Hashimoto Encephalopathy-Still More Questions than Answers.

The normal function of the nervous system is conditioned by the undisturbed function of the thyroid gland and its hormones. Comprehensive clinical manifestations, including neurological disorders in Hashimoto's thyroiditis, have long been understood and, in recent years, attention has been paid to neurological symptoms in euthyroid patients. Hashimoto encephalopathy is a controversial and poorly understood disease entity and the pathogenesis of the condition remains unclear. We still derive our understanding of this condition from case reports, but on the basis of these, a clear clinical picture of this entity can be proposed. Based on a review of the recent literature, the authors present the current view on the subject, discuss controversies and questions that still remain unanswered, as well as ongoing research in this area and the results of our own work in patients with Hashimoto's thyroiditis.

What we know about the relationship between autoimmune thyroid diseases and gut microbiota: a perspective on the role of probiotics on pediatric endocrinology.

INTRODUCTION: Autoimmune diseases account for a cumulative overall prevalence of about 3-5% worldwide. Among them, autoimmune thyroid diseases (ATDs) are the most common and comprise two main entities: Hashimoto's thyroiditis (HT) and Graves-Basedow disease (GD). The pathogenesis of ATDs remains not fully elucidated, however the role of microbioma has been proposed. Gut microbiota exert an important influence on the intestinal barrier, nutrient metabolism and immune system development and functions. EVIDENCE ACQUISITION: In this review, we describe on the main features of ATDs in pediatrics, focusing on the reciprocal influence between gut microbiota, thyroid hormone metabolism and thyroid autoimmunity and consider the role of probiotics and other microbiota-targeted therapies in thyroid diseases with a perspective on pediatric endocrinology. EVIDENCE SYNTHESIS: Microbiome affects both endogenous and exogenous thyroid hormone metabolism and influences the absorption of minerals important to the thyroid function, which are iodine, selenium, zinc and iron. The alteration of the gut microbiota, with the consequent modifications in the barrier function and the increased gut permeability, seems involved in the development of autoimmune and chronic inflammatory diseases, including ATDs. The supplementation with probiotics showed beneficial effects on the thyroid hormone and thyroid function because this strategy could restore the intestinal eubiosis and the good strain microorganism proliferation. CONCLUSIONS: Even though the evidence about the interaction between microbiota and ATDs in pediatric patients is limited, the promising results obtained in the adult population, and in other autoimmune disorders affecting children, highlight the need of for further research in the pediatric field.

High Prevalence of Common Human Viruses in Thyroid Tissue.

Introduction: Evidence points to viral infections as possible triggers of autoimmune thyroid disease (AITD), but little is known about the prevalence of common viruses in the thyroid gland. Using a novel approach based on virus enrichment in multiple cell lines followed by detection of the viral genome and visualization of viral proteins, we investigated the presence of multiple human viruses in thyroid tissue from AITD patients and controls. Methods: Thyroid tissue was collected by core needle biopsy or during thyroid surgery from 35 patients with AITD (20 Graves' disease and 15 Hashimoto's thyroiditis). Eighteen thyroid tissue specimens from patients undergoing neck surgery for reasons other than thyroid autoimmunity served as controls. Specimens were tested for the presence of ten different viruses. Enteroviruses and human herpesvirus 6 were enriched in cell culture before detection by PCR and immunofluorescence, while the remaining viruses were detected by PCR of biopsied tissue. Results: Forty of 53 cases (75%) carried an infectious virus. Notably, 43% of all cases had a single virus, whereas 32% were coinfected by two or more virus types. An enterovirus was found in 27/53 cases (51%), human herpesvirus 6 in 16/53 cases (30%) and parvovirus B19 in 12/53 cases (22%). Epstein-Barr virus and cytomegalovirus were found in a few cases only. Of five gastroenteric virus groups examined, only one was detected in a single specimen. Virus distribution was not statistically different between AITD cases and controls. Conclusion: Common human viruses are highly prevalent in the thyroid gland. This is the first study in which multiple viral agents have been explored in thyroid. It remains to be established whether the detected viruses represent causal agents, possible cofactors or simple bystanders.

[Thyroiditis]. / Les thyroïdites.

A thyroiditis is an inflammatory disease of the thyroid whether autoimmune, infectious or drug-induced. Autoimmune thyroid diseases (including Hashimoto's thyroiditis and Graves' disease) are the most frequent of all autoimmune pathologies. The clinical presentation and history are often revealing of the pathology and its etiology. Complementary examinations allow to confirm the diagnosis and to follow the evolution of the disease. Sometimes the disease could have a mixed presentation associating two different causes (like a mixed autoimmunity for Graves and Hashimoto diseases). In these cases, the treatment options are not always straightforward and may need to be adapted with the clinical evolution.

: Les thyroïdites désignent, au sens large, toutes les pathologies inflammatoires de la thyroïde, qu'elles soient auto-immunes, infectieuses ou médicamenteuses. Dans les maladies auto-immunes, les thyroïdites auto-immunes, dont la maladie de Hashimoto et la maladie de Basedow, sont les plus communes. Le tableau clinique et l'anamnèse sont parfois très révélateurs de la pathologie et de son étiologie. Les examens complémentaires permettent de confirmer l'hypothèse diagnostique et de suivre l'évolution de la maladie. Parfois, le tableau est moins typique avec des formes mixtes associant deux entités (comme une maladie de Basedow et de Hashimoto). Le diagnostic est, dans ces cas, moins évident et la prise en charge thérapeutique peut nécessiter une adaptation dans le temps.

Association Between Gut Microbiota and Autoimmune Thyroid Disease: A Systematic Review and Meta-Analysis.

Background: Autoimmune thyroid disease (AITD) is characterized by thyroid dysfunction and deficits in the autoimmune system. Growing attention has been paid toward the field of gut microbiota over the last few decades. Several recent studies have found that gut microbiota composition in patients with AITD has altered, but no studies have conducted systematic reviews on the association between gut microbiota and ATID. Methods: We searched PubMed, Web of Science, Embase, and Cochrane databases without language restrictions and conducted a systematic review and meta-analysis of eight studies, including 196 patients with AITD. Results: The meta-analysis showed that the alpha diversity and abundance of certain gut microbiota were changed in patients with AITD compared to the controls. Chao1,the index of the microflora richness, was increased in the Hashimoto's thyroiditis group compared to controls (SMD, 0.68, 95%CI: 0.16 to 1.20), while it was decreased in the Graves' disease group (SMD, -0.87, 95%CI: -1.46 to -0.28). In addition, we found that some beneficial bacteria like Bifidobacterium and Lactobacillus were decreased in the AITD group, and harmful microbiota like Bacteroides fragilis was significantly increased compared with the controls. Furthermore, the percentage of relevant abundance of other commensal bacteria such as Bacteroidetes, Bacteroides, and Lachnospiraceae was increased compared with the controls. Conclusions: This meta-analysis indicates an association between AITD and alteration of microbiota composition at the family, genus, and species levels. Systematic Review Registration: PROSPERO, identifier CRD42021251557.

Circulating Exosome Involves in the Pathogenesis of Autoimmune Thyroid Diseases Through Immunomodulatory Proteins.

Autoimmune thyroid diseases (AITDs) are chronic organ-specific autoimmune diseases, mainly including Graves' disease (GD) and Hashimoto's thyroiditis (HT). Exosomes, as extracellular vesicles, contain a variety of biologically active substances that play a role in information exchange, thereby affecting the occurrence and progression of diseases. However, it is unclear whether exosomes are involved in the pathogenesis of AITDs. In this study, the role of exosomes in AITDs was explored from a proteomics perspective. Plasma exosomes were isolated from 12 patients with GD, 10 patients with HT, and seven normal controls (NC). Protein profiles were detected using the data-independent acquisition (DIA) method and analyzed to investigate changes in plasma exosome proteins. In the setting of GD, 11 proteins were upregulated while 197 proteins were downregulated compared with healthy people. Among them, MAP1S (log2 FC = 4.669, p = 0.009) and VAMP8 (log2 FC = 3.216, p = 0.003) were the most significantly upregulated, and RSU1 (log2 FC = -6.797, p = 0.001), ACTB (log2 FC = -4.795, p < 0.001), and CXCL7 (log2 FC = -4.674, p < 0.001) were the most significantly downregulated. In the cases of HT, HGFL (log2 FC = 2.766, p = 0.001), FAK1 (log2 FC = 2.213, p < 0.001), and PTN12 (log2 FC = 1.624, p < 0.001) were significantly upregulated, while PSMF1 (log2 FC = -3.591, p < 0.001), PXL2B (log2 FC = -2.622, p = 0.001), and CYTM (log2 FC = -1.609, p < 0.001) were the most downregulated. These differential proteins were mainly enriched in the immune system and metabolic system, indicating that plasma exosomes may play an important role in systemic immune imbalance in AITDs.

Integrative Analyses of Genes Associated with Hashimoto's Thyroiditis.

OBJECTIVE: Hashimoto's thyroiditis, also known as chronic lymphocytic thyroiditis, is a common autoimmune thyroiditis, which mostly occurs in young and middle-aged women. It can be manifested as hyperthyroidism in the early stage; hypothyroidism may appear with the progression of the disease. Studies have shown that multiple factors such as heredity, environment, and autoimmunity are involved in the pathogenesis, but the specific mechanism is not clear. In our study, we tried to find key genes and potential molecular mechanisms of Hashimoto's thyroiditis to provide new ideas for the therapeutic targets of Hashimoto's thyroiditis. METHOD: GSE138198 and GSE54958 were downloaded from the GEO database, and two datasets were combined for analysis. The combined data were normalized to identify the differentially expressed genes (DEGs), and GO and KEGG enrichment analyses were performed. Protein-protein interaction (PPI) networks and hub genes between DEGs were identified. We also used the miRWalk database to identify regulatory miRNAs associated with expressions of DEGs. RESULT: We identified 182 DEGs (160 upregulated and 22 downregulated) between Hashimoto's disease patients and the healthy control group. GO analysis showed that DEGs were mostly concentrated in detection of chemical stimulus involved in sensory perception, intermediate filament cytoskeleton, and olfactory receptor activity. KEGG pathway analysis showed that DEGs were mainly related to olfactory transduction. Some members of the KRTAP family and HTR5A, KNG1, DRD3, HTR1D, TAS2R16, INSL5, TAS2R42, and GRM7 are the most important hub genes in the PPI network. In addition, we recognized that OTUD4, LLPH, and ECHDC1 were the most important hub genes in the miRNA-target gene network. CONCLUSION: In this study, a series of bioinformatics analyses of DEGs were performed to identify the key genes and pathways associated with Hashimoto's thyroiditis. These genes and pathways provide a more detailed understanding of the pathogenesis of Hashimoto's disease and provide new ideas for the therapeutic targets of Hashimoto's thyroiditis.

Interferon-gamma Expression Profile as Diagnostic Signatures of Unexplained Infertility in Female Patients Suffer from Hashimoto's Thyroiditis.

Diagnosis of unexplained infertility (UEI) is made by exclusion and a relatively common problem that affects couples worldwide. Unfortunately, it is a not uncommon for females to suffer from Hashimoto's thyroiditis (HT). Interferon-gamma (IFN- γ) has a central key role in HT and in the ability to conceive. We aimed to estimate serum IFN- γ level and its expression profile in Egyptian women with HT and assess their possible association with UEI. In this study, we examined 120 women with HT. We evaluated fertility in all patients; female patients who suffer from UEI were detected. Diagnosis of HT was based on the clinical data and the laboratory measures, enzyme-linked immunosorbent assay was used to measure serum IFN- γ, and the expression of IFN-γ messenger ribonucleic acid (mRNA) was assayed by real-time polymerase chain reaction (PCR). According to the results of this study, 37.5 % of the studied females who suffered from HT were diagnosed with UEI. The serum level of IFN-γ and its gene expression showed a significant positive correlation with thyroid-stimulating hormone (TSH) and thyroid autoantibodies. However, a negative correlation was found with anti-müllerian hormone (AMH), free T4 (FT3), and free T4 (FT4). Analysis by linear regression revealed that TSH and FT3 were associated with serum level of IFN-γ; while FT3 was associated with IFN-γ gene expression. We concluded that both are valued markers in diagnosing UEI in female patients suffering from HT.

Oxidative Stress-Induced Sirtuin1 Downregulation Correlates to HIF-1α, GLUT-1, and VEGF-A Upregulation in Th1 Autoimmune Hashimoto's Thyroiditis.

In Hashimoto's thyroiditis (HT), oxidative stress (OS) is driven by Th1 cytokines' response interfering with the normal function of thyrocytes. OS results from an imbalance between an excessive production of reactive oxygen species (ROS) and a lowering of antioxidant production. Moreover, OS has been shown to inhibit Sirtuin 1 (SIRT1), which is able to prevent hypoxia-inducible factor (HIF)-1α stabilization. The aims of this study were to determine the involvement of NADPH-oxidases (NOX), SIRT1, and HIF-1α in HT pathophysiology as well as the status of antioxidant proteins such as peroxiredoxin 1 (PRDX1), catalase, and superoxide dismutase 1 (SOD1). The protein expressions of NOX2, NOX4, antioxidant enzymes, SIRT1, and HIF-1α, as well as glucose transporter-1 (GLUT-1) and vascular endothelial growth factor A (VEGF-A), were analyzed by Western blot in primary cultures of human thyrocytes that were or were not incubated with Th1 cytokines. The same proteins were also analyzed by immunohistochemistry in thyroid samples from control and HT patients. In human thyrocytes incubated with Th1 cytokines, NOX4 expression was increased whereas antioxidants, such as PRDX1, catalase, and SOD1, were reduced. Th1 cytokines also induced a significant decrease of SIRT1 protein expression associated with an upregulation of HIF-1α, GLUT-1, and VEGF-A proteins. With the exception of PRDX1 and SOD1, similar results were obtained in HT thyroids. OS due to an increase of ROS produced by NOX4 and a loss of antioxidant defenses (PRDX1, catalase, SOD1) correlates to a reduction of SIRT1 and an upregulation of HIF 1α, GLUT-1, and VEGF-A. Our study placed SIRT1 as a key regulator of OS and we, therefore, believe it could be considered as a potential therapeutic target in HT.

Genetic Susceptibility to Joint Occurrence of Polycystic Ovary Syndrome and Hashimoto's Thyroiditis: How Far Is Our Understanding?

Polycystic ovary syndrome (PCOS) and Hashimoto's thyroiditis (HT) are endocrine disorders that commonly occur among young women. A higher prevalence of HT in women with PCOS, relative to healthy individuals, is observed consistently. Combined occurrence of both diseases is associated with a higher risk of severe metabolic and reproductive complications. Genetic factors strongly impact the pathogenesis of both PCOS and HT and several susceptibility loci associated with a higher risk of both disorders have been identified. Furthermore, some candidate gene polymorphisms are thought to be functionally relevant; however, few genetic variants are proposed to be causally associated with the incidence of both disorders together.

Orbital inflammatory disorders: new knowledge, future challenges.

PURPOSE OF REVIEW: This review aims to bring together recent advances in basic, translational and clinical research on the pathogenesis and treatment of orbital inflammatory conditions. RECENT FINDINGS: Basic science studies provide mechanistic insights into why the orbit is targeted for inflammation by autoimmune inflammatory disorders. Using Graves' disease as a test case reveals that endocrine pathways, such as the TSH and IGF1 receptor pathways play important roles in stimulating orbital inflammation. Furthermore, orbital tissues contain high concentrations of retinoids - byproducts of the visual pathway that diffuse across the sclera and can activate de novo transcription of inflammatory cytokines. Such cytokine expression places the orbit in a hyper-inflammatory 'resting' state, prone to respond to any additional systemic or local pro-inflammatory signals. The HIF2A--LOX pathway appears important for orbital tissue fibrosis. Lastly, bench-to-bedside studies of the IGF1R pathway have led to an FDA-approved drug, teprotumumab that represents a novel treatment approach for Graves' orbitopathy. Unfortunately, high drug costs and misplaced insurance company 'step-therapy' policies may block patients from receiving therapy that can protect vision and improve quality of life. SUMMARY: Improved understanding of orbital inflammatory conditions has led to a new drug and promises additional breakthroughs. Translational research is successful, but requires time, resources, and patience.

[GABAB receptor autoimmune encephalitis presenting as transient epileptic amnesia].

This case was a 50-year-old healthy woman. After repeated transient amnesia, she developed tonic-clonic seizures and was admitted to our hospital. The brain MRI showed FLAIR hyperintensities in the left temporal lobe and EEG showed an epileptic discharge starting from the left temporal region. Based on these findings, we diagnosed temporal lobe epilepsy associated with acute limbic encephalitis. While she experienced recurrent transient amnesia, her cognitive functions were preserved except for her memory. These symptoms and EEG findings were consistent with transient epileptic amnesia (TEA). Acute limbic encephalitis that occurred in a healthy middle-aged woman may be antibody-mediated encephalitis, requiring immediate immunotherapies. In this case, GABAB receptor antibodies in cerebrospinal fluid were found positive. This is the first report showing that TEA was caused by GABAB receptor autoimmune encephalitis.

Dioscin alleviates hashimoto's thyroiditis by regulating the SUMOylation of IRF4 to promote CD4+CD25+Foxp3+ treg cell differentiation.

Dioscin has been used as a treatment for Hashimoto's thyroiditis (HT) in China. However, the molecular mechanisms governing the modes of action of dioscin have not been elucidated. In this study, flow cytometry and Western blotting were used to identify the proportions of CD4+CD25+ regulatory T (Treg) cells and the expression of forkhead box P3 (Foxp3) and SUMO-specific protease 1 (SENP1) in HT patients' peripheral blood mononuclear cells (PBMCs). A pTg-induced rat model of HT was established by injection of 100 µg pTg. Then, the model rats were randomly divided into three groups (n = 5): control (NC), model (HT) and dioscin treatment. After oral administration of dioscin each day for two weeks, CD4+CD25+Foxp3+ Treg cells were analysed by flow cytometry, and the protein expression levels of SENP1, Foxp3, SUMO-1 and SUMO-2/3 were measured by Western blotting. Co-immunoprecipitation (Co-IP) was used to identify the SUMOylation of interferon regulatory factor 4 (IRF4). The results showed that the proportions of CD4+CD25+ Treg cells and the expression of Foxp3 were significantly decreased in HT patients, but the expression of SENP1 was enhanced compared to healthy controls (HCs). However, compared to the pTg-induced HT rat group, the expression of Foxp3, SUMO-1, and SUMO-2/3 and the proportions of CD4+CD25+Foxp3+ Treg cells were increased, whereas the expression of SENP1 was decreased, in the dioscin-treated group. Furthermore, the SUMOylation of IRF4 was increased after SENP1 was knocked down. The results of our study indicate that dioscin can promote the differentiation of the CD4+CD25+Foxp3+ Treg cells and subsequently upregulate the SUMOylation of IRF4 by downregulating SENP1 expression.

Evolution of Hashimoto thyroiditis in children with type 1 diabetes mellitus (TIDM).

OBJECTIVES: Treatment of children with Hashimoto thyroiditis (HT) and particularly of those with coexistent diabetes mellitus type 1 (TIDM) and normal/mildly elevated serum TSH is controversial. The aim of the study was to evaluate the natural course of HT in children with TIDM compared with children with no other coexistent autoimmunity and investigate for possible predictive factors of thyroid function deterioration. METHODS: Data from 96 children with HT, 32 with T1DM (23 girls, nine boys) mean (sd) age: 10.6 (2.3) years, and 64 age and sex-matched without T1DΜ (46 girls, 18 boys), mean (sd) age: 10.2 (2.9) years were evaluated retrospectively. They all had fT4 and TSH values within normal ranges and available data for at least three years' follow-up. RESULTS: During the follow-up period, 11 children (34.4%) with TIDM exhibited subclinical hypothyroidism and two children (6.2%) progressed to overt hypothyroidism compared to 12 (18.8%) and two (3.1%) among children without TIDM, respectively. Among children with HT, a higher percentage (40.6%) of children with T1DM progressed to subclinical or overt hypothyroidism, compared with children (21.9%) with similar characteristics but without TIDM or other coexistent autoimmunity. CONCLUSIONS: The annual conversion rate from euthyroidism to hypothyroidism in children with T1DM was significantly higher compared to sex and age-matched children without TIDM. Prospective randomized trials are needed to support the view of an earlier intervention therapy even in milder degrees of thyroid failure in these children.

Autoimmune switch from hyperthyroidism to hypothyroidism in Graves' disease.

We report a case of a 21-year-old young woman who was initially diagnosed with hyperthyroidism secondary to Graves' disease and spontaneously switched to hypothyroidism in a year. While most autoimmune hypothyroidism is due to Hashimoto's disease, in her case, we suspect that her hypothyroidism is due to a switch of antibody dominance from thyroid stimulating hormone (TSH) receptor-stimulating antibody (TS Ab) to TSH receptor-blocking antibody (TB Ab). Switching from dominant TS Ab activity to dominant TB Ab activity is a rare phenomenon. Optimal management of this condition is not known. Loss of follow-up and medication non-adherence has made medical management in this young woman of reproductive age further challenging.

Association of Hemorrhoids With Hashimoto's Thyroiditis and Associated Comorbidities: A Nationwide Population-Based Cohort Study.

Background: To evaluate the relationship between hemorrhoids and Hashimoto's thyroiditis (HT). Methods: Using Taiwan's Longitudinal Health Insurance Database, we compared the incident risk of HT between the study cohort (comprising patients with hemorrhoids) and the comparison cohort (comprising patients without hemorrhoids). Both cohorts were followed from index date until the date of HT diagnosis, withdrawal from the National Health Insurance program, or the end of 2015. Results: The study cohort and comparison cohort comprised 6,486 patients with hemorrhoids and 25,944 patients without, respectively. The mean follow-up time was ~3 years. The incidence rate of HT in the study cohort was 5.37 per 1,000 person-years, which was higher than that of the control cohort (2.46 per 1,000 person-years). The risk of developing HT in the study cohort was 2.06 times (95% confidence interval [CI] = 1.02, 4.19) higher than that in the comparison cohort. Conclusion: In our study, patients with hemorrhoids could be at increased risk of HT compared with patients with other comorbidities of HT, such as cardiovascular disease.

Unidentified Neuronal Surface IgG Autoantibodies in a Case of Hashimoto's Encephalopathy.

Hashimoto's encephalopathy is an encephalitis of presumed autoimmune origin characterized by the presence of autoantibodies against thyroid proteins. We present a case of a young patient with pre-existing Hashimoto's thyroiditis and progressive cognitive complaints, absence-like episodes, and sporadic bilateral epileptiform frontal and frontotemporal activity. No abnormalities were observed during the neurological examination and on MRI. Antibodies to thyroid peroxidase (TPO) were elevated and remained positive while the symptoms were present. Levothyroxine and methylprednisolone did not ameliorate the complaints. Subsequent treatment with high-dose intravenous immunoglobulins (IVIG) led to improved cognitive functions and to the disappearance of the absence-like-episodes. Patient's serum, but not CSF, gave a characteristic IgG-specific hippocampal pattern in rat brain immunohistochemistry; this immunoreactivity was maintained after specific and complete depletion of TPO antibodies. Serum IgG bound to primary neurons in cell culture, likely targeting a yet unidentified neuronal surface antigen. The clinical response to IVIG suggests but does not prove, that the circulating novel autoantibodies may induce the encephalopathy. It would be of interest to investigate more patients with Hashimoto's encephalopathy for the presence of neuronal surface autoantibodies, to define their role in the disease and their target antigen(s).

Th17 lymphocytes drive vascular and neuronal deficits in a mouse model of postinfectious autoimmune encephalitis.

Antibodies against neuronal receptors and synaptic proteins are associated with a group of ill-defined central nervous system (CNS) autoimmune diseases termed autoimmune encephalitides (AE), which are characterized by abrupt onset of seizures and/or movement and psychiatric symptoms. Basal ganglia encephalitis (BGE), representing a subset of AE syndromes, is triggered in children by repeated group A Streptococcus (GAS) infections that lead to neuropsychiatric symptoms. We have previously shown that multiple GAS infections of mice induce migration of Th17 lymphocytes from the nose into the brain, causing blood-brain barrier (BBB) breakdown, extravasation of autoantibodies into the CNS, and loss of excitatory synapses within the olfactory bulb (OB). Whether these pathologies induce functional olfactory deficits, and the mechanistic role of Th17 lymphocytes, is unknown. Here, we demonstrate that, whereas loss of excitatory synapses in the OB is transient after multiple GAS infections, functional deficits in odor processing persist. Moreover, mice lacking Th17 lymphocytes have reduced BBB leakage, microglial activation, and antibody infiltration into the CNS, and have their olfactory function partially restored. Th17 lymphocytes are therefore critical for selective CNS entry of autoantibodies, microglial activation, and neural circuit impairment during postinfectious BGE.