Development Of Thyroid Dysfunction Research Articles

Post-Treatment Thyroid Diseases in Children with Brain Tumors: A Single-Center Experience at "Prof. Dr. Ion Chiricuță" Institute of Oncology, Cluj-Napoca.

Aim of study: The purpose of the study was to evaluate the association of thyroid dysfunction occurring in pediatric patients treated for brain tumors. Patients and methods: A total of 255 patients with brain tumors were treated between 2001 and 2018 at the “Prof. Dr. Ion Chiricuță” Institute of Oncology, Cluj-Napoca. Due to a minimum follow-up of 4 years, we studied 184 out of the 255 patients. The cohort included 69 girls (37.5%) and 109 boys (62.5%), with a median age of 8.4 years. The evaluated tumors included medulloblastomas (47 patients), astrocytomas (44 patients), ependymomas (22 patients), gliomas (20 patients), germ cell tumors (12 patients), primitive neuroectodermal tumors (4 patients), as well as other types of tumors (15 patients); in 20 of the cases, biopsy could not be performed. Results: There was a 60% overall survival rate; among the 120 surviving patients, 11 (9.1%) were diagnosed with iatrogenic thyroid disease. We observed an important number of iatrogenic thyroid disease cases in this group of patients, thus revealing the importance of long-term thyroid function evaluation in all children who finalized their treatment for brain tumors. Through this study, we aimed to provide an accurate image of the methodology of monitoring for thyroid dysfunction in childhood brain tumor survivors. Conclusion: Given the fact that the probability of developing thyroid dysfunction in the pediatric population treated for brain tumors is not rare, we recommend that childhood brain tumor survivors be monitored for iatrogenic thyroid disease, in order to provide early diagnosis and treatment.

Anti-thyroid antibodies and thyroid echo pattern at baseline as risk factors for thyroid dysfunction induced by anti-programmed cell death-1 antibodies: a prospective study

BackgroundAnti-programmed cell death-1 (PD-1) antibodies can cause thyroid dysfunction. However, no predictive biomarkers enabling stratification of thyroid dysfunction risk have been identified.MethodsA total of 209 patients treated with an anti-PD-1 antibody were evaluated for anti-thyroid antibodies at baseline and prospectively for thyroid function every 6 weeks for 24 weeks after treatment initiation, and then observed until the visits stopped. Thyroid ultrasonography was performed if the patient was positive for anti-thyroid antibodies at baseline.ResultsOf the 209 patients, 19 (9.1%) developed thyroid dysfunction (destructive thyroiditis or hypothyroidism). The cumulative incidence of thyroid dysfunction was significantly higher in patients who were positive vs. negative for anti-thyroid antibodies (15/44 [34.1%] vs. 4/165 [2.4%], p < 0.001). Forty-two patients positive for anti-thyroid antibodies at baseline were divided into two groups according to the presence of an irregular echo pattern. The cumulative incidence of thyroid dysfunction was significantly higher in those with an irregular vs. a regular echo pattern (13/23 [56.5%] vs. 1/19 [5.3%], p = 0.001). None of the patients developed thyroid dysfunction after the initial 24-week period.ConclusionsThe risk of thyroid dysfunction induced by anti-PD-1 antibodies can be predicted by evaluation of anti-thyroid antibodies and the thyroid echo pattern at baseline.Trial registrationUMIN000019024.

Thyroid Dysfunction in Iraqi Patients with Acromegaly

Acromegaly is a chronic endocrine disorder caused by hypersecretion of growth hormone (GH) mostly because of pituitary adenoma. GH induces the formation of Insulin like Growth Factor1 (IGF1)from the liver. Both GH andIGF1 lead to sign and symptom of acromegaly.Aim: This study designed to identify the prevalence of thyroid dysfunction in Iraqi patients with acromegaly ,to identify the factors responsible for thyroid dysfunction in patients with acromegaly.Is the treatment modalities for acromegaly has a role in thyroid dysfunction?Study design: A cross sectional case control studyPatients and Method: seventy patients with acromegaly were enrolled from 2 different tertiary centers of endocrinology from Jan. -Dec. 2017 compared with 70 non acromeglic subjects. Their mean age 46 +/-11 years ;forty one (58.5%) males and 29(41.5%)females. Thyroid function test conducted to both patients and control groups including TSH, free T4 and total T3 in both centers. In addition to other variables.Results: Out of 70 (100%) patients with acromegaly; (51.5%) were euthyroid, (20%) had primary hypothyroidism , (15.7%)had central hypothyroidism and (12.8%) had hyperthyroidism that is significantly higher than normal population (p<0.001).Patient with acromegaly had significant systolic and diastolic hypertension vs. control (p=0.015 ,0.004 respectively).Age of the patients, diastolic blood pressure ,first GH and history of hypophysectomy were significant risk factors for thyroid dysfunction (p=0.02,0.008,0.008 and 0.02 respectively)Conclusion : Thyroid dysfunction is more prevalent in patient with acromegaly whether hypothyroidism (both primary and secondary) and hyperthyroidism. The Age and diastolic blood pressure are independent risk factors of thyroid dysfunction. There is significant role of hypophysectomy in thyroid dysfunction development while Sandostatin (Octreotide LAR) treatment had no role.

Thyroid Dysfunction, Recovery, and Prognosis in Melanoma Patients Treated with Immune Checkpoint Inhibitors: A Retrospective Review

Objective: To describe thyroid dysfunction, factors associated with thyroid recovery, and survival in melanoma patients treated with immune checkpoint inhibitors that developed thyroid immune-related adverse events (irAEs). Methods: This was a retrospective study in a tertiary center from 2010-2017. We reviewed the charts of patients with melanoma that developed thyroid dysfunction after checkpoint inhibitor therapy. Cases with thyroid irAEs were grouped by recovery of thyroid function at 1 year. We collected a timeline of thyroid function tests, medication exposure, and survival and compared variables between the groups. We studied survival in comparison to a matched group without thyroid dysfunction. Results: A total of 186 melanoma patients received checkpoint inhibitors, and 17 (9%) had thyroid irAEs. Median time to abnormal thyroid-stimulating hormone was 38 days and followed a pattern of thyroiditis. Seven of 17 had thyroid recovery. In the no-recovery group, free thyroxine (T4) was often above 2 ng/dL (5/10 in no recovery, 0/7 in recovery; P = .04). In the recovery group, irAE grade was significantly lower, with 7/7 grade 1 (P = .004). Exposure to glucocorticoids was associated with recovery (3/10 in no recovery, 6/7 in recovery; P = .049). There was no difference in overall survival between the thyroid dysfunction group and controls, or between those that received glucocorticoids or not. Conclusion: Certain aspects of thyroid irAEs may correlate with thyroid recovery, including grade 1 thyroid irAEs, exposure to glucocorticoids, and peak free T4 levels less than 2 ng/dL. Thyroid irAEs did not appear to be associated with change in survival nor did exposure to glucocorticoids. Abbreviations: ASCO = American Society of Clinical Oncology; CTLA-4 = cytotoxic T-lymphocyte-associated protein 4; irAE = immune-related adverse event; PD-1 = programmed cell death protein 1; T4 = thyroxine; TSH = thyroid-stimulating hormone.

Prevalence and risk factors of thyroid dysfunction in young age

We examined people aged from 17 to 22 on the state of the thyroid gland. Analyzed results of the ultrasonography, laboratory test data, health assessment questionnaires and food records of the 300 study participants. Risk factors of thyroid dysfunction development for young people were analyzed. Signs of structural changes of the thyroid gland were detected amongst 57 % of study participants. The laboratory test results confirmed 44 % of the primary outcome received after palpation and ultrasonography. As a result 67 % of the examined volunteers from the in need of treatment group and 35 % intact volunteers were transferred into the group of dynamic follow-up thyroid gland monitoring. Discovered a less number of cases of the structural and/or functional thyroid disorders amongst people who have lived for 5 years in ecologically clean regions. All study participants had chronic alimentary iodine insufficiency which didn’t allow us to confirm the fundamental role of the iodine deficiency in the thyroid gland dysfunction development amongst young people. Laboratory confirmed diagnoses autoimmune thyroid disorders were found only amongst volunteers that consumed less than ¼ of the daily dose of iodine and lived in ecologically unsafe districts.

The association between cigarette smoking and serum thyroid stimulating hormone, thyroid peroxidase antibodies and thyroglobulin antibodies levels in Chinese residents: A cross-sectional study in 10 cities.

ObjectivesAlthough several studies have shown that cigarette smoking is associated with thyroid stimulating hormone (TSH), thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb), the exact relationship between smoking and thyroid function is controversial. As little is known about the effects of smoking on TSH, TPOAb and TgAb in Chinese residents. This study aimed to evaluate the association between cigarette smoking and TSH, TPOAb and TgAb in ten-city residents of China.Study designThis was a population-based cross-sectional study.MethodsIn this cross-sectional study, 15,181 subjects from ten major cities of China were investigated. Data regarding demographic characteristics, smoking status and consumption of iodine status were collected using in-person interviews based on a self-designed structured questionnaire. Serum concentrations of TSH, TPOAb and TgAb were measured using electrochemiluminescence immunoassays. Univariate analysis and multivariate linear stepwise regression analyses were used to analyze the data.ResultsThe regular smokers had lower concentrations of TSH, TPOAb and TgAb than occasional smokers, former smokers and never smokers. Multivariate analysis demonstrated that regular smoking was associated with the decreased concentrations of TSH (β = -0.178), TPOAb (β = -0.287) and TGAb (β = -0.453) after adjusting other factors. Furthermore, daily smoking number was significantly associated with the decreased level of TSH (β = -0.045) and TPOAb(β = -0.080), and smoking duration was associated with the decreased TSH level (β = -0.030).ConclusionsOur findings suggest that cigarette smoking is related to a significant decline in the concentrations of TSH, TPOAb and TgAb. In addition, daily smoking number and long-term smoking decrease serum TSH and TPOAb levels. Cigarette smoking plays a significant role in the development of thyroid dysfunction.

Incidence and Risk of Thyroid Dysfunction in Advanced or Metastatic Non-small Cell Lung Cancer Patients Treated with Pembrolizumab: A Meta-analysis.

Thyroid dysfunction is one of the major side effects associated with Pembrolizumab in the treatment of advanced or metastatic non-small cell lung cancer (NSCLC). We performed a systematic review and meta-analysis of randomized clinical trials to determine its overall incidence. A literature search was conducted using the electronic database engines PubMed and Google Scholar from inception to March 2019. Eligible studies were prospective randomized clinical trials with advanced or metastatic NSCLC. The pooled incidence, risk ratio (RR), and 95% confidence interval (CI) of thyroid dysfunction were calculated using the random-effect model. Given the possibility of a between-study variance, we used the random-effect model rather than the fixed-effect model.A total of four studies, including 1603 patients, were selected for analysis. Among patients receiving Pembrolizumab, the overall incidence of all-grade thyroid dysfunction was 19.8% (95% CI: 16.6-23.3%). Pembrolizumab was associated with a significantly increased risk of thyroid dysfunction of all grades, with a relative risk of 3.9 (95% CI: 2.08-7.42%, p= 0.084) in comparison with the controls. Therefore, there is a significant increase in developing thyroid dysfunction in advanced or metastatic NSCLC patients treated with Pembrolizumab.

Time-to-onset analysis of amiodarone-associated thyroid dysfunction.

Amiodarone (AMD) treatment is associated with a number of significant adverse effects including thyroid dysfunction. However, the relationship between the development of thyroid dysfunction and the dosage and treatment duration of AMD remains unclear. The purpose of this study was to examine the onset profiles of amiodarone-associated thyroid dysfunction using a spontaneous adverse drug reaction (ADR) reporting database. Data were obtained from the US Food and Drug Administration Adverse Event Reporting System (FAERS). For signal detection of spontaneous ADRs, the reporting odds ratio (ROR) and information component (IC) were calculated. Cumulative incidences of hyperthyroidism and hypothyroidism were assessed using the Kaplan-Meier method, and time-to-onset profiles were analysed using the Weibull shape parameter (WSP) test. The median time-to-onset of hyperthyroidism associated with AMD and other drugs was 720.0 (range: 225.5-1145.0) and 101.5 (range: 14.0-468.8) days, respectively. Patients treated with AMD showed a significantly longer time-to-onset of hyperthyroidism than those treated with other drugs (P<.001). The median time-to-onset of hypothyroidism associated with AMD and other drugs was 183.0 (range: 35.0-727.8) and 153.0 (range: 19.0-608.0) days, respectively. There was no significant difference in the time-to-onset of hypothyroidism between patients treated with AMD and those treated with other drugs (P=.13). For hyperthyroidism, the WSP test showed that AMD had a wear-out failure-type profile and other drugs had early failure-type profiles. For hypothyroidism, the WSP test showed that both AMD and other drugs had early failure-type profiles. Amiodarone-associated hyperthyroidism had a different onset profile than hyperthyroidism associated with other drugs. Because the time-to-onset of AMD-associated hyperthyroidism is widely distributed, sustained and continuous attention is required to detect and treat hyperthyroidism during AMD treatment. In contrast, AMD-associated hypothyroidism had an onset profile that was similar to that of other drugs, suggesting that attention should be focused on the earlier stages of treatment.

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.

Thyroid dysfunction prevalence and relation to glycemic control in patients with type 2 diabetes mellitus

ObjectiveIt is usually difficult to clinically identify thyroid abnormalities in diabetics as features of thyroid dysfunction may simulate diabetes symptoms or complications. So, assessing thyroid dysfunction prevalence in patients with type 2 diabetes mellitus (DM) would help better control of DM and its complications. Several studies reported this prevalence, however, some included small sample size or lacked a control group. We aimed to determine thyroid dysfunction prevalence in diabetic patients as well as its relation to glycemic control. MethodsA cross-sectional study included 200 patients having type 2 DM and 200 apparently healthy controls. Each participant was tested for fasting and 2-h post-prandial blood glucose, glycated haemoglobin (HbA1C), thyroid function tests: thyroid-stimulating hormone (TSH), free tri-iodothyronine (FT3), free thyroxine (FT4), serum total cholesterol and triglycerides and thyroid antibodies; anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) for hypothyroidism only. ResultsThere was a significant increase in serum TSH and T3 levels in diabetics when compared with the controls, (P < 0.001, P = 0.001), respectively. Thyroid dysfunction was significantly more prevalent in patients with HbA1c ≥ 8%, (P = 0.0001), and in those having longer diabetes duration, (P < 0.001). ConclusionThere was a higher prevalence of thyroid dysfunction among patients with type 2 DM. This dysfunction increased with the rise of HbA1c. This could suggest that poor glycemic control may have a role in the development of thyroid dysfunction in type 2 DM patients. Subclinical hypothyroidism was the most prevalent type of thyroid dysfunction in diabetic patients.

An underestimated comorbidity of COPD: Thyroid dysfunction.

Chronic obstructive pulmonary disease (COPD) has many systemic effects influencing morbidity and mortality of the disease. Thyroid diseases which are more common in COPD patients than who do not have COPD are underestimated despite important clinical consequences. Similar to general population, thyroid dysfunctions are more common in females than males among COPD patients. Both hypothyroidism and hyperthyroidism may be associated to COPD. As well as systemic inflammation hypoxia, age, glucocorticoid use and smoking are some of the effective factors on developing thyroid dysfunction in COPD patients. In this article thyroid dysfunctions that are underrecognized comorbidities of COPD patients, their mechanisms of action and clinical outcomes were reviewed.

Predictors and outcomes of thyroid dysfunction with immunotherapy: A single institution observational experience.

e14134 Background: Immune-related endocrine dysfunction is unique to immunotherapy (IT). We aimed to explore the clinical parameters associated with development of thyroid disorder (TD) in patients receiving IT and their outcome. Methods: We designed a retrospective study of patients treated with anti-CTLA4 and/or anti-PD1/PDL1 IT at Cook County Hospital, Chicago between January 2015 to January 2018. Patients with incomplete charts and those who received less than two cycles of IT were excluded. Demographics, clinical and pathologic data were recorded at the time of diagnosis and prior to start of IT. Pearson Chi-square, independent sample t-test and logistic regression were used for data analysis. Results: We included 104 patients in the study, out of whom 66 were male and 38 were female. Most common diagnosis was non-small cell lung cancer (42.4%) followed by squamous cell cancer of head and neck (21.2%), renal cell cancer (12.5%), small cell lung cancer (12.5%) and melanoma (8.7%). Majority of patients (91.4%) had metastasized and were treated with either Nivolumab (71.1%) or Pembrolizumab (21.2%) in the 2nd (50%) or 3rd line (29.8%) setting. Twenty-eight patients developed TD while on IT, out of whom, 13 developed hypothyroidism, 12 developed hyperthyroidism followed by hypothyroidism and 3 developed hyperthyroidism. TD developed between 1st to 6th cycle of IT in 96.5% patients. Older age (p-0.009), history of radiation (RT) to neck (p-0.007), history of RT to chest (p-0.015), history of venous thrombosis (p-0.007) and higher thyroid stimulating hormone (TSH) level (17.76±35.67) prior to starting IT (p-0.029) were significantly associated with TD. Multivariate logistic regression showed that history of RT to neck was a significant predictor of developing TD after adjustment for age, race and sex (adjusted OR 9.64, 95% CI 1.88-49.36, p-0.007). No patient reported thyroid related symptom and IT was continued uninterrupted in all patients. Levothyroxine was the drug of choice for treating hypothyroidism. No patient received steroids or antithyroid medications. Conclusions: History of radiation therapy to neck is significantly associated with development of thyroid dysfunction in patients receiving immunotherapy. Thyroid replacement therapy is sufficient to bring down the levels of TSH and immunotherapy need not be interrupted.

Immunotherapy-induced endocrinopathies: A multi-center experience.

e14251 Background: Endocrinopathies account for approximately 10% of immune-related adverse events.1 Methods: We carried out a retrospective review of 100 patients who received immunotherapy at two hospital sites between 2012 and 2019. Our aim was to ascertain the overall rate of immunotherapy-induced endocrinopathy and assess the impact of immunotherapy on pre-existing diabetes and thyroid dysfunction. Results: 28 out of 100 patients had pre-existing thyroid dysfunction, 36% of these experienced further thyroid dysfunction on immunotherapy. 41 patients had a diagnosis of renal cell cancer, and had treatment with a tyrosine kinase inhibitor prior to treatment with Nivolumab. Eighteen of these patients had a pre-existing thyroid dysfunction. Of these 18 patients, 44% experienced further thyroid dysfunction following immunotherapy. Of the 23 patients who received a tyrosine kinase inhibitor, who had no pre-existing thyroid dysfunction, 17% developed thyroid dysfunction on Nivolumab. 15% of patients without a pre-existing thyroid dysfunction developed a new thyroid dysfunction while on immunotherapy. Seven patients had diabetes mellitus prior to commencing immunotherapy, diabetes control did not disimprove during treatment. One case of diabetes was diagnosed on immunotherapy(1%). One case of adrenalitis(1%) and two cases of hypophysitis(2%) were diagnosed on immunotherapy. The adrenalitis occurred on Nivolumab (1.35%). Both cases of hypophysitis occurred on ipililumab(14%). The overall rate of new immunotherapy-induced endocrinopathy was 15%. Conclusions: The rates of endocrinopathy observed de novo are in line with published rates.1,2,3,4 In this small study, an increased rate of thyroid dysfunction was observed in patients with pre-existing thyroid dysfunction. Prior treatment with a tyrosine kinase inhibitor did not cause an increase in the rate of thyroid dysfunction. Ipilimumab was observed to be a risk factor for development of hypophysitis. [Table: see text]

Biochemical and histological evidence of thyroid gland dysfunction in estradiol valerate model of the polycystic ovary in Wistar rats

Thyroid defects and polycystic ovary (PSO) disease are prevalent endocrine problems among humans. While various studies investigated the ovarian function and histological alterations during estradiol valerate model of PCO, yet, there were no available studies examining thyroid gland function and histology. Therefore, the present study aimed to investigate linkage between estradiol valerate-induced PCO and the development of thyroid dysfunction in rats. The study comprises 2 groups of male Wistar rats (n = 12), control group and PCO group. PCO was induced by injecting two doses of estradiol valerate with 6 weeks lag period in between. After twelve weeks, PCO was confirmed by vaginal smear examination which showed marked vaginal cornification. In addition, the light microscopic examination of the ovaries revealed chief histological signs of PCO like numerous cysts and damaged follicles. In addition, PCO-induced rats showed decreased serum LH and increased serum FSH levels. Thyroid hypoactivity was confirmed by increased serum TSH and decreased serum thyroid hormones (T3, and T4). Histologically, the thyroid tissue revealed small-size follicles devoid of the colloid and increased connective tissue between follicles. Semithin sections showed hypertrophied and/or flat follicular cells as well as increased resorption colloidal granules. Ultrathin sections showed low height cells with dark nucleus and heterochromatin. Furthermore, PCO-induced rats thyroid gland tissue revealed increased expression of the apoptotic mediator caspase-3. There was also a decrease in the expression of proliferating cell nuclear antigen. In summary, this study provides several effective biochemical and histological evidences for thyroid gland dysfunction in PCO-induced rats.

MON-LB007 Incidence and Characteristics of Thyroid and Pituitary Dysfunction in Patients Treated with Immunotherapy

Background Endocrinopathies are well recognised immune-related adverse events associated with immunotherapy. Incidence rates of hypophysitis and thyroid dysfunction are widely variable in the literature. Hypophysitis has been reported in between 0.4% and 27% in patients treated with CTLA-4 inhibitors such as ipilimumab (1) while the incidence of thyroid dysfunction varies between 8% and 20% in patients treated with PD-1 inhibitors such as nivolumab and pembrolizumab (1). Aims Our aim was to determine real world rates of thyroid and pituitary dysfunction in patients treated with immunotherapy. We also sought to evaluate the characteristics of same-e.g. time to onset of adverse events and presence of autoantibodies. Methods A retrospective cohort study was performed in 347 patients who received treatment with PD-1 inhibitors nivolumab and pembrolizumab, anti-CD52 antibody alemtuzumab and CTLA-4 inhibitor ipilimumab between January 2013 and December 2017 at a tertiary referral metropolitan hospital in Melbourne, Australia. Patients were identified from pharmacy records and assessment of the clinical and biochemical records pertaining to thyroid function (TFT) and serum cortisol was performed. Results 45 patients (12.9%) had evidence of thyroid or pituitary dysfunction from the therapies. 34 of the 267 (12.7%) patients on PD-1 inhibitors developed thyroid dysfunction, 15 (5.6%) of whom had a clear thyroiditis picture-i.e. thyrotoxic phase with subsequent hypothyroidism. 3 of the 34 (8.8%) patients who received CTLA-4 inhibitor ipilimumab developed hypophysitis, all of whom were on combined treatment with a PD-1 inhibitor. Median time to onset of adverse effects was 30days. 12 out of 27 patients with thyroid dysfunction had positive anti-thyroid peroxidase antibodies. 25 of the 45 (55.6%) patients were reviewed in endocrine outpatient clinics. Only 2 of the 45 endocrinopathies were recorded in the hospital’s adverse drug reactions database. Conclusions In our tertiary centre, endocrinopathies are common in patients treated with immunotherapies; however reportage to the adverse drug reaction database is low and endocrinology services appear underutilised. Current guidelines suggest TFT monitoring every 4-6weeks on therapy (2) with baseline monitoring of early morning ACTH and cortisol concentrations to be considered in patients treated with CTLA-4 inhibitors. Greater clinician awareness and adherence to guidelines is needed for optimal patient care.

Diffusely Increased 18F-FDG Uptake in the Thyroid Gland and Risk of Thyroid Dysfunction: A Cohort Study.

The impact of incidentally identified diffuse thyroid FDG uptake on 18F-FDG PET/CT scan on the incidence of thyroid dysfunction remains unclear. We examined the association of diffuse thyroid FDG uptake with the development of thyroid dysfunction. This cohort study involved 39,098 Korean adults who were free of malignancy and thyroid disease at baseline and underwent regular health checkup examinations including an 18F-FDG whole body PET/CT scan, thyroid-stimulating hormone and free thyroxine. The participants were annually or biennially followed for up to 5 years. A parametric proportional hazard model was used to estimate the adjusted hazard ratio (HR) and 95% confidence interval (CI). Diffuse thyroid uptake was positively associated with increased risk of thyroid dysfunction in both the cross-sectional and cohort studies. During 104,261.4 person-years of follow-up, 102 incident hypothyroidism cases and 172 hyperthyroidism cases were identified. Multivariable-adjusted HR (95% CI) for incident hypothyroidism or hyperthyroidism comparing diffuse thyroid uptake to no uptake were 15.72 (9.23–26.77) and 7.38 (4.23–12.87), respectively. In this large cohort, incidentally, identified diffuse thyroid uptake on 18F-FDG PET/CT was associated with increased risk of both prevalent and incident thyroid dysfunction. Therefore, baseline and follow-up evaluations in individuals with diffuse thyroid uptake may help identify individuals with thyroid dysfunction.

Autoantibody Development under Treatment with Immune-Checkpoint Inhibitors.

Immune-checkpoint inhibitors (ICIs) activate the immune system to assault cancer cells in a manner that is not antigen specific. We hypothesized that tolerance may also be broken to autoantigens, resulting in autoantibody formation, which could be associated with immune-related adverse events (irAEs) and antitumor efficacy. Twenty-three common clinical autoantibodies in pre- and posttreatment sera from 133 ipilimumab-treated melanoma patients were determined, and their development linked to the occurrence of irAEs, best overall response, and survival. Autoantibodies developed in 19.2% (19/99) of patients who were autoantibody-negative pretreatment. A nonsignificant association was observed between development of any autoantibodies and any irAEs [OR, 2.92; 95% confidence interval (CI) 0.85-10.01]. Patients with antithyroid antibodies after ipilimumab had significantly more thyroid dysfunction under subsequent anti-PD-1 therapy: 7/11 (54.6%) patients with antithyroid antibodies after ipilimumab developed thyroid dysfunction under anti-PD1 versus 7/49 (14.3%) patients without antibodies (OR, 9.96; 95% CI, 1.94-51.1). Patients who developed autoantibodies showed a trend for better survival (HR for all-cause death: 0.66; 95% CI, 0.34-1.26) and therapy response (OR, 2.64; 95% CI, 0.85-8.16). We conclude that autoantibodies develop under ipilimumab treatment and could be a potential marker of ICI toxicity and efficacy.

Longitudinal Characterization of Autoantibodies to the Thyrotropin Receptor (TRAb) During Alemtuzumab Therapy: Evidence that TRAb May Precede Thyroid Dysfunction by Many Years.

Thyroid autoimmunity, especially Graves' disease or hypothyroidism with positive autoantibodies (TRAb) to the thyrotropin receptor (TSHR), occurs in 30-40% of patients with relapsing multiple sclerosis following treatment with alemtuzumab (ALTZ). ALTZ therapy therefore provides a unique opportunity to study the evolution of TRAb prior to clinical presentation. TRAb can stimulate (TSAb), block (TBAb), or not affect ("neutral") the TSHR function, causing hyperthyroidism, hypothyroidism, or euthyroidism, respectively. A longitudinal retrospective analysis was conducted of TRAb bioactivity over a period of nine years in 45 multiple sclerosis patients receiving ALTZ using available stored serum. Of these 45 patients, 31 developed thyroid dysfunction (TD) and 14 remained euthyroid despite being followed for a minimum of five years (NO-TD). The presence of TRAb was evaluated at standardized time points: (i) before ALTZ, (ii) latest time available following ALTZ and before TD onset, and (iii) following ALTZ during/after TD onset. Serum TRAb were detected by published in-house assays (ihTRAb): flow cytometry detecting any TSHR-binding TRAb, and luciferase bioassays detecting TSAb/TBAb bioactivity. Purified immunoglobulin G was used to verify TSAb/TBAb in selected hypothyroid cases. Standard clinical automated measurements of TRAb, antithyroid peroxidase autoantibodies (TPOAb), thyrotropin, free thyroxine, and free triiodothyronine were also collected. Before ALTZ, combined ihTRAb (positive with flow cytometry and/or luciferase bioassay) but not automated TRAb were present in 5/16 (31.2%) TD versus 0/14 (0%) NO-TD (p = 0.017). Detectable ihTRAb preceded TD development in 9/28 (32.1%) and by a median of 1.2 years (range 28 days-7.3 years). Combination testing of ihTRAb and TPOAb at baseline predicted 20% of subsequent cases of hyperthyroidism and 83% of hypothyroidism. Evidence is presented that TRAb measured with custom-made assays can be detected prior to any change in thyroid function in up to a third of cases of ALTZ-related TD. Furthermore, the presence of ihTRAb prior to ALTZ treatment was strongly predictive of subsequent TD. The findings suggest that a period of affinity maturation of TRAb may precede clinical disease onset in some cases. Combined testing of TPOAb and ihTRAb may increase the ability to predict those who will develop TD following ALTZ.

Association of antithyroglobulin antibodies with the development of thyroid dysfunction induced by nivolumab.

Thyroid dysfunction (TD) induced by immune checkpoint inhibitors is not sufficiently understood. The purpose of this retrospective observational study was to identify risk factors and the clinical course of TD induced by nivolumab. Patients with advanced solid tumors who were treated with nivolumab from March 2009 through to March 2016 at the National Cancer Center Hospital (Tokyo, Japan) were included. Thyroid function and antithyroid Abs from serum samples among all patients were evaluated at baseline and during nivolumab treatment. Overt hypothyroidism was defined as low serum‐free T4 together with elevated thyroid‐stimulating hormone (TSH) >10 μIU/mL. Thyrotoxicosis was defined as low TSH with elevated free T4 and/or free T3. We defined thyroid autoimmunity as the presence of antithyroid Abs at baseline, including antithyroid peroxidase Abs and antithyroglobulin Abs (TgAb). Twenty‐three (14%) of a total of 168 patients developed TD, including 17 cases of hypothyroidism and 20 of thyrotoxicosis. Thyrotoxicosis followed by hypothyroidism occurred in 14 cases. Fourteen of 35 patients (40%) with thyroid autoimmunity developed TD vs 9 of 133 (7%) without (odds ratio 9.19; 95% confidence interval [CI], 3.53‐23.9). In multivariate analysis, elevated TSH and TgAb at baseline were significantly associated with the development of TD, with odds ratio of 7.36 (95% CI, 1.66‐32.7) and 26.5 (95% CI, 8.18‐85.8), respectively. Association between TD and elevated antithyroid peroxidase Abs at baseline was not significant. These results suggest that patients with pre‐existing TgAb and elevated TSH at baseline are at high risk of TD.

The spectrum of 45,X/46,XY mosaicism in Taiwanese children: The experience of a single center.

45,X/46,XY mosaicism is a rare sex chromosome abnormality. Here, we present our experience in the management of 45,X/46,XY Taiwanese children. We enrolled 19 patients from January 1981 to September 2016. The diagnosis of 45,X/46,XY mosaicism was made by karyotyping peripheral blood lymphocytes. All medical records were thoroughly reviewed. Of the 19 patients, 16 were reared as females and 3 as males. The age at diagnosis ranged from 1 month to 15 years and 9 months. Atypical genitalia, short stature, and Turner stigmata were common manifestations. No patient exhibited a cardiac malformation but 29% had renal malformations and 12.5% had autoimmune thyroid disease who developed thyroid dysfunction later. Nine girls with short stature received growth hormone therapy and their height standard deviation score rose from -3.4±1.1 to -1.4±0.9 in adulthood (P<0.01). The gonadal phenotypes included bilateral streak gonads in nine patients, a streak gonad with contralateral gonadal agenesis in one, mixed gonadal dysgenesis in five, bilateral dysgenetic testes in two, and bilateral gonadoblastomas in one. The 45,X/46,XY phenotype varies widely and a high index of suspicion is important to ensure early diagnosis. Cardiac and renal malformations should be screened ultrasonically at diagnosis and thyroid status should be monitored annually. Growth hormone effectively improves adult height in short girls. Prophylactic gonadectomy is indicated for those with intra-abdominal streaks or dysgenetic gonads to prevent the development of a malignancy.