Overproduction Of Thyroid Hormones Research Articles

Genetic and Protein Expression Comparison of Tissues of Differing Embryonic Origin.

Non-syndromic Craniosynostosis (CS) has an unknown etiology. The overproduction of thyroid hormones (THs) during pregnancy known as maternal hyperthyroidism has been cited by the CDC as a potential cause of CS. Elucidation of the mechanism for TH induced CS may allow for the creation of a novel more suitable treatment option. There are several signaling pathways involved in the differentiation and development of the tissues of the skull such as, BMP, Ihh, and Wnt. Wnt signaling has been linked to the differentiation of both embryonic mesoderm as well as neural crest cells, from which the relevant tissues of the skull originate. The goal of this study is to quantify and compare genetic and protein expression of relevant Wnt signaling molecules and their target genes within the Sagittal and Coronal sutures. Beta-Catenin is a Wnt signaling molecule that acts as a transcription factor modulating the expression of genes such as Runx2 and Twist1. These genes were selected as they are known to be involved in cranial development. Sutures were collected from an avian model of induced thyrotoxicosis and analyzed using qRT-PCR and western blotting. Results of the qRT-PCR showed a significant downregulation in Runx2 and Twist1 expression in the coronal sutures with no change in Twist1 and a significant upregulation of Runx2 expression in the sagittal sutures. Western blot results are still pending. While further investigation into these pathways is necessary, our findings conclude that these key pathways react differently to modulation by thyroid hormones in tissues of differing embryonic origin.

Commentary on the role of berberine in addition to methimazole compare to methimazole alone in the treatment of Graves’ Diseas

Graves’ Disease (GD) is the most common form of hyperthyroidism. It affects 3% of female patients and 0.5% of male patients usually between the age of 30-60. It is the cause of 80% of hyperthyroid cases in the USA. The pathogenesis of the disease is complex and autoimmunity plays a key role. The antibodies stimulating the thyrotropin receptor (TRAb) lead to uncontrolled Thyroid-stimulating Hormone (TSH) overproduction of thyroid hormones from the overactive thyroid gland. The disease is frequently associated with Graves's ophthalmopathy, dermatopathy, and clubbing. It affects the whole body with deleterious effects on the Cardiovascular system, vision, bones, etc. The treatment of the disease is with anti-thyroid medications, Radioactive iodine, or thyroid surgery each one of which has its pluses and minuses. Other factors like Genetic, inflammatory, immune, environmental factors, etc. play critical roles in disease pathogenesis as well. In this article, we are discussing the newfound role of the gut-thyroid axis in the pathogenesis of GD. We are describing the role of the probiotic Berberine added to the anti-thyroid medication Methimazole in changing the gut microbiota by increasing the benefits and decreasing the deleterious bacteria in the gut. This can lead to the induction of anti-inflammatory cytokines and reduction of inflammatory ones which can regulate the immune system faster and better than with treatment with Methimazole alone. This treatment combination can eventually lead through the effect on the gut-thyroid axis to faster disappearance of the TRAb and remission and cure of GD.

Estimation of Salivary IL-6 Level in relation of Periodontal Status in Patients with Hyperthyroidism

Background: The overproduction of thyroid hormones is known as hyperthyroidism. Increased susceptibility to caries and periodontal disease are two potential oral symptoms. The interleukin-6 (IL-6) was observed to significantly increased in the hyperthyroid group. According to multiple research, IL-6 dysregulation has been linked to a number of oral disorders, including periodontal diseases. The study aimed to evaluate periodontal health status in relation to IL6 among hyperthyroidism patients. Subjects and Methods: The sample was composed of 90 female patients aged 25-45 years attending endocrine disorder center in al-Najaf Governorate/Iraq which include hyperthyroid group and healthy group, the hyperthyroid patients were diagnosed by specialist and under treatment with carbimazole. The clinical examination of periodontal health status assessment was performed according to WHO (2013) in addition to evaluation the Plaque and gingival condition. The Saliva was collected to evaluate IL-6 concentrations. Results: The plaque index (PLI) in the study group was more than the control with a significant difference (P<0.05). The gingival index (GI) in the study was more than the control but with no significant difference (P>0.05). Both periodontal pocket depth (PPD) and clinical attachment loss (CAL) were higher in the study group than in the control group, with a significant difference. IL-6 was higher in the study group than in control with a significant difference. There was a positive non-significant correlation between PPD and CAL with IL-6 in hyperthyroid patients.

Thyroid storm in a postpartum and uncontrolled graves' disease patient: the challenges of accurate and multidisciplinary disease management

Background: Graves' disease is an immune system disorder that results in the overproduction of thyroid hormones (hyperthyroidism). Although pregnancy hyperthyroidism is a relatively uncommon, thyroid crisis is a medical emergency caused by hyperthyroidism exacerbation with symptoms of organ decompensation in one or more organs. Therefore, managing this disease in pregnant women is critical as well as the safety of using antithyroid drugs for pregnant women and the foetus. Case presentation: A 26-year-old woman presented to the Dr Soetomo General Academic Hospital Surabaya, Indonesia with complaints of shortness of breath that had worsened one hour before the admission as well as sudden fever, diarrheal, anxiety, and decreased consciousness. The patient had hyperthyroidism for three years, and the controls were inconsistent. The patient was diagnosed with P1101 postpartum day 1, thyrotoxicosis due to Graves' disease, thyroid crisis, hypertension, microcytic hypochromic anemia, hypoglycemia, hypoalbuminemia, keratitis, and lagophthalmos. The patient was treated with supportive therapy with an oxygen mask 8 liters per minute (lpm), intravenous fluids, and antipyretic acetaminophen 500 mg every 8 hours. Propylthiouracil 400 mg loading dose followed by maintenance 6x100 mg, 8 drops of Lugol's solution after propylthiouracil administration, intravenous (IV) dexamethasone 2 mg every 6 hours, and oral propranolol 20 mg every 6 hours. The patient was discharged from the hospital after presented favorable improvement. Conclusion: This case demonstrates that the stage of the disease determines the management of Grave's disease during pregnancy, and that multidisciplinary involvement could improve the success and reduce the patient mortality.

Cardiovascular Health by Graves’ Disease Management Modality – Surgery Versus Radioactive Iodine Versus Antithyroid Medications: A Network Meta-Analysis

IntroductionGraves' disease is an autoimmune disorder of the thyroid gland associated with the overproduction of thyroid hormones. Excess secretion of thyroid hormones leads to cardiovascular consequences. Treatment options include antithyroid medications (ATM), radioactive iodine (RAI) ablation, and total thyroidectomy. We examined the cardiovascular outcomes following Graves’ disease management modality. MethodsA systematic search was performed up to September 22nd, 2021, using PubMed, EMBASE, and Web of Science databases. We conducted a network meta-analysis analyzing cardiovascular outcomes of interest, including congestive heart failure (CHF), arrhythmia, atrial fibrillation (AF), and hypertension. ResultsThree studies were included in this analysis totaling 6700 patients with Graves’ disease, of which 74% were female. The mean age was 44.34 y. When compared to pretreatment, management options lowered the risk of maintaining arrhythmia 81% with surgery (relative risk [RR] = 0.19; 95% confidence interval [CI] = 0.12 to 0.31), 67% with ATM (RR = 0.33; 95% CI = 0.23 to 0.49), and 50% with RAI (RR = 0.50; 95% CI = 0.13 to 1.95). Risk of maintaining CHF was reduced 80% with surgery (RR = 0.20; 95% CI = 0.08 to 0.49), 41% with ATM (RR = 0.59; 95%CI = 0.52 to 0.67), and only 7% with RAI (RR = 0.93; 95%CI = 0.68 to 1.26). Treatment-ranking analysis found all parameters, including CHF, arrhythmia, AF, and hypertension, to be in favor of surgical treatment over medical treatment and RAI ablation. ConclusionsThis is the first network meta-analysis analyzing the cardiovascular outcomes in Graves’ disease patients by treatment option. Our study demonstrated that surgery is superior to RAI and medical treatment.

Association between IL 37 gene variants (rs4241122 and rs2723186) and Graves disease risk

Introduction: Graves Disease (GD) is the most common cause of primary hyperthyroidism. It is an autoimmune disorder characterized by the presence of thyrotropin related antibodies that stimulate thyroidal cells, resulting in an overproduction of thyroid hormones. It has been reported that cytokines might be involved in the GD pathogenesis. So, aim of the present study was to investigate the possible associations between IL-37 Single Nucleotide Polymorphisms (SNPs) and susceptibility to GD.

Graves diseases with severe progressive ophthalmopathy after thyroidectomy. Case report.

Graves’ disease is an autoimmune disease that may consist of hyperthyroidism, goiter, orbitopathy, and occasionally a dermopathy referred to as pretibial or localized myxedema. Graves’ disease is caused by autoantibodies that bind to the thyrotropin receptor, stimulating growth of the thyroid and overproduction of thyroid hormone. Clinical manifestations of Graves’ disease include diffuse goiter and symptoms and signs resulting from hyperthyroidism. Thyroid hormones excess affects several different body systems, and for this reason, signs and symptoms associated with Graves’ disease can vary strongly, and significantly influence the general well-being. Common symptoms are: tremor, heat sensitivity and warm, weight loss even if with normal eating habits, anxiety and irritability, enlargement of the thyroid gland, alterations in menstrual cycles, erectile dysfunction or decreased libido, fatigue, frequent bowel movements, palpitations, and others. Graves’ orbitopathy is present in about 30-50% of patients with Graves disease. Graves’ orbitopathy is an autoimmune disease of the retroocular tissues occurring in patients with Graves’ disease.We present the clinical case report with progressive ophthalmopathy after a total thyroidectomy. In our case after surgery his ophthalmopathy did not regress and, in fact, was progressive. In the vast majority of cases of Grave’s ophthalmopathy, the periorbital edema regresses significantly after a total thyroidectomy. This patient’s ophthalmopathy did not regress after surgery even the ophtalmopathy progressed. Only after initiation of pulsatile therapy of 500 mg of methylprednisolone weekly did the ophthalmopathy regress noticeably.

Does Marine Lenhart Syndrome really exist?

Primary hyperthyroidism is the result of overproduction of thyroid hormone resulting in the classic symptoms of tachycardia, weight loss, diaphoresis, and hyperdefecation. There are multiple common causes to include Graves’ disease, toxic multinodular goiter, and solitary toxic adenomas. Marine Lenhart Syndrome (MLS) is a rare cause of hyperthyroidism, caused by a coexistence of constitutively active thyroid nodules and Graves’ disease. In the original document of Marine and Lenhart, there is no distinction made between the autoimmune phenomenon of Graves’ disease and the solitary toxic nodule of Plummer’s disease. Rather they are both considered to be the manifestation of the same disease. However, in the current era of radionuclide technology, a clear distinction of MLS can be seen with diffuse uptake in the thyroid gland and focused enhancement in the toxic nodules. Therefore what was previously described as one entity is now distinct as Graves’ disease and Plummer’s disease. It is also becoming increasingly clear within the literature that there is also a new phenomenon of post-radioiodine immunogenic hyperthyroidism in patients with toxic nodules and elevated autoantibodies. Therefore in order to properly treat and manage patients, a new definition of MLS may need to be proposed.

Graves' disease: pathophysiological aspects and considerations about using the chemometric analysis in the study of the disease.

Graves' disease is an immune system disorder that results in the overproduction of thyroid hormones (hyperthyroidism). Thyroid disorders are a societal problem of great public concern because of their high prevalence. This problem can affect the well-being and quality of life of patients. The predisposing factors leading to this disease are not yet fully established and are likely to be interconnected in a complex way.Chemometric analysis allows for the detection of specific relationships between the medical parameter measurements obtained from the patients in an observation group, and the identification of patterns of similarity between these patients. It is not commonly used in clinical trials; however, it can provide reliable information which may help in creating more successful, individualised treatment strategies for established groups (patterns) of patients.The aim of this review is to summarize the latest knowledge about the risk factors for Graves' disease and considerations about using the chemometric analysis in the study of the disease.

Impact of SSKI vs. Corticosteroids on Total Thyroidectomy for Graves Disease: A Retrospective Review

Background: Graves disease is an autoimmune disorder resulting in overproduction of thyroid hormone. While medical management can be used to reestablish euthyroid state, definitive management includes radioactive iodine or total thyroidectomy. For patients undergoing thyroidectomy, SSKI is frequently prescribed preoperatively to decrease thyroid vascularity and intraoperative blood loss. However, corticosteroids is often given when rapid preparation is necessary prior to surgery. This study explores the impact of SSKI compared to corticosteroids and hypothesizes that replacement of SSKI with corticosteroid will improve surgical outcomes. 
 Methods: We performed a retrospective review of 26 Graves patients undergoing total thyroidectomy from 2015-2020. 18 patients received SSKI prior to surgery, 2 received a corticosteroid in addition to SSKI, 1 received a corticosteroid alone, and 5 received neither. Symptomatology, length of stay, intraoperative blood loss, transient hypoparathyroidism, and thyroid weight were compared. 
 Results: Patients receiving corticosteroids experienced shorter stays (1.0 day vs 1.3 days), greater postoperative parathyroid hormone levels (43.0 pg/mL vs 28.9 pg/mL), less intraoperative blood loss (14.4 mL vs 41.4 mL), and presented with smaller thyroid glands (30 g vs 47 g) compared to those who received SSKI. There was a statistically significant difference in estimated blood loss between the groups (p = 0.0348). For some patients, the addition of a steroid to SSKI decreased surgery time (1.98 hours vs 2.32 hours). 
 Conclusion: Despite limitations in sample size and the retrospective nature of this study, results suggest a positive impact of corticosteroid use on surgical and patient outcomes compared to SSKI alone. Future examination may benefit from greater sample size and equal distribution of patients among groups. We propose further exploration with a prospective study to evaluate the impact of SSKI vs. corticosteroids on surgical difficulty and postoperative complications for Graves disease patients.

The Association of Obesity with Autoimmune Thyroiditis and Thyroid Function-Possible Mechanisms of Bilateral Interaction.

A growing number of patients suffer from autoimmune diseases, including autoimmune thyroid disease. There has simultaneously been a significant increase in the prevalence of obesity worldwide. It is still an open question whether adiposity can directly influence activation of inflammatory processes affecting the thyroid in genetically predisposed individuals. Adipokines, biologically active substances derived from the adipocytes, belong to a heterogenic group of compounds involved in numerous physiological functions, including the maintenance of metabolism, hormonal balance, and immune response. Notably, the presence of obesity worsens the course of selected autoimmune diseases and impairs response to treatment. Moreover, the excess of body fat may result in the progression of autoimmune diseases. Nutritional status, body weight, and energy expenditure may influence thyroid hormone secretion. Interestingly, thyroid hormones might influence the activity of adipose tissue as metabolic alterations related to fat tissue are observed under pathological conditions in which there are deficits or overproduction of thyroid hormones. Functioning TSH receptors are expressed on adipocytes. Thermogenesis may presumably be stimulated by TSH binding to its receptor on brown adipocytes. There could be a bilateral interaction between the thyroid and adipose. Obesity may influence the onset and course of autoimmune disease.

Acute Drug-Induced Cholestatic Syndrome in Basedow Graves’ Disease

Abstract Introduction: Graves’ disease (GD), an autoimmune disorder caused by high levels of auto-antibodies against the thyroid-stimulating hormone receptor, is considered the most common cause of thyrotoxicosis, characterized by features such as goiter, ophthalmopathy and dermopathy. In our country, the administration of antithyroid drugs (ATD) is the first line of treatment in this disease. Side effects are rare but some of them, such as agranulocytosis or liver damage, may become serious. Case presentation: We report the case of a 20-year-old female patient who was diagnosed with GD after being previously diagnosed with viral hepatitis A. Treatment was initiated with methimazole 30 mg/day, and three weeks later she developed intense hepatic cytolysis and cholestatic syndrome, therefore the ATD was stopped. A suspicion of autoimmune liver disease was raised, and a liver biopsy was performed in order to establish the diagnosis. The next therapeutic option for hyperthyroidism was radioactive iodine (RAI). Three months following RAI, the patient presented severe hypothyroidism, thereupon treatment with levothyroxine was initiated. Conclusions: Although severe acute liver injury is rare, mild liver dysfunction is quite common in patients with GD. The overproduction of thyroid hormones, or the treatment with ATD through immune mediated processes or drug reactions, represent possible mechanisms responsible for liver damage.

MON-579 Toxic Multinodular Goiter And Thyroid Cancer Risk

Toxic multinodular goiter (TMNG) occurs when there is overproduction of thyroid hormones by one or more autonomously functioning nodule. The hyperthyroidism of TMNG does not remit spontaneously, thus patients with TMNG are usually treated with radioiodine (RAI) or surgery. Many studies have reported the prevalence of incidental cancers found in thyroidectomy specimens of MNG to range from 4-10 %, and the majority of these incidental cancers are micro-papillary. But whether these cancers progress to clinical disease is not well established. The objective of this study was to assess the clinical outcomes of patients with TMNG following radio-iodine ablation therapy. We conducted a retrospective chart review of subjects who received radio-iodine ablation therapy in a single academic medical center from January 2010 to March 2018. Medical records of all subjects were reviewed to determine those with TMNG, and the outcomes of their treatment. Results: A total of 228 subjects who received radio-iodine therapy were reviewed. 33 were identified with a diagnosis of TMNG based on thyroid US, TSH and free T4 levels, and the findings of a thyroid -uptake scan. 12 of 33 subjects had follow-up US and sufficient clinical data. Their median age was 61 yrs (range 38-87 yrs), 11 females (91.7%) and 1 male (8.3%), with follow-up of 9-103 months. Subsequent US revealed a decrease in nodule size in 8 (66.7%), and no change in 2 (16.7%), while in 2 patients (16.7%) the nodules were thought to have increased in size, and will have an FNA. 3 patients with suspicious nodules on US underwent FNA; all were negative for malignancy. One patient underwent total thyroidectomy concurrent with surgery for a parathyroid adenoma; thyroid pathology was negative. No patients have been diagnosed with thyroid cancer. From these preliminary results, we believe that the risk of developing thyroid cancer in patient with TMNG who undergo radio-iodine ablation therapy is low. Nodules in patients with TMNG with suspicious US characteristics should be managed like thyroid nodules in euthyroid patients according to guidelines. Surgery as first line treatment in TMNG patients may not be justified

Comparative assessment of Graves\u2019 disease and main extrathyroidal manifestation, Graves\u2019 ophthalmopathy, by non-targeted metabolite profiling of blood and orbital tissue

Graves’ disease (GD) is an autoimmune disorder that causes the overproduction of thyroid hormones and consequent cascade of systemic metabolism dysfunction. Moreover, Graves’ ophthalmopathy (GO) is the main extrathyroidal manifestation of Graves’ disease (GD). The goal of the study was to identify metabolic signatures in association with diagnostic biomarkers of GD without GO and GO, respectively. Ninety metabolites were profiled and analyzed based on a non-targeted primary metabolite profiling from plasma samples of 21 GD patients without GO, 26 subjects with GO, and 32 healthy subjects. Multivariate statistics showed a clear discrimination between healthy controls and disease group (R2Y = 0.518, Q2 = 0.478) and suggested a biomarker panel consisting of 10 metabolites. Among them, most of metabolites showed the positive association with the levels of thyrotropin receptor antibodies. With combination of proline and 1,5-anhydroglucitol, which were identified as GO-specific modulators, the re-constructed biomarker model greatly improved the statistical power and also facilitated simultaneous discrimination among healthy control, GO, and GD without GO groups (AUC = 0.845–0.935). Finally, the comparative analysis of tissue metabolite profiles from GO patients proposed putative metabolic linkage between orbital adipose/connective tissues and the biofluidic consequences, in which fumarate, proline, phenylalanine, and glycerol were coordinately altered with the blood metabolites.

Pathogenesis of Hyperthyroidism.

Hyperthyroidism is a form of thyrotoxicosis in which there is excess thyroid hormone synthesis and secretion. Multiple etiologies can lead to a common clinical state of "thyrotoxicosis," which is a consequence of the high thyroid hormone levels and their action on different tissues of the body. The most common cause of thyrotoxicosis is Graves' disease, an autoimmune disorder in which stimulating thyrotropin receptor antibodies bind to thyroid stimulating hormone (TSH) receptors on thyroid cells and cause overproduction of thyroid hormones. Other etiologies include: forms of thyroiditis in which inflammation causes release of preformed hormone, following thyroid gland insult that is autoimmune, infectious, mechanical or medication induced; secretion of human chorionic gonadotropin in the setting of transient gestational thyrotoxicosis and trophoblastic tumors; pituitary thyrotropin release, and exposure to extra-thyroidal sources of thyroid hormone that may be endogenous or exogenous. © 2017 American Physiological Society. Compr Physiol 7:67-79, 2017.

Changes in cardiac function and structure in newly diagnosed Graves' disease. A conventional and 2D-speckle tracking echocardiography study.

Overproduction of thyroid hormones leads to structural as well as functional cardiac changes. Conventional echocardiography but also recently developed sophisticated two-dimensional echocardiography speckle (2D-STE) tracking allow elaborate evaluation of these changes. Our purpose was to investigate the effects of thyroid hormones overproduction on the heart in patients with Graves' disease and changes that occur after 6 months thyrostatic therapy. We conducted a prospective, case-control study of 6 months duration. Full echocardiographic assessment at diagnosis and after 6 months of thyrostatic therapy were performed in 44 patients with Graves' disease, aged 37.6 ± 9.1 years. Additionally, 43 euthyroid controls were studied for the same time period. Left ventricular end diastolic diameter (LVEDD) and left ventricular end systolic diameter (LVESD) were higher in the patient group while triscupid annular plane systolic excursion (TAPSE) was lower in the patient group. Moreover, left ventricular (LV) mass index and left atrium (LA) volume index were higher in the Graves' disease group. Diastolic impairment as assessed with conventional echocardiography including tissue Doppler was present in the patient group (E/A ratio 0.87 ± 0.10,). 2D-STE analysis, revealed an increase in the strain rate at the isovolumic relaxation time (SRIVRT, 0.310 ± 0.07 patients versus 0.298 ± 0.09s-1 controls). Improvement in diastolic and right systolic function as well as in left ventricular structural parameters was observed after restoration of euthyroidism (E/A ratio from 0.87 ± 0.10 versus 0.9 ± 0.08, p < 0.05). Patients with newly diagnosed Graves' showed an improvement in diastolic function, right systolic function and structural parameters after 6 months of thyrostatic treatment.

Thyrotoxic storm during sepsis: study of a rare complication, clinical and biological observations

We describe an uncommon severe clinical complication of sepsis – thyrotoxic storm (TS). Common biologic, pathogenic, clinical conditions that can determine sepsis can cause a TS. High circulating values of vascular cellular adhesive molecules-1 and various pro-inflammatory citochines are related with thyroid damage. During sepsis, moderate dysfunctions are not expression of actual disease, but severe damage in pituitary-thyroid hormonal axis. Thyroid stimulated hormon release, and consequent overproduction of thyroid hormones can cause TS. In critical patients, presence of hormonal dysfunctions determines more elevated clinical score of sepsis severity and higher risk of death than control groups (without thyroid disease) or survived patients.

Therapeutic Effects of Blue Honeysuckle on Lesions of Hyperthyroidism in Rats.

Hyperthyroidism is a hypermetabolic syndrome characterized by an overproduction of thyroid hormones, which enhances the hormone-induced oxidative stress responsible for some complications in the liver, heart and muscle. Blue honeysuckle (BH) is an edible berry, rich in polyphenols, especially flavonoids or anthocyanins, known as strong antioxidants. The chemo-protective activities of the berry have been connected to the improvement of symptoms in cancer, diabetes mellitus, tumor or cardiovascular diseases. Therefore, the therapeutic effects of BH were examined in hyperthyroidism rat model. The hyperthyroidism was induced by injection with levothyroxine (LT4), and the model was treated with distilled water (LT4 control), propylthiouracil (PTU) or BH at 3 dosages of 500, 250 and 125[Formula: see text]mg/kg. The treatment was performed once a day for 15 days. Compared to LT4 control, the oral administration of BH dose-dependently ameliorated the hyperthyroidism, reducing thyroid hormones and increasing thyroid stimulating hormones. These effects were accompanied by improvement of body weight loss and atrophy in the thyroid gland, liver and epididymal fat pads. BH treatments also reduced the levels of hepatic enzymes (AST and ALT), which suggests BH exerts protective effects on hepatocytes. BH might also be involved in the augmentation of the anti-oxidant activities, supported by increased endogenous antioxidant (glutathione). In addition, the histopathological analyses revealed the beneficial effects of BH on the atrophic changes and cellular injuries in the thyroid gland, liver and epididymal fat pads. The therapeutic potentials of BH were either similar or more effective than PTU. These results provide valuable information that will guide more detailed studies to use the BH as a complementary and alternative medicine.

Measurement of thyroid stimulating immunoglobulins using a novel thyroid stimulating hormone receptor–guanine nucleotide-binding protein, (GNAS) fusion bioassay

Hyperthyroidism, defined by overproduction of thyroid hormones, has a 2-3% prevalence in the population. The most common form of hyperthyroidism is Graves' disease. A diagnostic biomarker for Graves' disease is the presence of immunoglobulins which bind to, and stimulate, the thyroid stimulating hormone receptor (TSHR), a G-protein coupled receptor (GPCR). We hypothesized that the ectopically expressed TSHR gene in a thyroid stimulating immunoglobulin (TSI) assay could be engineered to increase the accumulation of the GPCR pathway second messenger, cyclic AMP (cAMP), the molecule measured in the assay as a marker for pathway activation. An ectopically expressing TSHR-mutant guanine nucleotide-binding protein, (GNAS) Chinese hamster ovary (CHO) cell clone was constructed using standard molecular biology techniques. After incubation of the new clone with sera containing various levels of TSI, GPCR pathway activation was then quantified by measuring cAMP accumulation in the clone. The clone, together with a NaCl-free cell assay buffer containing 5% polyethylene glycol (PEG)6000, was tested against 56 Graves' patients, 27 toxic thyroid nodule patients and 119 normal patients. Using receiver operating characteristic analysis, when comparing normal with Graves' sera, the assay yielded a sensitivity of 93%, a specificity of 99% and an efficiency of 98%. Total complex precision (within-run, across runs and across days), presented as a percentage coefficient of variation, was found to be 7·8, 8·7 and 7·6% for low, medium and high TSI responding serum, respectively. We conclude that the performance of the new TSI assay provides sensitive detection of TSI, allowing for accurate, early detection of Graves' disease.

Receptor-activating autoantibodies and disease: preeclampsia and beyond

The research reviewed in this article provides examples of autoantibody-mediated receptor activation that likely contributes to disease. The classic example is Graves’ hyperthyroidism, in which autoantibodies activate the thyroid-stimulating hormone receptor resulting in overproduction of thyroid hormones. Other compelling examples come from the cardiovascular literature and include agonistic autoantibodies targeting the cardiac β1-adrenergic receptor, which are associated with dilated cardiomyopathy. Autoantibodies capable of activating α1-adrenergic receptors are associated with refractory hypertension and cardiomyopathy. A prominent example is preeclampsia, a hypertensive disease of pregnancy, characterized by the presence of autoantibodies that activate the major angiotensin receptor, AT1. AT1 receptor-activating autoantibodies are also observed in kidney transplant recipients suffering from severe vascular rejection and malignant hypertension. AT1 receptor-activating autoantibodies and antibodies that activate the endothelin-1 receptor, ETA, are prevalent in individuals diagnosed with systemic sclerosis. Thus, the presence of agonistic autoantibodies directed to G protein-coupled receptors has been observed in numerous cardiovascular disease states. Rapidly emerging evidence indicates that receptor-activating autoantibodies contribute to disease, and that efforts to detect and remove these pathogenic autoantibodies or block their actions will provide promising therapeutic possibilities.