Association of COVID-19 Infection with Subsequent Thyroid Dysfunction: An International Population-Based Propensity Score Matched Analysis.

Background: The COVID-19 pandemic's impact on thyroid function is a growing concern. Previous studies have produced inconclusive results, and there is a lack of comprehensive research into the long-term risks of thyroid dysfunction following COVID-19 infection. Methods: In this retrospective cohort study, we used data from the TriNetX international database, which includes electronic health records from a broad, diverse patient population. We compared patients with COVID-19 (cases) to those without (controls), matching for age, sex, race, and comorbidities using propensity score matching. The primary outcome was the diagnosis of thyroid dysfunction (thyrotoxicosis or hypothyroidism) within a 12-month period, analyzed using hazard ratios (HRs) and Kaplan-Meier curves, and stratified by age and sex. Results: Initially, the study included 1,379,311 COVID-19 patients and 6,896,814 non-COVID-19 patients from the TriNetX database. After matching, the cohorts were comparable in demographics and baseline characteristics. This study consistently demonstrated a significant increase in the risk of thyroid dysfunction, including thyrotoxicosis and hypothyroidism, among COVID-19 patients compared to non-COVID-19 patients. In the short term (3 months postexposure), the COVID-19 group exhibited a HR of 2.07 (95% confidence interval [CI] 2.01-2.12) for thyroid dysfunction, which included both thyrotoxicosis (HR 2.10, CI 1.92-2.29) and hypothyroidism (HR 2.08, CI 2.01-2.13). This heightened risk persisted over the long term (up to 12 months), with HRs indicating an ∼2.01-fold increased risk for overall thyroid dysfunction, a 1.8-fold increased risk for thyrotoxicosis, and a 2.04-fold increased risk for hypothyroidism. Subgroup analysis, stratified by age and sex, revealed a notably higher risk of thyroid dysfunction in patients aged 65 and above (HR 2.18, CI 2.11-2.25), compared to those in the under-65 age group (HR 1.97, CI 1.91-2.03). Both male and female patients were associated with an elevated risk, with females showing a slightly higher association with thyroid dysfunction (HR 2.12, CI 2.06-2.16) compared to males (HR 1.76, CI 1.69-1.82). Conclusions: COVID-19 infection was associated with an increased risk of thyroid dysfunction, including thyrotoxicosis and hypothyroidism, regardless of age or sex, during a 12-month follow-up period. Further research is required to validate these findings.

Retracting the thyroid matters: Who develops asymptomatic transient thyrotoxicosis after parathyroidectomy.

BACKGROUND: Hyperthyroidism after parathyroidectomy is not a well-understood complication. We sought to determine the incidence and risk factors of hyperthyroidism after parathyroidectomy. MATERIALS AND METHODS: This is a prospective study of 91 patients undergoing parathyroidectomy. Pre- and post-operative thyroid-stimulating hormone(TSH) and free thyroxine(T4) levels at two-week follow-ups were collected. Bivariate analyses were conducted to compare demographics, laboratory results, and intraoperative findings between patients with normal and suppressed post-parathyroidectomy TSH. RESULTS: Twenty-two(24.2 â€‹%) patients had suppressed TSH after parathyroidectomy and 2(2.2 â€‹%) reported symptoms of hyperthyroidism. All hyperthyroidism resolved within 6 weeks. No patients required medical treatment. Compared to the normal TSH group, the suppressed TSH group had significantly more bilateral explorations(91.0 â€‹% vs. 58.0 â€‹%, p â€‹= â€‹0.006), and superior parathyroid resections(95.5 â€‹% vs. 65.2 â€‹%, p â€‹= â€‹0.006). CONCLUSION: Transient hyperthyroidism is common following parathyroidectomy, which is likely associated with intraoperative thyroid manipulation. Gentle retraction of thyroid glands in parathyroidectomy is warranted, especially during superior parathyroid gland resection.

Endogenous and Exogenous Thyrotoxicosis and Risk of Incident Cognitive Disorders in Older Adults.

Importance: Thyroid hormone is among the most common prescriptions in the US and up to 20% may be overtreated. Endogenous hyperthyroidism may be a risk factor for dementia, but data are limited for iatrogenic thyrotoxicosis. Objective: To determine whether thyrotoxicosis, both endogenous and exogenous, is associated with increased risk of cognitive disorders. Design, Setting, and Participants: This cohort study performed a longitudinal time-varying analysis of electronic health records for patients receiving primary care in the Johns Hopkins Community Physicians Network between January 1, 2014, and May 6, 2023. Patients 65 years and older with at least 2 visits 30 days apart to their primary care physicians were eligible. None of the 65 931 included patients had a history of low thyrotropin (TSH) level or cognitive disorder diagnoses within 6 months of their first visit. Data analysis was performed from January 1 through August 5, 2023. Exposure: The exposure variable was a low TSH level, characterized based on the clinical context as due to endogenous thyrotoxicosis, exogenous thyrotoxicosis, or unknown cause, excluding those attributable to acute illness or other medical factors such as medications. Main Outcomes and Measures: The outcome measure was cognitive disorders, including mild cognitive impairment and all-cause dementia, to improve sensitivity and account for the underdiagnosis of dementia in primary care. Results: A total of 65 931 patients were included in the analysis (median [IQR] age at first visit, 68.0 [65.0-74.0] years; 37 208 [56%] were female; 46 106 [69.9%] were White). Patients exposed to thyrotoxicosis had cognitive disorder incidence of 11.0% (95% CI, 8.4%-14.2%) by age 75 years vs 6.4% (95% CI, 6.0%-6.8%) for those not exposed. After adjustment, all-cause thyrotoxicosis was significantly associated with risk of cognitive disorder diagnosis (adjusted hazard ratio, 1.39; 95% CI, 1.18-1.64; P < .001) across age groups. When stratified by cause and severity, exogenous thyrotoxicosis remained a significant risk factor (adjusted hazard ratio, 1.34; 95% CI, 1.10-1.63; P = .003) with point estimates suggestive of a dose response. Conclusions and Relevance: In this cohort study among patients 65 years and older, a low TSH level from either endogenous or exogenous thyrotoxicosis was associated with higher risk of incident cognitive disorder. Iatrogenic thyrotoxicosis is a common result of thyroid hormone therapy. With thyroid hormone among the most common prescriptions in the US, understanding the negative effects of overtreatment is critical to help guide prescribing practice.

Risk of Thyroid Dysfunction in PD-1 Blockade Is Stratified by the Pattern of TgAb and TPOAb Positivity at Baseline.

CONTEXT: Positive antithyroglobulin (TgAb) and/or antithyroid peroxidase antibodies (TPOAb) at baseline indicate a high risk of thyroid immune-related adverse events (irAEs) induced by antiprogrammed cell death-1 antibodies (anti-PD-1-Ab). However, whether the positivity patterns of both antibodies are associated with the risk of thyroid irAEs is unknown. OBJECTIVE: The aim of the present study was to clarify the association of the pattern of TgAb and TPOAb positivity at baseline with the risk of thyroid irAEs induced by anti-PD-1-Ab. METHODS: Patients (n = 516) were evaluated for TgAb and TPOAb at baseline and prospectively for thyroid function every 6 weeks for 24 weeks after initiating anti-PD-1-Ab. RESULTS: Fifty-one (9.9%) patients developed thyroid irAEs (thyrotoxicosis in 34, hypothyroidism without prior thyrotoxicosis in 17). Twenty-five patients subsequently developed hypothyroidism following thyrotoxicosis. The cumulative incidence of thyroid irAEs differed among 4 groups classified by the presence of TgAb/TPOAb at baseline (group 1: TgAb-(-)/TPOAb-(-), 4.6% [19/415]; group 2: TgAb-(-)/TPOAb-(+), 15.8% [9/57]; group 3: TgAb-(+)/TPOAb-(-), 42.1% [8/19]; group 4: TgAb-(+)/TPOAb-(+), 60.0% [15/25]) as follows: groups 1 vs 2-4 (P ≤ .001) and groups 2 vs 3 (P = .008) and 4 (P < .001). There were different incidences of thyrotoxicosis (groups 1-4, 3.1%, 5.3%, 31.6%, 48.0%, respectively; P < .001) in groups 1 vs 3 and 4, and groups 2 vs 3 and 4, and of hypothyroidism (groups 1-4: 2.9%, 15.8%, 31.6%, 60.0%, respectively; P < .001) in groups 1 vs 2 to 4, and groups 2 vs 4. CONCLUSION: The risk of thyroid irAEs was affected by the pattern of TgAb and TPOAb positivity at baseline; there were high risks of thyrotoxicosis in patients with TgAb-(+) and of hypothyroidism in patients with TgAb-(+) and those with TPOAb-(+).

Real-life Data on the Effect of Medical Therapy for Amiodarone-induced Thyrotoxicosis on CV Events and Hospitalizations.

CONTEXT: Patients with amiodarone-induced thyrotoxicosis (AIT) often receive initial therapy for thyrotoxicosis in several different medical settings before admission to a referral center. OBJECTIVE: This work aimed to determine whether first-line medical therapy (ie, therapies for thyrotoxicosis at first diagnosis of AIT) affects the outcome of AIT patients. METHODS: A single-center historical-prospective cohort study was conducted on 313 AIT patients. Clinical and biochemical data were collected at first diagnosis, at a referral center, and during the course of AIT. Primary outcomes were cardiovascular (CV) events and hospitalizations. First-line therapies were considered appropriate when they included glucocorticoids for type 2 AIT and methimazole for type 1 AIT at the approved dose, either alone (optimal medical therapy, OMT) or in combination (right-dose combination therapy, RCT). Other therapies were considered not appropriate, including no therapy. Duration of exposure to thyrotoxicosis was the time from first diagnosis of AIT to its remission. RESULTS: A total of 34.5% patients received appropriate therapies (28.1% OMT, 6.4% RCT), whereas the remaining (65.5%) received inappropriate therapies. CV events and hospitalizations were more frequent in patients who received inappropriate therapies (33.2% vs 4.5%, and 24.9% vs 6.5%, respectively; P < .0001 for both). Appropriate therapies reduced serum thyroid hormone concentrations (P = .018) from first diagnosis to referral, unlike the inappropriate therapies. The duration of exposure to thyrotoxicosis was longer in patients receiving inappropriate therapies and was a risk factor for arrhythmias (hazard ratio [HR] 1.004; P = .0008), major acute CV events (HR 1.004; P = .020), and hospitalizations (HR 1.006; P < .0001). CONCLUSION: The first medical therapy of AIT influences the exposure time to thyrotoxicosis and the occurrence of CV events and hospitalizations.

Prevalence of amiodarone-induced hypothyroidism; A systematic review and meta-analysis.

Amiodarone is a common anti-arrhythmic agent mostly used to treat and prevent different kinds of arrhythmia with several considerable side effects, most commonly on the thyroid gland. We aimed to assess the frequency of hypothyroidism among chronic amiodarone users. PubMed/Medline, Web of Science, and Scopus databases were screened in the title and abstract sections with no time limitation. Relevant published records reported amiodarone-induced hypothyroidism (AIH) among patients with normal thyroid function at baseline were recruited with further analysis according to gender and study locations. We found 29 records on 14143 individuals. Total population age ranged from 18 to 92 years (males: 58.2% (8158 out of 13,999)). The AIH prevalence was found to be 14% (95% confidence interval (CI): 12-17%). Further gender stratified showed an insignificant higher AIH frequency in females versus males (17%, 95% CI: 13-22% vs. 14%, 95% CI: 11-19% P= 0.304, respectively). Despite no significant difference in AIH prevalence according to different continents, African subjects had marginally lower AIH frequency compared to Asian (7%, 95% CI: 4-13% vs. 15%, 95% CI: 12-19%, P= 0.012) and South American persons (7%, 95% CI: 4-13% vs. 54%, 95% CI: 9-93%, P= 0.038). This review suggests the occurrence of AIH is quite considerable regardless of gender and area of residence, and several periodic thyroid assessment strategies should be developed for earlier recognition and therapeutic interventions in clinical settings.

The association between Takotsubo cardiomyopathy and thyrotoxicosis: A systematic review.

PURPOSE: This study aims to review all published cases on the association between thyrotoxicosis and Takutsubo Syndrome by describing clinical characteristics, diagnostic work-up, treatment, and outcome. METHODS: We searched PubMed and Embase databases from inception to the 17th of February 2022 for case reports or series reporting the above-mentioned association. We extracted data on demographic characteristics, clinical features, diagnostic work-up, treatment, and clinical outcomes. Cases were stratified into groups based on the presumed cause of the thyrotoxicosis (iatrogenic vs non-iatrogenic and Graves' diseases vs non-Graves' disease, respectively). RESULTS: We identified 25 cases from 24 articles. The mean age was 61.7 years (+/- SD 14.5). Most patients were women (88%). Graves' disease (52%) was the leading cause of thyrotoxicosis. Previous cancer was significantly more common in patients with iatrogenic thyrotoxicosis (P = 0.03). The most common symptoms were respiratory symptoms (68%), chest pain (56%), and palpitations (40%). The most common ECG characteristics were T-wave abnormalities (48%) and ST-elevations (36%). Elevated troponin levels were found in 92% of the cases. Patients with Graves's disease and Takutsubo Syndrome had higher plasma levels of serum thyroxine (P = 0.03) and were more often treated with beta-blockers (P = 0.01) compared to patients with thyrotoxicosis of other origins. Notably, 40% of cases experienced in-hospital complications. No deaths were reported. All patients had improved cardiac function within a median follow-up of 42 days. CONCLUSION: Evidence-based on current case reports suggests an increased risk of Takutsubo Syndrome and subsequently increased risk of in-hospital complications in patients with thyrotoxicosis.

Management of thyrotoxicosis and pregnancy: Review of the current literature and an update of the care pathway.

Pregnancy can be complicated by hyperthyroidism or thyrotoxicosis. Diagnosis is founded on an increase in free thyroid hormones and low TSH. The most frequent etiologies are Graves' disease, an autoimmune disease linked to stimulatory anti-TSH receptor antibodies, and non-autoimmune gestational hyperthyroidism linked to the TSH-like activity of the chorionic growth hormone (hCG). During pregnancy, thyrotoxicosis can entail maternal, obstetrical and fetal or neonatal complications. Graves' hyperthyroidism may be responsible for fetal and neonatal hyperthyroidism due to placental transfer of stimulatory anti-TSH receptor antibodies. During pregnancy, treatment of thyrotoxicosis must restore normal thyroid function in the mother without affecting fetal thyroid function. The recent reassessment of the prevalence of teratogenic effects in children of women treated with antithyroid drugs in the first weeks of gestation should orient the care pathway before and during pregnancy for women of child-bearing age with hyperthyroidism linked to Graves' disease.

[AMIODARONE-INDUCED THYROTOXICOSIS - RISK FACTORS AND PREDICTORS OF OUTCOME: A RETROSPECTIVE STUDY].

BACKGROUND: Amiodarone induced thyrotoxicosis (AIT) occurs with considerable incidence and is associated with significant morbidity and mortality. Factors that predict poor prognosis in this disease have not yet been sufficiently investigated. OBJECTIVES: We examined the characteristics and short-term clinical outcomes of patients with AIT (up to six months from diagnosis). We evaluated the relationship between T3 and T4 levels at time of presentation and complications associated with AIT. METHODS: A retrospective epidemiological study was conducted reviewing all cases diagnosed with thyrotoxicosis and amiodarone consumption of patients treated in the Carmel Medical Center between the years 2004-2008. We examined the characteristics of patients who tend to develop AIT. In addition, we examined whether T3 and T4 levels at the time of presentation were a predictor of a poor prognosis. Three major complications associated with AIT were defined as primary outcomes within six months of diagnosis: 1. mortality; 2. development of AIT-related complications that required hospitalization; 3. the need for thyroidectomy. RESULTS: A total of 400 patients were diagnosed with thyrotoxicosis and consumed amiodarone. However, only 39 patients met the definition of AIT. The composite outcome of mortality, AIT-related complications and thyroidectomy were found in the vast majority of patients (94.8%, 37 out of 39 participants); 3 (7.6%) died and 35 (89.7%) were hospitalized with AIT-related complications and 8 (20.5%) required thyroidectomy. We found a statistically significant relationship between high T4 levels (above 64.3 mcg/dL or above 3 times the upper limit of the norm) and the composite of two main endpoints: mortality and the need for thyroidectomy in the first half year of diagnosis (P=0.009). CONCLUSIONS: AIT is associated with significant morbidity and mortality. An elevated level of free T4 reflects the severity of AIT. In patients with significantly increased T4 values, an early surgical intervention should be considered.

Thyrotoxicosis and dilated cardiomyopathy in developing countries.

BACKGROUND: Thyrotoxicosis is the state of thyroid hormone excess. But, in sub-Saharan Africa (SSA), specifically Northern Ethiopia, scientific evidence about thyrotoxicosis and its cardiac complications like dilated cardiomyopathy is limited. Therefore, this study aimed to explore the thyrotoxicosis presentation and management and identify factors associated with dilated cardiomyopathy in a tertiary hospital in Northern Ethiopia. METHODS: An institution-based cross-sectional study was conducted in Ayder Comprehensive Specialized Hospital from 2017 to 2018. Data from 200 thyrotoxicosis cases were collected using a structured questionnaire. After describing variables, logistic regression was conducted to identify independent predictors of dilated cardiomyopathy. Statistical significance was declared at p < 0.05. RESULTS: Mean age at presentation of thyrotoxicosis was 45 years and females accounted for 89 % of the cases. The most frequent etiology was multinodular toxic goiter (51.5 %). As well, the most common symptoms and signs were palpitation and goiter respectively. Thyroid storm occurred in 6 % of the cases. Out of 89 patients subjected to echocardiography, 35 (39.3 %) of them had dilated cardiomyopathy. And, the odds of dilated cardiomyopathy were higher in patients who had atrial fibrillation (AOR = 15.95, 95 % CI:5.89-38.16, p = 0.001) and tachycardia (AOR = 2.73, 95 % CI:1.04-7.15, p = 0.040). All patients took propylthiouracil and 13.0 % of them experienced its side effects. Concerning ß-blockers, propranolol was the most commonly (78.5 % of the cases) used drug followed by atenolol (15.0 %). Six patients underwent surgery. CONCLUSIONS: In developing countries like Ethiopia, patients with thyrotoxicosis have no access to methimazole which is the first-line anti-thyroid drug. Besides, they greatly suffer from dilated cardiomyopathy (due to late presentation) and side effects of propylthiouracil. Therefore, we recommend that patients should get adequate health information about thyrotoxicosis and anti-thyroid drugs including their side effects. Additionally, hospitals and other concerned bodies should also avail of TSH tests and methimazole at an affordable cost. Furthermore, community awareness about iodized salt and iodine-rich foods should be enhanced.

Outcome of Sars-COV-2-related thyrotoxicosis in survivors of Covid-19: a prospective study.

PURPOSE: To evaluate the post- coronavirus disease-19 (COVID-19) outcome of thyroid function in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related thyrotoxicosis. METHODS: This was a single-center prospective study involving 29 patients (11 females, 18 males; median age 64 years, range: 43-85) with thyrotoxicosis diagnosed after hospitalization for COVID-19 and then followed-up for a median period of 90 days (range: 30-120) after hospital discharge. At follow-up, patients were evaluated for serum thyrotropin (TSH), free-thyroxine (FT4), free-triiodiothyronine (FT3), TSH receptor antibodies (TRAb), thyroglobulin antibodies (TgAb), thyroperoxidase antibodies (TPOAb) and ultrasonographic thyroid structure. RESULTS: After recovery of COVID-19, serum TSH values significantly increased (P < 0.001) and FT4 values significantly decreased (P = 0.001), without significant change in serum FT3 (P = 0.572). At follow-up, 28 subjects (96.6%) became euthyroid whereas overt hypothyroidism developed in one case. At the ultrasound evaluation of thyroid gland, hypoecogenicity was found in 10 patients (34.5%) and in these cases serum TSH values tended to be higher than those without thyroid hypoecogenity (P = 0.066). All subjects resulted to be negative for TgAb, TPOAb and TRAb. CONCLUSION: In a short-term follow-up, thyroid function spontaneously normalized in most subjects with SARS-CoV-2-related thyrotoxicosis. However, thyroid hypoecogenicity was found in a remarkable number of them and future longer-term studies are needed to clarify whether this ultrasonographic alteration may predispose to develop late-onset thyroid dysfunction.

[Nodular toxic goiter in children: clinical features, morphological variants].

BACKGROUND: Toxic nodular goiter (TNG) is a rare disease in which the cause of hyperthyroidism is the presence of a node or nodes that autonomously secrete thyroid hormones. With children and adolescents this condition is extremely rare - in 5-7.5% of all cases of nodular goiter. Therapy of toxic nodular goiter is aimed at relieving the symptoms of hyperthyroidism taking into account the malignant potential of the nodular formation. In the available literature, there are no data on the clinical course, comparative results of cytological and histological data in patients with toxic nodular goiter, which debuted in their childhood. AIM: Analysis of the features of the clinical course, comparison of the results of cytological and histological studies of toxic nodular goiter in children and adolescents. MATERIALS AND METHODS: A retrospective, single-center study of 21 patients with single-nodular toxic goiter, hospitalized at the Endocrinology Research Centre in the period from January 2016 to December 2019. RESULTS: The mean age at the time of the survey was 13.9 years. Thirteen patients (65%) had manifest thyrotoxicosis, and seven (35%) had subclinical hyperthyroidism. More than half of children - 57.1% (n = 12) did not receive thyreostatic therapy. The cytological picture in 11 patients (61.1%) corresponded to benign changes (nodular colloid goiter or adenomatous goiter) - Bethesda II, in 4 patients - follicular tumor - Bethesda IV, in 4 children the study was not informative. 19 patients (90.5%) underwent surgical treatment (hemithyroidectomy). According to the results of histological examination, follicular adenoma was found in 44.4% of children with nodular toxic goiter with benign results of TAB (Bethesda II) and was found in 50% with revealing follicular neoplasia (Bethesda IV). CONCLUSION: For the first time in the Russian Federation was carried out a comparative analysis of the characteristics of cytological and histological studies in children with toxic nodular goiter. It is significant that only in 10.5% (n=2) cytological and morphological results were consistent. The choice of radical treatment tactics should take into account the high frequency of mismatches between histological and morphological studies.

Thyroid Immune-related Adverse Events Following Immune Checkpoint Inhibitor Treatment.

CONTEXT: Thyroid dysfunction occurs commonly following immune checkpoint inhibition. The etiology of thyroid immune-related adverse events (irAEs) remains unclear and clinical presentation can be variable. OBJECTIVE: This study sought to define thyroid irAEs following immune checkpoint inhibitor (ICI) treatment and describe their clinical and biochemical associations. METHODS: We performed a retrospective cohort study of thyroid dysfunction in patients with melanoma undergoing cytotoxic T-lymphocyte antigen-4 (CTLA-4) and/or programmed cell death protein-1 (PD-1) based ICI treatment from November 1, 2009, to December 31, 2019. Thyroid function was measured at baseline and at regular intervals following the start of ICI treatment. Clinical and biochemical features were evaluated for associations with ICI-associated thyroid irAEs. The prevalence of thyroid autoantibodies and the effect of thyroid irAEs on survival were analyzed. RESULTS: A total of 1246 patients were included with a median follow-up of 11.3 months. Five hundred and eighteen (42%) patients developed an ICI-associated thyroid irAE. Subclinical thyrotoxicosis (n = 234) was the most common thyroid irAE, followed by overt thyrotoxicosis (n = 154), subclinical hypothyroidism (n = 61), and overt hypothyroidism (n = 39). Onset of overt thyrotoxicosis occurred a median of 5 weeks (interquartile range [IQR] 2-8) after receipt of a first dose of ICI. Combination immunotherapy was strongly associated with development of overt thyrotoxicosis (odds ratio [OR] 10.8, 95% CI 4.51-25.6 vs CTLA-4 monotherapy; P < .001), as was female sex (OR 2.02, 95% CI 1.37-2.95; P < .001) and younger age (OR 0.83 per 10 years, 95% CI 0.72-0.95; P = .007). By comparison, median onset of overt hypothyroidism was 14 weeks (IQR 8-25). The frequency of overt hypothyroidism did not differ between different ICI types. The strongest associations for hypothyroidism were higher baseline thyroid-stimulating hormone (OR 2.33 per mIU/L, 95% CI 1.61-3.33; P < .001) and female sex (OR 3.31, 95% CI 1.67-6.56; P = .01). Overt thyrotoxicosis was associated with longer progression free survival (hazard ratio [HR] 0.68, 95% CI 0.49-0.94; P = .02) and overall survival (HR 0.57, 95% CI 0.39-0.84; P = .005). There was no association between hypothyroidism and cancer outcomes. CONCLUSION: Thyroid irAEs are common and there are multiple distinct phenotypes. Different thyroid irAE subtypes have unique clinical and biochemical associations, suggesting potentially distinct etiologies for thyrotoxicosis and hypothyroidism arising in this context.

Behavioral assessment of children and adolescents with Graves' disease: A prospective study.

Previous studies have identified frequent comorbid neuropsychiatric disorders and conditions in adults with thyrotoxicosis. These studies are scarce or even lacking in pediatric population. This work aimed to study the behavior of children and adolescents with Graves' disease (GD). This study included 35 children with GD (boys = 15; girls = 25; mean age: 11.45±1.50yrs) and 40 healthy children (boys = 20; girls = 20; mean age: 12.54±1.62yrs). Behavior was assessed using Child Behavior Checklist (CBCL). Children with GD were assessed during periods of thyroid hormone elevation (active disease) and normalized thyroid hormones (with anti-thyroid drugs or ATDs). Compared to healthy children, patients during periods of thyroid hormone elevation (74.29%) and normalized thyroid hormones (31.43%) had higher frequencies of behavioral abnormalities and scorings of total CBCL scale (P = 0.01; P = 0.04, respectively) and its subscales' [Anxious/Depressed (P = 0.02; P = 0.04), Withdrawn/Depressed (P = 0.03; P = 0.04) and Somatic Complaints (P = 0.03; P = 0.127) and Social (P = 0.01; P = 0.225), Thought (P = 0.01; P = 0.128) and Attention (P = 0.01; P = 0.01) problems], indicating internalizing and externalizing problems. The majority of patients had at least two different behavioral problems. Marked improvement was found during period of normalized thyroid hormones (P = 0.001). Correlation analyses showed significant associations between total CBCL scoring and age at onset (P = 0.01; P = 0.001) and lower concentrations of thyroid stimulating hormone (TSH) (P = 0.001; P = 0.04) and higher concentrations of free thyroxine (fT4) (P = 0.01; P = 0.02), triiodothyronine (fT3) (P = 0.01; P = 0.03) and thyrotropin receptor antibodies (TRAbs) (P = 0.001; P = 0.01) during periods of thyroid hormone elevation and normalized thyroid hormones, respectively. Multiple linear regression analysis showed that "at presentation" lower concentrations of TSH (P = 0.001; P = 0.03) and higher concentrations of fT4 (P = 0.001, P = 0.01), fT3 (P = 0.01; P = 0.06) and TRAbs (P = 0.001; P = 0.001) were predictors of behavioral problems during periods of active disease and normalized thyroid hormones. We conclude that GD is associated with higher frequencies and severities of anxiety, depression and inattention during periods of thyroid hormone elevation as well as normalized thyroid hormones with ATDs. Therefore, early diagnosis and optimizing management are required to improve children's social life.

A Genome-First Approach to Characterize DICER1 Pathogenic Variant Prevalence, Penetrance, and Phenotype.

Importance: Genetic disorders are historically defined through phenotype-first approaches. However, risk estimates derived from phenotype-linked ascertainment may overestimate severity and penetrance. Pathogenic variants in DICER1 are associated with increased risks of rare and common neoplasms and thyroid disease in adults and children. This study explored how effectively a genome-first approach could characterize the clinical traits associated with germline DICER1 putative loss-of-function (pLOF) variants in an unselected clinical cohort. Objective: To examine the prevalence, penetrance, and phenotypic characteristics of carriers of germline DICER1 pLOF variants via genome-first ascertainment. Design, Setting, and Participants: This cohort study classifies DICER1 variants in germline exome sequence data from 92 296 participants of the Geisinger MyCode Community Health Initiative. Data for each MyCode participant were used from the start of the Geisinger electronic health record to February 1, 2018. Main Outcomes and Measures: Prevalence of germline DICER1 variation; penetrance of malignant tumors and thyroid disease in carriers of germline DICER1 variation; structured, manual review of electronic health records; and DICER1 sequencing of available tumors from an associated cancer registry. Results: A total of 92 296 adults (mean [SD] age, 59 [18] years; 98% white; 60% female) participated in the study. Germline DICER1 pLOF variants were observed in 1 in 3700 to 1 in 4600 participants, more than double the expected prevalence. Malignant tumors (primarily thyroid carcinoma) were observed in 4 of 25 participants (16%) with DICER1 pLOF variants, which is comparable (by 50 years of age) to the frequency of neoplasms in the largest registry- and clinic-based (phenotype-first) DICER1 studies published to date. DICER1 pLOF variants were significantly associated with risks of thyroidectomy (odds ratio [OR], 6.0; 95% CI, 2.2-16.3; P = .007) and thyroid cancer (OR, 9.2; 95% CI, 2.1-34.7; P = .02) compared with controls, but there was not a significant increase in the risk of goiter (OR, 1.8; 95% CI, 0.7-4.9). A female patient in her 80s who was a carrier of a germline DICER1 hotspot variant was apparently healthy on electronic health record review. The term DICER1 did not appear in any of the medical records of the 25 participants with a pLOF DICER1 variant, even in those affected with a known DICER1-associated tumor or thyroid phenotype. Conclusions and Relevance: This cohort study was able to ascertain individuals with germline DICER1 variants based on a genome-first approach rather than through a previously established DICER1-related phenotype. Use of the genome-first approach may complement more traditional approaches to syndrome delineation and may be an efficient approach for risk estimation.

Higher baseline TSH levels predict early hypothyroidism during cancer immunotherapy.

BACKGROUND AND PURPOSE: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that enhance the immune response against cancer cells. ICIs are generally well tolerated, although endocrine immune-related adverse events (irAEs) are common. We investigated the risk factors for thyroid irAEs in patients treated with ICIs. Moreover, we evaluated the clinical outcome of subjects who became hypothyroid compared to euthyroid patients. PATIENTS AND METHODS: We retrospectively analyzed a series of 195 consecutively subjects treated with ICIs for metastatic tumors at the University of Naples "Federico II" between January 2014 and March 2020. Only subjects tested for thyroid function before and during the treatment with ICIs were included. RESULTS: In the 96 patients treated with ICIs who were included [66 males, median age: 62 years (27-87)], thyroid irAEs occurred in 36 (37.5%), 16 (16.7%) a transient thyrotoxicosis, and 20 (20.8%) an hypothyroidism (in nine subjects hypothyroidism was preceded by a transient thyrotoxicosis). Only baseline TSH levels above 1.67 mIU/L and positive anti-thyroid antibodies (Ab-T) were associated with a higher risk of hypothyroidism. Patients with hypothyroidism during ICI treatment showed an improved 2-year PFS (HR = 0.82 CI 0.47-1.43; p = 0.0132) and OS (HR = 0.38 CI 95% 0.17-0.80; p = 0.011) compared to euthyroid patients. CONCLUSIONS: Baseline TSH levels above 1.67 mIU/L and presence of Ab-T are risk factors for the development of thyroid irAEs. Patients affected by thyroid irAEs showed a longer survival than patients who remained euthyroid.

Interplay Between Thyroid Hormone Status and Pulmonary Hypertension in Graves' Disease: Relevance of the Assessment in Thyrotoxic and Euthyroid Patients.

Background: Graves' disease (GD) is the most common cause of hyperthyroidism and can cause cardiac changes, such as pulmonary hypertension. Methods: This is a prospective study in which we obtained demographic, clinical, laboratory data and characteristics of the GD, in addition to investigating cardiorespiratory function, focusing on the detection of pulmonary hypertension. Patients were separated into two groups: thyrotoxicosis and euthyroidism. Ninety patients with GD of both sexes, over 18 years of age, were included. The cardiorespiratory assessment included an echocardiographic evaluation, a questionnaire of specific symptoms, spirometry and a six-minute walk test. Results: The hyperthyroid group included 42 patients (47.73%) and the euthyroid group 46 patients (52.27%); 78 were women (86.67%). The prevalence of pulmonary hypertension between the hyperthyroidism (48.57%) and the euthyroidism (29.41%) groups was not different. Free thyroxine levels (FT4) (OR 1.266), higher left atrium volume (OR 1.113) and right ventricle diameter were associated with pulmonary hypertension. A direct correlation between FT4 with forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1), as also an inverse correlation between initial oxygen saturation (SpO2) with diagnostic time and drop SpO2 with the ratio between the diastolic velocity E of the mitral flow and the diastolic velocity of the mitral ring (E/e') were observed in the euthyroid group. An inverse correlation between FT4 levels with walked distance as % of predicted value, and a direct correlation between E/e' ratio and walked distance as % of predicted value were observed in the hyperthyroid group. Conclusion: We emphasize the importance of a cardiorespiratory reassessment in GD, even after a long-term control of the thyrotoxic state, as we demonstrate that about 30% of these patients remain with PH and are subject to specific treatment.

Bidirectional association between alopecia areata and thyroid diseases: a nationwide population-based cohort study.

Alopecia areata (AA) has long been associated with thyroid diseases; however, the temporality of their association remains unclear. This study aimed to investigate the bidirectional association between AA and thyroid diseases. In analysis 1, we included 5929 AA patients and 59,290 matched controls to assess the risk of thyroid diseases. In analysis 2, we included 35,071 patients with thyrotoxicosis, 19,227 patients with Graves' disease, 5460 patients with thyroiditis, 3352 patients with Hashimoto's thyroiditis, and their matched controls (1:10) to assess the risk of AA. Incidence of thyroid diseases and AA were the outcomes in analysis 1 and analysis 2, respectively. After adjusting the potential confounders, AA patients had an increased risk of all thyroid diseases, including toxic nodular goiter, (aHR 10.17; 95% confidence interval [CI] 5.32-19.44), nontoxic nodular goiter (aHR 5.23; 95% CI 3.76-7.28), thyrotoxicosis (aHR 7.96; 95% CI 6.01-10.54), Graves' disease (aHR 8.36; 95% CI 5.66-12.35), thyroiditis (aHR 4.04; 95% CI 2.12-7.73), and Hashimoto thyroiditis (aHR 4.35; 95% CI 1.88-10.04). On the contrary, a significantly increased risk of developing AA was observed among patients with thyrotoxicosis (aHR 9.29; 95% CI, 7.11-12.14), Graves' disease (aHR 8.66; 95% CI 6.03-12.42), and thyroiditis (aHR 6.42; 95% CI 3.15-13.11) but not in patients with Hashimoto's thyroiditis. In conclusion, our study found a bidirectional association between AA and thyroid diseases, suggesting shared biological mechanisms underlying these two diseases.

Thyroid Dysfunction in Relation to Immune Profile, Disease Status, and Outcome in 191 Patients with COVID-19.

OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related thyroiditis is increasingly recognized. The role of thyroid autoimmunity and SARS-CoV-2 viral load in SARS-CoV-2-related thyroid dysfunction is unclear. We evaluated the thyroid function of a cohort of coronavirus disease 2019 (COVID-19) patients, in relation to their clinical features, and biochemical, immunological, and inflammatory markers. METHODS: Consecutive adult patients, without known thyroid disorders, admitted to Queen Mary Hospital for COVID-19 from July 21 to August 21, 2020, were included. Serum levels of thyroid-stimulating hormone (TSH), free thyroxine, free triiodothyronine (fT3), and antithyroid antibodies were measured on admission. RESULTS: Among 191 patients with COVID-19 (mean age 53.5 ±â€…17.2 years; 51.8% male), 84.3% were mild, 12.6% were moderate, and 3.1% were severe. Abnormal thyroid function was seen in 13.1%. Ten patients had isolated low TSH, suggestive of subclinical thyrotoxicosis due to thyroiditis, although the contribution of autoimmunity was likely in 2 of them. Autoimmune thyroiditis probably also contributed to subclinical hypothyroidism in another patient. Ten patients had isolated low fT3, likely representing nonthyroidal illness syndrome. Lower SARS-Cov-2 polymerase chain reaction cycle threshold values and elevated C-reactive protein were independently associated with occurrence of low TSH (P = .030) and low fT3 (P = .007), respectively. A decreasing trend of fT3 with increasing COVID-19 severity (P = .032) was found. Patients with low fT3 had more adverse COVID-19-related outcomes. CONCLUSION: Around 15% of patients with mild to moderate COVID-19 had thyroid dysfunction. There may be a direct effect of SARS-CoV-2 on thyroid function, potentially leading to exacerbation of pre-existing autoimmune thyroid disease. Low fT3, associated with systemic inflammation, may have a prognostic significance.