Frequency and characteristics of immune-related thyroid adverse events in patients with resected stage III/IV melanoma treated with adjuvant PD-1 inhibitors: a national cohort study.

PURPOSE: Immune-related thyroid adverse events (irTAEs) occur frequently following immune checkpoint inhibitor (ICI) therapy. The purpose of this study is to provide knowledge about the incidence, clinical timeline characteristics, associated factors of irTAEs, and potential impact on treatment efficacy in patients with melanoma receiving adjuvant ICI therapy. METHODS: A national multicenter retrospective cohort study of patients with resected stage III/IV melanoma treated with adjuvant PD-1 inhibitors between November 2018 and December 2020. Data were extracted from the Danish Metastatic Melanoma Database. The irTAEs were defined as two consecutive abnormal TSH values and subdivided into transient or persistent. RESULTS: Of 454 patients, 99 developed an irTAE (21.8%), of these were 46 transient (46.5%) and 53 persistent (53.5%). Median time to transient and persistent irTAE was 55 and 44 days, respectively (p = 0.57). A hyperthyroid phase followed by hypothyroidism was seen in 73.6% of persistent irTAEs, whereas 87% of transient irTAEs developed an isolated hypo- or hyperthyroid phase. Multiple variable analysis demonstrated an association between irTAE and female sex (HR 2.45; 95% CI 1.63-3.70; p < 0.001), but no association with recurrence-free survival (HR 0.86; 95% CI 0.50-1.48; p = 0.587) or overall survival (HR 1.05; 95% CI 0.52-2.12, p = 0.891). CONCLUSIONS: IrTAE is a common side effect to PD-1 inhibitors primarily occurring within the first 3 months, with a high risk of persistency. Female sex is a strong predictive factor. IrTAE was not associated with improved clinical outcome.

Increased risk of dementia in hypothyroidism: A Danish nationwide register-based study.

OBJECTIVE: Globally, the prevalence of individuals with dementia is increasing, and identification of risk factors is of paramount interest. Using population-based registers, we evaluated whether hypothyroidism is a risk factor for dementia. DESIGN: Register-based cohort study. PATIENTS AND METHODS: Risk of dementia was evaluated in two cohorts. The DNPR cohort comprises 111,565 hypothyroid patients, diagnosed between 1995 and 2012, and 446,260 euthyroid age- and sex-matched individuals (median follow-up 6.2 years). The OPENTHYRO cohort comprises 233,844 individuals with at least one measurement of serum thyrotropin (TSH) between 1995 and 2011, of whom 2,894 had hypothyroidism (median follow-up 7.2 years). Primary outcome was dementia defined as an International Classification of Diseases 10 code, or prescription of medicine for dementia. RESULTS: In the DNPR cohort, risk of dementia was significantly increased in subjects with hypothyroidism (HR 1.22; 95% CI: 1.17-1.27), which attenuated after adjusting for pre-existing comorbidity (HR 0.82; 95% CI: 0.79-0.86). Stratification of age into ≤56 and >56 years showed an inverse relationship between age and risk of dementia (HR≤56 years. 2.03; 95% CI: 1.62-2.53 and HR>56 years . 1.00; 95% CI: 0.96-1.05). In the OPENTHYRO cohort, the risk of dementia was significantly increased for each 6 months of elevated TSH (HR 1.12; 95% CI: 1.07-1.16). CONCLUSIONS: Hypothyroidism is associated with increased risk of dementia. The association is influenced by comorbidity and age. Every 6 months of elevated TSH increased the risk of dementia by 12%, suggesting that also the length of hypothyroidism influences the risk of dementia.

Common genetic variants associated with thyroid function may be risk alleles for Hashimoto's disease and Graves' disease.

BACKGROUND: Recent studies have identified common genetic variants associated with TSH, free T4 and thyroid peroxidase antibodies, but it is unclear whether these differ between patients with Hashimoto's disease and Graves' disease. OBJECTIVE: To examine whether 11 common genetic variants differ between Graves' disease and Hashimoto's disease. PATIENTS AND MEASUREMENTS: We genotyped 11 common variants in a discovery cohort of 203 Australian patients with autoimmune thyroid disease (AITD). Two variants with significant or suggestive associations were analysed in a replication cohort of 384 Danish patients. RESULTS: For rs753760 (PDE10A), the minor allele frequency in Graves' disease and Hashimoto's disease was 0·38 vs. 0·23, respectively, (P = 6·42 × 10-4 ) in the discovery cohort, 0·29 vs. 0·24 (P = 0·147) in the replication cohort and 0·32 vs. 0·24 in combined analysis (P = 0·0021; all analyses adjusted for sex). In healthy controls from Busselton, the frequency was 0·29, significantly different from Hashimoto's disease but not Graves' disease. For rs4889009 (MAF gene region), the frequency of the minor G-allele in Graves' disease and Hashimoto's disease was 0·48 vs. 0·36 (P = 0·0156) in the discovery cohort, 0·48 vs. 0·34 (P = 1·83 × 10-4 ) in the replication cohort and 0·48 vs. 0·35 in the combined analysis (P = 7·53 × 10-6 ); in controls, the frequency was 0·38, significantly different from Graves' disease but not Hashimoto's disease. After further adjustment for smoking, associations with rs4889009 remained significant, whereas those with rs753760 were not. CONCLUSION: Common variants in PDE10A and MAF gene regions may influence whether patients with AITD develop Graves' disease or Hashimoto's disease.

Pendrin and NIS antibodies are absent in healthy individuals and are rare in autoimmune thyroid disease: evidence from a Danish twin study.

OBJECTIVE: Antibodies against thyroglobulin, thyroid peroxidase and the TSH receptor are accepted as pathophysiological and diagnostic biomarkers in autoimmune thyroid disease (AITD). In contrast, the prevalence, aetiology and clinical relevance of autoantibodies against the human sodium-iodine symporter (NISAb) and pendrin (PenAb) remain unclear. The objectives of the study were to investigate the presence of NISAb and PenAb in Danish twins, with and without AITD, to study whether the published variations in NISAb and PenAb frequencies were related to differences in methodology or study populations, and to evaluate whether the presence of NISAb or PenAb most likely results from genetic or nongenetic factors. METHODS: Sera from 93 patients with AITD and 230 healthy controls were evaluated for NISAb and PenAb using radioligand binding assays (RBA). RESULTS: Patients with AITD had a higher prevalence than the controls: NISAb: 17% vs 0% (P < 0·001) and PenAb: 11% vs 0% (P < 0·001). Subdividing according to cause of AITD yielded similar results: 20% (11/56) of patients with Graves' disease (GD) and 14% (5/37) of patients with Hashimoto's thyroiditis (HT) had NISAb, (P < 0·05, vs control population). Seven of 56 (13%) patients with GD and three of 37 (8%) patients with HT had PenAb (P < 0·05 vs control population). No twin pairs were concordant for NISAb or PenAb, not even among twin pairs concordant for AITD. CONCLUSIONS: In accord with studies using the same RBAs, the frequency of NISAb and PenAb was low in Danish patients with AITD and absent in healthy individuals, suggesting that differences between studies rely on assay differences. The skewed distribution of NISAb and PenAb within AITD concordant twin pairs suggests that NISAb and PenAb are likely attributable to the effects of environmental factors acting in genetic susceptible individuals.

Epigenome-wide Association Study Shows Differential DNA Methylation of MDC1, KLF9, and CUTA in Autoimmune Thyroid Disease.

CONTEXT: Autoimmune thyroid disease (AITD) includes Graves disease (GD) and Hashimoto disease (HD), which often run in the same family. AITD etiology is incompletely understood: Genetic factors may account for up to 75% of phenotypic variance, whereas epigenetic effects (including DNA methylation [DNAm]) may contribute to the remaining variance (eg, why some individuals develop GD and others HD). OBJECTIVE: This work aimed to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs) comparing GD to HD. METHODS: Whole-blood DNAm was measured across the genome using the Infinium MethylationEPIC array in 32 Australian patients with GD and 30 with HD (discovery cohort) and 32 Danish patients with GD and 32 with HD (replication cohort). Linear mixed models were used to test for differences in quantile-normalized ß values of DNAm between GD and HD and data were later meta-analyzed. Comb-p software was used to identify DMRs. RESULTS: We identified epigenome-wide significant differences (P < 9E-8) and replicated (P < .05) 2 DMPs between GD and HD (cg06315208 within MDC1 and cg00049440 within KLF9). We identified and replicated a DMR within CUTA (5 CpGs at 6p21.32). We also identified 64 DMPs and 137 DMRs in the meta-analysis. CONCLUSION: Our study reveals differences in DNAm between GD and HD, which may help explain why some people develop GD and others HD and provide a link to environmental risk factors. Additional research is needed to advance understanding of the role of DNAm in AITD and investigate its prognostic and therapeutic potential.

Hypothyroid women have persistently higher oxidative stress compared to healthy controls.

Objective: Some studies suggest that hypothyroidism is associated with increased oxidative stress. Urinary excretion of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) represents whole-body RNA and DNA oxidation, respectively. These biomarkers have only been explored sparsely in patients with thyroid disorders. Methods: In 45 Danish women with newly diagnosed hypothyroidism, we compared 8-oxoGuo and 8-oxodG before or shortly after initiating levothyroxine with the excretion rates at euthyroidism. We also compared the excretion of 8-oxoGuo and 8-oxodG in the patients after restored euthyroidism with 18 healthy control subjects. Results: Compared with baseline, none of the biomarkers changed significantly in the patients after becoming euthyroid. The geometric mean of 8-oxoGuo was 1.63 (95% CI: 1.49-1.78) nmol/mmol creatinine at baseline and 1.67 nmol/mmol at euthyroidism (95% CI: 1.53-1.83) (P = 0.39), while that of 8-oxodG was 1.28 nmol/mmol creatinine at baseline (95% CI: 1.14-1.44) and 1.32 nmol/mmol at euthyroidism (95% CI: 1.18-1.48), respectively (P = 0.47). The relative mean differences were 0.97 (95% CI: 0.91-1.04) for 8-oxoGuo and 0.97 (95% CI: 0.88-1.06) for 8-oxodG. At baseline, multiple linear regression revealed a positive association between free thyroxine and both biomarkers (8-oxoGuo, P < 0.001; 8-oxodG, P = 0.04). Furthermore, 8-oxoGuo was positively associated with age (P = 0.04) and negatively associated with thyrotropin (P = 0.02). In the control group, the geometric mean of 8-oxoGuo was 1.23 nmol/mmol creatinine (95% CI: 1.07-1.42), while that of 8-oxodG was 1.04 nmol/mmol creatinine (95% CI: 0.88-1.23). Thus, compared with control subjects, euthyroid patients showed a significantly higher level of both 8-oxoGuo (P < 0.001) and 8-oxodG (P = 0.03). Conclusion: In hypothyroid women, no significant effect of levothyroxine treatment on the oxidative stress biomarkers 8-oxoGuo and 8-oxodG could be demonstrated. However, the excretion of these biomarkers was significantly higher than in healthy controls.

The clinical presentation of autoimmune thyroid disease in men is associated with IL12B genotype.

BACKGROUND: Common variants in the interleukin 12B (IL12B) gene are associated with predominantly inflammatory (Th1) or antibody-mediated (Th2) immune responses. As Hashimoto's disease and Graves' disease are thought to arise from mainly Th1 and Th2 immune responses respectively, we hypothesized that IL12B genotype may influence the clinical presentation of autoimmune thyroid disease. OBJECTIVE: We tested for differences in IL12B genotype between Graves' disease and Hashimoto's disease. PATIENTS: We studied a discovery cohort of 203 Australian women and 37 men with autoimmune thyroid disease, a replication cohort of 100 European men and a cohort of 146 Chinese men. INTERVENTION: We analysed three IL12B variants: rs41292470, in the promoter; rs3212227, in the 3' untranslated region and rs6887695, located 60 kilobases upstream from the coding region. RESULTS: In the discovery cohort, rs41292470 and rs3212227 genotypes did not differ significantly between Hashimoto's disease and Graves' disease. In Australian men (but not women), rs6887695 genotype differed between Hashimoto's disease and Graves' disease, with a minor allele frequency (MAF) of 14% and 41%, respectively (P=0·034). This result was confirmed in the European men (MAF 24% and 41%; P=0·013). On combined analysis of Australian, European and Chinese men (N=285), the difference was highly significant (MAF 23% and 45%; P=3×10(-5) ). In 233 men without thyroid disease, the MAF was 34%, significantly different from Graves' disease (P=0·005) and Hashimoto's disease (P=0·029). CONCLUSION: In men with autoimmune thyroid disease, a common variant located upstream of the IL12B coding region may influence whether patients present with Graves' disease or Hashimoto's disease.

A randomized trial evaluating a block-replacement regimen during radioiodine therapy.

BACKGROUND: Lack of consensus regarding the antithyroid drug regimen in relation to radioiodine ((131) I) therapy of hyperthyroidism prompted this randomized trial comparing two strategies. DESIGN: Patients with Graves' disease (GD, n = 51) or toxic nodular goitre (TNG, n = 49) were randomized to (131) I either 8 days following discontinuation of methimazole (-BRT, n = 52, median dose: 5 mg) or while on a continuous block-replacement regimen (+BRT, n = 48, median dose 15 mg methimazole and 100 µg levothyroxine). results: Patients in the +BRT group required more radioactivity. In this group, thyroid function did not change in the early post (131) I period, while serum-free T3 index was higher in the -BRT group (P < 0·05). One year posttherapy, the fraction of cured patients (euthyroid or hypothyroid) was 48% and 61% in the +BRT and -BRT group, respectively (P = 0·014 unadjusted; P = 0·004 adjusted), but the outcome depended on the type of disease. In GD, treatment failure in the +BRT group correlated positively with the 24-h thyroid (131) I uptake (P = 0·017), while no correlations existed in the -BRT group. In addition to +BRT allocation, patients with TNG were at higher risk of treatment failure with lower thyroid radiation doses (P = 0·048), higher doses of methimazole (P = 0·026) and lower levels of serum TSH (P = 0·009). CONCLUSIONS: A continuous block-replacement regimen results in a stable thyroid function during (131) I therapy but is hampered by the higher amounts of radioactivity required. The study demonstrates that the outcome in GD is highly unpredictable, while treatment failure in patients with TNG is correlated with a number of factors.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and thyroid disease. An update.

PURPOSE OF REVIEW: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with excess morbidity and mortality in patients with hypertension and diabetes but little is known about thyroid diseases. Thus, our goal was to review the literature with respect to: (i) Are patients with underlying hypo- or hyperthyroidism at increased risk of contracting SARS-CoV-2 infection? (ii) do underlying hypo- and hyperthyroidism impact the prognosis of SARS-CoV-2 infection? (iii) does SARS-CoV-2 infection cause de novo thyroid dysfunction? RECENT FINDINGS: Patients with hypo- or hyperthyroidism do not have an increased risk of contracting SARS-CoV-2, and a diagnosis of hypo- or hyperthyroidism is not associated with a worsened prognosis of SARS-CoV-2 infection. SARS-CoV-2 infection has been associated with subsequent thyrotoxicosis, euthyroid sick syndrome, subacute thyroiditis, and autoimmune thyroid disease. SUMMARY: These findings suggest that receiving treatment for thyroid dysfunction does not per se impact the patients' risk of acquiring SARS-CoV-2 infection, or the management of those who already contracted it. Additional studies with larger numbers of patients and long-term follow-up are required in order to clarify whether patients with SARS-CoV-2 infection are more or less prone to develop thyroid dysfunction and/or thyroid autoimmunity than patients recovering from other virus infections.

2021 European Thyroid Association Guidelines for the Management of Iodine-Based Contrast Media-Induced Thyroid Dysfunction.

Given the fact that a large number of radiological examinations using iodine-based contrast media (ICM) are performed in everyday practice, clinicians should be aware of potential ICM-induced thyroid dysfunction (TD). ICM can induce hyperthyroidism (Hyper) or hypothyroidism (Hypo) due to supraphysiological concentrations of iodine in the contrast solution. The prevalence of ICM-induced TD varies from 1 to 15%. ICM-induced Hyper is predominantly found in regions with iodine deficiency and in patients with underlying nodular goiter or latent Graves' disease. Patients at risk for ICM-induced Hypo include those with autoimmune thyroiditis, living in areas with sufficient iodine supply. Most cases of ICM-induced TD are mild and transient. In the absence of prospective clinical trials on the management of ICM-induced TD, an individualized approach to prevention and treatment, based on patient's age, clinical symptoms, pre-existing thyroid diseases, coexisting morbidities and iodine intake must be advised. Treatment of ICM-induced Hyper with antithyroid drugs (in selected cases in combination with sodium perchlorate) should be considered in patients with severe or prolonged hyperthyroid symptoms or in older patients with underlying heart disease. It is debated whether preventive therapy with methimazole and/or perchlorate prior to ICM administration is justified. In ICM-induced overt Hypo, temporary levothyroxine may be considered in younger patients with symptoms of Hypo, with an underlying autoimmune thyroiditis and in women planning pregnancy. Additional clinical trials with clinically relevant endpoints are warranted to further aid in clinical decision-making in patients with ICM-induced TD.

Treatment of Hyperthyroidism Reduces Systemic Oxidative Stress, as Measured by Markers of RNA and DNA Damage.

BACKGROUND: Whole-body oxidative stress can be estimated by the urine excretion of oxidized guanosine species, 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), derived from RNA and DNA, respectively. These oxidative stress markers are not well explored in thyroid disorders. OBJECTIVE: We aimed to determine whether treatment of hyperthyroid patients affects the levels of these oxidative stress markers. METHODS: Urinary excretion of 8-oxoGuo and 8-oxodG was measured in 51 hyperthyroid patients (toxic nodular goiter [TNG], n = 30; Graves disease [GD], n = 21) before or shortly after initiation of therapy and when stable euthyroidism had been achieved for at least 12 months. RESULTS: Adjusting for age, the baseline urinary excretion of oxidative stress markers correlated positively with plasma thyroxine (8-oxoGuo, P = 0.002; 8-oxodG, P = 0.021) and was significantly higher in GD than in TNG patients (P = 0.001 for both oxidative stress markers). Restoration of euthyroidism significantly affected the excretion of the oxidative stress markers. In TNG, 8-oxoGuo decreased from geometric mean 2.11 nmol/mmol creatinine (95% CI, 1.85-2.39) to 1.91 nmol/mmol (95% CI, 1.67-2.19; P = 0.001), while 8-oxodG decreased from 1.65 nmol/mmol (95% CI, 1.41-1.93) to 1.48 nmol/mmol (95% CI, 1.27-1.74; P = 0.026). In GD, 8-oxoGuo decreased from 2.25 nmol/mmol (95% CI, 1.95-2.59) to 1.79 nmol/mmol (95% CI, 1.63-1.97; P = 0.0003), while 8-oxodG decreased from 2.02 nmol/mmol (95% CI, 1.73-2.38) to 1.54 nmol/mmol (95% CI, 1.31-1.81; P = 0.001). In the euthyroid state, there were no differences between groups. CONCLUSION: Restoration of euthyroidism in patients with hyperthyroidism significantly decreased the systemic oxidative stress load by 10% to 25%. Our findings may help to explain the higher morbidity and mortality linked to hyperthyroid diseases, as shown in observational studies.

The pituitary-thyroid axis set point in women is uninfluenced by X chromosome inactivation pattern? A twin study.

OBJECTIVE: The pituitary-thyroid axis (PTA) set point is determined by a combination of genetic and environmental factors. However, despite considerable efforts to characterize the background, the causative genes as well as environmental factors are not well established. Theoretically, as shown for autoimmune thyroid disease, the pattern of X chromosome inactivation (XCI) could offer a novel explanation for the observed variability of the PTA set point in women. DESIGN AND PATIENTS: To examine the impact of XCI pattern on the PTA set point, we studied whether within-cohort (n = 318 subjects) and within-twin pair (n = 159 pairs) differences in XCI are correlated with serum concentrations of thyrotropin (TSH), free triiodothyronine (FT3) and free thyroxine (FT4). METHODS: X chromosome inactivation was determined by PCR analysis of a polymorphic CAG repeat in the first exon of the androgen receptor gene. Thyroid variables were measured using a solid-phase time-resolved fluoroimmunometric assay. Zygosity was established by DNA fingerprinting. RESULTS: In the overall study population (within cohort), no significant correlations were found between TSH [regression coefficient (ß) = -0·28 (95% confidence intervals, -0·66 to 0·11), P = 0·158], FT3 [ß = -0·25 (-0·85 to 0·34), P = 0·403], FT4 [ß = 0·08 (-0·91 to 1·07), P = 0·876] and XCI pattern. Essentially similar results were found in the within-pair analysis. Controlling for confounders such as age, body mass index, smoking and zygosity did not change the findings. CONCLUSIONS: In a sample of female twins, we found no evidence of a relationship between XCI pattern and PTA set point.

A role for autoantibodies in enhancement of pro-inflammatory cytokine responses to a self-antigen, thyroid peroxidase.

The role of thyroid peroxidase (TPO) antibodies (TPOAbs) in the pathogenesis of autoimmune thyroid disease is unclear. We selected sera with a high concentration of TPOAbs from eleven patients with Hashimoto's thyroiditis (HT), ten healthy monozygotic co-twins to HT patients, and twelve healthy individuals with no familiar disposition to AITD, and mixed each serum with normal mononuclear cells (MNCs). Following challenge with TPO, the MNCs' production of the pro-inflammatory cytokines TNF-alpha, IL-6 and IFN-gamma, and the anti-inflammatory cytokine IL-10, correlated with the TPOAb content of the serum present in the culture (p=0.0002-0.05). Enrichment of foetal calf serum-containing media with IgG with a high content of TPOAbs enhanced the TPO-elicited production of TNF-alpha, IL-6 and IFN-gamma by normal MNCs in a dose- and Fcgamma-receptor dependent manner (p<0.0002-0.05). The data indicate that TPO-induced release of pro-inflammatory cytokines from phagocytic cells and T-cell responses to TPO are promoted by TPOAbs.

Too early to dismiss Yersinia enterocolitica infection in the aetiology of Graves' disease: evidence from a twin case-control study.

BACKGROUND: Yersinia enterocolitica (YE) infection has long been implicated in the pathogenesis of Graves' disease (GD). The association between YE and GD could, however, also be due to common genetic or environmental factors affecting the development of both YE infection and GD. This potential confounding can be minimized by investigation of twin pairs discordant for GD. AIM: To examine whether YE infection is associated with GD. DESIGN: We first conducted a classical case-control study of individuals with (61) and without (122) GD, and then a case-control study of twin pairs (36) discordant for GD. METHODS: Immunoglobulin (Ig)A and IgG antibodies to virulence-associated Yersinia outer membrane proteins (YOPs) were measured. MAIN OUTCOME MEASURES: The prevalence of YOP IgA and IgG antibodies. RESULTS: Subjects with GD had a higher prevalence of YOP IgA (49%vs. 34%, P = 0.054) and YPO IgG (51%vs. 35%, P = 0.043) than the external controls. The frequency of chronic YE infection, reflected by the presence of both IgA and IgG YOP antibodies, was also higher among cases than controls (49%vs. 33%, P = 0.042). Similar results were found in twin pairs discordant for GD. In the case-control analysis, individuals with GD had an increased odds ratio (OR) of YE infection: IgA 1.84 (95% CI 0.99-3.45) and IgG 1.90 (95% CI 1.02-3.55). In the co-twin analysis, the twin with GD also had an increased OR of YE infection: IgA 5.5 (95% CI 1.21-24.81) and IgG 5.0 (95% CI 1.10-22.81). CONCLUSION: The finding of an association between GD and YE in the case-control study and within twin pairs discordant for GD supports the notion that YE infection plays an aetiological role in the occurrence of GD, or vice versa. Future studies should examine the temporal relationship of this association in more depth.

Epitope recognition patterns of thyroid peroxidase autoantibodies in healthy individuals and patients with Hashimoto's thyroiditis*.

OBJECTIVE: Thyroid peroxidase antibodies (TPOAb) are markers of autoimmune thyroid disease (AITD), including Hashimoto's thyroiditis (HT), but naturally occurring TPOAb are also detectable in healthy, euthyroid individuals. In AITD, circulating TPOAb react mainly with two immunodominant regions (IDR), IDR-A and IDR-B. The present study was undertaken in order to compare the epitope recognition pattern of TPOAb in HT patients and healthy subjects. DESIGN: Sera from 21 out of 98 healthy controls were selected on the basis of high TPOAb values, required for determination of TPOAb recognition pattern; as were sera from 92 HT patients. MEASUREMENTS: Measurement of IDR-reactivity was possible in 90 patients and 12 controls. IDR-A-, IDR-B- and non-IDR-A/non-IDR-B-Ab constituted 24 +/- 11%, 50 +/- 15% and 26 +/- 12%, respectively, in the patients. The distribution in the controls was distinctly different, only 12 +/- 13% being directed against IDR-A (P < 0.002) and 66 +/- 22% against IDR-B (P < 0.002). Half of the healthy individuals, vs. none of the HT patients, lacked IDR-A reactivity completely (P < 0.0001). In HT patients, IDR-B-Ab proportions increased slightly with increasing TPOAb levels (P < 0.05), while IDR-B-Ab of the controls showed a strong opposite trend (P < 0.0001). Accordingly, the proportion of non-A/non-B-Ab correlated with TPOAb levels in the healthy controls (P < 0.008), and an inverse correlation was seen in HT patients (P < 0.02). CONCLUSION: The data suggest that TPOAb do not differ only in quantity between HT patients and healthy individuals, but may also follow distinct qualitative patterns. Larger studies are required to confirm this, and to determine whether the propensity to produce antibodies to certain TPO epitopes, for example, IDR-A, is of pathogenic relevance.

European Thyroid Association (ETA) and Thyroid Federation International (TFI) Joint Position Statement on the Interchangeability of Levothyroxine Products in EU Countries.

Several European countries have seen major health issues after a switch from one levothyroxine brand to another, as well as following the introduction of several levothyroxine formulation changes. While the relationship between these health issues and brand or formulation changes merits further investigation, the current position statement on behalf of both health-care providers and patients summarizes recent events in several European countries and provides a number of recommendations to limit the burden for patients, so as to prevent increased health-care consumption and health-care expenses in this context.

Mortality in Graves' orbitopathy is increased and influenced by gender, age and pre-existing morbidity: a nationwide Danish register study.

INTRODUCTION: It is unclear whether the excess mortality associated with Graves' disease differs between individuals with Graves' orbitopathy (GO) or without (GD). SUBJECTS AND METHODS: A nationwide, register-based cohort study in which all adult Danes diagnosed with GD (n = 28 461) and GO (n = 3965) between 1995 and 2012 were matched for age and gender with four control subjects. Median follow-up time was 7.9 years (range 0-17.5). Mortality risk in GO patients compared to the control population and compared to GD patients was calculated using Cox regression analyses, adjusting for pre-existing morbidity using the Charlson score. RESULTS: Adjusted mortality in Graves' disease overall (GD + GO) was significantly increased compared to that in the background population (HR = 1.18 (95% confidence interval: 1.15-1.21)). In GD and GO separately, adjusted mortality was also significantly higher than that in their respective control populations (HR: 1.19 (1.16-1.22) and HR: 1.23 (1.12-1.35) respectively). However, mortality in GO compared to that in GD was decreased (HR: 0.64 (0.59-0.69)), although this difference attenuated after adjustment for pre-existing morbidity, age and gender. Both GD and GO males had a significantly higher mortality than those in females. For GO, but not for GD, mortality risk was the highest in the youngest and decreased with increasing age. CONCLUSIONS: GD and GO were associated with increased mortality, especially in males. In GO, but not in GD patients, there was an inverse relationship between age and mortality. Surprisingly, and in need of further study, mortality was not higher in GO than that in GD individuals.