Quantitative assessment of extraocular muscles in Graves' ophthalmopathy using T1 mapping.

OBJECTIVE: To evaluate the performance of T1 mapping in the characterization of extraocular muscles (EOMs) of Graves' ophthalmopathy (GO) patients and investigate its feasibility in assessing the response to glucocorticoid therapy in active GO patients. METHODS: A total of 133 participants (78 active GO, 23 inactive GO, 18 Graves' disease (GD) patients, and 14 healthy volunteers) were consecutively enrolled from July 2018 to December 2020. Native T1 (nT1) and postcontrast T1 (cT1) values of EOMs were measured and compared. The variations in T1 mapping metrics of EOMs were compared pre/post glucocorticoid treatment in 23 follow-up active GO patients. Logistic regression analysis and receiver operating characteristic (ROC) curve analysis were performed. RESULTS: The nT1 of EOMs in GO patients was higher than that in GD patients and healthy volunteers. The nT1 of superior rectus (SR) in active GO was higher than that in inactive GO patients, and it could be used as a potential marker of GO activity (OR: 1.003; 95% CI: 1.001, 1.004), with a diagnostic sensitivity of 86.3% and specificity of 43.7%. Meanwhile, the cT1 of SR, inferior rectus (IR), and medial rectus (MR) in inactive GO patients were higher than those in active GO patients. The nT1 of EOMs achieved sufficient diagnostic performance in evaluating the response to glucocorticoid therapy for follow-up active GO patients (AUC, 0.797; sensitivity, 71.9%; specificity, 85.7%). CONCLUSIONS: T1 mapping could quantitatively assess the activity of GO and the response to glucocorticoid therapy in active GO patients and may even potentially reflect the fibrosis of EOMs. CLINICAL RELEVANCE STATEMENT: T1 values can reflect the pathological status of the extraocular muscle. T1 mapping could help to quantitatively assess the clinical activity of GO and the response to glucocorticoid therapy in active GO patients. KEY POINTS: • Graves' ophthalmopathy patients had greater nT1 of extraocular muscles than Graves' disease patients and healthy volunteers, and nT1 of the superior rectus could be a potential marker of Graves' ophthalmopathy activity. • The cT1 of extraocular muscles in inactive Graves' ophthalmopathy patients was higher than that in active Graves' ophthalmopathy patients, and it might be associated with muscle fibrosis. • nT1 of extraocular muscles could offer sufficient diagnostic performance in evaluating the response to glucocorticoid therapy for follow-up active Graves' ophthalmopathy patients.

Does Age or Sex Relate to Severity or Treatment Prognosis in Graves' Disease?

Background: The prognosis of Graves' disease (GD) is reportedly related to sex, age, and genetic factors, although there is no consensus. The objective of this study was to investigate the relationship between severity and prognosis of GD and sex or age. Methods: Subjects were patients newly diagnosed with GD between January 2005 and June 2019, and medical records were retrospectively reviewed. Patients diagnosed between January 2009 and December 2010 and followed up for at least 12 months were enrolled. Patients were divided into nine age-stratified groups. Remission was defined as maintenance of a euthyroid state for more than one year after withdrawal of antithyroid drugs (ATDs). Results: Participants comprised 21,633 patients (3954 males, 17,679 females). Initial free triiodothyronine (fT3) and free thyroxine (fT4) levels significantly decreased with increasing age, including after sex stratification. fT4 was significantly higher in males than females aged 20-39 years. In 2191 patients treated with ATDs alone, median durations until remission were 37.7 and 30.6 months in males and females, respectively. Remission and recurrence were observed in 1391 patients (204 males, 1187 females) and 262 patients (37 males, 225 females), respectively. By Kaplan-Meier analyses, males required a significantly longer time to achieve remission than females (p < 0.0001), although there were no significant age-related differences (p = 0.08). Cox proportional hazard modeling showed a 41% higher hazard ratio (HR) for remission in females than males (adjusted HRs [aHR] confidence interval [CI] = 1.41 [1.21-1.64]), and each additional 10 years of age had a 14% lower rate of recurrence (age [per 10-year increase], aHR [CI] = 0.86 [0.78-0.94]); no significant relationship between recurrence rate and sex was identified. Conclusions: Severity of hyperthyroidism in GD was significantly higher in males in their 20s and 30s, declining with advancing age in both sexes. Females were more likely to achieve remission than males, and younger patients had a higher risk of recurrence, although recurrence was unrelated to sex.

Assessment of subclinical left ventricular dysfunction with speckle-tracking echocardiography in hyperthyroid and euthyroid Graves' disease and its correlation with serum TIMP-1.

BACKGROUND: Graves' disease has a multitude of effects on the cardiovascular system. In the detection of subclinical left ventricular dysfunction, speckle-tracking echocardiography is more useful than conventional echocardiography. The aim of the present study was to compare the longitudinal global strain values and venous blood concentration of (tissue inhibitor of metalloproteinase-1) TIMP-1, a regulator of the extracellular matrix, among hyperthyroid patients with Graves' disease, euthyroid patients with Graves' disease and healthy control subjects. MATERIALS AND METHODS: The study enrolled 40 hyperthyroid patients with newly diagnosed Graves' disease, 40 patients with Graves' disease who were euthyroid for at least 6 months and 40 control subjects with normal thyroid function. Participants underwent conventional echocardiography and speckle-tracking echocardiography to obtain segmental and global longitudinal strain values. In addition, the serum TIMP-1 value was assessed in the venous blood samples of the participants. RESULTS: The hyperthyroid Graves' patients showed greater serum TIMP-1 levels versus the control group and the euthyroid Graves' group. Compared to the control group, the TIMP-1 level was also significantly higher in the euthyroid Graves' group. Lower GLS (global longitudinal strain) average and GLS2C, GLS3C, GLS4C values were observed in both the hyperthyroid and euthyroid Graves' patients compared to the control group. The euthyroid Graves' patients and hyperthyroid Graves' patients had similar GLS values. The serum TIMP-1 level was negatively correlated with global strain values. CONCLUSION: Graves' disease coexists with impaired segmental and global longitudinal strain and increased TIMP-1 levels. This coexistence seems to be independent of serum thyroid hormone levels.

Thyroid Hormone Tests Ordering Practice and Cost-Effectiveness in Samples Referred to International Clinical Laboratories from Addis Ababa Health Facilities.

BACKGROUND: Thyroid dysfunction accounts for majority of endocrine disorders. In sub-Saharan Africa Graves' disease and hypothyroidism have accounted for 13.1% and 8.8% while the burden of thyroid disorder has ranged from 6.18 to47.34% among countries in the Arab world. The cost for a primary thyroid test done to evaluate the gland function constituted a large proportion of the public health budget. For instance, 10 million thyroid functions have been done each year by laboratories which cost 30 million UK pounds, and they represent 8% of laboratory charge in the US. When a TSH-only protocol (guideline) was used, 95% of the requests were sufficient for diagnosis without requiring further tests, thereby resulting in 50% savings on FT4 reagent and reducing the annual TFT reagent cost by 25%. This is an original study, and its objective was to assess the ordering pattern of TSH tests and their cost-effectiveness in patients' samples referred to ICL from Addis Ababa health facilities between July2015 to June 2016. METHOD: An institution-based cross-sectional study design was utilized to study the ordering pattern of thyroid function tests using one-year retrospective data from ICL. RESULTS: Thyroid profiles were ordered more frequently (49.5%) compared to TSH only (24.3%). An additional 2625.70 USD was paid by patients for individual components in the profile tests that turned out normal. CONCLUSION: Guidelines advocate TSH as the initial test for thyroid dysfunction, but the use of a combination of tests is more common.

Disease Burden and Outcome in Children and Young Adults With Concurrent Graves Disease and Differentiated Thyroid Carcinoma.

Context: Adults with differentiated thyroid cancer (DTC) and Graves disease (GD) demonstrate a greater reported disease burden and aggressive DTC behavior. To date, no studies have examined the impact and long-term outcome of concurrent GD and DTC (GD-DTC) in children and young adults. Design: Single institution, retrospective longitudinal cohort study between 1997 and 2016. Participants: One hundred thirty-nine children and young adults with DTC, diagnosed at median age 15 (range, 5 to 23) years, compared with 12 patients with GD-DTC, median age 18 (range, 12 to 20) years. Major Outcome Measures: Patient demographics, preoperative imaging, fine needle aspiration (FNA) cytology, operative and pathological reports, laboratory studies, treatment, and subsequent 2-year outcomes. Results: Compared with DTC, patients with GD-DTC were significantly older at the time of DTC diagnosis (P < 0.01). Patients with GD-DTC were more likely to exhibit microcarcinoma (P < 0.01), and 2 of 12 (17%) demonstrated tall cell variant papillary thyroid cancer (PTC) vs 2 of 139 (2%) in patients who had DTC alone (P = 0.03). Although patients with DTC showed greater lymphovascular invasion (60% vs 25%; P = 0.03), no group differences were noted in extrathyroidal extension, regional lymph node, and distant or lung metastasis. There were no group differences in the 2-year outcome for remission, persistent disease, or recurrence. Conclusions: Concurrent DTC in pediatric patients with GD is not associated with a greater disease burden at presentation and shows no significant difference in 2-year outcomes compared with DTC alone. Similar to adults, microcarcinoma and tall cell variant PTC is prevalent in pediatric patients with GD-DTC. For patients who have GD-DTC with an identified nodule on ultrasound imaging prior to definitive therapy, FNA biopsy is recommended to guide definitive treatment.

Functional assessment of the BMPR2 gene in lymphoblastoid cell lines from Graves' disease patients.

In this study, we analysed the possible influence of the c.419-43delT BMPR2 variant in patients with Graves' disease (GD), in a molecular basis, focusing our efforts on possible alterations in the mRNA processing and synthesis. The molecular assessment of this variant in patients with GD would shed light on the association between the BMPR2 gene and the disease. The variant was detected in 18%, 55% and 10% of patients with pulmonary arterial hypertension, GD and in general population, respectively. Patients with GD fold change showed increased BMPR2 expression when matched against the controls, with a mean of 4.21 ± 1.73 (P = 0.001); BMPR2 was overexpressed in the analysed cell cycle stages. Fold change analysis of variant carriers and non-carriers showed slight overexpression and differences between phases, but none of them were statistically significant. BMPR2 expression was confirmed in the lymphoblastoid cell lines (LCLs) with a molecular weight of 115 kD, and no differences between variant carriers and non-carriers were detected. To conclude, the BMPR2 variant c.419-19delT appears in high frequency in patients with GD, and independently of its presence, BMPR2 is overexpressed in the LCLs from the GD patients tested. This increase could be paired with the described decreased expression of transforming growth factor-ß1 in thyroid tissue from patients with GD.

Socioeconomic Disparities in the Presentation and Treatment of Graves' Disease and Thyroid Eye Disease.

Thyroid eye disease (TED) is an inflammatory, autoimmune orbitopathy with multifactorial etiology. Clinical presentation of TED spans a range from mild surface irritation to vision threatening compressive optic neuropathy. Potential vision loss underscores the importance of understanding genetic and environmental factors influencing the severity of TED presentation. This review will describe the classic risk factors for TED, outline treatments for Graves' disease (GD) and TED, and describe newer evidence of socioeconomic disparities in TED presentation.

Development and Validation of a Pediatric Endocrine Knowledge Assessment Questionnaire: Impact of ac Pediatric Endocrine Knowledge Assessment Questionnaire Intervention Study.

OBJECTIVE: While there is general agreement that patient education is essential for compliance, no objective tools exist to assess knowledge in children and parents of children with endocrine disorders. We aimed to design and validate a Pediatric Endocrine Knowledge Assessment Questionnaire (PEKAQ) for congenital hypothyroidism, Hashimoto's thyroiditis, isolated growth hormone deficiency, Graves' disease, and congenital adrenal hyperplasia. We evaluated baseline knowledge of children and parents of children with these disorders and assessed impact of educational intervention. METHODS: At baseline, 77 children (12-18 years) and 162 parents of children 1-18 years participated in this prospective intervention study. Educational handouts for five targeted disorders were designed. Following one-on-one educational intervention, 55 children and 123 parents participated. Baseline and post-intervention knowledge scores were compared using McNemar's test. RESULTS: Adequate multi-rater Kappa measure of agreement was achieved for children's (0.70) and parent's (0.75) PEKAQs. Flesch Reading Ease Score for both PEKAQs (15 questions each) was 65. Post-intervention, significantly higher proportion of parents and children answered majority of questions correctly (p<0.05). Sixteen percent more parents and 22% more children knew their diagnosis correctly (p<0.05). Significant improvement was noted among all participants regarding reason for treatment, steps to take in a situation of missed dose, exercise and diet with these disorders, and long-term prognosis. Parent's knowledge score was an independent predictor of child's score. CONCLUSIONS: To our knowledge, this is the first validated PEKAQ that can be used widely in pediatric endocrinology clinics. We noted significant improvement in knowledge of children and parents of children with endocrine disorders.

TSI assay utilization: impact on costs of Graves' hyperthyroidism diagnosis.

OBJECTIVES: Thyroid-stimulating immunoglobulins (TSIs) are autoantibodies that bind to the thyroid-stimulating hormone (TSH) receptor on thyroid cells, resulting in Graves' disease (GD), the most common cause of hyperthyroidism. Recently published guidelines recognize the value of anti-TSH receptor antibodies, and a TSI test with high sensitivity and specificity for GD, recently cleared by the US Food and Drug Administration, is now available. Despite this, existing diagnostic algorithms for hyperthyroidism do not currently include TSI testing except in specific cases like pregnancy. The objectives of this analysis are to understand whether incorporating a test that specifically detects TSIs into existing algorithms results in cost savings and reduces time to diagnosis for payers and managed care organizations. STUDY DESIGN: An evidence-based economic model was developed to determine the average time to diagnosis and annual costs associated with various diagnostic algorithms for GD in a population of 100,000 managed care enrollees. Diagnostic algorithms used in current practice and hypothetical algorithms that include the TSI test were identified using published clinical guidelines and interviews with practicing endocrinologists. The model estimates costs of current and TSI test-based diagnostic algorithms using payment amounts for laboratory tests, procedures, and physician visits. RESULTS: Compared with non-TSI algorithms, 100% use of algorithms that include the TSI test result in 46% faster time to diagnosis and generate 47% overall cost savings due in large part to reductions in costly procedures and specialist office visits. CONCLUSIONS: Incorporation and early utilization of the TSI in vitro diagnostic test into current diagnostic algorithms confers cost savings and shortens time to diagnosis.

Detours on the road to diagnosis of Graves disease.

OBJECTIVES: The aims of this study were to determine the frequency at which spurious diagnoses and unnecessary treatment occurs prior to the diagnosis of Graves disease (GD) and to evaluate the economic consequences of these events. METHODS: Retrospective chart review of children diagnosed with GD. RESULTS: A total of 76 children (61 girls) aged 11.9 ± 3.8 years were identified. In all, 17 (22.4%) were referred to other subspecialists prior to diagnosis of GD. Six were hospitalized, and 2 visited emergency rooms. A total of 15 (19.7%) underwent nonthyroid-related studies. Estimated cost of testing and procedures ranged from $49 to $14,000. Twelve (15.8%) were diagnosed with attention deficit/hyperactivity disorder, and 16 (21.1%) were started on medications for other conditions prior to diagnosis of GD. CONCLUSIONS: Evaluation and treatment for presumed other disorders are common in children with GD. A high index of suspicion for hyperthyroidism by primary care providers may help to avoid clinical detours that may be costly and delay diagnosis.

Radioactive iodine 1311 (RAI) treatment. The nearest to the "magic bullet" but should always be preceded by a risk assessment, especially in the pediatric patient.

Radioactive iodine treatment is very frequently the best approach, but it should be optimized by dosimetric and risk considerations.

Treatment options for Graves disease: a cost-effectiveness analysis.

BACKGROUND: First-line treatment for Graves disease is frequently 18 months of antithyroid medication (ATM). Controversy exists concerning the next best line of treatment for patients who have failed to achieve euthyroidism; options include lifelong ATM, radioactive iodine (RAI), or total thyroidectomy (TT). We aim to determine the most cost-effective option. STUDY DESIGN: We performed a cost-effectiveness analysis comparing these different strategies. Treatment efficacy and complication data were derived from a literature review. Costs were examined from a health-care system perspective using actual Medicare reimbursement rates to an urban university hospital. Outcomes were measured in quality-adjusted life-years (QALY). Costs and effectiveness were converted to present values; all key variables were subjected to sensitivity analysis. RESULTS: TT was the most cost-effective strategy, resulting in a gain of 1.32 QALYs compared with RAI (at an additional cost of 9,594 US dollars) and an incremental cost-effectiveness ratio of 7,240 US dollars/QALY. RAI was the least costly option at 23,600 US dollars but also provided the least QALY (25.08 QALY). Once the cost of TT exceeds 19,300 US dollars, the incremental cost-effectiveness ratio of lifelong ATM and TT reverse and lifelong ATM becomes the more cost-effective strategy at 15,000US dollars/QALY. CONCLUSIONS: This is the first formal cost-effectiveness study in the US of the optimal treatment for patients with Graves disease who fail to achieve euthyroidism after 18 months of ATM. Our findings demonstrate that TT is more cost effective than RAI or lifelong ATM in these patients; this continues until the cost of TT becomes > 19,300 US dollars.

Self assessment questions in general surgery.

The advent of Modernising Medical Careers has meant that many more junior doctors are coming into contact with general surgical patients either as part of Foundation Year 2 or Core Training rotation or during the course of cross covering other specialities due to the hours constraints of the European Working Time Directive. These scenarios are all common general surgical cases that such a junior doctor may be expected to manage.

Assessment of the volume of intraorbital structures using the numerical segmentation image technique (NSI): the extraocular muscles.

INTRODUCTION: In recent years the use of computer systems has allowed numerical analysis of medical images to be introduced and has speeded up the conversion of numerical data into clinically valuable information. The creation of a software application that could almost automatically calculate the volume of anatomical structures imaged by MRI has seemed possible. The aim of our study was to determine the clinical usefulness of an numerical segmentation image technique (NSI) software application in estimating the volume of extraocular muscles. MATERIAL AND METHODS: The study group was formed of 45 patients (90 orbits). All the patients underwent MRI examinations of the orbits by a 1.5 T scanner using a head coil. The degree of exophthalmos was determined clinically and radiologically in relation to the interzygomatic line. The quantitative assessment of all eye muscles was carried out using the NSI application, a new software program introduced by the authors. RESULTS: A close correlation between muscle volume and the degree of exophthalmos was revealed and confirmed by statistical analysis (r = 0.543, p = 3.13396E-08) in agreement with other papers. CONCLUSIONS: The NSI software program is an application which offers a reliable and precise estimation of eye muscle volume. It is therefore useful in the diagnosis of the pathological processes leading to exophthalmos. It has special clinical value for monitoring discrete volume changes of muscles during treatment.

[Assessment of autoimmune disease activity in endocrine orbitopathy: comparison of SPECT using 99m-Tc-DTPA or 99m-Tc-depreotide and MRI scores]. / Az autoimmun folyamat aktivitásának megítélése izotópdiagnosztikai módszerekkel endokrin orbitopathiában: a 99mTc-DTPA, a 99m-Tc-depreotid SPECT és az MR összehasonlítása.

INTRODUCTION: Currently there is no ideal imaging technique which could estimate the degree of inflammation in thyroid eye disease. AIM: A new, rapid and cost-effective method, using 99mTc-labelled DTPA and 4-headed SPECT, was developed which is able to diagnose inflammatory activity in patients with endocrine orbitopathy (EOP). METHODS: The MRI T2 relaxation time was used as reference. Comparative orbital SPECT with the more specific 99mTc-Neospect (depreotide) was also performed in the same patients. RESULTS: Visual evaluation of orbital SPECT frames of patients suffering from active EOP could be easily distinguished from inactive EOP patients'. Despite the supposedly different characteristics of the two tested radiopharmaceuticals, there was essentially no difference between their accumulation in the orbit and the information obtained. The MRI activity scores correlated well with 99mTc-DTPA activity uptake (AU). The mean AU value in patients with inactive EOP was 6.26 +/- 1.6 10(-6) ID/cm3, while in active EOP 10.78 +/- 0.61 10(-6) ID/cm3, significantly higher. The 99mTc-DTPA accumulation in the orbital region in active disease was similar to that of depreotide. There was a good correlation (r = 0.91, P < 0.0001) between the two methods. CONCLUSION: The authors concluded that 99mTc-DTPA orbital SPECT is a potentially useful method, which--after initial clinical and MRI staging--gives useful quantitative estimation of disease activity in endocrine orbitopathy. It may provide important visual and quantitative information during the follow up of patients.

Controversies in the clinical evaluation of active thyroid-associated orbitopathy: use of a detailed protocol with comparative photographs for objective assessment.

Despite many learned publications over recent decades, the assessment of active thyroid-associated orbitopathy (TAO) remains difficult and controversial. There are no biochemical, immunological or imaging investigations which can identify active disease reliably, and clinical assessment is still of paramount importance. We therefore review the strengths and weaknesses of all methods of clinical assessment. A new atlas for clinical assessment of soft tissue signs has been developed, and its reproducibility assessed. It details a suggested protocol that could help standardize descriptions of TAO and allow more objective assessment of its activity and severity. This is relevant to general endocrinologists, who have a crucial role in the identification of patients who require ophthalmological assessment. Certain aspects are more relevant to ophthalmologists and endocrinologists who have a special clinical and research interest in TAO. Unless a reproducible system of assessment is devised and widely adopted, it will remain difficult to interpret research meaningfully, particularly if results appear to contradict.

Are serum neopterin concentrations superior to other parameters in the differential diagnosis and prognostic assessment of Graves' disease?

There is a lack (1.) of a single criterion for the definitive differentiation between immunogenic (IH) and non-immunogenic hyperthyroidism (NIH), and (2.) also a lack of an unequivocal prognostic predictor for the individual course of patients with immunogenic hyperthyroidism. In 152 patients scheduled for iodine-131 therapy, serum neopterin concentrations were measured using a commercially available RIA, and the neopterin concentrations of IH (n = 84) and NIH (n = 42) patients were compared. Of these patients, 83 and 26 per cent respectively were treated with antithyroid drugs which did not have a significant impact on neopterin levels. In patients with IH and NIH, the concentrations [mean +/- SD] of neopterin were 1.89 +/- 0.79 milligrams and 1.98 +/- 0.9 milligrams, respectively (p = 0.4). After therapy with iodine-131, 28% of the IH-patients were euthyroid, 32% hyperthyroid, and 40% hypothyroid. In finally euthyroid patients, pretherapeutic neopterin concentrations were higher (3.1 +/- 2.8 milligrams) than in finally hyperthyroid (1.8 +/- 0.7 milligrams), or hypothyroid (1.6 +/- 0.7 milligrams) patients. These results argue against a relevant clinical role of neopterin concentrations for the differential diagnosis of IH versus NIH in these patients. However, a prognostic significance of neopterin concentrations in patients with IH is suggested.

MR T2 relaxation time for the assessment of retrobulbar inflammation in Graves' ophthalmopathy.

The results of 39 patients with severe Graves' ophthalmopathy (GO), who were monitored by magnetic resonance imaging (MRI) and tonography before and after combined immunosuppressive treatment with cyclosporine and corticosteroids, are presented. A correlation was found between the decrease in T2 relaxation time of the superior, medial, and inferior rectus muscle (p < 0.01) and the response to the immunosuppressive treatment. Muscle thickness and intraocular pressure showed less improvement (p < 0.05). The infiltrative eye signs improved partially in correlation with the T2 relaxation time. By distinguishing inflammation of the extraorbital muscles from fibrosis, the T2 relaxation time can help to select patients that benefit from immunosuppressive treatment as well as to monitor the therapeutic effect.