Induced Thyroid Dysfunction Research Articles

Immune checkpoint inhibitor induced thyroid dysfunction is a frequent event post-treatment in NSCLC

IntroductionThyroid dysfunction is the most frequent endocrine immune related adverse event (irAE) in non-small cell lung cancer (NSCLC), typically arising 3–6 months into immune checkpoint inhibitor (ICI) therapy, but arising after ICI cessation, in some cases. Due to limited post-treatment adverse event reporting requirements on ICI trials, the incidence of ICI-induced thyroid dysfunction arising after therapy is unclear. We investigated ICI-induced thyroid dysfunction in a cohort of 294 NSCLC patients, with a specific focus on the post-treatment setting. MethodsRetrospective analysis of ICI-induced thyroid dysfunction (clinically acted upon or laboratory only) was performed in 294 UCLA NSCLC patients treated 2012–2018. Clinically acted upon thyroid dysfunction was defined as thyroid diagnosis documentation and/or thyroid medication administration. Laboratory only dysfunction was defined as abnormal thyroid labs in the absence of clinical action. Timing of thyroid dysfunction relative to ICI treatment and thyroid monitoring patterns were also assessed. Results82% (241/294) of ICI treated NSCLC patients had thyroid labs during treatment. Of these 241 patients, 13% (31/241) had clinically acted upon thyroid dysfunction prior to, 8% (18/241) during, and 4% (9/241) after ICI. Most patients, 66% (159/241), did not have thyroid labs after ICI, but in the 53 patients with labs and no prior clinical dysfunction, 17% (9/53) developed clinical dysfunction after ICI. In these 9 patients, median time from ICI initiation to dysfunction was 253 days. Two patients with post-treatment laboratory only dysfunction were observed. ConclusionsICI-induced thyroid dysfunction arising post-treatment appears more common than previously appreciated, warranting additional evaluation.

Perchlorate and Nitrate Treatments Disrupt the Endoderm and Thyroid Development Through Epigenetic Mechanisms

Nitrate and perchlorate competitively inhibit iodide uptake in thyrocytes and disrupt thyroid function in rodents and humans. Our previous data indicated that the intrauterine exposure to perchlorate or nitrate induced thyroid dysfunction in the offspring rats during adult life. Therefore, this study aimed to investigate the effects of these endocrine disruptors during the embryonic period on the endoderm and thyroid development. Additionally, it was also investigated the role of epigenetic modifications in the programming of gene expression of the evaluated tissues. For this purpose, CD1 pregnant female mice received filtered water (control) or filtered water supplemented with sodium perchlorate (0.3 or 1 ppm) or sodium nitrate (20 or 50 ppm). At gestational day 16.5 (GD16.5), the embryonic thyroid lobes were collected and processed for molecular analysis. Besides the in vivo model, the effect of these thyroid disruptors was also evaluated during the differentiation of mouse embryonic stem cells (mESc) into endoderm and thyroid cells. Endoderm cells differentiation was achieved through the treatment of mESc with several growth factors. During the entire protocol the cells were exposed or not to sodium perchlorate or sodium nitrate (10-5 or 10-7 M). The effects of perchlorate and nitrate were also evaluated during the differentiation of mESC into thyroid cells. For this purpose, mESC-derived endoderm cells were transiently transfected with Pax8/Nkx2.1 expressing vectors. During the endoderm-to-thyrocytes differentiation protocol, the cells were also exposed or not to perchlorate or nitrate (10-5 or 10-7 M). The results demonstrated that both thyroid disruptors reduced the mRNA and protein expression of several endoderm markers (Foxa1, Gata4, Sox17) in the mESc-derived endoderm cells. Moreover, perchlorate or nitrate treatment also reduced the expression of thyroid transcription factors (Pax8, Nkx2.1, Foxe1) and thyroid differentiation markers (Slc5a5, Tpo, Tshr, Tg) both in the embryonic thyroid lobes and in the mESc-derived thyrocytes. Epigenetic mechanisms related to transcription repression seem to be involved in the gene expression downregulation both in vivo and in vitro, since perchlorate and nitrate increased the mRNA expression of Dnmt1, Dnmt3, Hdac and reduced the expression of Hat. Additionally, the methylation of histone H3 was increased, and the acetylation status of this histone was decreased in perchlorate- or nitrate-exposed thyroid lobes and mESc-derived endoderm/thyroid cells. In conclusion, our data strongly suggest that the programming of thyroid dysfunction induced by intrauterine exposure to perchlorate or nitrate involve the disruption of the endoderm and thyroid development during embryonic life through epigenetic mechanisms.

Visceral and subcutaneous adipose tissue, which one induced thyroid dysfunction in patients with morbid obesity.

Thyroid dysfunction in patients with morbid obesity usually resolves after bariatric surgery. However, the role of diverse types of adipose tissue in the process remains unknown. We aim to investigate the effects of visceral and subcutaneous fat on thyroid function in a Chinese population with morbid obesity who underwent sleeve gastrectomy (SG). University hospital, Shanghai, China METHODS: Repeated measurement data of thyroid hormone and body fat were collected at 0, 3, 6, 12, 24, and 36 months after sleeve gastrectomy. Dual-energy X-ray absorptiometer and quantitative computerized tomography (CT) were used to compute visceral fat and subcutaneous fat. Repeated measures correlation (rmmcorr) package was employed for correlation analysis with generalized additive mixed model (GAMM) determining the independent factors. Thyroid stimulating-hormone (TSH) showed notable decrease at 36 months after surgery, coupled with reduction of BMI (38.08 kg/cm2 versus 24.28 kg/cm2), C-reactive protein (CRP), visceral adipose tissue (786.74 cm2 versus 367.44 cm2), body fat rate, and waistline (118.13 cm versus 100.87 cm). Only visceral fat, diabetes, and CRP proved to be independent variables for TSH decline, without correlation with subcutaneous fat. The present study is first to report the effects of different types of body fat on thyroidfunction in a Chinese population with morbid obesity, revealing that loss of visceral fat is the key to improving endocrine and metabolic activity after bariatric surgery.

Thyroid dysfunction in non-small cell lung cancer patients treated with epidermal growth factor receptor and anaplastic lymphoma kinase inhibitors: Results of a prospective cohort

ObjectivesEpidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK) Tyrosine Kinase Inhibitors (TKIs) are the preferred treatment option for patients with advanced/metastatic non-small cell lung cancer (NSCLC) harboring EGFR mutations and ALK rearrangements respectively. TKIs can theoretically induce thyroid dysfunction via actions on many levels of the hypothalamic-pituitary-thyroid axis. However, there are no published studies on occurrence of thyroid dysfunction related to use of EGFR/ALK TKIs in lung cancer. The current study aimed to prospectively and comprehensively evaluate incidence of thyroid dysfunction in NSCLC patients treated with EGFR and ALK inhibitors. MethodsThis prospective observational study at a tertiary care referral hospital included histologically/cytologically proven advanced/metastatic NSCLC patients treated with EGFR and ALK inhibitors over a period of 15 months. Thyroid function tests (including anti-TPO antibody) were done at baseline and repeated every month for first three months and then every three monthly for 12 months. ResultsSix different drugs (EGFR and ALK inhibitors) were used for treatment of 50 NSCLC patients enrolled. Of these, four drugs caused thyroid dysfunction (EGFR inhibitors erlotinib, gefitinib and ALK inhibitors ceritinib, crizotinib). Thyroid dysfunction typically occurred at 1 month following start of TKI treatment. Prevalence of thyroid dysfunction was 8%. Distribution of subclinical (not requiring treatment) and overt thyroid dysfunction (requiring specific treatment) was 4% each. All patients were asymptomatic. Both patients with overt thyroid dysfunction had hypothyroidism while subclinical dysfunction was equally distributed between hypo- and hyper- thyroidism. All patients who developed thyroid dysfunction derived expected clinical benefit and none required TKI dose interruption or stoppage. ConclusionsNSCLC patients may need to be monitored for occurrence of thyroid dysfunction during treatment with EGFR and ALK TKIs.

SUN-414 Tyrosine Kinase Inhibitors Induced Thyroid Dysfunction: An Experience from a Tertiary Care Hospital

Tyrosine kinase inhibitors (TKI) belong to a new class of molecular multi-targeted anticancer therapy which targets different growth factor receptors and hence attenuates cancer cell survival and growth. TKI-induced thyroid dysfunction is recognized as a common adverse effect of treatment., but the onset of thyroid dysfunction is variable. This study analysed correlation between initiation of TKIs and the onset of thyroid dysfunction in non-thyroid cancers patients without any background thyroid dysfunction.METHODS:This was a retrospective cohort study to evaluate thyroid dysfunction in adult patients (n=227, M:F=153:74) with non-thyroidal cancers treated with TKIs. Patients having pre-existing thyroid disease including euthyroid goitres were excluded. Demographic, clinical, and cancer treatment data were collected. Thyroid function tests (TFTs) were done prior to initiation, at 2 months, 6 months and at 1 year. TFTs were classified as euthyroid (thyrotropin [TSH] normal), subclinical (SCH; TSH 5-10 mIU/L, or higher TSH if free thyroxine normal), or overt hypothyroidism (OH; TSH >10 mIU/L, low free thyroxine, or requiring replacement).RESULTS:Of the 227 patients in the study, OH occurred in 57 patients (25.1%)(M:F = 19:38) and SCH occurred in 89 patients (39.2%) (M:F=39:50) with TKI therapy at the end of 12 months. 37 patients (M:F=13:24) developed OH in first 6 months after initiation of TKIs. Female patients were more likely to have OH in the first 6-month period following TKIs irrespective of type of TKI or the cancers. SCH was also more common after 2 months in female patients (n=23) (M:F=6:17) but the conversion of SCH to OH was more common in male patients at the end of 12 months. The symptoms were variable and most the patients did have any thyroid specific symptoms. After adjustment for age, sex, cancer type, cancer stage, performance status, and type of TKI, OH remained significantly associated with survival at 1-year (hazard ratio=0.461; p<0.0001), whereas SCH did not (hazard ratio=0.591; p=0.165). Analysis of hypothyroid patients (SCH and OH) with TSH >5 and <10 mIU/L stratified by hormone replacement status showed improved survival associated with hormone replacement, although 1 year follow-up is too short to comment on overall survival rates.CONCLUSIONS:New onset hypothyroidism, both OH and SCH is common in non-thyroidal cancer patients treated with TKI. SCH is more common after 2 months and OH after 6 months following TKI initiation. Female sex is more predisposed to develop thyroid dysfunction irrespective of underlying cancer or type of TKI used but male patients progressed to OH at the end of 12 months.

Chemically or surgically induced thyroid dysfunction altered gut microbiota in rat models.

Thyroid hormones are essential for the regulation of energy homeostasis and metabolic processes. However, the relationship between thyroid function and host gut microbial communities is not properly understood. To determine whether and how gut microbiota is associated with thyroid function, metagenomics analysis of the bacterial population in fecal samples of rat models of hyperthyroidism (induced by levothyroxine) and hypothyroidism (induced by propylthiouracil or thyroidectomy) was conducted through 16S rRNA gene sequencing. Our results revealed that all thyroid dysfunction models were definitely established and gut microbial composition varied according to different thyroid functional status. The relative abundance of Ruminococcus was significantly higher in the hyperthyroidism group (HE) vs both the normal and hypothyroidism groups (HO) while S24-7 was significantly higher in the HO group. The population of Prevotellaceae and Prevotella were significantly lower in the HO group vs the normal. Firmicutes and Oscillospira were significantly higher in the SHO (surgery-induced hypothyroidism) group, while Prevotellaceae and Prevotella showed lower abundance in the SHO group than the SHAM group. Present results suggest that thyroid functions may have the potential to influence the profile of gut microbiota and could be used as foundation to investigate interaction mechanism between thyroid and gut microbiome.

Thyroid Peroxidase Antibody (TPO) as a Predictor of Radiation Induced Thyroid Dysfunction Among Nurses and Technicians Working in Mansoura Specialized Medical Hospital: Cross Sectional Study

Thyroid gland is a probable goal tissue for radiation-related injury. Occupational exposure to ionizing radiation leads to thyroid dysfunction and exposure to high dose may lead to thyroid carcinoma. Evaluation of the role of Thyroid peroxidase antibody as a predictor for thyroid dysfunction among nurses and technicians in the radiology department in Mansoura Specialized Medical hospital (MSMH). Subjects were Nurses and technicians who are working in (MSMH) with persistent daily duty in the last 3 years and fulfilling the inclusion and exclusion criteria. All subjects included in the study were recruited in one month and divided into two groups; Group 1: 50 subjects who were working in radiology, coronary angiography and ERCP unit, Radiation -exposed group. Group 2: 33 subjects who were working in In-patient departments and in out- patient clinics and not exposed to any type of radiation. Non fasting blood sample was taken from all enrolled subjects for measurement of TSH and Anti-TPO. TPO was positively and significantly correlated to age, TSH, duration of radiology/ y (r=0.388, 0.364, 0.342respectively) p value <0.05. Roc curve was done to detect the sensitivity and specificity of TSH in relation to TPO that revealed the cutoff value of TSH > 1.69 with Sensitivity and Specificity. PPV, NPV and accuracy at cutoff >1.69 were 70.6%, 51.5%, 42.8%, 77.3% and 58%. Working personnel with positive anti TPO and their TSH levels are more than 1.69 associated with symptoms of hypothyroidism, a trial of treatment is mandatory to relieve symptoms.

Rosmarinic acid alleviates di-2-ethylhexyl phthalate (DEHP) -induced thyroid dysfunction via multiple inflammasomes activation.

DEHP (di-2-ethylhexyl phthalate), an environmental endocrine disruptor, is widely used in industrial products, particularly as plasticizers and softeners which could disrupt the function of the hypothalamic-pituitary-thyroid (HPT) axis. Rosmarinic acid (RA) possesses potential antioxidant and anti-inflammatory capacities in disease models. Nevertheless, evidence on the association between DEHP-induced thyroid dysfunction and inflammation, as well as the molecular mechanism underlying the protective effects of RA-mitigated DEHP-induced thyroid injury remains inconclusive. Male Sprague Dawley (SD) rats were intragastrically administered DEHP (150 mg/kg, 300 mg/kg, 600 mg/kg) once a day for 90 consecutive days. Also, FRTL-5 cells were treated with a wide range of DEHP concentrations (10-8, 10-7, 10-6, 10-5, 10-4, 10-3, 10-2 M) for 24 hr. Subsequently, RA (50 μM) was administered for 24 hr before 10-4 M DEHP challenge. We found that DEHP induced thyroid damage and inflammatory infiltration in vivo. In addition, we showed that DEHP triggered inflammatory cell death, which is mediated by multiple inflammasomes. Moreover, RA, pyroptosis inhibitor (Ac-YVAD-cmk) and antioxidant inhibitor (NAC) treatment significantly alleviated DEHP-induced thyrocyte death, suppressing pro-inflammatory cytokine production, inhibiting multiple inflammasomes activation and attenuating thyrocyte death, respectively. Collectively, our results reveal that a critical role of inflammasomes activation in DEHP-induced thyroid injury, and suggest that RA confers protection against DEHP-induced thyroid inflammation, and facilitating control of the effects of DEHP after given pyroptosis inhibitor or antioxidant inhibitor. These results indicate that it should be possible to provide novel insights into toxicologically and pharmacologically targeting this molecule to DEHP-induced inflammation.

Factors predicting endocrine late effects in childhood cancer survivors from a Japanese hospital.

We retrospectively analyzed endocrine late effects in 81 childhood cancer survivor (CCS) patients who had been referred to our endocrinology department in Chiba Children's Hospital between January 1, 2008 and December 31, 2016. Among 69 eligible patients (33 male, 36 female), endocrine late effects were identified in 56 patients (81.1%). The median age at the last visit to our endocrinology department was 17.4 years (range: 7.1-35.3 years). The most common primary cancer was acute lymphoblastic leukemia (22 patients, 31.8%). Forty-four patients (64%) were treated using radiation therapy. A primary brain tumor and high doses (≥6 g/m2) of cyclophosphamide were significantly associated with growth hormone deficiency (GHD). Our present study suggests that high doses of cyclophosphamide is a risk factor for GHD. Adult heights and pubertal growth spurts of patients treated with radiation therapy were significantly lower than patients not treated with radiation therapy. Our retrospective study reconfirmed that hematopoietic stem cell transplantation and chronic graft versus host disease (GVHD) were associated with elevated risks of primary hypothyroidism. However, it is unclear whether GVHD induces thyroid dysfunction. Gonadal radiation and busulfan were associated with primary hypogonadism as reported in previous studies. We found high doses of cyclophosphamide to be involved in pituitary disorders. We suggest that pediatric endocrinologists should discuss the potential effects of radiation therapy on adult height and pubertal growth spurt in CCS patients. Moreover, patients who have been treated with high doses of cyclophosphamide or have chronic GVHD require long-term follow-up for endocrine late effects.

Hepatitis C Virus Infection of Human Thyrocytes: Metabolic, Hormonal, and Immunological Implications.

Hepatitis C virus (HCV) infection is a prevalent disease worldwide. Thyroid dysfunction is one of the most common extrahepatic manifestations of HCV infection. We hypothesized that HCV can directly infect human thyrocytes thereby causing thyroid dysfunction. Human thyrocytes in primary cell culture, ML-1 human thyroid cell line, and Huh7.5 human hepatocyte cell line were infected with HCV using the Huh7.5JFH1 cell line that releases infectious HCV virions. After infection, the release of new virions, production of proinflammatory cytokines, and expression of miR-122 were evaluated. Ribonucleic acid (RNA) extracted from HCV-infected cells and mock-infected cells was subjected to RNA sequencing and transcriptomic analysis. Ingenuity pathway analysis was used to detect up- and down-regulated pathways. Human thyrocytes express major HCV entry factors including CD81, occludin, claudin-1, and scavenger receptor class B1. Viral infection of thyroid cells was confirmed by detection of HCV core protein in supernatants and negative-sense HCV RNA in cell lysates. HCV infection of thyrocytes induced the production of the chemokine CXCL-8 and the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and significantly increased the expression of miR-122. Moreover, HCV infection of thyrocytes decreased expression of the thyroid peroxidase and thyroglobulin genes and increased expression of the deiodinase 2 gene. The top upregulated pathways in HCV-infected thyrocytes were immune pathways and metabolic pathways, while infected hepatocytes upregulated lipid and glucose metabolism pathways as previously reported. HCV infection may induce thyroid dysfunction by different mechanisms including direct infection of thyrocytes leading to activation of inflammatory pathways and upregulation of miR-122. These findings support a general mechanism for viral induction of autoimmunity through direct infection of target tissues.

Exposure to deltamethrin in adolescent mice induced thyroid dysfunction and behavioral disorders.

Deltamethrin (DM) has become one of the most widely used insecticides in the world due to its low toxicity, high efficiency and low persistence in soil. However, it is still unknown whether DM exposure has any effects on the Hypothalamic-Pituitary-Thyroid (HPT) axis in adolescent mice. In this study, the open field test and circadian activity test showed that DM exposure increased activity. There was no significant difference between the groups in the light/dark box test and nest building test. Forced swimming test showed that after 6 and 12 mg kg-1 DM exposure 28 days, the immobility time was increased and the swimming time was reduced. After 6 mg kg-1 DM treatment, the thyroid stimulating hormone (TSH) content increased, and thyrotropin releasing hormone (TRH), triiodothyronine (T3) and thyroxine (T4) decreased. After exposure to 6 and 12 mg kg-1 DM, mRNA levels of HPT axis-related genes were destroyed. The histological examination showed that, the DM groups mice thyroid tissues appeared expanded thyroid follicles, scanty colloid and hyperplastic thyroid cells. Western blot results showed that the expression level of tyrosine hydroxylase (TH) protein decreased and the content of dopamine transporter (DAT) protein increased in DM treated mice striatum. Collectively, our results indicated that DM exposure could induce thyroid dysfunction and behavioral disorders in adolescent mice.

Intake of seaweed as part of a single sushi meal, iodine excretion and thyroid function in euthyroid subjects: a randomized dinner study.

Globalisation has extended to the kitchen and the Asian cuisine has gained international popularity with sushi and seaweed now being widespread. We explored the possible acute adverse effects of an iodine load from a single sushi-and-seaweed meal as seaweed iodine may induce thyroid dysfunction. Nine euthyroid participants were randomized into three groups: Halibut maki roll with either (A) newly harvested Greenlandic seaweed salad, (B) no seaweed salad on the side, or (C) Japanese seaweed salad purchased at a local store. We collected spot urine and blood samples daily for a week for measurement of iodine and creatinine in urine, thyroid stimulating hormone (TSH), and estimated-free T4 (fT4) in serum. All participants ingested the full meal and the drop-out was nil. No adverse effects were reported. Pre-meal urinary iodine excretion (UIE) was 75µg/g. UIE rose (p < 0.001) by 385%, 59% and 43% for groups A, B, and C, peaked in the 6-h spot urine sample at 393, 120, and 109µg/g, and was down to pre-meal values by day 2. Serum TSH rose (p = 0.012) 150% on day 2 and was down to pre-meal values by day 3. Serum fT4 remained at the same level. No adverse reactions were reported. A sushi meal increased urinary iodine excretion by 40µg/g, or 400µg/g if a newly harvested seaweed salad was added. An ensuing rise in serum TSH was brief, and a single sushi meal with seaweed salad did not cause any adverse events.

The Immune Landscape of Thyroid Cancer in the Context of Immune Checkpoint Inhibition.

Immune cells play critical roles in tumor prevention as well as initiation and progression. However, immune-resistant cancer cells can evade the immune system and proceed to form tumors. The normal microenvironment (immune cells, fibroblasts, blood and lymphatic vessels, and interstitial extracellular matrix (ECM)) maintains tissue homeostasis and prevents tumor initiation. Inflammatory mediators, reactive oxygen species, cytokines, and chemokines from an altered microenvironment promote tumor growth. During the last decade, thyroid cancer, the most frequent cancer of the endocrine system, has emerged as the fifth most incident cancer in the United States (USA), and its incidence is steadily growing. Inflammation has long been associated with thyroid cancer, raising critical questions about the role of immune cells in its pathogenesis. A plethora of immune cells and their mediators are present in the thyroid cancer ecosystem. Monoclonal antibodies (mAbs) targeting immune checkpoints, such as mAbs anti-cytotoxic T lymphocyte antigen 4 (anti-CTLA-4) and anti-programmed cell death protein-1/programmed cell death ligand-1 (anti-PD-1/PD-L1), have revolutionized the treatment of many malignancies, but they induce thyroid dysfunction in up to 10% of patients, presumably by enhancing autoimmunity. Combination strategies involving immune checkpoint inhibitors (ICIs) with tyrosine kinase (TK) or serine/threonine protein kinase B-raf (BRAF) inhibitors are showing considerable promise in the treatment of advanced thyroid cancer. This review illustrates how different immune cells contribute to thyroid cancer development and the rationale for the antitumor effects of ICIs in combination with BRAF/TK inhibitors.

Baseline TSH Level is Associated with Risk of Anti–PD-1–Induced Thyroid Dysfunction

Objective: To characterize anti-programmed cell death 1 (PD-1)-induced thyroid immune-related adverse events (irAEs) in metastatic melanoma patients treated at our institution and to identify risk factors associated with their development. Methods: We reviewed the files of 154 patients with metastatic melanoma treated with PD-1 inhibitors at a single institution from November 1, 2011, to February 28, 2017. The association of thyroid irAEs within 120 days posttreatment initiation with age, gender, melanoma characteristics, treatment protocol, and baseline thyroid-stimulating hormone (TSH) was examined. Results: Overall, 42.4% developed thyroid dysfunction following treatment, including 20.2% (20/99) subclinical thyroid dysfunction, 13.1% (13/99) overt hypothyroidism, and 9.1% (9/99) overt hyperthyroidism. Of those that developed overt hyperthyroidism, 8 progressed to overt hypothyroidism, consistent with thyroiditis. Age, gender, melanoma characteristics, or treatment protocol did not modify the risk of developing thyroid irAEs. Higher baseline TSH was observed in patients who developed overt hypothyroidism versus hyperthyroidism versus those who remained euthyroid (P = .05). A pretreatment TSH >2.19 mIU/mL was associated with an increased risk of overt thyroid dysfunction (odds ratio, 3.46; 95% confidence interval, 1.2 to 9.8). Conclusion: Thyroid dysfunction following treatment with PD-1 inhibitors is common, and patients with a higher baseline TSH appear to be at increased risk. Such patients may benefit from closer monitoring of their thyroid function following initiation of anti PD-1 agents. Abbreviations: CTLA-4 = cytotoxic T-lymphocyte antigen 4; FT3 = free triiodothyronine; FT4 = free thyroxine; irAE = immune-related adverse event; PD-1 = programmed cell death 1; TFT = thyroid function test; TPO = thyroid peroxidase; TSH = thyroid-stimulating hormone.

Chemically or Surgically Induced Thyroid Dysfunction Altered Gut Microbiota in Rat Models

Background: The role of gut microbiota in metabolic diseases has recently been widely verified. Thyroid hormones are essential for the regulation of energy homeostasis and metabolic processes. However, the relationship between thyroid function and host gut microbial communities is not properly understood. Method: To determine whether and how gut microbiota is associated with thyroid function, metagenomics analysis of the bacterial population in fecal samples of rat models of hyperthyroidism (induced by levothyroxine) and hypothyroidism (induced by propylthiouracil or thyroidectomy) was conducted through 16SrRNA gene sequencing. Finding: Our results revealed that all thyroid dysfunction models were definitely established and gut microbial composition varied according to different thyroid functional status. The relative abundance of Ruminococcus was significantly higher in the hyperthyroidism group (HE) vs both the normal and hypothyroidism (HO) groups while S24-7 was significantly higher in the HO group compared to both the normal and HE groups. The relative abundance of Prevotellaceae and Prevotella were significantly lower in the HO group vs the normal. Firmicutes and Oscillospira was significantly higher in the SHO (surgery-induced hypothyroidism) group than the SHAM group, while Prevotellaceae andPrevotella showed lower abundance in the SHO group compared to the SHAM group. Interpretation: This is the first perspective study of the relationship between thyroid gland and gut microbiota using Next Generation Sequencing-based microbial identification technology. We demonstrated that thyroid status and function influenced the gut microbial composition, and the results presented here can be used as reference in future studies to identify potential mechanism(s) by which thyroid modulates gut microbial population. Funding Statement: This work was supported by a National Research Foundation (NRF) of Korea Grant funded by the Korean Government (NRF- 2019R1A2B5B01070365). This work was also supported by the Main Research Program (E0170602-02) of the Korea Food Research Institute (KFRI) funded by the Ministry of Science and ICT. Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The animal experimental protocol was approved by the Institutional Animal Care and Use Committee of Dongguk University (approval no. 2015-08128) and all experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals

Amiodarone induced thyroid dysfunction

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Ameliorating Efficacy of Curcumin on Cadmium Induced Thyroid Dysfunction in Albino Rats

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Genetic background and window of exposure contribute to thyroid dysfunction promoted by low-dose exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice

Genetic and environmental factors contribute to thyroid diseases. Although still debated, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is thought to induce thyroid dysfunction in humans and rodents. The data here reported point out the contribution of the exposure window and genetic background in mediating the low-dose TCDD effects on thyroid. Indeed, early (from E0.5 to PND30) and low-dose (0,001 μg/kg/day) TCDD exposure reduced the circulating fT4 and altered the expression of thyroid specific transcripts. The role of genetic components was estimated monitoring the same markers in Pax8+/− and Nkx2-1+/− mice, susceptible to thyroid dysfunction, exposed to 0, 1 μg/kg/day TCDD from E15.5 to PND60. Haploinsufficiency of either Pax8 or Nkx2-1 genes exacerbated the effects of the exposure impairing the thyroid enriched mRNAs in sex dependent manner. Such effect was mediated by mechanisms involving the Nkx2-1/p53/p65/IĸBα pathway in vitro and in vivo. Foetal exposure to TCDD impaired both thyroid function and genes expression while thyroid development and differentiation did not appear significantly affected. In mouse, stronger effects were related to earlier exposure or specific genetic background such as either Pax8 or Nkx2-1 haploinsufficiency, both associated to hypothyroidism in humans. Furthermore, our data underline that long exposure time are needed to model in vitro and in vivo results.

Nivolumab-induced thyroid dysfunction lacking antithyroid antibody is frequently evoked in Japanese patients with malignant melanoma

BackgroundNivolumab, an anti-programmed cell death-1 monoclonal antibody, has improved the survival of patients with malignant melanoma. Despite its efficacy, nivolumab inconsistently induces thyroid dysfunction as an immune-related adverse event (irAE). This study aimed to evaluate nivolumab-induced thyroid dysfunction to determine the risks and mechanisms of thyroid irAEs.MethodsAfter excluding 10 patients, data of 24 patients with malignant melanoma (aged 17–85 years; 54% female) were retrospectively analyzed.ResultsThyroid irAEs were observed in seven patients (29%). Three patients had hypothyroidism after preceding transient thyrotoxicosis, and the other four patients had hypothyroidism without thyrotoxicosis. Levothyroxine-Na replacement was required in three patients. Antithyroid antibody (ATA) titer was elevated in one of four assessable patients. The average (±SD) time to onset of thyroid irAE was 33.6 (±21.9) weeks. The administration period of nivolumab was longer in patients with thyroid irAEs than in those without thyroid irAEs (P < 0.01). There were no significant differences between patients with and without thyroid irAEs regarding age, sex, tumor stage, response to nivolumab therapy, baseline thyroid function, antithyroid peroxidase antibody (anti-TPO Ab) and antithyroglobulin antibody (anti-Tg Ab).ConclusionsThyroid dysfunction was a common irAE of nivolumab in malignant melanoma. Neither anti-TPO Ab nor anti-Tg Ab was associated with the risk for nivolumab-induced thyroid dysfunction. A conventional ATA-independent mechanism might be involved in thyroid irAEs. Further studies are required to clarify the mechanism and identify the predictive factors of thyroid irAEs.

Oleuropein and hydroxytyrosol protect rats’ pups against bisphenol A induced hypothyroidism

Bisphenol A (BPA) can disturb the endocrine system and the organs that respond to endocrine signals in organisms, indirectly exposed during prenatal and/or early postnatal life. The present study was designed to assess the protective effect of phenolic compounds from olive leaves against BPA induced thyroid dysfunction and growth perturbation in young rats during lactation. The BPA disrupting effect on thyroid function was investigated by measuring changes in plasma levels of thyroid hormones. Free triiodothyronine (FT3) and thyroxine (FT4) were decreased in young rats breast-fed from mothers treated with bisphenol A. This effect was associated with an increase in the plasma level of thyroid-stimulating hormone (TSH). The histological and immunohistochemical study of the thyroid gland revealed a disturbance in morphological structure and thyroid cells function. Thyroid dysfunction led to a disruption in the skeletal bone growth of young rats. In fact, the infrared microspectroscopic analysis and histological examination of femoral bone showed significant changes in their histoarchitecture associated with a perturbation in the mechanism of bone tissue mineralization. The administration of oleuropein or hydroxytyrosol in BPA treated lactating mothers improved the thyroid cells function by enhancing thyroid hormone levels. Moreover, these phenolics increased the body growth characterized by an amelioration in the structure and the microstructure of femoral bone tissue. HPLC analysis of rats-breast milk indicated the presence of oleuropein and hydroxytyrosol, which could contribute to the protective effect against bisphenol A induced hypothyroidism in pups rats.