical examination. Immunological data were obtained by an automatic chemiluminescence immunoanalyzer. C-reactive protein (CRP) concentrations and the white blood cell count were measured. Serum IL-38 levels were determined by an enzyme-linked immunosorbent assay. RESULTS: Serum IL-38 levels were significantly lower in the GD and HT groups than in the HC group (both p < 0.01). Serum CRP concentrations were significantly lower in the HT group than in the HC group (p < 0.05). Receiver operating characteristic curve analysis showed that the area under the curve was 0.7736 (p < 0.01) for IL-38 and 0.7972 (p < 0.01) for IL-38 combined with CRP in the GD group. In the HT group, the area under the curve was 0.7276 (p < 0.01) for IL-38 and 0.7300 for IL-38 combined with CRP (p < 0.01). CONCLUSIONS: The results suggest that serum IL-38 level is a potential new diagnostic biomarker in patients with GD and HT.

High prevalence of thyroid hormone autoantibody and low rate of thyroid hormone detection interference.

OBJECTIVE: Thyroid hormone autoantibody (THAb) is a common antibody in autoimmune disease and can interfere with the detection of thyroid hormone (TH). There was no research reporting the prevalence of THAb in Chinese and the rate of THAb interfering with TH detection. METHODS: We collected 114 patients with autoimmune thyroid disease (AITD) (Hashimoto's thyroiditis, 57 cases; Graves' disease, 57 cases), 106 patients with nonthyroid autoimmune diseases (NTAID), and 120 healthy subjects. According to the presence or absence of thyroid antibodies, patients with NTAID were divided into two groups: NTAID-AITD and NTAID groups. Radioimmunoprecipitation technique was used to detect THAb in all subjects. TH was detected on Abbot and Roche platforms in patients with positive THAb. RESULTS: The prevalence of THAb was 22.8% in Hashimoto's thyroiditis and 45.6% in Graves' disease. The prevalence of THAb in AITD group was lower than that in NTAID or NTAID-AITD groups (34.2% vs. 61.5%, p = 0.014; 34.2% vs. 71.3%, p < 0.01). Among total 98 patients with positive THAb, TH levels of 9 patients were falsely elevated (9.18%). CONCLUSION: The prevalence of THAb in AITD patients was lower than that in NTAID patients. Although THAb had a high frequency in various autoimmune diseases, the prevalence of THAb interfering with TH detection was only 9.18%.

A cyclic peptide significantly improves thyroid function, thyrotropin-receptor antibodies and orbital mucine /collagen content in a long-term Graves' disease mouse model.

BACKGROUND: BALB/c mice which received long-term immunizations of adenovirus (Ad) expressing thyrotropin receptor A-subunits (TSHR) developed stable Graves' disease (GD). TSHR-derived cyclic peptide 19 (P19) was identified as effective therapy in this model. METHODS: In Ad-TSHR mice, we investigated shorter disease intervals up to 4 months for histological alterations of the orbits, fine tuning of anti-TSHR antibodies (Ab) and free thyroxine (fT4) hormone levels by using novel detection methods in an independent laboratory. Therapy (0.3 mg/kg P19 or vehicle) was given intravenously after the fourth Ad-TSHR immunization (week 11) and continued until week 19. RESULTS: Thyrotropin binding inhibitory immunoglobulins (TBII, bridge immunoassay), blocking (TBAb) and stimulating (TSAb) TSHR-Ab (both cell-based bioassays) and serum levels of fT4 were significantly elevated at week 11 in Ad-TSHR-immunized mice versus none in control mice. For the first time, TSAb, TBAb, and thyroperoxidase-Ab were detected in 17 of 19, 12/19 and 6/19 Ad-TSHR immunized mice, respectively at week 21. Also, for the first time, this study showed that P19 treatment markedly reduced serum TBII (p < 0.0001), serum fT4 (p = 0.02), and acidic mucins and collagen content in the orbital tissue of Ad-TSHR-immunized mice. CONCLUSION: P19 significantly improved thyroid function, confirming previous results in an independent second laboratory. A relevant shift of anti-TSHR antibody subpopulations in response to P19 therapy may help explain its immunological effects. Moreover, P19 exerted a beneficial effect on mucine and collagen content of orbital tissue. Hence, P19 offers a potential novel therapeutic approach for GD and associated orbitopathy.

Serum interferon levels associated with the disease activity in women with overt Graves' disease.

BACKGROUND: Inflammatory cytokines participate in immune reactions and the pathogenesis of autoimmunity. Herein, we quantified four groups of inflammatory cytokines, including interferons (IFNs), the tumor necrosis factor (TNF) superfamily (TNFSF), interleukin (IL)-related cytokines, and bone and extracellular matrix remodeling-related cytokines to determine their contributions in women with overt Graves' disease (GD). METHODS: Forty-three women with GD were enrolled in this cross-sectional study. Thirty-seven cytokines, thyroid-stimulating hormone (TSH), free thyroxine, and TSH receptor antibody (TSHRAb) were quantified. GD patients with a low TSH level at the time of sample collection were defined as having active GD. RESULTS: Patients with active GD had higher IFN-α2, IFN-γ, IFN-λ1, and IFN-λ2 levels than those with inactive GD. In addition, certain TNFSF cytokines, including soluble cluster of differentiation 30 (sCD30), TNFSF member 14 (TNFSF14), pentraxin (PTX)-3, soluble TNF receptor 2 (sTNF-R2), and thymic stromal lymphopoietin (TSLP) were higher in active GD than in inactive GD. Moreover, active GD patients had higher IL-2, IL-12(p40), osteocalcin (OCN), and matrix metalloproteinase (MMP)-3 than inactive GD patients. All IFNs except IFN-λ1 were correlated with TSHRAb titers. Moreover, TNFSF cytokines, consisting of B-cell-activating factor, sCD30, TNFSF14, PTX-3, sTNF-R2, and TSLP, were associated with TSHRAb levels. CONCLUSIONS: Serum IFNs could be the most remarkable cytokines in modulating the disease severity and TSHRAb titers in women with full-blown GD. Further molecular-based research to clarify the actual role of IFNs in the disease progression of GD is needed.

Altered expression profile of BAFF receptors on peripheral blood B lymphocytes in Graves' disease.

BACKGROUND: B lymphocyte activating factor (BAFF) is a growth factor regulating B lymphocytes survival and maturation. Serum BAFF levels were elevated in patients affected with autoimmune thyroid diseases (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT). The aim of this study is to explore the association of expression levels of BAFF and its receptors with AITD. METHODS: Fifty-two GD patients, 39 Hashimoto's thyroiditis (HT) patients and 23 healthy controls (HC) were recruited in this study. Serum BAFF levels were measured by ELISA. Expression of BAFF receptors, including BAFF receptor 3 (BR3) and transmembrane activator and calcium-modulating and cyclophilin ligand interactor (TACI), on B lymphocytes were analyzed by flowcytometry. Effects of steroids on serum BAFF levels and expression of BR3 and TACI were also observed in 10 patients with Graves' orbitopathy (GO) receiving steroids therapy. RESULTS: Serum BAFF levels were significantly elevated from 0.93 ± 0.24 ng/ml in HC to 1.18 ± 0.33 ng/ml in GD (P = 0.0027) and 1.02 ± 0.24 ng/ml in HT (P = 0.0331). BR3 expression on peripheral B lymphocytes were elevated in GD (mean MFI: 4.52 ± 2.06 in GD vs. 3.00 ± 0.87 in HC, P = 0.0015), while TACI expression on peripheral B lymphocytes were decreased in GD without significance (mean MFI: 7.96 ± 4.06 in GD vs. 9.10 ± 3.37 in HC, P = 0.1285). Expression of BR3 and TACI was not changed significantly in HT patients. Steroids significantly suppressed serum BAFF concentrations (from 1.18 ± 0.27 ng/ml to 0.97 ± 0.10 ng/ml, P = 0.0364) and BR3 expression in GO patients (mean MFI from 6.26 ± 4.91 to 4.05 ± 1.58, P = 0.0083). CONCLUSIONS: Altered expression of BAFF and its receptor may mediate the autoimmunity in GD. Restoring the normal expression profile of receptors for BAFF could be a new strategy to treat GD.

Change in newly diagnosed Graves' disease phenotype between the twentieth and the twenty-first centuries: meta-analysis and meta-regression.

PURPOSE: According to a few recent studies, the clinical phenotype of Graves' disease (GD) at onset is becoming milder in recent years, in terms of prevalence and severity of hyperthyroidism, goiter and overt eye disease. The aim of this study was to assess the change in GD phenotype across the late twentieth and the early twenty-first centuries. MATERIALS AND METHODS: We carried out a systematic search of studies published between 1/1/1980 and 12/31/2017 describing naïve GD patients at diagnosis. We collected epidemiological, clinical, biochemical and serological data reported in the selected studies, and (1) conducted a single-arm meta-analysis to compare clinical and biochemical characteristics of naïve GD patients before and after year 2000 and (2) performed a meta-regression to identify the trend of the observed clinical presentations. RESULTS: Eighty selected articles were related to the period before the year 2000, 30 to the years 2000-2017. According to demographics, the two defined populations were homogeneous at meta-analysis: overall estimated female prevalence was 81% [95% CI 79-82], mean estimated age of the entire population was 39.8 years [95% CI 38.4-41.1], with no significant differences between pre- and post-2000 groups (p > 0.05). The overall estimated prevalence of smokers was 40% [95% CI 33-46], with no significant difference between the two groups (p > 0.05). Mean estimated free thyroxine (FT4) and free triiodothyronine (FT3) levels at diagnosis were higher in the pre-2000 group: 4.7 ng/dl [95% CI 4.5-4.9] for FT4 and 14.2 pg/ml [95% CI 13.3-15.1] for FT3, as compared to the post-2000 group: 3.9 ng/dl [95% CI 3.6-4.2] for FT4 and 12.1 pg/ml [95% CI 11.0-13.3] for FT3 (all p < 0.01). Goiter estimated prevalence was higher in the pre-2000 group, 87% [95% CI 84-90], than in the post-2000 group, 56% [95% CI 45-67]. Estimated prevalence for Graves' Orbitopathy (GO) was 34% [95% CI 27-41] in the pre-2000 group and 25% [95% CI 19-30] in the post-2000 group (p = 0.03). Accordingly, meta-regression adjusted for covariates showed an average annual reduction of FT4 (- 0.040 ± 0.008 ng/dl, p < 0.0001), FT3 (- 0.316 ± 0.019 pg/ml, p < 0.0001), goiter prevalence (- 0.023 ± 0.008%, p = 0.006), and goiter size (- 0.560 ± 0.031 ml, p < 0.0001). CONCLUSIONS: Our meta-analysis and meta-regression confirmed that GD phenotype at diagnosis is nowadays milder than in the past; we hypothesize that conceivable factors involved in this change are iodoprophylaxis, worldwide decrease in smoking habits, larger use of contraceptive pill and micronutrient supplementation, as well as earlier diagnosis and management.

Serum thyroglobulin is associated with orbitopathy in Graves' disease.

PURPOSE: Serum thyroglobulin levels are often elevated in Graves' disease (GD) and in most cases decrease during treatment. Its relation to Graves' orbitopathy (GO) has not been clarified. Previously, a risk of GO has been linked to smoking, TSH receptor stimulation, high TSH-receptor antibodies (TRAb), low thyroid peroxidase and thyroglobulin antibodies (TPOAb, TgAb). METHODS: We examined Tg levels in 30 consecutive patients with GD were given drug therapy (methimazole + thyroxine) for up to 24 months. GO was identified by clinical signs and symptoms. 17 patients had GO, 11 of whom had it at diagnosis while 6 developed GO during treatment. During the study, 5 subjects were referred to radioiodine treatment, 3 to surgery. The remaining 22 subjects (GO n = 12, non-GO n = 10) completed the drug regimen. RESULTS: At diagnosis, Tg levels in GO patients (n = 11) were higher (84, 30-555 µg/L, median, range) than in non-GO patients (n = 19) (38, 3.5-287 µg/L), p = 0.042. Adding the 6 subjects who developed eye symptoms during treatment to the GO group (n = 17), yielded p = 0.001 vs. non-GO (n = 13). TRAb tended to be higher, while TPOAb and TgAb tended to be lower in the GO group. For the 22 patients who completed the drug regimen, Tg levels were higher in GO (n = 12) vs. non-GO (n = 10), p = 0.004, whereas TRAb levels did not differ. CONCLUSION: The data may suggest that evaluation of thyroglobulin levels in GD could contribute to identify patients at increased risk of developing GO. Possibly, thyroidal release of Tg in GD reflects a disturbance that also impacts retroorbital tissues.

Serum thyroid stimulating hormone level for predicting utility of thyroid uptake and scan.

BACKGROUND: Thyroid uptake and scan (TUS) is a clinical tool used for differentiation of thyrotoxicosis etiologies. Although guidelines recommend ordering a TUS for evaluation of low TSH levels, no specific value is defined. This study aimed to determine a TSH cutoff at which TUSs yield a greater likelihood of successful determination of etiology to avoid unnecessary testing. METHODS: This was a retrospective study on 137 patients seen by an endocrinologist who underwent TUS for evaluation of low TSH (<0.4 µU/mL). A receiver operating curve analysis was performed to determine the TSH cutoff with maximal sensitivity and specificity for prediction of diagnostic utility. RESULTS: Ninety percent of TUSs (n = 123) led to a diagnosis, while 10% (n = 14) were inconclusive or normal. Diagnoses included Graves' diseases (52%), toxic multinodular goiter (19%), thyroiditis (12%), and solitary toxic adenoma (7%). The median TSH value was 0.008 µU/mL (IQR 0.005, 0.011), and the median free T4 value was 1.7 µU/mL (IQR 1.3, 2.8). The ROC analysis produced an area under the curve of 0.86. The optimal TSH cutoff value was 0.02 µU/mL (sensitivity 80%, specificity 93%) for prediction of diagnostic yield. CONCLUSION: This study demonstrates that TSH is a useful predictor of the utility of TUS in yielding an etiology of thyrotoxicosis. Our analysis showed that TUS had a greater likelihood of determining an etiology when TSH was ≤0.02 µU/mL. This information can help clinicians avoid unnecessary cost and patient time burden when TUS is unlikely to aid in determining the etiology of thyrotoxicosis.

Expression of Circulating Rennin-Angiotensin-Aldosterone-Related microRNAs in Patients with Thyrotoxic Heart Disease.

Thyrotoxic heart disease (THD) is a common and severe complication of hyperthyroidism and the etiology of this complication remains poorly understood. Activation of the rennin-angiotensin- aldosterone system by excess thyroxin is one of the major factors that contribute to the pathogenesis of THD. Several microRNAs such as miR-21, miR-155, miR-208a, and miR-499 are closely related to the rennin-angiotensin-aldosterone system and therefore should be involved in this process. Our study intends to explore whether these miRNAs are involved in the pathogenesis of THD, and if these miRNAs could be secreted into the circulation and serve as sentinel indicators for THD. Though there is a trend of elevation of miR- 155 in THD than in simple hyperthyroidism patients, we did not find statistically significant differences in the expression of these miRNAs in the blood of THD patients, but we found that miR-155 was significantly up-regulated in patients with Graves' disease with or without THD in comparison with healthy controls. Thus, miR-155 can serve as a novel biomarker for Graves' disease and can play important roles in pathogenesis of Graves' disease.