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Extracellular vesicles in Graves’ disease and Graves’ orbitopathy: immunoregulatory mechanisms, biomarkers, and therapeutic potentials
Graves’ disease (GD) is a common autoimmune thyroid disorder and is often accompanied by Graves’ orbitopathy (GO), an inflammatory eye disease that can significantly reduce the quality of patients’ life. Despite understanding of GD and GO has progressed, the mechanisms driving disease progression remain incompletely defined. Emerging evidence highlights extracellular vesicles (EVs), particularly exosomes, as important mediators of immune regulation and tissue remodeling in autoimmune disorders, including GD and GO. This review summarizes current knowledge of EVs biogenesis and molecular compositions, highlighting their contributions to GD and GO pathogenesis. We also discuss the diagnostic and prognostic potential of EV-associated miRNAs and proteins, and consider findings from other immune-mediated ocular diseases to place these observations in a broader immunopathological context. Overall, EVs appear to be actively involved in GD and GO and may serve as useful tools for disease monitoring and therapy development. Nonetheless, challenges such as methodological variability and limited functional validation remains. Standardized protocols and larger, multicenter studies are needed to support the clinical translation of EV-based approaches.
Journal Article
Management of Graves Thyroidal and Extrathyroidal Disease: An Update
Abstract
Context
Invited update on the management of systemic autoimmune Graves disease (GD) and associated Graves orbitopathy (GO).
Evidence acquisition
Guidelines, pertinent original articles, systemic reviews, and meta-analyses.
Evidence synthesis
Thyrotropin receptor antibodies (TSH-R-Abs), foremost the stimulatory TSH-R-Abs, are a specific biomarker for GD. Their measurement assists in the differential diagnosis of hyperthyroidism and offers accurate and rapid diagnosis of GD. Thyroid ultrasound is a sensitive imaging tool for GD. Worldwide, thionamides are the favored treatment (12-18 months) of newly diagnosed GD, with methimazole (MMI) as the preferred drug. Patients with persistently high TSH-R-Abs and/or persistent hyperthyroidism at 18 months, or with a relapse after completing a course of MMI, can opt for a definitive therapy with radioactive iodine (RAI) or total thyroidectomy (TX). Continued long-term, low-dose MMI administration is a valuable and safe alternative. Patient choice, both at initial presentation of GD and at recurrence, should be emphasized. Propylthiouracil is preferred to MMI during the first trimester of pregnancy. TX is best performed by a high-volume thyroid surgeon. RAI should be avoided in GD patients with active GO, especially in smokers. Recently, a promising therapy with an anti-insulin-like growth factor-1 monoclonal antibody for patients with active/severe GO was approved by the Food and Drug Administration. COVID-19 infection is a risk factor for poorly controlled hyperthyroidism, which contributes to the infection–related mortality risk. If GO is not severe, systemic steroid treatment should be postponed during COVID-19 while local treatment and preventive measures are offered.
Conclusions
A clear trend towards serological diagnosis and medical treatment of GD has emerged.
Journal Article
Going up! : Elisha Otis's trip to the top
The story of the invention of the elevator, which made possible the construction of skyscrapers.
Book
Insulin-like Growth Factor-I Receptor and Thyroid-Associated Ophthalmopathy
Abstract
Thyroid-associated ophthalmopathy (TAO) is a complex disease process presumed to emerge from autoimmunity occurring in the thyroid gland, most frequently in Graves disease (GD). It is disfiguring and potentially blinding, culminating in orbital tissue remodeling and disruption of function of structures adjacent to the eye. There are currently no medical therapies proven capable of altering the clinical outcome of TAO in randomized, placebo-controlled multicenter trials. The orbital fibroblast represents the central target for immune reactivity. Recent identification of fibroblasts that putatively originate in the bone marrow as monocyte progenitors provides a plausible explanation for why antigens, the expressions of which were once considered restricted to the thyroid, are detected in the TAO orbit. These cells, known as fibrocytes, express relatively high levels of functional TSH receptor (TSHR) through which they can be activated by TSH and the GD-specific pathogenic antibodies that underpin thyroid overactivity. Fibrocytes also express insulin-like growth factor I receptor (IGF-IR) with which TSHR forms a physical and functional signaling complex. Notably, inhibition of IGF-IR activity results in the attenuation of signaling initiated at either receptor. Some studies suggest that IGF-IR-activating antibodies are generated in GD, whereas others refute this concept. These observations served as the rationale for implementing a recently completed therapeutic trial of teprotumumab, a monoclonal inhibitory antibody targeting IGF-IR in TAO. Results of that trial in active, moderate to severe disease revealed dramatic and rapid reductions in disease activity and severity. The targeting of IGF-IR with specific biologic agents may represent a paradigm shift in the therapy of TAO.
Journal Article
The chocolate chip cookie queen : Ruth Wakefield and her yummy invention
\"A biography of Ruth Wakefield's life, and her invention of the chocolate chip cookie\"--Provided by publisher.
Book
Thyroid Function Affects the Risk of Stroke via Atrial Fibrillation: A Mendelian Randomization Study
Abstract
Context
Observational studies suggest that variations in normal range thyroid function are associated with cardiovascular diseases. However, it remains to be determined whether these associations are causal or not.
Objective
To test whether genetically determined variation in normal range thyroid function is causally associated with the risk of stroke and coronary artery disease (CAD) and investigate via which pathways these relations may be mediated.
Design, Setting, and Participants
Mendelian randomization analyses for stroke and CAD using genetic instruments associated with normal range thyrotropin (TSH) and free thyroxine levels or Hashimoto’s thyroiditis and Graves’ disease. The potential mediating role of known stroke and CAD risk factors was examined. Publicly available summary statistics data were used.
Main Outcome Measures
Stroke or CAD risk per genetically predicted increase in TSH or FT4 levels.
Results
A 1 standard deviation increase in TSH was associated with a 5% decrease in the risk of stroke (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.91-0.99; P = 0.008). Multivariable MR analyses indicated that this effect is mainly mediated via atrial fibrillation. MR analyses did not show a causal association between normal range thyroid function and CAD. Secondary analyses showed a causal relationship between Hashimoto’s thyroiditis and a 7% increased risk of CAD (OR, 1.07; 95% CI, 1.01-1.13; P = 0.026), which was mainly mediated via body mass index.
Conclusion
These results provide important new insights into the causal relationships and mediating pathways between thyroid function, stroke, and CAD. We identify variation in normal range thyroid function and Hashimoto’s thyroiditis as risk factors for stroke and CAD, respectively.
Journal Article
How the cookie crumbled : the true (and not-so-true) stories of the invention of the chocolate chip cookie
Everyone loves chocolate chip cookies! But not everyone knows where they came from. Meet Ruth Wakefield, the talented chef and entrepreneur who started a restaurant, wrote a cookbook, and invented this delicious dessert st how did she do it, you ask? That's where things get messy!
Book
Graves’ Disease
Graves' disease is an autoimmune disorder in which the thyroid is activated by antibodies to the thyrotropin receptor. The hyperthyroidism that develops is one of many somatic and psychiatric manifestations of the disease that can affect the quality and length of life.
Graves’ disease was first recognized in the 19th century as a syndrome comprising an enlarged and overactive thyroid gland, an accelerated heart rate, and ocular abnormalities (Figure 1). Critical for our current understanding of this disease was the discovery of its autoimmune basis, which results from complex interactions between genetic and environmental factors.
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,
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Graves’ disease has adverse effects on quality of life,
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as a consequence of somatic
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and psychiatric
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symptoms and an inability to work,
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and is associated with an increased risk of death.
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Activating thyrotropin-receptor antibodies induce thyroid hormone overproduction. Many characteristic signs and symptoms of Graves’ disease . . .
Journal Article