Inhibition of TSH/IGF-1 receptor crosstalk by Teprotumumab as a treatment modality of Thyroid Eye Disease

Context We previously presented evidence that TSH receptor (TSHR)-stimulating autoantibodies (TSAbs) bind to and activate TSHRs but do not bind to IGF1 receptors (IGF1Rs). Nevertheless, we showed that IGF1Rs were involved in thyroid eye disease (TED) pathogenesis because TSAbs activated crosstalk between TSHR and IGF1R. Teprotumumab, originally generated to inhibit IGF1 binding to IGF1R, was recently approved for the treatment of TED (Tepezza®). Objective To investigate the role of TSHR/IGF1R crosstalk in teprotumumab treatment of TED. Design We used orbital fibroblasts from patients with TED (TEDOFs) and measured stimulated hyaluronan (HA) secretion as a measure of orbital fibroblast activation by TED immunoglobulins (TED-Igs) and monoclonal TSAb M22. We previously showed that M22, which does not bind to IGF1R, stimulated HA in a biphasic dose-response with the higher-potency phase dependent on TSHR/IGF1R crosstalk and the lower-potency phase independent of IGF1R. Stimulation by TED-Igs and M22 was measured in the absence or presence of Teprotumumab Biosimilar (Tepro) or K1-70, an antibody that inhibits TSHR. Results We show: 1) Tepro dose-dependently inhibits stimulation by TED-Igs; 2) Tepro does not bind to TSHRs; 3) Tepro inhibits IGF1R-dependent M22-induced HA production, which is mediated by TSHR/IGF1R crosstalk, but not IGF1R-independent M22 stimulation; and 4) β-arrestin 1 knockdown, which blocks TSHR/IGF1R crosstalk, prevents Tepro inhibition of HA production by M22 and by a pool of TED-Igs. Conclusion We conclude that Tepro inhibits HA production by TEDOFs by inhibiting TSHR/IGF1R crosstalk and suggest that inhibition of TSHR/IGF1R crosstalk is the mechanism of its action in treating TED.

Unilateral gynecomastia as an initial presentation of hyperthyroid Graves’ disease

Summary Graves’ disease is an autoimmune condition leading to the activation of and an increase in thyroid hormone secretion. Manifestations of hyperthyroidism in Graves’ disease can vary among people. In this case, we report a 24-year-old Thai man with a rare presentation of unilateral gynecomastia along with symptoms of thyrotoxicosis. Physical examination revealed a 3 cm non-tender palpable glandular tissue beneath and around the left areola without nipple discharge and moderately diffuse thyroid enlargement with thyroid bruit. Thyroid function test showed a typical thyrotoxicosis state with elevated serum-free T4 and decreased serum TSH. His diagnosis of Graves’ disease was confirmed biochemically with a highly elevated anti-TSH receptor antibody. Early treatment with anti-thyroid medication was given first, followed by Radioiodine treatment (RAI) for definitive treatment due to high level of anti-TSH receptor antibody, enlarged thyroid and severe thyrotoxicosis presentation at a young age, which might not resolve by anti-thyroid medication alone. The patient responded well to treatment and achieved complete resolution of unilateral gynecomastia with clinically and biochemically euthyroid within 3 months after treatment. No recurrent gynecomastia was found during the 2-year follow-up. Learning points Characteristic of gynecomastia in hyperthyroidism is usually presented with bilateral progressive gynecomastia; however, unilateral gynecomastia is occasionally found as a presentation of hyperthyroidism. Complete resolution of gynecomastia without recurrence can be achieved within a few months of treatment after thyrotoxicosis is resolved in patients with hyperthyroidism with the recent development of gynecomastia. RAI for definitive treatment is recommended in young adult patients expressing very high anti-TSH antibody level with severe thyrotoxicosis.

Recurrence of Graves’ Disease (a Th1-type Cytokine Disease) Following SARS-CoV-2 mRNA Vaccine Administration: A Simple Coincidence?

Graves’ disease is the most frequent cause of hyperthyroidism in young women. This auto-immune disease is due to the production of class 1 IgG stimulating the TSH receptor. These antibodies are produced secondary to a Th1 immune response in which interferon gamma plays a key role. Vaccination is ongoing worldwide against SARS-CoV-2 and some of the vaccines include mRNA which seems to stimulate the Th1 immune response. Here, we report a case of recurrence of hyperthyroidism due to Graves’ disease following mRNA vaccination and discuss the possible implicated mechanism. This observation argues for a systematic study of a population of patients with previous Graves’ disease in order to assess the risk of recurrence following vaccination.

Caracterización de recién nacidos hijos de madres portadoras de enfermedad de Graves

El hipertiroidismo neonatal es una enfermedad que puede asociarse a mortalidad y secuelas. No existe a la fecha, una serie clínica de casos que permita conocer la realidad local de esta condición.Objetivo: Caracterizar desde el punto de vista clínico y de laboratorio a recién nacidos (RN) hijos de madres con Enfermedad de Graves (EG).Sujetos y Método: Estudio prospectivo de RN hijos de madres con antecedente de EG, en dos hospitales públicos de Santiago, por un período de 5 años. Se analizaron variables clínicas y de laboratorio de los binomios madre-hijo. Se analizaron los anticuerpos antireceptor de hormona tiroestimulante (por su acrónimo en inglés: TSH receptor antibodies, TRAbs). Se buscaron asociaciones entre estas variables y el desarrollo de hipertiroidismo neonatal.Resultados: Se incluyeron 76 binomios madre-hijo (0,2% del total de partos). Cinco neonatos (6,6%) presentaron hipertiroidismo bioquímico, y 3 de ellos desarrollaron enfermedad clínica y requirieron tratamiento. Los 5 RN que desarrollaron hipertiroidismo tenían madres con TRAbs positivos o indeterminados. Ningún hijo de madre con TRAbs negativo desarrolló la enfermedad. Sólo un 65% de las madres y un 72% de los RN pudieron tener determinación de TRAbs. Hubo una correlación significativa entre los títulos de TRAbs maternos (p < 0,03), TRAbs neonatales (p < 0,008) y la TSH neonatal tomada entre los días 2-6 (p < 0,006), con el desarrollo posterior de hipertiroidismo. Todos los casos de hipertiroidismo neonatal fueron transitorios. No hubo mortalidad en nuestra casuística.Conclusiones: En esta primera serie nacional de casos de hijos de madres con EG. Los TRAbs maternos, neonatales y la TSH entre los días 2-6 de vida fueron predictores de hipertiroidismo neonatal.

Thyroid-related ophthalmopathy development in concurrence with growth hormone administration

Background Thyroid stimulating hormone (TSH) receptor and local infiltrate lymphocytes have been considered as major pathological factors for developing thyroid-related ophthalmopathy. Overexpression of insulin-like growth factor-I (IGF-I) receptor has emerged as a promising therapeutic target for refractory patients. However, the relationship between activation of growth hormone (GH)/IGF-I receptor signaling and development or exacerbation of thyroid ophthalmopathy has not been elucidated. Herein we describe a case that provides further clarification into the association between thyroid-related ophthalmopathy and GH/IGF-I receptor signaling. Case presentation A 62-year-old Japanese female diagnosed with thyroid-related ophthalmopathy was admitted to Kurume University Hospital. She had received daily administration of GH subcutaneously for severe GH deficiency; however, serum IGF-I levels were greater than + 2 standard deviation based on her age and sex. She exhibited mild thyrotoxicosis and elevation in levels of TSH-stimulating antibody. Discontinuation of GH administration attenuated the clinical activity scores of her thyroid-related ophthalmopathy. Additionally, concomitant use of glucocorticoid and radiation therapies resulted in further improvement of thyroid-related ophthalmopathy. The glucocorticoid administration was reduced sequentially, followed by successful termination. Thereafter, the patient did not undergo recurrence of thyroid-related ophthalmopathy and maintained serum IGF-I levels within normal physiological levels. Conclusions We describe here a case in which development of thyroid-related ophthalmopathy occurred upon initiation of GH administration. GH/IGF-I signaling was highlighted as a risk factor of developing thyroid-related ophthalmopathy. Additionally, aberrant TSH receptor expression was suggested to be a primary pathophysiological mechanism within the development of thyroid-related ophthalmopathy. Physicians should be aware of the risks incurred via GH administration, especially for patients of advanced age, for induction of thyroid-related ophthalmopathy.

Hyperthyroidism in Children

Hyperthyroidism is the state of excessive synthesis and release of the thyroid hormones by thyrocytes. Graves’ disease is the most common cause of hyperthyroidism in children. The condition may occur at any age but the prevalence increases with age. According to the classical paradigm, coexistence of genetic susceptibility, environment triggers and immunological dysfunction are responsible for its development. Diagnosis of Graves’ disease is based on presence of characteristic clinical symptoms, TSH receptor antibodies and excess of thyroid hormones. The management in pediatric population involves mainly pharmacotherapy (thyrostatics, β-adrenolitics), in resistant cases radical radioiodine I131 therapy or surgical treatment is necessary.

Predicting the Course of Graves’ Orbitopathy Using Serially Measured TSH-Receptor Autoantibodies by Automated Binding Immunoassays and the Functional Bioassay

The aim of the study was to investigate the use of serial measurements of TSH-receptor autoantibodies (TRAb) with the newest available assay technology to predict the course of Graves’ Orbitopathy (GO) during the first 24 months from disease onset. Serial serum samples from patients with GO (103 mild/135 severe) were collected between 2007 and 2017 and retrospectively analyzed. The course of GO were classified into mild/severe 12 months after manifestation (severe: NOSPECS≥5; mild<5). TRAb were measured with automated binding immunoassays (IU/l): TRAb Elecsys (Cobas, Roche), TRAb bridge assay (IMMULITE, Siemens), and a cell-based bioassay (percent of specimen to reference ratio - SRR%) (Thyretain, Quidel). Variable cut off levels of measured TRAb were calculated at specificity of 90% from receiver operator curve (ROC) analysis for several timepoints during the course of GO. To select one: 5–8 months after first GO symptoms, which is the timepoint for usual referals for treatment mild course could be predicted at cut offs of 1.5 IU/l (Elecsys), 0.8 IU/l (Immulite) and 402% SRR (Thyretain) and the risc of severe course has to be anticipated if TRAb are above 11.6 IU/l (Elecsys), 6.5 IU/l (Thyretain), and 714% SRR (Thyretain). The Thyretain bioassay showed the highest diagnostic sensitivity (using the commercial cut off’s) over the entire follow up period. TRAb measurements during the 24-month follow up of GO provide added value to the GO clinical activity and severity scores and should be used especially in the event of an unclear decision-taking situation with regard to therapy.

The Amino Acid Transporter Mct10/Tat1 Is Important to Maintain the TSH Receptor at Its Canonical Basolateral Localization and Assures Regular Turnover of Thyroid Follicle Cells in Male Mice

Cathepsin K-mediated thyroglobulin proteolysis contributes to thyroid hormone (TH) liberation, while TH transporters like Mct8 and Mct10 ensure TH release from thyroid follicles into the blood circulation. Thus, thyroid stimulating hormone (TSH) released upon TH demand binds to TSH receptors of thyrocytes, where it triggers Gαq-mediated short-term effects like cathepsin-mediated thyroglobulin utilization, and Gαs-mediated long-term signaling responses like thyroglobulin biosynthesis and thyrocyte proliferation. As reported recently, mice lacking Mct8 and Mct10 on a cathepsin K-deficient background exhibit excessive thyroglobulin proteolysis hinting towards altered TSH receptor signaling. Indeed, a combination of canonical basolateral and non-canonical vesicular TSH receptor localization was observed in Ctsk−/−/Mct8−/y/Mct10−/− mice, which implies prolonged Gαs-mediated signaling since endo-lysosomal down-regulation of the TSH receptor was not detected. Inspection of single knockout genotypes revealed that the TSH receptor localizes basolaterally in Ctsk−/− and Mct8−/y mice, whereas its localization is restricted to vesicles in Mct10−/− thyrocytes. The additional lack of cathepsin K reverses this effect, because Ctsk−/−/Mct10−/− mice display TSH receptors basolaterally, thereby indicating that cathepsin K and Mct10 contribute to TSH receptor homeostasis by maintaining its canonical localization in thyrocytes. Moreover, Mct10−/− mice displayed reduced numbers of dead thyrocytes, while their thyroid gland morphology was comparable to wild-type controls. In contrast, Mct8−/y, Mct8−/y/Mct10−/−, and Ctsk−/−/Mct8−/y/Mct10−/− mice showed enlarged thyroid follicles and increased cell death, indicating that Mct8 deficiency results in altered thyroid morphology. We conclude that vesicular TSH receptor localization does not result in different thyroid tissue architecture; however, Mct10 deficiency possibly modulates TSH receptor signaling for regulating thyrocyte survival.