Incidence of thyroid dysfunction caused by immune checkpoint inhibitors combined with chemotherapy: A systematic review and meta-analysis.

BACKGROUND: The combination of immune checkpoint inhibitors (ICIs) and chemotherapy as a first-line treatment for triple-negative breast cancer (TNBC) has been associated with many adverse reactions. Thyroid dysfunction, the most common adverse reaction of the endocrine system, has also attracted significant attention. This study aimed to analyse the effect of ICIs combined with chemotherapy on thyroid function in patients with TNBC. METHODS: As of November 4, 2023, we searched the PubMed, Web of Science, and Cochrane Library databases for clinical trials of ICIs combined with chemotherapy for the treatment of TNBC. The incidence of hypothyroidism and hyperthyroidism was calculated using a random-effects model. RESULTS: In the final analysis, 3,226 patients from 19 studies were included. The total incidence of all-grade hypothyroidism induced by the combination of ICIs and chemotherapy in treating TNBC (12% (95% confidence intervals(CI): 0.10-0.15)) was higher than that of hyperthyroidism (5% (95% CI: 0.04-0.06)). Pembrolizumab combined with chemotherapy caused the highest incidence of all grades of hypothyroidism for 13% (95% CI: 0.05-0.06). Durvalumab combined with chemotherapy caused the highest incidence of all grades of hyperthyroidism, at 7% (95% CI: 0.03-0.11). ICIs combined with chemotherapy caused a higher incidence of all grades of hypothyroidism in advanced TNBC (15% (95% CI: 0.13-0.17)) than in early stage TNBC (10% (95% CI: 0.07-0.13)). CONCLUSION: In TNBC, the incidence of hypothyroidism caused by the combination of ICIs and chemotherapy was significantly higher than that caused by hyperthyroidism. Pembrolizumab combined with chemotherapy resulted in the highest incidence of hypothyroidism. The incidence of hypothyroidism in patients with advanced TNBC was significantly higher than that in patients with early stage TNBC. In addition, ICIs combined with chemotherapy resulted in 16 out of 3,226 patients experiencing grade ≥ 3 thyroid dysfunction. Although the incidence of severe thyroid dysfunction is low, it requires attention. PROSPERO: CRD42023477933.

Thyroid dysfunction caused by exposure to environmental endocrine disruptors and the underlying mechanism: A review.

Thyroid disease has been rapidly increasing, but its causes remain unclear. At present, many studies have focused on the relationship between environmental endocrine disruptors (EEDs) and the pathogenesis of thyroid disease. Herein, we summarize such studies exploring the effects of exposure to common EEDs on thyrotoxicosis, finding that EEDs appear to contribute to the pathogenesis of thyroid-related diseases such as thyroid cancer, goiter, thyroiditis, hyperthyroidism, and hypothyroidism. To explore this causative effect in detail, we have analyzed the following three aspects of how EEDs are believed to exert their impacts on the occurrence and development of thyroid disease: (1) damage to the thyroid tissue structure, including disrupted mitochondria and the stratification of thyroid follicular epithelial cells; (2) disruption of thyroid hormone signaling, including thyroid hormone synthesis and secretion disorders, destruction of normal function of the hypothalamus-pituitary-thyroid axis, disturbed estrogen signaling in the body, alterations to the level of thyroid-stimulating hormone, inhibition of the release of thyroglobulin from thyroid cells, and reductions in the levels of sodium iodide co-transporters, thyroid peroxidase, deiodinase, and transthyretin; and (3) molecular mechanisms underlying the disruption of thyroid function, including competitive binding to T3 and T4 receptors, disturbance of the hypothalamic-pituitary-thyroid axis, activation of the ERK and Akt pathways, oxidative stress, regulation of the expression of the proto-oncogene k-Ras, tumor suppressor gene PTEN, and thyroid TSHR gene, and induction of autophagy in thyroid cells. Overall, this article reviews how EEDs can affect the occurrence and development of thyroid disease via multiple routes, thus providing new ideas to intervene for the prevention, diagnosis, treatment, and prognosis of thyroid disease.

Prevalence and Associated Factors for Thyroid Dysfunction Among Patients On Targeted Therapy for Cancers: A Single-Center Study from Thailand.

Objective: This study aimed to explore the prevalence and associated factors of thyroid dysfunction among cancer patients treated with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). Methodology: A cross-sectional study was done in patients who received TKIs at Rajavithi Hospital in 2019. For patients treated with ICI, a retrospective chart review for patients seen in 2018 to 2019 was conducted. If there were abnormal thyroid function tests (TFT), thyroid autoantibodies were tested. Results: There were 144 patients on TKIs with a mean age of 56.0 years. Thyroid dysfunction was found in 14.6% of patients and most had subclinical hypothyroidism (n = 16, 11.1%). Imatinib (n = 11, 10.8%) and sunitinib (n = 4, 100%) were the 2 most common TKIs given to patients with thyroid dysfunction. Thyroid dysfunction was associated with male sex, chronic kidney disease and hepatitis B virus infection but not with previous thyroid disease and presence of thyroid autoantibodies.There were 18 patients who received ICIs. The mean age was 63.3 years. Twelve patients (66.7%) used programmed cell death protein-1 antibody (anti-PD1), mainly nivolumab. Thyroid dysfunction was found in 50%, which occurred at a median duration of 46 days. Most patients had overt hypothyroidism and 55.6% needed levothyroxine replacement. Conclusion: Thyroid dysfunctions from TKIs were mostly asymptomatic and mild in severity. Some types of TKIs might be associated with thyroid dysfunction. On the other hand, thyroid dysfunction from ICIs usually occurs within 6 months and requires levothyroxine replacement.

Immune checkpoint inhibitor-induced hypothyroidism predicts treatment response in Japanese subjects.

Background: Immune checkpoint inhibitors (ICIs) cause a variety of immune-related adverse events (irAEs). Among them, thyroid dysfunction is most frequently observed. Patients with irAEs have higher survival rates than those without irAEs, but there is no certainty as to whether the degree of thyroid dysfunction is associated with treatment response or survival with ICIs. Method: This is a single-center, retrospective, observational study. The study included 466 patients who received ICI at Kawasaki Medical School Hospital from September 1, 2014, to May 31, 2022 and evaluated the degree of abnormal thyroid function and survival and remission rates after treatment with ICIs. Primary hypothyroidism of less than 10 µIU/mL TSH was classified as grade 1, and primary hypothyroidism requiring more than 10 µIU/mL TSH or levothyroxine as grade 2-4. Result: The mean age of the study participants was 68.2 ± 10.3 years, and the percentage of male participants was 72.6%. The frequency of ICI-induced thyroid dysfunction in the study participants was 28.2%. TSH levels were significantly higher in Grade 1 and Grades 2-4 when treated with ICI compared to NTF (p<0.0001). The survival rate at 1 year after ICI administration was significantly higher with 64.9% for grade 1 and 88.9% for grades 2-4 compared to 52.1% for NTF (p<0.0001). Cancer stage at the time of ICI administration did not differ among the groups (p=0.68). Nevertheless, the remission rate assessed by RECIST criteria was significantly higher in grades 2-4 compared to NTF (p<0.0001). Conclusion: ICI-induced thyroid dysfunction was significantly correlated with survival, mean observation time, and treatment remission rate. It is important to monitor thyroid hormone levels regularly in patients receiving ICIs.

Iodine status and its association with prevalence of thyroid diseases in adults from Jiangxi Province, China.

BACKGROUND: Iodine is an essential element for the biosynthesis of thyroid-stimulating hormone (TSH). Both excessive and deficient iodine are major risk factors for thyroid diseases, including thyroid dysfunction, thyroid nodules, and thyroid autoimmunity (TAI). This study aimed to elucidate the relationship between iodine status and the prevalence of thyroid diseases through a national cross-sectional epidemiological survey in Jiangxi province (China). METHODS: This population-based, cross-sectional study enrolled 2636 Chinese local inhabitants who aged over 18 years old from April to August in 2015. Physical examination was performed and biochemical indices, urinary iodine concentration (UIC), and TSH level were measured. The Chi-square test, nonparametric test, and 4 multivariate logistic regression models adjusted for risk factors were applied to analysis. Spearman correlation coefficients were calculated to investigate the relationship between iodine intake level and the prevalence of thyroid diseases. RESULTS: The median UIC was 176.4 µg/L, and a significant difference was found in median UIC between men (182.45 µg/L) and women (169.25 µg/L) (P = 0.03). Among these study subjects, 14.4%, 44.5%, 26.1%, and 15.0% had deficient, adequate, more than adequate, and excessive iodine concentrations, respectively. The prevalence rates of hyperthyroidism, subclinical hyperthyroidism, hypothyroidism, subclinical hypothyroidism, thyroid nodules, and TAI were 0.91%, 0.57%, 0.34% and 7.89%, 9.45%, and 12.7%, respectively. Significant differences were found in iodine status, waist circumstance, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), TSH, thyroid nodules, and TAI between men and women (P < 0.05). Compared with those with adequate UIC, subjects with excessive UIC had higher prevalence rates of thyroid dysfunction (odds ratio (OR) = 1.74, 95% confidence interval (CI): 1.40-2.54) and thyroid nodules (OR = 3.33, 95%CI 1.32-8.42). In addition, subjects with deficient and excessive UIC were at the higher risk of TAI compared with those with adequate UIC (OR = 1.68, 95%CI: 1.19-2.60; OR = 1.52, 95%CI: 1.04-2.96, respectively). UIC was positively correlated with the prevalence rates of thyroid nodules (r = -0.44, P < 0.01) and TAI (r = -0.055, P < 0.01). On the contrary, UIC was negatively correlated with the risk of thyroid dysfunction (r = -0.24, P > 0.05). CONCLUSION: Adult inhabitants from Jiangxi province in the TIDE study were in the adequate iodine status. Excessive iodine status was noted as a risk factor for thyroid dysfunction and thyroid nodules. In addition, both iodine deficiency and excessive iodine were risk factors for TAI.

Clinical Characters and Influence Factors of Immune Checkpoint Inhibitor-related Thyroid Dysfunction.

CONTEXT: Explore the clinical characteristics and influencing factors of immune thyroid dysfunction (ITD) caused by immune checkpoint inhibitors (ICIs) in the treatment of malignant tumors. METHODS: This was a retrospective study of cancer patients treated with ICIs between January 2019 and December 2021 at the Second Affiliated Hospital of Nanchang University. According to the occurrence of thyroid dysfunction, patients were divided into an ITD group and non-ITD group. We describe the clinical characteristics, autoantibody levels, and their impact on prognosis of patients with ICI-related ITD. RESULT: A total of 560 cases meeting the criteria were included, with a median follow-up time of 11.0 months. The incidence of ITD was 50.7%. Baseline TSH levels (OR, 1.935/mcIU/L; 95% CI, 1.613-2.321; P < .001) and combination targeted therapy (OR, 2.101; 95% CI, 1.433-3.079; P < .001) were most strongly associated with the occurrence of ITD. The median time to ITD in patients receiving medication with ICIs was 73 (34.5-149) days. Of the 87 patients initially diagnosed with hyperthyroid ITD, 46 (52.9%) progressed to hypothyroidism over the course of the disease. Baseline anti-thyroglobulin antibody abnormalities were strongly associated with the occurrence of ITD (OR, 67.393; 95% CI, 5.637-805.656; P = .001). Overall survival was significantly lower in patients who did not develop ITD than in those who did (hazard ratio, 0.523; 95% CI, 0.599-0.97; P < .001). CONCLUSION: The incidence of ICI-related ITD is high, and the course of the disease is rapidly changing, and thyroid function in patients treated with immunotherapy should be monitored to detect ITD and permit early intervention.

Predictors of thyroid adverse events during cancer immunotherapy: a real-life experience at a single center.

BACKGROUND: Thyroid dysfunction is among the most common immune-related adverse events (irAEs) of immune checkpoint inhibitors (ICIs) therapy. Data regarding potential predictors of the development of thyroid irAEs are still limited and sometimes conflicting. PATIENTS AND METHODS: We assessed potential risk factors and clinical outcomes associated with the onset of thyroid irAEs in a cohort of patients with different types of cancer treated with ICIs at a single center. Clinical and biochemical data, including thyroid function tests and autoantibodies at baseline and during treatment, were collected, and the onset of thyroid irAEs was recorded. Patients with thyroid dysfunction and/or under levothyroxine therapy before starting ICI were excluded. RESULTS: 110 patients (80 M, 30 F, aged 32-85 years; 56.4% non-small-cell lung cancer, 87% treated with anti-PD-1) with complete information were included in the study. Among them, 32 (29%) developed thyroid irAEs during ICIs therapy. Primary hypothyroidism was the most common irAEs, occurring in 31 patients (28.18% of the whole cohort), including 14 patients who experienced a transient thyrotoxicosis. About 60% of irAEs occurred within the first 8 weeks of therapy. At multivariate analysis, anti-thyroid autoantibodies positivity at baseline (OR 18.471, p = 0.022), a pre-existing (autoimmune and non-autoimmune) thyroid disorder (OR 16.307, p < 0.001), and a family history of thyroid diseases (OR = 9.287, p = 0.002) were independent predictors of the development of thyroid irAEs. CONCLUSION: Our data confirm the high frequency of thyroid dysfunctions (mostly hypothyroidism) during ICIs, and provide data on valuable predictors of thyroid toxicities that may help clinicians in identifying patients at risk for developing irAEs.

A Study to Assess Tyrosine Kinase Inhibitors Induced Thyroid Dysfunction in Newly Diagnosed Chronic Myeloid Leukemia Patients.

INTRODUCTION: The use of TKIs has dramatically improved the prognosis of CML. The aim of this study was to evaluate the effects of TKIs on thyroid function in a prospective manner. MATERIALS: In this prospective study, 55 newly diagnosed adult subjects with positive Philadelphia chromosome in chronic phase of CML without any other apparent underlying diseases were enrolled. Total T3, Free T4, TSH and Anti TPO antibodies were measured at starting and after 12 & 24 weeks of treatment respectively. The study also included a same number control group of sex- and age-matched healthy individuals. RESULT: Approximately 10% of the patients were having subclinical hypothyroidism while the rest were normal regarding thyroid function. There were statistically significant changes within reference ranges in serum concentration of TSH (p = 0.022 and 0.011) 12 weeks and 24 weeks after TKIs initiation, respectively. CONCLUSION: This study showed some significant changes on thyroid function tests.However, without any clinical abnormalities in the course of treatment we didn't initiate replacement. We recommend other studies with larger sample size and longer duration of follow-up. References Singha H, Chakrabarty SK, Sherpa PL, et al. Tyrosine kinase inhibitors induced thyroid dysfunction in newly diagnosed chronic myeloid leukemia patients. Singha H, et al. Thyroid dysfunction caused by tyrosine kinase inhibitors in Philadelphia chromosome-positive chronic myeloid leukemia.

Thyroid dysfunction after immune checkpoint inhibitor treatment in a single-center Chinese cohort: a retrospective study.

BACKGROUND: Thyroid dysfunction is a common adverse event after immune checkpoint inhibitor (ICI) therapy. The clinical manifestations of thyroid immune-related adverse events (irAEs) are variable and the underlying mechanisms remain unclear. PURPOSE: To identify the clinical and biochemical characteristics of Chinese patients with ICI-related thyroid dysfunction. METHODS: We retrospectively reviewed patients with carcinoma who received ICI therapy and underwent evaluation of thyroid function during hospitalization at Peking Union Medical College Hospital between January 1, 2017 and December 31, 2020. Clinical and biochemical features were analyzed in patients who developed ICI-related thyroid dysfunction. Survival analyses were performed to determine the effect of thyroid autoantibodies on thyroid abnormalities and the impact of thyroid irAEs on clinical outcomes. RESULTS: The cohort included 270 patients with a median follow-up of 17.7 months; 120 (44%) of these patients developed thyroid dysfunction on immunotherapy. The most common thyroid irAE was overt hypothyroidism (with/without transient thyrotoxicosis), which occurred in 38% of patients (n = 45), followed by subclinical thyrotoxicosis (n = 42), subclinical hypothyroidism (n = 27), and isolated overt thyrotoxicosis (n = 6). The median time to first clinical presentation was 49 days (interquartile range 23, 93) for thyrotoxicosis and 98 days (interquartile range 51, 172) for hypothyroidism. In patients treated with PD-1 inhibitors, hypothyroidism was strongly associated with younger age (odds ratio [OR] 0.44, 95% confidence interval [CI] 0.29-0.67; P < 0.001), previous thyroid disease (OR 4.30, 95% CI 1.54-11.99; P = 0.005), and a higher baseline thyroid-stimulating hormone level (OR 2.76, 95% CI 1.80-4.23; P < 0.001). Thyrotoxicosis was only associated with the baseline thyroid-stimulating hormone (TSH) level (OR 0.59, 95% CI 0.37-0.94; P = 0.025). Thyroid dysfunction after initiation of ICI therapy was associated with better progression-free survival (hazard ratio [HR] 0.61, 95% CI 0.44-0.86; P = 0.005) and overall survival (hazard ratio 0.67, 95% CI 0.45-0.99; P = 0.046). Anti-thyroglobulin antibody positivity increased the risk of thyroid irAEs. CONCLUSIONS: The occurrence of thyroid irAEs with diverse phenotypes is common. Distinct clinical and biochemical characteristics suggest heterogeneity among different subgroups of thyroid dysfunction, which requires further research to explore the under mechanism.

Immune checkpoint inhibitor-related thyroid dysfunction.

Immune checkpoint inhibitors (ICIs) are currently the key therapy for several cancers. Among immune-related adverse events, thyroid dysfunction is the most frequent. We review this thyroid dysfunction, with recent data on epidemiology, diagnostic considerations, management and risk factors.

Endocrine-related adverse conditions induced by tyrosine kinase inhibitors.

Tyrosine kinase inhibitors (TKIs) have improved outcome for many tumors. Although better tolerated than cytotoxic chemotherapy, they may cause several adverse events (AEs) and various endocrine-related toxicities have been reported under TKI treatment. The toxicity profile varies between the different TKI compounds. This review focuses on the main endocrinopathies caused by TKIs. Thyroid dysfunction and, in particular, hypothyroidism are the most frequent and best described. Several potential mechanisms have been hypothesized, including thyroid gland dysfunction, hormone metabolism impairment and hypothalamus-pituitary-thyroid axis imbalance. TKIs have been reported to influence almost all glands. In particular, they are associated with adrenal insufficiency, growth retardation due to growth hormone (GH) and/or insulin-like growth factor-1 (IGF1) deficiency, hypogonadism, and male and female fertility impairment. TKIs may affect bone metabolism, in particular decreasing osteoclastogenesis and bone turnover and, in turn, they may cause secondary hyperparathyroidism. Hypocalcemia has been reported under lenvatinib and vandetanib treatment and parathyroid hormone (PTH)-dependent and PTH-independent mechanisms have been hypothesized. Metabolic alterations during TKI treatment range from hypoglycemia with imatinib and dasatinib to hyperglycemia with nilotinib; dyslipidemia improved with imatinib and worsened with nilotinib, sunitinib, pazopanib, sorafenib, and famitinib. Endocrine-related AEs should be managed by dedicated endocrinologists. Hormone deficiencies are easily managed by replacement therapy, while endocrine hyperfunction may be improved by symptomatic treatment. Severe situations should be managed in coordination with the oncologist, trying to limit the need for TKI dose reduction or interruption.

In silico assessment of mixture toxicity mechanisms involved in the pathogenesis of thyroid diseases: The combination of toxic metal(oid)s and decabrominated diphenyl ether.

The current study aimed to assess the connection between the mixture of lead (Pb), cadmium (Cd), arsenic (As), methylmercury (MeHg) and decabrominated diphenyl ether (decaBDE) and thyroid function, by using in silico toxicogenomic data-mining approach. To obtain the linkage between investigated toxic mixture and thyroid diseases (TDs), the Comparative Toxicogenomics Database (CTD) was used, while gene ontology (GO) enrichment analysis was performed by ToppGeneSuite portal. The analysis has shown 10 genes connected to all chemicals present in the mixture and TDs (CAT, GSR, IFNG, IL1B, IL4, IL6, MAPK1, SOD2, TGFB1, TNF), most of which were in co-expression (45.68%), or belonged to the same pathway (30.47%). Top 5 biological processes and molecular functions affected by the investigated mixture emphasized the role of two common mechanisms - oxidative stress and inflammation. Cytokines and inflammatory response was listed as the main molecular pathway that may be triggered by simultaneous exposure to toxic metal(oid)s and decaBDE and connected to TDs. The direct relations between Pb/decaBDE and redox status impairment in thyroid tissue was confirmed by our chemical-phenotype interaction analysis, while the strongest linkage between Pb, As and decaBDE and thyroid disorders was found. The obtained results provide better understanding of molecular mechanisms involved in the thyrotoxicity of the investigated mixture, and can be used to direct further research.

Thyroid dysfunction during treatment with systemic antineoplastic therapy for childhood cancer: A systematic review.

Thyroid dysfunction is known to occur following radiotherapy or chemotherapy for childhood cancer. Thyroid dysfunction during treatment for childhood cancer has, however, not been studied extensively, although thyroid hormones are of utmost importance during childhood. This information is needed to develop adequate screening protocols and may be of special importance with upcoming drugs, such as checkpoint inhibitors, which are highly associated with thyroid dysfunction in adults. In this systematic review we have evaluated the occurrence and risk factors for thyroid dysfunction in children during treatment with systemic antineoplastic drugs, up to three months after the end of therapy. Two review authors independently performed the study selection, data extraction and risk of bias assessment of included studies. After an extensive search (January 2021), in total six heterogeneous articles were included, reporting on 91 childhood cancer patients with a thyroid function test during treatment with systemic antineoplastic therapy for childhood cancer. All studies had risk of bias issues. Primary hypothyroidism was found in 18% of children treated with high dose interferon-α (HDI-α) and in 0-10% after tyrosine kinase inhibitors (TKIs). Transient euthyroid sick syndrome (ESS) was common (in 42-100%) during treatment with systematic multi-agent chemotherapy. Only one study addressed possible risk factors, showing different types of treatment to increase the risk. However, the exact prevalence, risk factors and clinical consequences of thyroid dysfunction remain unclear. Prospective high-quality studies including large study samples are needed to longitudinally assess the prevalence, risk factors and possible consequences of thyroid dysfunction during childhood cancer treatment.

Thyroid autoimmunity following alemtuzumab treatment in multiple sclerosis patients: a prospective study.

Autoimmune thyroid disease (AITD) is the most common adverse effect in alemtuzumab (ALZ) treated relapsing-remitting (RR) multiple sclerosis (MS) patients. The objective of this prospective study was to analyze the occurrence, timing of onset, clinical course, and laboratory characteristics of AITD post-ALZ. We evaluated 35 RRMS patients treated with ALZ at a single academic MS center; clinical and laboratory data were collected before ALZ initiation and thereafter quarterly on follow-up with a median of 43.5 months. Seventeen out of 31 patients (54.8%) with no prior history of thyroid dysfunction developed AITD with a mean onset of 19.4 months ± 10.2 (SD) after the first ALZ cycle; Graves' disease (GD) (n = 9); hypothyroidism with positive stimulating thyrotropin receptor antibodies (TRAb) (n = 1); Hashimoto thyroiditis (HT) (n = 6); HT with hypothyroidism (n = 1). Interestingly, seven of nine (77.7%) GD patients showed a fluctuating course. Three out of four patients with preexisting thyroid disease remained stable, whereas one with prior HT and hypothyroidism developed fluctuating GD. All patients with GD commenced antithyroid drugs (ATDs); five continued on "block and replace" treatment; one required radioactive iodine, and one total thyroidectomy. Our analysis showed earlier onset of ALZ-induced AITD in comparison to most other ALZ cohorts; overall, these patients required complex therapeutic approaches of the AITD. We observed a higher rate of fluctuating GD, with earlier onset and lower remission rate than previously reported, which in the majority of patients required prolonged "block and replace" therapy in the minimum dose of each therapeutic agent or more definitive interventions.

Thyroid Function: A Target for Endocrine Disruptors, Air Pollution and Radiofrequencies.

Thyroid diseases, including congenital hypothyroidism, thyroiditis, and childhood thyrotoxicosis, are progressively increasing. The incidence of thyroid cancer in children and adolescents has also increased in recent decades, mirroring the trends observed in adults. These epidemiologic trends develop in parallel with the rising costs associated with diagnosis and treatment of thyroid diseases. Both genetic and environmental factors are involved in these diseases, and a number of widely diffused toxic chemicals of anthropogenic origin can impair thyroid function and make thyroid cancer worse. Synthetic substances persistently contaminate environmental matrices (i.e., air, soil, water) and the food chain and bio-accumulate in humans, starting from in utero life. Environmental toxins such as air pollutants, endocrine disruptors, and high-frequency electromagnetic fields can act on common targets through common pathways, combined mechanisms, and with trans-generational effects, all of which contribute to thyroid damage. Both experimental and epidemiologic observations show that mechanisms of damage include: modulation of synthesis; transportation and metabolism of thyroid hormones; direct interference with hormone receptors: modulation of gene expression; and autoimmunity. We should not underestimate the available evidence linking environmental pollutants with thyroid disease, cancer included, since toxic substances increasingly diffuse and thyroid hormones play a key role in maintaining systemic metabolic homeostasis during body development. Thus, primary prevention measures are urgently needed in particular to protect children, the most exposed and vulnerable subjects.

Thyroid Dysfunction in Non-Small Cell Lung Cancer With Immune Checkpoint Inhibitors: A Meta-Analysis.

Immune checkpoint inhibitors (ICIs) have been established as the cornerstone for advanced non-small cell lung cancer, while thyroid adverse events (AEs) associated with ICIs have not been systematically documented. Therefore, we performed a meta-analysis to evaluate the effect of ICI applications on the thyroid of patients with non-small cell lung cancer. We performed a systematic search of PubMed, the Cochrane Library, Web of Science, and Embase for eligible randomized controlled trials up to December 2021. Clinical trials reporting thyroid AEs including hypothyroidism, hyperthyroidism, and thyroiditis were enrolled. The I2  statistic was also calculated to quantify the heterogeneity. Data were evaluated as risk ratio (RR) and corresponding 95%CIs. A total of 10 randomized clinical trials involving 6154 patients were included in this meta-analysis. ICI application was found to have a statistically significant higher risk of all grade hypothyroidism (RR, 7.03; P < 0.0001), hyperthyroidism (RR, 4.88; P < 0.0001), and thyroiditis (RR, 6.58; P = 0.0014) compared with the chemotherapy group. Moreover, we demonstrated that second-line therapy significantly increased the risk of all-grade hypothyroidism (RR, 7.03 [95%CI, 4.69-10.55]) and hyperthyroidism (RR, 4.88 [95%CI, 3.11-7.65]). Our meta-analysis manifested that regimens with ICIs may significantly increase all grades of hypothyroidism, hyperthyroidism, and thyroiditis. ICIs may induce the occurrence and exacerbation of endocrine AEs compared with chemotherapy.

Thyroid Inconveniences With Vaccination Against SARS-CoV-2: The Size of the Matter. A Systematic Review.

After the beginning of COVID-19 vaccination campaigns, several reports of thyroid disease possibly related to the COVID-19 vaccination progressively appeared in the literature, raising the question of whether the thyroid disorder might be a SARS-CoV-2 vaccine complication. The aim of this study was to analyze the data about COVID-19 vaccination and thyroid disease, evaluate the size and quality of related literature, assess the type of these events, and investigate their timing of onset with respect the vaccination. Pubmed/MEDLINE and Cochrane were systematically reviewed until February 2022 to retrieve the largest number of original papers, case reports, and case series articles reporting thyroid disease after SARS-CoV-2 vaccination. Forty-six articles were included with a total of 99 patients aged from 26 to 73 years were described, of whom 74.75% female. Regarding the vaccination received, 49.49% of patients received Comirnaty (Pfizer/BioNTech), 14.14% CoronaVac (Sinovac), 12.12% Vaxzevria (Oxford/Astrazeneca), 11.11% Spikevax (Moderna), 3.03% Ad26.COV2.S (Janssen, Johnson & Johnson), one patient Covaxin (Bharat Biotech) and one patient Convidecia (Cansino). In 7 cases the thyroid disorder developed after the third dose with a combination of different vaccines. Regarding the type of thyroid disorder, 59 were subacute thyroiditis (SAT), 29 Graves' disease (GD), 2 co-occurrence of SAT and GD, 6 painless thyroiditis (PT), and single cases of thyroid eye disease and hypothyroidism associated with mixedema. The timeline between vaccination and thyroid disorder ranged between 0.5 to 60 days, with an average of 10.96 days. Considering the limited follow-up time, a complete remission was reported in most of SAT and PT cases while a persistence was observed in GD. In conclusion, both size and quality of published data about thyroid inconveniences after COVID-19 vaccination are limited; thyroid disorders may occur within 2 months after COVID-19 vaccination; among all thyroid diseases after COVID-19 vaccination, GD and SAT seem to be more frequent.

Immune Checkpoint Inhibitor-related New-onset Thyroid Dysfunction: A Retrospective Analysis Using the US FDA Adverse Event Reporting System.

OBJECTIVES: The study aimed to investigate the prevalence and demographic characteristics of an immune checkpoint inhibitor (ICI)-related thyroid dysfunction (ICI-TD), and to explore risk factors of poor clinical outcome using data from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). METHODS: This is a retrospective study. All cases, aged over 18-year olds, of new-onset or new-diagnosed thyroid dysfunction related to FDA-approved ICIs from January 1, 2011 to December 31, 2020 were identified using FAERS. Data of age, gender, other combined endocrinopathies related to ICIs besides ICI-TDs, and the prognosis was analyzed. RESULTS: In total, 2.60% (2971/114 121) cases of ICI-TDs were identified. Among them, 1842 (62.0%) developed hypothyroidism, 675 (22.7%) were hyperthyroidism, and 454 (15.3%) presented in thyroiditis without the mention of thyroid function. Patients on anti- programmed cell death protein-1 (PD-1) therapy displayed higher risk of hypothyroidism compared with other 3 regimens, respectively (P < .01 for all). The likelihood of other immune-related endocrinopathies in patients on the combination therapy of anti-cytotoxic T-cell-associated protein-4 (CTLA-4) and anti-PD-1 was significantly elevated than anti-PD-1 (odds ratio [OR] 2.362, 95% confidence interval [CI] [1.925-2.898], P < .001) and anti-programmed death-ligand 1 (PD-L1) regimens (OR 4.857, 95%CI [3.228-7.308], P < .001). The risk of severe cases was positively related to hypothyroidism in individuals on anti-PD-1 therapy (OR 1.587, 95%CI [1.146-2.197], P = .005) and those on anti-CTLA-4 therapy (OR 3.616, 95%CI [1.285-10.171], P = .015). The risk of severe cases was positively associated with the comorbidity with other endocrinopathies (anti-PD-1 group, OR 0.285, 95%CI [0.200-0.467], P < .001; anti-PD-1+anti-CTLA-4 group, OR 0.574, 95%CI [0.371-0.890], P = .013). CONCLUSIONS: Regular monitor of thyroid function is indispensable, since ICI-TDs manifested as hypothyroidism or hyperthyroidism, especially those on the combination therapy. Awareness among health care professionals is critical when hypothyroidism occurs, which might indicate poor clinical outcomes.

Androgen deprivation therapy for prostate cancer and the risk of thyroid diseases.

BACKGROUND: Androgen deprivation therapy (ADT) is the major treatment for metastatic prostate cancer (PCa), but few studies have investigated the effects of ADT on thyroid diseases. METHODS: This population-based, nationwide cohort study utilized the Taiwan National Health Insurance Research Database (NHIRD) with 17,192 PCa patients between 1997 and 2013. We used the Cox proportional hazards models and propensity score-matched analysis to analyze the association between ADT and the development of thyroid diseases. RESULTS: A total of 17,192 newly diagnosed men with PCa were selected from the NHIRD. There were 6200 ADT users and 6200 non-ADT users after 1:1 propensity score matching. There was a significantly decreased risk of thyroid diseases among ADT users compared with non-ADT users (adjusted hazard ratio (aHR): 0.79, 95% confidence interval (CI): 0.65-0.95, p < 0.001). Further analysis showed a significantly decreased risk of thyroid diseases with increasing ADT duration (p < 0.001). CONCLUSIONS: The result showed that ADT use in men with PCa was associated with a decreased risk of thyroid disease development.

Divergent prognostic effects of pre-existing and treatment-emergent thyroid dysfunction in patients treated with immune checkpoint inhibitors.

BACKGROUND: Thyroid dysfunction is among the most common autoimmune diseases and immune checkpoint inhibitor (ICI)-induced immune-related adverse events (irAE). We determined the association between longitudinal thyroid function and clinical outcomes in patients treated with ICI. METHODS: We identified all patients treated with ICI at UT Southwestern Medical Center from January 1, 2011, through December 31, 2020. We defined normal thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels according to institutional reference range. We defined clinical thyroid dysfunction using established criteria incorporating labs and treatment. We determined the association between thyroid function and overall survival (OS) using Kaplan-Meier curves, log-rank tests, and multivariate Cox proportional hazards model. RESULTS: A total of 1781 patients were included in analyses, of whom 381 (21%) had abnormal baseline TSH. Patients with abnormal baseline TSH were more likely to be female, have kidney cancer, and initiate levothyroxine after ICI initiation (all P < 0.001). Patients with abnormal baseline TSH had inferior OS (median 16 vs 27 months; P < 0.001). Among patients with normal baseline TSH, those who had abnormal TSH after ICI initiation had improved OS (median 41 vs 22 months; P < 0.001). In a multivariate Cox model, abnormal baseline TSH was associated with worse OS (HR 1.62; 95% CI, 1.30-2.02; P < 0.001), while initiation of levothyroxine after ICI initiation was associated with improved OS (HR 0.62; 95% CI, 0.44-0.88; P = 0.008). CONCLUSIONS: ICI-induced thyroid dysfunction is associated with improved survival, although abnormal TSH prior to ICI initiation is associated with inferior survival. PRECIS: Thyroid abnormalities occur commonly in the general population and as immunotherapy toxicities. We found that immunotherapy-induced thyroid dysfunction is associated with better survival, but pre-existing thyroid abnormalities convey worse outcomes.