A combined transcriptomics and proteomics approach reveals S100A4 as a potential biomarker for Graves' orbitopathy.

Background: There are no reliable biomarkers to identify Graves' disease patients who will develop severe Graves' orbitopathy (GO). We hypothesize that integrating various omics platforms can enhance our understanding of disease mechanisms and uncover potential biomarkers. This study aimed to (1) elucidate the differential gene expression profile of orbital fibroblasts in GO during early adipogenesis to better understand disease mechanisms and (2) compare tear protein profiles from our earlier study and the transcriptome profiles of orbital fibroblasts (OFs) to identify possible biomarkers of the disease. Methods: OFs were grown from orbital adipose tissue obtained from nine GO patients (three for discovery and six for validation experiments). Total RNA was extracted from OFs on day 0 as the baseline for each sample and from differentiated OFs on days 4 and 8. Protein-protein interaction (PPI) analysis and functional enrichment analysis were also carried out. The differentially expressed genes (DEGs) from the RNA sequencing experiments were then compared to the full tear proteome profile from the author's previous study, which examined the tear protein changes of GO patients based on fold change > 1.6 or < -1.6. FDR < 0.05 was applied within all datasets. Further validation of S100 calcium-binding protein A4 (S100A4) downregulation in GO was performed via quantitative real-time PCR (qPCR). Results: The whole transcriptomic analysis revealed 9 upregulated genes and 15 downregulated genes in common between the discovery and validation experiments. From the PPI network analysis, an interaction network containing six identified DEGs (ALDH2, MAP2K6, MT2A, SOCS3, S100A4, and THBD) was observed. The functional enrichment network analysis identified a set of genes related to oxysterol production. S100A4 was found to be consistently downregulated in both our transcriptome studies and the full-tear proteome profile from the author's previous study. Conclusion: Our study identified several DEGs and potential gene pathways in GO patients, which concurred with the results of other studies. Tear S100A4 may serve as a biomarker for the propensity to develop thyroid eye disease (TED) in patients with autoimmune thyroid disease (AITD) before clinical manifestation and should be confirmed in future studies.

Application of artificial intelligence in the assessment of thyroid eye disease (TED) - a scoping review.

Background: There is emerging evidence which suggests the utility of artificial intelligence (AI) in the diagnostic assessment and pre-treatment evaluation of thyroid eye disease (TED). This scoping review aims to (1) identify the extent of the available evidence (2) provide an in-depth analysis of AI research methodology of the studies included in the review (3) Identify knowledge gaps pertaining to research in this area. Methods: This review was performed according to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA). We quantify the diagnostic accuracy of AI models in the field of TED assessment and appraise the quality of these studies using the modified QUADAS-2 tool. Results: A total of 13 studies were included in this review. The most common AI models used in these studies are convolutional neural networks (CNN). The majority of the studies compared algorithm performance against healthcare professionals. The overall risk of bias and applicability using the modified Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool led to most of the studies being classified as low risk, although higher deficiency was noted in the risk of bias in flow and timing. Conclusions: While the results of the review showed high diagnostic accuracy of the AI models in identifying features of TED relevant to disease assessment, deficiencies in study design causing study bias and compromising study applicability were noted. Moving forward, limitations and challenges inherent to machine learning should be addressed with improved standardized guidance around study design, reporting, and legislative framework.

A retrospective study of pediatric thyroid eye disease: the Asian experience.

AIM: To study the clinical presentation, disease characteristics, and management approach for children with thyroid eye disease (TED) over a 10 year period in a multidisciplinary Paediatric Thyroid Eye Disease Clinic at a tertiary care referral center. METHODS: Retrospective case series of patients with TED at Kandang Kerbau Women's and Children's Hospital (KKWCH) Singapore between August 2006 to June 2015. The diagnosis of TED was clinical based on the Bartley criteria. Ophthalmic examination findings, systemic thyroid function and ophthalmological intervention were recorded. RESULTS: Nineteen subjects with pediatric TED were studied. The median age at diagnosis was 12.5 years (range 6-17). The onset of TED was at the same time as their thyroid disease in half of these patients (52.6%) of which all were hyperthyroid except one. The most common signs at TED diagnosis were proptosis (84.2%), lid retraction (63.2%), acquired epiblepharon (63.2%). All patients were inactive and none had evidence of compressive optic neuropathy. TED remained stable in all patients except for one who developed worsening proptosis with exposure keratopathy. No patients were prescribed steroids (oral or intravenous) or had orbital decompression surgery. The most debilitating morbidity was acquired epiblepharon of which out of 12 patients, one had everting sutures and three were offered surgical correction. CONCLUSIONS: Paediatric TED subjects exhibit milder clinical manifestations compared to adults. Acquired epiblepharon causes most significant visual morbidity by compromising the corneal surface. Being cognizant of the subtleties of pediatric TED will permit the discerning clinician to effectively manage such cases accordingly.

De Novo Extra-Thyroidal Manifestations of Graves' Disease presenting 16 Years after Total Thyroidectomy for Thyroid Cancer.

We present a 61-year-old Chinese female who had a history of angioinvasive follicular thyroid cancer (FTC) treated with total thyroidectomy 16 years ago, without radioactive iodine (RAI) treatment who now presents with de novo pretibial myxedema (PTM) followed by active severe Graves' ophthalmopathy (GO) requiring pulse steroids and radiotherapy.

Severe radiation thyroiditis after radioactive iodine for treatment of Graves' disease.

Radiation thyroiditis resulting from radioactive iodine-131 treatment for Graves' disease is an uncommon complication. Although a majority of patients are asymptomatic or manifest mild symptoms that can be managed conservatively, published literature describing severe radiation thyroiditis resulting in significant morbidity is lacking. We herein report on six patients with severe radiation thyroiditis that resulted in hospitalisation, including an unusual complication of myopericarditis.

High Thyroid Stimulating Receptor Antibody Titre and Large Goitre Size at First-Time Radioactive Iodine Treatment are Associated with Treatment Failure in Graves' Disease.

INTRODUCTION: Our study aimed to identify the factors associated with successful first-time radioactive iodine (RAI) treatment in patients with Graves' disease (GD). MATERIALS AND METHODS: This is a restrospective study of patients with GD who were treated with RAI. Treatment success was defined as onset of permanent hypothyroidism or euthyroidism after 1 dose of RAI at 1-year follow-up. RESULTS: There were 388 GD patients who underwent RAI treatment between January 2014 and December 2015. Of these, 74% achieved treatment success. Median time to achieve permanent hypothyroidism was 2 months. Male gender, smoking, higher antithyroid drug dosage, lower thyroid stimulating hormone (TSH) level, large goitre size and TSH receptor antibody (TRAb) titre at time of RAI were significantly associated with treatment failure. Multivariate analysis showed that larger goitre size and higher TRAb titre were associated with lower first-time RAI success. CONCLUSION: Larger goitre size and higher TRAb titre predict lower success of RAI therapy in GD patients. Treatment decisions and strategies should be customised for patients who present with these characteristics.

Methotrexate as an Adjuvant in Severe Thyroid Eye Disease: Does It Really Work as a Steroid-Sparing Agent?

PURPOSE: To compare the efficacy and safety of adjunctive oral methotrexate with intravenous pulsed methylprednisolone against methylprednisolone alone in the treatment of severe thyroid eye disease. METHODS: Retrospective review of clinical data of patients with severe sight-threatening thyroid eye disease with compressive optic neuropathy treated with methylprednisolone with and without methotrexate. Eye disease outcome measures (e.g., VISA inflammatory score and vision) at 0, 3, 6, 12, and 18 months were recorded. RESULTS: There were 72 subjects including 33 who had methylprednisolone alone and 39 with methylprednisolone with methotrexate. There were no statistical differences in demographics and baseline measures of disease activity or vision between the 2 treatment groups. No significant statistical differences in the cumulative dosage of methylprednisolone or occurrence of restrictive myopathy, raised intraocular pressure, proptosis, and exposure keratopathy between the groups at 0, 3, 6, 12, and 18 months were found. However, subjects who received methylprednisolone with methotrexate had better visual acuity of more than 2 lines on Snellen chart (p = 0.026) and VISA inflammatory score (p = 0.034) at 3 months, but no differences at 6, 12, and 18 months. Three patients who received methylprednisolone with methotrexate had transient worsening of liver function. No patient developed severe adverse reaction. CONCLUSIONS: The results demonstrated improved vision and disease activity at 3 months in the combination treatment group. This may suggest that the addition of methotrexate to methylprednisolone is beneficial for accelerating suppression of disease activity and hastens visual recovery. Addition of methotrexate to methylprednisolone did not reduce the requirement for steroids.

Tear Proteins Calcium binding protein A4 (S100A4) and Prolactin Induced Protein (PIP) are Potential Biomarkers for Thyroid Eye Disease.

There are no reliable biomarkers to predict thyroid eye disease (TED) in patients with autoimmune thyroid disease (AITD) currently. Several evidences support the involvement of the lacrimal gland in TED. The aim of our study was to quantitatively correlate the changes in tear protein profile with increasing severity of TED. Tear samples were collected from four groups of patients; AITD without TED (AITD), AITD with mild TED (mild TED), AITD with severe TED (severe TED) and normal controls. A total of 72 patients were recruited for the study. In discovery phase, isobaric tags for relative and absolute quantification (iTRAQ) 4-plex was used for quantitative proteomics analysis. For verification of results from discovery phase, sequential window acquisition of all theoretical fragment ion spectra (SWATH) was used to analyze an independent cohort from normal controls, AITD, mild TED and severe TED. Two proteins, S100A4 and PIP showed consistent dysregulation trends in the discovery and validation phase experiments. Our study demonstrated the differences in tear proteome across the spectrum of different severity and activity of TED in patients with AITD. Two tear proteins, S100A4 and PIP may serve as potential biomarkers to predict progression to severe TED in patients with AITD.

Diagnostic performance of ATA, BTA and TIRADS sonographic patterns in the prediction of malignancy in histologically proven thyroid nodules.

INTRODUCTION: We aimed to compare the malignancy risk stratification of histologically proven thyroid nodules using the 2015 American Thyroid Association (ATA) Management Guidelines, 2014 British Thyroid Association (BTA) Guidelines for the Management of Thyroid Cancer and the Thyroid Imaging Reporting and Data System (TIRADS). METHODS: Thyroid nodules measuring > 1 cm resected over 5.5 years were retrospectively studied. Demographic information as well as cytology and histopathology results were collected. Static ultrasonography (US) images and radiologists' reports of each resected nodules were reviewed and classified based on the above risk classification systems. RESULTS: A total of 167 thyroid nodules from 150 patients were examined. More malignant nodules were solid (78.4% vs. 62.5%; p = 0.049) or hypoechoic (70.6% vs. 28.6%; p < 0.001), and had irregular margins (35.3% vs. 8.0%; p < 0.001), taller-than-wide morphology (9.8% vs. 2.7%; p = 0.031), microcalcifications (33.3% vs. 8.0%; p < 0.001), disrupted rim calcifications (9.8% vs. 0.9%; p = 0.012) or associated abnormal cervical lymphadenopathy (13.7% vs. 0.9%; p = 0.001) compared with benign nodules. The guidelines' diagnostic performance was: ATA - sensitivity 98.0%, specificity 17.3%, positive predictive value (PPV) 35.0%, negative predictive value (NPV) 95.0%; BTA - sensitivity 90%, specificity 50.9%, PPV 45.5%, NPV 91.8%; and TIRADS - sensitivity 94.0%, specificity 28.2%, PPV 37.3%%, NPV 91.2%. CONCLUSION: Sonographic patterns outlined by the three guidelines displayed high sensitivity and NPV. Although isolated suspicious US features cannot predict malignancy risk, they should be considered when risk stratifying nodules that do not fit into particular sonographic patterns based on current guidelines.

Radioiodine associated de novo Graves' opthalmopathy in an Asian cohort.

Radioactive iodine in the treatment of Graves' disease has been associated with the development of de novo Graves' ophthalmopathy (GO). In this report, we describe five individuals who required extensive ophthalmic treatment for post-RAI de novo GO.

Persistent hyperthyroidism and de novo Graves' ophthalmopathy after total thyroidectomy.

We report a patient with Graves' disease who remained persistently hyperthyroid after a total thyroidectomy and also developed de novo Graves' ophthalmopathy 5 months after surgery. She was subsequently found to have a mature cystic teratoma containing struma ovarii after undergoing a total hysterectomy and salpingo-oophorectomy for an incidental ovarian lesion. LEARNING POINTS: It is important to investigate for other causes of primary hyperthyroidism when thyrotoxicosis persists after total thyroidectomy.TSH receptor antibody may persist after total thyroidectomy and may potentially contribute to the development of de novo Graves' ophthalmopathy.

Physiological and Metabolic Changes During the Transition from Hyperthyroidism to Euthyroidism in Graves' Disease.

BACKGROUND: The serum metabolomic profile and its relationship to physiological changes during hyperthyroidism and restoration to euthyroidism are not known. This study aimed to examine the physiological, adipokine, and metabolomic changes that occur when subjects with Graves' disease transition from hyperthyroidism to euthyroidism with medical treatment. METHODS: Chinese women between 21 and 50 years of age and with newly diagnosed Graves' disease attending the endocrine outpatient clinics in a single institution were recruited between July 2012 and September 2014. All subjects were treated with thioamides to achieve euthyroidism. Clinical parameters (body weight, body composition via bioelectrical impedance analysis, resting energy expenditure and respiratory quotient via indirect calorimetry, and reported total energy intake via 24 h food diary), biochemical parameters (thyroid hormones, lipid profile, fasting insulin and glucose levels), serum leptin, adiponectin, and metabolomics profiles were measured during hyperthyroidism and repeated in early euthyroidism. RESULTS: Twenty four Chinese women with an average age of 36.3 ± 8.6 years were included in the study. The average duration of treatment that was required to reach euthyroidism for these subjects was 38 ± 16.3 weeks. There was a significant increase in body weight (52.6 ± 9.0 kg to 55.3 ± 9.4 kg; p < 0.001) and fat mass (14.3 ± 6.9 kg to 16.8 ± 6.5 kg; p = 0.005). There was a reduction in resting energy expenditure corrected for weight (28.7 ± 4.0 kcal/kg to 21.5 ± 4.1 kcal/kg; p < 0.001) and an increase in respiratory quotient (0.76 to 0.81; p = 0.037). Resting energy expenditure increased significantly with increasing free triiodothyronine levels (p = 0.007). Significant increases in total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were noted. There was no significant change in leptin levels, but adiponectin levels increased significantly (p = 0.018). Significant reductions in fasting C2, medium-chain, long-chain, and total acylcarnitines were observed, but no changes in the fat-free mass, branched chain amino acid levels, or insulin sensitivity during recovery from hyperthyroidism were noted. CONCLUSIONS: Serum metabolomics profile changes complemented the physiological changes observed during the transition from hyperthyroidism to euthyroidism. This study provides a comprehensive and integrated view of the changes in fuel metabolism and energy balance that occur following the treatment of hyperthyroidism.

Plasma exchange in the treatment of thyroid storm secondary to type II amiodarone-induced thyrotoxicosis.

UNLABELLED: Type II amiodarone-induced thyrotoxicosis (AIT) is an uncommon cause of thyroid storm. Due to the rarity of the condition, little is known about the role of plasma exchange in the treatment of severe AIT. A 56-year-old male presented with thyroid storm 2months following cessation of amiodarone. Despite conventional treatment, his condition deteriorated. He underwent two cycles of plasma exchange, which successfully controlled the severe hyperthyroidism. The thyroid hormone levels continued to fall up to 10h following plasma exchange. He subsequently underwent emergency total thyroidectomy and the histology of thyroid gland confirmed type II AIT. Management of thyroid storm secondary to type II AIT can be challenging as patients may not respond to conventional treatments, and thyroid storm may be more harmful in AIT patients owing to the underlying cardiac disease. If used appropriately, plasma exchange can effectively reduce circulating hormones, to allow stabilisation of patients in preparation for emergency thyroidectomy. LEARNING POINTS: Type II AIT is an uncommon cause of thyroid storm and may not respond well to conventional thyroid storm treatment.Prompt diagnosis and therapy are important, as patients may deteriorate rapidly.Plasma exchange can be used as an effective bridging therapy to emergency thyroidectomy.This case shows that in type II AIT, each cycle of plasma exchange can potentially lower free triiodothyronine levels for 10h.Important factors to consider when planning plasma exchange as a treatment for thyroid storm include timing of each session, type of exchange fluid to be used and timing of surgery.

Safety Profile and Effects of Pulsed Methylprednisolone on Vital Signs in Thyroid Eye Disease.

Objective. To analyze changes in vital signs (heart rate (HR), systolic (SBP), and diastolic blood pressure (DBP)) during and after intravenous methylprednisolone (IVMP) and any other adverse effects. Methods. Retrospective review of charts of patients who received IVMP as treatment regime for thyroid eye disease. All subjects had vital signs charted during and after infusions. Results. This study included 38 subjects and a total of 242 infusions administered. IVMP resulted in a small but significant percentage drop in mean SBP at 30 min (p < 0.001) and 60 min (p = 0.03) but no difference at 90 min. There was also small but significant percentage drop in mean DBP and HR (DBP: p < 0.001 for 30 min, p = 0.001 for 60 min, and p = 0.02 for 90 min and HR: p < 0.001 for 30 min, 60 min, and 90 min). There were no cumulative effects on change of blood pressure or HR. There were 6 episodes of bradycardia (2.5%) and 12 episodes of moderate to severe hypertension (5%). No significant cardiovascular or hepatic toxicity was found. Conclusion. IVMP is relatively safe and efficacious. IVMP demonstrated mild and noncumulative effects on vital signs. Severe hypertension may occur in susceptible individuals such as those with underlying hypertension and uncontrolled thyroid dysfunction, whereas bradycardia may be more likely in those on beta-blockers.

Thyroid carcinoma with pituitary metastases: 2 case reports and literature review.

We present 2 patients with pituitary metastases from thyroid carcinoma-the first from anaplastic thyroid carcinoma and the second from follicular thyroid carcinoma. The first patient, a 50-year-old lady, presented with 2-week history of hoarseness of voice, dysphagia, dyspnoea, and neck swelling. Imaging revealed metastatic thyroid cancer to lymph nodes and bone. Histology from surgery confirmed anaplastic thyroid cancer. She was found to have pituitary metastases postoperatively when she presented with nonvertiginous dizziness. She subsequently underwent radiotherapy and radioiodine treatment but passed away from complications. The second patient, a 65-year-old lady, presented with loss of appetite and weight with increased goitre size and dyspnoea. Surgery was performed in view of compressive symptoms and histology confirmed follicular thyroid carcinoma. Imaging revealed metastases to bone, lung, and pituitary. She also had panhypopituitarism with hyperprolactinemia and diabetes insipidus. She received radioiodine therapy but eventually passed away from complications.

Clinical characteristics and outcome of thyroid storm: a case series and review of neuropsychiatric derangements in thyrotoxicosis.

OBJECTIVE: The objectives of this study were (1) to describe the presentation, demographics, and clinical course of patients admitted for thyroid storm, and (2) to identify factors associated with mortality. METHODS: A retrospective review of subjects admitted to a single academic hospital from 2006 through 2011 was conducted. Medical records for all patients who were admitted with a diagnosis of thyrotoxicosis were systematically reviewed for clinical features of thyroid storm. RESULTS: A total of 28 cases were identified. Thyroid storm was the first clinical presentation of thyrotoxicosis in 13 patients (46.4%). Noncompliance with treatment was a major trigger in previously diagnosed patients, followed by infection. The mortality rate was 25% in this series. Cardiac manifestations were predominant, with >60% of patients having severe tachycardia (heart rate >140 beats per minunte) and/or atrial fibrillation. Although central nervous system (CNS) involvement was less frequent (n = 8, 28.6%), CNS derangement of worse than mild severity was statistically associated with mortality (P = .021). There was good agreement between the Burch-Wartofsky Point Scale and Japanese Thyroid Association criteria in the diagnosis of thyroid storm in this study cohort. CONCLUSION: Thyroid storm was the first presentation of thyrotoxicosis in a significant proportion of patients, highlighting the importance of a high index of suspicion in an appropriate clinical context. The presence of neuropsychiatric manifestations appeared to portend greater risk of mortality. Prevailing evidence suggests that there are complex interactions between thyroid hormones and neurotransmitter circuits in the pathogenesis of CNS symptomology in thyrotoxicosis.