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.

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.

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.

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.

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.

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.

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.

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.

The excess risk of major osteoporotic fractures in hypothyroidism is driven by cumulative hyperthyroid as opposed to hypothyroid time: an observational register-based time-resolved cohort analysis.

The long-term relationship between hypothyroidism and fracture risk is challenging to dissect because of the modifying influence of subsequent thyroxine replacement with the potential for excessive replacement doses. We studied changes in serum thyrotropin concentration (TSH) over time and association with fracture risk in real-world patients presenting with elevated TSH. All TSH determinations were done in the same laboratory, which served all hospitals and general practices. The study population consisted of all adults with a first measurement of TSH >4.0 mIU/L (n = 8414) or normal TSH (n = 222,138; comparator). We used a Cox proportional hazards analysis incorporating additional time-dependent covariates to represent initiation of thyroxine replacement and cumulative number of periods with high versus low TSH after index date with a mean follow-up of 7.2 years. Elevated baseline TSH was not associated with an increased risk of hip fracture (HR 0.90; 95% CI, 0.80 to 1.02) or major osteoporotic fractures (HR 0.97; 95% CI, 0.90 to 1.05), nor was subsequent thyroxine prescription predictive of increased risk of fractures. The number of subsequent 6-month periods with low TSH-suggesting excessive thyroxine dosing-was significantly associated with increased risk of both hip fracture (HR 1.09; 95% CI, 1.04 to 1.15) and major osteoporotic fracture (HR 1.10; 95% CI, 1.06 to 1.14). When gender- and age-stratified analyses for major osteoporotic fractures were undertaken, hyperthyroid time was identified as a predictor of fracture risk in postmenopausal women whereas hypothyroid time predicted increased fracture risk in men below age 75 years. In conclusion, among patients who present with an elevated TSH, the long-term risk of hip and other osteoporotic fractures is strongly related to the cumulative duration of periods with low TSH-likely from excessive replacement. An independent effect of elevated TSH could only be observed in young and middle-aged men, suggesting gender-discrepant consequences on risk.

Impact of month of birth on the development of autoimmune thyroid disease in the United Kingdom and Europe.

CONTEXT: Viral/bacterial infection is proposed as a trigger for the autoimmune thyroid diseases (AITD): Graves' disease (GD) and Hashimoto's thyroiditis (HT). Previous studies in European Caucasian AITD subjects found higher birth rates in the autumn/winter, suggesting those born in the autumn/winter experience increased viral/bacterial exposure after birth, impacting upon immune system development and predisposing to AITD later in life. OBJECTIVE: Month of birth effects were investigated in three independent European Caucasian AITD datasets. DESIGN: Variation in GD and HT onset was compared across months and seasons, with fluctuations across all 12 months analyzed using a Walter-Elwood test. SETTING: The study was conducted at a research laboratory. PATIENTS: National UK Caucasian AITD Case Control Collection (2746 GD and 502 HT compared with 1 423 716 UK births), National UK Caucasian GD Family Collection (239 GD and 227 unaffected siblings), and OXAGEN AITD Caucasian Family Collection (885 GD, 717 HT, and 794 unaffected siblings of European Caucasian decent). MAIN OUTCOME MEASURES: Case-control and family-based association studies were measured. RESULTS: No consistent month of birth effects were detected in GD females or males across all three collections. In HT females from the OXAGEN AITD Caucasian Family Collection, slightly higher birth rates were detected in autumn (Walter's test statistic = 7.47, P = .024) however, this was not seen in the HT females from the case-control cohort. CONCLUSION: Our results suggest in UK/Northern European Caucasian GD subjects, month of birth does not impact on AITD development. Although some month of birth effects for HT females in one collection cannot be excluded, only further work in larger European Caucasian AITD collections can confirm these effects.

Low serum thyrotropin level and duration of suppression as a predictor of major osteoporotic fractures-the OPENTHYRO register cohort.

The relationship between thyrotoxicosis and osteoporotic fractures remains controversial, particularly in men. Register-based cohort study including all patients with a serum thyrotropin (TSH) measurement in the region of Funen 1996-2010. All TSH determinations were done in the same lab, which served all hospitals and General Practice (GP) practices in the region. Persons with raised TSH or a history of thyroid/pituitary disease or use of thyroid medications were excluded. The study population consisted of 222,138 (96%) persons with normal and 9217 (4%) with low TSH (<0.3 mIU/L). A single low TSH at baseline was associated with increased risk of hip fractures (adj HR 1.16, 95% CI 1.07-1.26, p < 0.001) but not major osteoporotic fractures (MOF, adj HR 1.06, 95% CI 0.99-1.12, p = 0.058) over a median follow-up of 7.5 years. When men were analyzed separately, results did not reach statistical significance. We found a significant association between duration of thyrotoxicosis and fracture. For each 6 months in which the mean TSH value was decreased (<0.3 mIU/L), hip fracture risk increased by a factor 1.07 (adj HR, 95% CI 1.04-1.10, p < 0.001) and MOF by 1.05 (adj HR, 95% CI 1.03-1.07, p < 0.001). Overt thyrotoxicosis was associated with an increased risk of hip fractures but not MOF. In euthyroid patients, the risk of fractures increased significantly with each SD unit of TSH decrease: Hip fracture (HR 1.45, 95% CI 1.22-1.71, p < 0.001) and MOF (HR 1.32, 95% CI 1.19-1.46, p < 0.001). In a population-based cohort, a single, first measurement of decreased TSH in patients without known thyroid disease was associated with an increased long-term risk of hip fracture, which remained significant in women but not in men after adjusting for confounders. Moreover, the risk of both hip fracture and MOF increased exponentially by the length of time during which TSH had remained low.

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.