A Rare and Unusual Evolution of Hypothyroidism in Hashimoto's Thyroiditis to Graves' Disease: A Case Report and Literature Review.

Our article examines a rare case where hypothyroidism due to Hashimoto's thyroiditis progressed, after a long period (three years) of L-thyroxine substitution, into confirmed hyperthyroidism due to Graves' disease in a 69-year-old man. The article explores possible mechanisms of this unusual transition based on our case and others reported in the literature. Findings suggest that the coexistence of Hashimoto's thyroiditis and Graves' disease can lead to transitions between hypothyroidism and hyperthyroidism, influenced by the predominance of involved antibodies and residual capacity of thyroid tissue. The authors emphasize the importance of further studies to better understand these transitions and identify at-risk patients. In conclusion, the article highlights the necessity of considering the rare possibility of transition to Graves' disease in patients presenting with persistent hyperthyroidism despite cessation of L-thyroxine.

New Insights into the Biological Functions of Essential TsaB/YeaZ Protein in Staphylococcus aureus.

TsaB/YeaZ represents a promising target for novel antibacterial agents due to its indispensable role in bacterial survival, high conservation within bacterial species, and absence of eukaryotic homologs. Previous studies have elucidated the role of the essential staphylococcal protein, TsaB/YeaZ, in binding DNA to mediate the transcription of the ilv-leu operon, responsible for encoding key enzymes involved in the biosynthesis of branched-chain amino acids-namely isoleucine, leucine, and valine (ILV). However, the regulation of ILV biosynthesis does not account for the essentiality of TsaB/YeaZ for bacterial growth. In this study, we investigated the impact of TsaB/YeaZ depletion on bacterial morphology and gene expression profiles using electron microscopy and deep transcriptomic analysis, respectively. Our results revealed significant alterations in bacterial size and surface smoothness upon TsaB/YeaZ depletion. Furthermore, we pinpointed specific genes and enriched biological pathways significantly affected by TsaB/YeaZ during the early and middle exponential phases and early stationary phases of growth. Crucially, our research uncovered a regulatory role for TsaB/YeaZ in bacterial autolysis. These discoveries offer fresh insights into the multifaceted biological functions of TsaB/YeaZ within S. aureus.

Correlation between extraocular muscle enlargement and thyroid autoantibodies in thyroid eye disease.

PURPOSE: This study aimed to investigate the factors affecting extraocular muscle enlargement in thyroid eye disease (TED). STUDY DESIGN: Retrospective study. METHODS: The thyroid-stimulating hormone (TSH) receptor antibody (TRAb), thyroid-stimulating antibody (TSAb), antithyroid peroxidase antibody (ATPO), and antithyroglobulin antibody (ATG) levels in patients diagnosed with TED who underwent orbital magnetic resonance imaging were assessed. The control group comprised the contralateral eye of patients who underwent orbital magnetic resonance imaging (MRI) for unilateral eyelid tumors or orbital disease. The thickness of the bilateral rectus muscles and superior oblique muscles was measured on orbital MRI. Muscle enlargement was classified as unilateral/bilateral and symmetric/asymmetric. The effects of age, sex, smoking history, TSH, thyroid hormone, and thyroid autoantibodies on the muscle thickness and number of enlarged muscles were assessed by use of simple and multiple regression analyses. RESULTS: The TED and control groups comprised 41 and 44 cases, respectively. The positivity rate of TSAb in patients with TED was 92.7% higher than that of the other autoantibodies. Muscle enlargement was observed in 29 of the 41 cases (70.7%). Older age and higher TSAb levels were identified as significant factors affecting the total muscle thickness and number of enlarged muscles. Bilateral muscle enlargement and asymmetrical muscle enlargement were observed in 17 (58.6%) and 23 (79.3%) of the 29 cases, respectively. The TSAb levels and age had no significant effect on the type of muscle enlargement. CONCLUSIONS: TSAb showed significant associations with extraocular muscle enlargement. Measurement of TSAb, rather than of TRAb, may be more useful for diagnosing extraocular muscle enlargement in patients with TED.

Transition from Hashimoto thyroiditis to Graves's Disease: an unpredictable change?

PURPOSE: Hashimoto thyroiditis and Graves's disease are two related autoimmune disorders, representing the leading causes of hypothyroidism and hyperthyroidism. Autoimmune hypothyroidism is generally irreversible but very rarely, some patients would shift to hyperthyroidism. The aim of the study was to seek for possible clinical predictors of the transition from hypo to hyperthyroidism in patients with Hashimoto thyroiditis and to outline their clinical phenotype. METHODS: Twelve patients with overt autoimmune hypothyroidism who had at least one transition from hypothyroidism to autoimmune hyperthyroidism were compared with 294 consecutive patients with autoimmune hypothyroidism and 69 consecutive patients with autoimmune hyperthyroidism that accessed the outpatient clinic over six months. Demographic, hormonal data and autoantibodies titers were compared. RESULTS: Prevalence of smoking habit was significantly higher in switchers compared to controls. Switchers showed a significantly higher prevalence of personal and familial history of non-thyroidal autoimmune disorders. TSH levels were significantly lower in the switcher group during the hypothyroid phase and levothyroxine dose required was lower. TSH concentrations were significantly lower while free fT4 and free fT3 values were higher in GD patients compared to switchers during the hyperthyroid phase despite comparable TRAb levels. Prevalence and type of hyperthyroid symptoms and orbitopathy were similar between switchers and GD group. Mean dose of anti-thyroid drugs was significantly higher in GD patients compared to switchers. No differences were observed in the remission rate from hyperthyroidism between the two groups, despite switchers showed a significantly lower time-to-remission. CONCLUSIONS: Conversion of Hashimoto Thyroiditis towards Graves' disease is a rare phenomenon which can occur almost at any time after the development of autoimmune hypothyroidism. Our findings suggest active surveillance of hypothyroid patients who require frequent reduction of levothyroxine during follow up and testing for TSHR antibodies in these patients.

Characterizing the Interplay of Lymphocytes in Graves' Disease.

Graves' disease (GD) is a thyroid-specific autoimmune disease with a high prevalence worldwide. The disease is primarily mediated by B cells, which produce autoantibodies against the thyroid-stimulating hormone receptor (TSHR), chronically stimulating it and leading to high levels of thyroid hormones in the body. Interest in characterizing the immune response in GD has motivated many phenotyping studies. The immunophenotype of the cells involved and the interplay between them and their secreted factors are crucial to understanding disease progression and future treatment options. T cell populations are markedly distinct, including increased levels of Th17 and follicular helper T cells (Tfh), while Treg cells appear to be impaired. Some B cells subsets are autoreactive, and anti-TSHR antibodies are the key disease-causing outcome of this interplay. Though some consensus across phenotyping studies will be discussed here, there are also complexities that are yet to be resolved. A better understanding of the immunophenotype of Graves' disease can lead to improved treatment strategies and novel drug targets.

Conservation and Diversification of tRNA t6A-Modifying Enzymes across the Three Domains of Life.

The universal N6-threonylcarbamoyladenosine (t6A) modification occurs at position 37 of tRNAs that decipher codons starting with adenosine. Mechanistically, t6A stabilizes structural configurations of the anticodon stem loop, promotes anticodon-codon pairing and safeguards the translational fidelity. The biosynthesis of tRNA t6A is co-catalyzed by two universally conserved protein families of TsaC/Sua5 (COG0009) and TsaD/Kae1/Qri7 (COG0533). Enzymatically, TsaC/Sua5 protein utilizes the substrates of L-threonine, HCO3-/CO2 and ATP to synthesize an intermediate L-threonylcarbamoyladenylate, of which the threonylcarbamoyl-moiety is subsequently transferred onto the A37 of substrate tRNAs by the TsaD-TsaB -TsaE complex in bacteria or by the KEOPS complex in archaea and eukaryotic cytoplasm, whereas Qri7/OSGEPL1 protein functions on its own in mitochondria. Depletion of tRNA t6A interferes with protein homeostasis and gravely affects the life of unicellular organisms and the fitness of higher eukaryotes. Pathogenic mutations of YRDC, OSGEPL1 and KEOPS are implicated in a number of human mitochondrial and neurological diseases, including autosomal recessive Galloway-Mowat syndrome. The molecular mechanisms underscoring both the biosynthesis and cellular roles of tRNA t6A are presently not well elucidated. This review summarizes current mechanistic understandings of the catalysis, regulation and disease implications of tRNA t6A-biosynthetic machineries of three kingdoms of life, with a special focus on delineating the structure-function relationship from perspectives of conservation and diversity.

Identification of patients with Graves' disease who benefit from high-dose radioactive iodine therapy.

OBJECTIVE: Radioactive iodine (RAI) therapy is a useful treatment for Graves' disease (GD). Most RAI sessions administer ≤ 500 MBq of iodine (I)-131. Sometimes patients require repeated RAI, often for longer periods of remission. We investigated the characteristics of patients for whom high dose (mostly 1110 MBq of I-131) RAI was effective as RAI therapy for GD. METHODS: We retrospectively analyzed the cases of 79 patients who underwent RAI for GD in a multicenter setting. We divided the patients into two groups based on the I-131 dose administered: the low dose (LD) group who received ≤ 500 MBq (n = 44) and the high dose (HD) group who received > 500 MBq (n = 35). The therapeutic effect was defined as achieving remission and reaching the point of participating in thyroid hormone replacement therapy within 1 year after RAI. We compared the LD and HD groups' remission rates and conducted a multivariate logistic regression analysis of predictive factors for remission. In a simulation, using the formula for predicting the probability of remission obtained from the analysis results, we estimated how much the remission rate would change if the I-131 dose is increased from 500 to 1110 MBq. RESULTS: The mean ± standard deviation I-131 dose administered in the LD group was 480 ± 6 MBq, and that of the HD group was 1054 ± 265 MBq. Thirty-five patients (80%) in the LD group and 26 patients (74%) in the HD group achieved remission; this difference in the remission rate was not significant. The multivariate analysis results demonstrated that the absorbed dose and thyroid-stimulating antibody (TSAb) were independent predictors of remission. Seven patients (8.9%) showed an increased probability of remission from < 50% to > 50% when the higher RAI dose was applied (1110 MBq instead of 500 MBq). The thyroid volume and TSAb values in these patients were relatively large at 54.7 ± 34.2 mL and 1378.4 ± 586.3%, respectively. CONCLUSION: Although the overall remission rate was not significantly different between the patients who received high- or low-dose I-131, treatment with high-dose RAI may improve the probability of remission in patients with a massive thyroid volume and/or high-TSAb Graves' disease.

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) ß-arrestin 1 knockdown, which blocks TSHR/IGF1R crosstalk and 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.

Orbital Signaling in Graves' Orbitopathy.

Graves' orbitopathy (GO) is a complex and poorly understood disease in which extensive remodeling of orbital tissue is dominated by adipogenesis and hyaluronan production. The resulting proptosis is disfiguring and underpins the majority of GO signs and symptoms. While there is strong evidence for the thyrotropin receptor (TSHR) being a thyroid/orbit shared autoantigen, the insulin-like growth factor 1 receptor (IGF1R) is also likely to play a key role in the disease. The pathogenesis of GO has been investigated extensively in the last decade with further understanding of some aspects of the disease. This is mainly derived by using in vitro and ex vivo analysis of the orbital tissues. Here, we have summarized the features of GO pathogenesis involving target autoantigens and their signaling pathways.

Intestinal microbiota changes in Graves' disease: a prospective clinical study.

Graves' disease (GD) occurs due to an autoimmune dysfunction of thyroid gland cells, leading to manifestations consistent with hyperthyroidism. Various studies have confirmed the link between autoimmune conditions and changes in the composition of intestinal microbial organisms. However, few studies have assessed the relationship between the GD and the changes in intestinal microbiota. Therefore, the present study aimed to investigate changes in intestinal flora that may occur in the setting of GD. Thirty-nine patients with GD and 17 healthy controls were enrolled for fecal sample collection. 16S rRNA sequencing was used to analyze the diversity and composition of the intestinal microbiota. High-throughput sequencing of 16S rRNA genes of intestinal flora was performed on Illumina Hiseq2500 platform. Comparing to healthy individuals, the number of Bacilli, Lactobacillales, Prevotella, Megamonas and Veillonella strains were increased, whereas the number of Ruminococcus, Rikenellaceae and Alistipes strains were decreased among patients with GD. Furthermore, patients with GD showed a decrease in intestinal microbial diversity. Therefore, it indicates that the diversity of microbial strains is significantly reduced in GD patients, and patients with GD will undergo significant changes in intestinal microbiota, by comparing the intestinal flora of GD and healthy controls. These conclusions are expected to provide a preliminary reference for further researches on the interaction mechanism between intestinal flora and GD.

Painless Thyroiditis with Thyrotropin Receptor-blocking and Receptor-stimulating Autoantibodies.

We herein report a rare case of a 41-year-old woman with painless thyroiditis who was positive for thyrotropin (TSH) receptor-blocking (TBAbs) and receptor-stimulating autoantibodies (TSAbs) in the thyrotoxic phase. Her serum thyroid hormone levels were high, and TSH was undetectable. The low uptake of 99mTc led to the diagnosis of painless thyroiditis. M22-TRAb, TBAb and TSAb were detectable in the thyrotoxic phase. Three months later, she became severely hypothyroid. M22-TRAb and TBAb were still strongly positive, although the TSAb levels had decreased to just above the reference range. In this case, TBAb led to hypothyroidism.

Three Consecutive Pregnancies in a Patient with Chronic Autoimmune Thyroid Disease Associated with Hypothyroidism and Extremely High Levels of Anti-Thyrotropin Receptor Antibodies.

Background: Thyroid-stimulating hormone (TSH) receptor (TSHR) antibodies (TRAb) can be present in chronic autoimmune thyroiditis. Transplacental TRAb transfer can lead to fetal thyroid dysfunction and serious complications. Patient Findings: We report the case of a woman with autoimmune hypothyroidism and extremely high TRAb levels, with blocking and stimulating activities (biological activities characterized with Chinese hamster ovary cells expressing TSHR). At week 22 of her first pregnancy, sonography detected fetal growth retardation and cardiac abnormalities (extreme tachycardia, right ventricular dilatation, pericardial effusion). The mother's TRAb level, assayed later, was 4030 IU/L (n < 10). Delivered via caesarean section gestational week 30, the newborn girl had several malformations, signs of malnutrition, goiter and hyperthyroidism associated with elevated TRAb (1200 IU/L). The newborn died 26 days after delivery. Faced with persistently high TRAb levels and a desire to become pregnant again, the woman was treated with three consecutive 740-MBq activities of iodine-131, which resulted in a decrease in TRAb to 640 IU/L. The patient had two subsequent pregnancies 16 and 72 months after the radioiodine administration. During the close follow-ups, fetal development was normal, and initial TRAb levels during the two pregnancies were 680 and 260 IU/L, respectively, which initially decreased but then increased in late pregnancy. In both cases, labor was induced at 34 weeks. The newborns, mildly hyperthyroid at birth, required carbimazole treatment at days 5 and 2, respectively. The mild hyperthyroidism despite high TRAb levels was likely due to the concomitant presence of stimulating and blocking TRAb. The two girls, now aged 12 and 8 years, are in good health. The mother has no detectable thyroid gland tissue and is euthyroid on levothyroxine (175 µg/d). Her TRAb level gradually decreased to 136 IU/L. Summary and Conclusions: This remarkable case illustrates the severe consequences of untreated fetal hyperthyroidism and the need to assay and follow-up TRAb levels in women of reproductive age with autoimmune thyroiditis.

Usefulness of TSH receptor antibodies as biomarkers for Graves' ophthalmopathy: a systematic review.

PURPOSE: Over the past several decades, many papers have been published about the usefulness of thyrotropin receptor antibodies (TRAbs) as biomarkers of Graves' ophthalmopathy (GO). However, results have been inconsistent. The purpose of this analysis is to determine a possible cause of these discrepancies and to examine the usefulness of TRAbs as biomarkers for GO, especially 'thyrotropin-binding inhibiting immunoglobulin (TBII)' and 'thyroid-stimulating antibody (TSAb)'. METHOD: 26 articles discussing the association between TRAbs and GO were selected which were then divided into three groups based on the study method and whether or not the patients had been treated for hyperthyroidism. From the results of the papers reviewed, a provisional conclusion was made and a theoretical model on the TBII-TSAb coordinate plane was developed to confirm that conclusion. RESULTS: TSAb is reported to be significantly or strongly associated with GO in the studies of pre- and post-treated patients for hyperthyroidism. TBII is positively correlated, negatively correlated or uncorrelated with GO in studies of pre-treated patients. However, it is generally agreed upon that TBII and GO are closely correlated in studies of post-treated patients. CONCLUSION: We conclude that the level of TBII may not be a reliable indicator of the current state of GO in pre-treated patients. Whereas, in post-treated patients, due to changes in the correlation between TBII and TSAb due to the effect of hyperthyroidism treatment, the level of TBII can be a more reliable indicator of GO. Furthermore, the current level of TBII is closely associated with the onset and severity of GO in the future and it can be a valid predictor of GO. However, the TSAb level appears to be more reliable.

Cirripede Cypris Antennules: How Much Structural Variation Exists Among Balanomorphan Species from Hard-Bottom Habitats?

Barnacle cypris antennules are important for substratum attachment during settlement and on through metamorphosis from the larval stage to sessile adult. Studies on the morphology of cirripede cyprids are mostly qualitative, based on descriptions from images obtained using a scanning electron microscope (SEM). To our knowledge, our study is the first to use scanning electron microscopy to quantify overall structural diversity in cypris antennules by measuring 26 morphological parameters, including the structure of sensory organs. We analyzed cyprids from seven species of balanomorphan barnacles inhabiting rocky shore communities; for comparison, we also included a sponge-inhabiting balanomorphan and a verrucomorphan species. Multivariate analysis of the structural parameters resulted in two distinct clusters of species. From nonmetric multidimensional scaling plots, the sponge-inhabiting Balanus spongicola and Verruca stroemia formed one cluster, while the other balanomorphan species, all from hard bottoms, grouped together in the other cluster. The shape of the attachment disk on segment 3 is the key parameter responsible for the separation into two clusters. The present results show that species from a coastal hard-bottom habitat may share a nearly identical antennular structure that is distinct from barnacles from other habitats, and this finding supports the fact that such species also have rather similar reactions to substratum cues during settlement. Any differences that may be found in settlement biology among such species must therefore be due either to differences in the properties of their adhesive mechanisms or to the way that sensory stimuli are detected by virtually identical setae and processed into settlement behavior by the cyprid.

Oscillating hypothyroidism and hyperthyroidism - a case-based review.

OBJECTIVE/BACKGROUND: To discuss a unique clinical entity where inappropriate activity of inhibitory and stimulatory thyroid antibodies resulted in alternating hypothyroidism and hyperthyroidism. METHODS: We report the clinical history, laboratory data, and results of imaging studies, along with the pathophysiological mechanism and the subsequent treatment in a patient with fluctuating thyroid functional status. RESULTS: A 52-year-old female was treated for hypothyroidism for more than two decades. She started having symptoms of hyperthyroidism along with a suppressed thyroid-stimulating hormone (TSH). She continued to have persistent symptoms despite stopping her levothyroxine. Her free T3 and T4 were elevated along with an increased radioactive uptake scan. She was diagnosed with Graves' disease and started on methimazole, which relieved her symptoms for a few months. Subsequently, her TSH began to rise beyond expected level, her hypothyroid symptoms reappeared, and methimazole was discontinued. Following this, she again developed symptoms of hyperthyroidism and thyroid values revealed an undetectable TSH. She had at least two such documented cycles of hyperthyroidism alternating with hypothyroidism. She was eventually treated with radioactive iodine ablation followed by levothyroxine replacement. Swinging dominance of TSH-blocking autoantibodies (TBAb) and thyroid-stimulating autoantibodies (TSAb) triggered by methimazole and levothyroxine, respectively, is likely the underlying mechanism. CONCLUSIONS: Physicians should be vigilant to the phenomenon of spontaneous conversion of hypothyroidism to hyperthyroidism, or vice versa, in a subset of patients with autoimmune thyroid disease. Repeated assessment of thyroid function along with measurement of TBAb and TSAb are invaluable in identifying this rare clinical entity.

Structural basis for recognition of the type VI spike protein VgrG3 by a cognate immunity protein.

The bacterial type VI secretion system (T6SS) is used by donor cells to inject toxic effectors into receptor cells. The donor cells produce the corresponding immunity proteins to protect themselves against the effector proteins, thereby preventing their self-intoxication. Recently, the C-terminal domain of VgrG3 was identified as a T6SS effector. Information on the molecular mechanism of VgrG3 and its immunity protein TsaB has been lacking. Here, we determined the crystal structures of native TsaB and the VgrG3C-TsaB complex. VgrG3C adopts a canonical phage-T4-lysozyme-like fold. TsaB interacts with VgrG3C through molecular mimicry, and inserts into the VgrG3C pocket.

New insights into antibody-mediated hyperthyroidism.

The most common cause of hyperthyroidism is Graves' disease, which represents a typical example of an organ-specific autoimmune condition. The exact triggers for the disease remain unknown, but are likely to involve a complex interaction between multiple environmental factors in a genetically predisposed individual. The main feature of the condition is the presence of thyroid-stimulating antibodies, which activate the thyroid- stimulating hormone receptor, resulting in hyperthyroidism. These antibodies may also be involved in the extrathyroidal complications of the disease. The recent generation of thyroid-stimulating antibodies in animal models and the isolation of monoclonal thyroid-stimulating antibodies from a patient with Graves' disease should allow the detailed study of thyroid-stimulating antibodies-thyroid-stimulating hormone receptor interactions. This will help to shed more light on disease pathogenesis and may offer new treatment strategies in difficult cases, particularly in patients with extrathyroidal complications.