Altered Thyroid Status Research Articles

Mapping Thyroid Hormone Action in the Human Brain.

Background: Normal brain development, mood, and cognitive functions depend on thyroid hormone (TH) action. However, little is known about how TH mediates its actions in the human brain. This is due to limited access to human brains deprived of TH during fetal and early postnatal life, as well as from adults with altered thyroid status. One way to partially bypass these limitations is by using magnetic resonance imaging and spectroscopy, two neuroimaging techniques that provide detailed, noninvasive information on human brain structure and function. Another way is using human-induced pluripotent stem cell (hiPSCs)-derived three-dimensional in vitro systems, known as brain organoids, which allow for the study of fundamental aspects of the early stages of human brain development. Summary: This narrative review focuses on neuroimaging and brain organoid studies. Neuroimaging of human brains performed in individuals with different thyroid conditions provides information on the volume, myelination, blood flow, neural activity, and connectivity of different areas. Such studies show that suboptimal thyroid status can impact human brain development and its normal function throughout life. This is true not only for patients with sporadic congenital hypothyroidism, during pregnancy or early after birth, but also for adult patients with hypo- or hyperthyroidism, patients carrying mutations that manifest as impaired sensitivity to TH, and even for normal individuals during aging. Studies using brain organoids generated from hiPSCs of healthy individuals or patients with thyroid genetic conditions provide insights into how TH can impact the early development of the human cerebral cortex. Conclusions: The developmental alterations in children born to mothers with different degrees of gestational hypothyroidism or who developed hypothyroidism early in life are remarkable, affecting multiple brain regions and pathways, including the cerebral cortex, hippocampus, cerebellum, interhemispheric and corticospinal tracts, and associative nuclei. The data connecting such changes to poor neurological outcomes in adult patients with hypothyroidism represent an objective link between thyroid-specific functional brain alterations and behavior. Growing brain organoids require TH, which is critical for human neurogenesis and oligodendrogenesis. These models have proven useful in screening drugs with potential therapeutic effects for patients with genetic thyroid diseases.

Statistical Associations between Vestibular Pathologies and Hypothyroidism: A Retrospective Study.

The association between vestibular pathologies and thyroid hormone disorders has been known for several decades. However, very little information is available on the types of vestibular symptoms that may be affected by altered thyroid hormone levels. The aim of this study was to provide patient data in order to identify statistical associations between vestibular pathologies and thyroid hormone disorders. A retrospective review of the records of 422 patients seen for physiotherapy treatment of vertigo was carried out. Statistical analysis of the data was performed using logistic regression, providing Chi2 and Odds Ratio statistics. Our results show that hypothyroidism statistically significantly increases the expression of certain symptoms, such as vestibular instability and gait disorders, in vestibular pathologies such as Menière's disease or central vertigo. By analyzing patient data, our study provides new evidence of dependence between altered thyroid status and the expression of vestibular pathologies.

Abstract #1377584: Brain on Fire: A Case of Hashimoto's Encephalitis in a 29-Year-Old Female

A 29-year-old female presents to the hospital for insomnia, hallucination, and bizarre behavior. The patient had been feeling well until approximately three days early when she became psychotic after fasting from food for three days. She began having auditory and visual hallucinations and then started having seizures. Initially, the patient was admitted to a hospital in another city where she was diagnosed with Autoimmune Encephalitis for which she received IVIg. Brain MRI showed questionable T2 changes around the fourth ventricle on the left during hospital admission. The patient was discharged home after her symptoms improved. However, she was brought to our hospital for psychiatric consultation as her condition deteriorated. Upon arrival at Larkin Community Hospital, the patient was hemodynamically stable, breathing room air, and continued to complain of having delusions and hallucinations. Initial Vital Signs: BP: 122/74 mmHg, HR: 70 bpm, RR: 18, T: 98°F. weight 56.2 kg, BMI 24.21. She was in nonacute distress, although anxious with pressured speech. She was cooperative and able to follow commands and track the examiner. Her NIH Stroke Scale/Score (NIHSS) was 0 and Glasgow Coma Scale (GCS) was 15. She denied using illicit drugs, smoking, and alcohol. Neurology decided to repeat LP CSF r/o NMDA Antibody encephalitis and started empirically a 5-day course of azithromycin to cover for streptococcal infections while awaiting further results. Thyroglobulin antibodies were ordered to rule out Steroids Responsive Encephalopathy and it came back elevated (91.2). She was started on Solu-Medrol 500mg IV daily for 3 days which was increased to 1000mg IV daily to complete 5 days. Even though, she developed tachycardia in the 120s; she started feeling much better as well as improved her symptoms. “Steroid-responsive encephalopathy associated with autoimmune thyroiditis” (SREAT) is an uncommon condition that is associated with Hashimoto thyroiditis. It is also called Hashimoto encephalopathy (HE). This condition was originally described in 1966 by Brain et al1. HE is a rare disorder with an approximate prevalence of 2/100,0002. It affects women more often than men. This diagnosis is typically made when a patient has encephalopathy associated with antithyroid (anti-thyroid peroxidase [TPO]) and/or anti-thyroglobulin (TG) antibodies, when other causes have been excluded. The symptoms typically seen include subacute onset of confusion with altered level of consciousness, seizures, and myoclonus. Based on the literature review of 251 cases of SREAT by Laurent et al3, SREAT has various presentations including coma to isolated psychiatric disorder. This disorder is thought to be immune mediated as opposed to being the result of an altered thyroid state on the nervous system. In most of the reported cases of SREAT, the patients are euthyroid during the presentation of symptoms. However, the exact mechanism of SREAT is still unknown. The diagnosis is made after excluding other toxic, infectious, and metabolic causes of encephalopathy with examination of cerebrospinal fluid and neuroimaging.

Thyroid hormone disorder and the heart: The role of cardiolipin in calcium handling.

What is the central question of this study? Do alterations in thyroid status affect haemodynamic parameters and echocardiographic measurements in the rat postnatal heart, and calcium handling, contractility, relaxation and cardiolipin content in isolated rat cardiomyocytes? What is the main finding and its importance? An imbalance in phospholipids of the mitochondrial membrane such as cardiolipin is related to defects in mitochondrial function. T3 -dependent cardiolipin signals contribute to the maintenance of mitochondrial homeostasis and involve Ca2+ handling, this pathway being more important in hypothyroidism. The objective of this study was to evaluate whether alterations in thyroid status affect (1) haemodynamic parameters and echocardiographic measurements in the rat postnatal heart, and (2) calcium handling, contractility, relaxation and cardiolipin content in isolated rat cardiomyocytes. Sprague-Dawley rats aged 2months treated with T3 (hyperthyroid, 20μg/100g body weight) or 0.02% methimazole (hypothyroid, w/v) for 28 days. Heart function was evaluated by echocardiography. Measurements of mean arterial pressure (MAP), heart rate, Ca2+ transients, cardiomyocyte shortening, number of spontaneous contractions per minute and cardiolipin (CL) content were performed. Thyroid disorders were associated with changes in pacemaker activity without modifications of MAP. Thyroid disorder induced changes in left ventricular diameter which were correlated with modifications of cardiac contractility (altered cell shortening and sarcoplasmic reticulum Ca2+ content). Endocrine disorders altered cardiomyocyte relaxation (reduction in the time to 50% re-lengthening and the time to 50% Ca2+ decay). Thyroid disorder increased the number of spontaneous contractions per minute (an index of pro-arrhythmogenic behaviour). CL content was increased only in hypothyroid rats. Changes in CL content, CL composition and CL-protein interaction in mitochondria from hypothyroid animals are responsible for alterations of contractile and relaxation cardiac function. This mechanism may be not be involved in T3 -treated rats. Maintenance of euthyroidism is of crucial importance to preserve cardiac performance. An imbalance in relation to phospholipids of the mitochondrial membrane such as CL is related to defects in mitochondrial function. T3 -dependent CL signals contribute to the maintenance of mitochondrial homeostasis and involve Ca2+ handling, this pathway being more important in hypothyroidism.

Ioxynil and diethylstilbestrol increase the risks of cardiovascular and thyroid dysfunction in zebrafish

Endocrine disruption results from exposure to chemicals that alter the function of the endocrine system in animals. Chronic 60 days of exposure to a low dose (0.1 μM) of ioxynil (IOX) or diethylstilbestrol (DES) via food was used to determine the effects of these chemicals on the physiology of the heart and thyroid follicles in juvenile zebrafish. Immunofluorescence analysis and subsequent 3D morphometric analysis of the zebrafish heart revealed that chronic exposure to IOX induced ventricle deformation and significant volume increase (p < 0.001). DES exposure caused a change in ventricle morphology, but volume was unaffected. Alongside, it was found that DES exposure upregulated endothelial related genes (angptl1b, mhc1lia, mybpc2a, ptgir, notch1b and vwf) involved in vascular homeostasis. Both IOX and DES exposure caused a change in thyroid follicle morphology. Notably, in IOX exposed juveniles, thyroid follicle hypertrophy was observed; and in DES-exposed fish, an enlarged thyroid field was present. In summary, chronic exposure of juvenile zebrafish to IOX and DES affected the heart and the thyroid. Given that both chemicals are able to change the morphology of the thyroid it indicates that they behave as endocrine disruptive chemicals (EDCs). Heart function dynamically changes thyroid morphology, and function and hence it is likely that the observed cardiac effects of IOX and DES are the source of altered thyroid status in these fish.

Unexpected alterations in thyroid status: a case of alemtuzumab-induced Graves' disease with fluctuating course

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Influence of Pregnancy Stages on Thyroid Status and Blood Metabolites in Desert Ewes Raised under Range Conditions in West Kordufan State, Sudan

This study aimed to evaluate the influence of the stages of pregnancy in two ecotypes of sheep, located in different grazing areas on thyroid status and certain blood metabolites. Eighty clinically healthy ewes (40 Hamari and 40 Kabashi ecotype) aged 2-5 years were used in the study. For each ecotype, the ewes were divided into four groups according to the reproductive status. Group (A): 10 ewes non-pregnant non-lactating (dry) served as the control. Group (B): 10 ewes in the early stage of pregnancy (first trimester). Group (C): 10 ewes in mid-stage of pregnancy (second trimester). Group (D): 10 ewes in the late stage of pregnancy (third trimester). Blood samples were used to measure serum levels of thyroid stimulating hormone (TSH), thyroxine (T4), triiodothyronine (T3), plasma glucose concentration and serum triglyceride levels. The study detected that Hamari ecotype was supplied with salt and minerals block during watering by its owners. The results showed that in both ecotypes, the serum TSH levels were significantly (P&lt;0.05) higher during the early stage of pregnancy then, it decreased significantly (P&lt;0.01) as the pregnancy advanced. While serum T4 levels were higher during the early stage of pregnancy, then it decreased significantly (P&lt;0.01) during the late pregnancy in both ecotypes. Serum T3 level was significantly (P&lt;0.001) higher in both ecotypes during early and mid-pregnancy, then declined to the lowest value during the late stage. The plasma glucose level was significantly (P&lt;0.001) lower during mid and late pregnancy in both ecotypes. There was a significant (P&lt;0.05) decrease in serum triglyceride level when pregnancy advanced in both ecotypes. Kabashi ecotype showed significantly higher serum triglyceride levels in the control group (P&lt;0.001) during early pregnancy stage (P&lt;0.01) and mid pregnancy stage (P&lt;0.05) compared to the values of serum triglyceride levels in Hamari ecotypes. This study indicated that pregnancy altered thyroid status in both ecotypes, however, the influence of pregnancy on the thyroid status was less in the Hamary ecotype which supplemented by mineral and salt blocks. Therefore, supplementation with minerals during pregnancy might enhance the metabolic profile on the natural pasture grazing.

Thyroid Hormones-An Underestimated Player in Dilated Cardiomyopathy?

Dilated cardiomyopathy (DCM) is the most prevalent cardiomyopathy, typified by left ventricular dilation and systolic dysfunction. Many patients with DCM have altered thyroid status, especially lower levels of free triiodothyronine (T3) and elevated levels of thyroid-stimulating hormone. Moreover, growing evidence indicates that even subtle changes in thyroid status (especially low T3) are linked with a worse long-term prognosis and a higher risk of mortality. Notably, recent discoveries have shown that not only local myocardial thyroid hormones (THs) bioavailability could be diminished due to impaired expression of the activating deiodinase, but virtually all genes involved in TH biosynthesis are also expressed in the myocardium of DCM patients. Importantly, some studies have suggested beneficial effects of TH therapy in patients suffering from DCM. Our aim was to discuss new insights into the association between TH status and prognosis in DCM, abnormal expression of genes involved in the myocardial synthesis of TH in DCM, and the potential for TH use in the future treatment of DCM.

Effects of thyroxine and propylthiouracil on feeding behavior and the expression of hypothalamic appetite-regulating peptides and thyroid function in goldfish (Carassius auratus)

There is poor evidence for an association between thyroidal state, feeding and appetite regulation in fish. We assessed how an altered thyroid state influences feeding behavior, food intake and expression of hypothalamic appetite-regulating peptides (Klotho-α and Klotho-β; orexin, OX; cholecystokinin, CCK; agouti-related peptide, AgRP; cannabinoid receptor 1, CB1) in goldfish. We also measured the expressions of hypothalamic, pituitary and liver transcripts that regulate the thyroid [thyrotropin-releasing hormone (TRH), thyrotropin-releasing hormone receptor (TRH-R) type 1, thyroid stimulating hormone beta (TSHβ), deiodinases (DIO2, DIO3), UDP-glucuronosyltransferase (UGT1A1), thyroid receptor alpha and beta (TRα, TRβ)], and circulating levels of total thyroxine (tT4) and total triiodothyronine (tT3). Goldfish were implanted with propylthiouracil (PTU) or T4 osmotic pumps for 12 days. T4- treatment increased feeding behavior but not food intake, increased central TSHβ and DIO2, and hepatic DIO2 transcript expression and increased central DIO3 mRNA. Under hyperthyroid conditions, hypothalamic Klotho and CCK expressions were downregulated, suggesting an increased metabolic state and a hypothalamic response to regulate energy balance. AgRP, OX and CB1 were not affected by T4 treatment. PTU had no effect on any of the parameters examined, suggesting it is not a sensitive thyroid inhibitor in fish. Overall, we show that unlike in mammals, hyperthyroid conditions in goldfish do not lead to an increased desire or need to consume food, furthering evidence for a weak link between the thyroid and appetite.

Hsps70 and 90 protect the heart of hyperthyroid rats via nitric oxide production and VEGF inhibition of apoptosis

Background. Changes occur in the heart's contractile and metabolic demands during altered thyroid states. The changes may be associated with alterations in the cellular signaling of vascular endothelial growth factors (VEGF) and expressions of heat shock proteins (Hsp). Aim. This study examined the effects of thyroid dysfunction on VEGF, hsp70, and hsp 90 concentrations in the heart tissues of dysthyroid rats. Methods. Wistar rats were allocated into control, hypothyroid (Carbimazole-treated), and hyperthyroid (Levothyroxine-treated) groups randomly (n=7). Thyroid function test, body weight changes, serum creatinine kinase (CK-MB), cardiac troponin I (cTnI) and troponin T (cTnT), NO, VEGF, Hsp70, and Hsp 90 were determined using standard methods. Results. There was a significant increase (P<0.05) in NO, VEGF, Hsp70, and Hsp 90 levels in the hyperthyroid group and reduced expression in the hypothyroid group compared to the control. Carbimazole treatment led to a significant increase in lipid peroxidation and CK-MB level, with a substantial decrease in the superoxide dismutase (SOD) activity in the hypothyroid group. Conclusion. Increased expression of Hsp70 and 90 in hyperthyroid rats' heart tissue play essential roles in protecting the heart from oxidative damage and cardiovascular derangements via enhancement of nitric oxide production and apoptosis inhibition by VEGF.

When Your Thyroid Causes Muscle Paralysis

Background: Periodic paralysis represents a spectrum of disorders characterized by ion channel dysfunction, mainly Na-K-ATPase channels. Thyrotoxic periodic paralysis (TTP) is defined by the presence of hypokalemia and diffuse muscular paralysis in a pre-existing hyperthyroid state. Diagnosis can be challenging, especially in cases of undiagnosed hyperthyroidism due to the non-specific presentation of this illness. We present a case of a young male who presented with recurrent, spontaneous paralysis found to have Graves’ disease. Clinical Case: A 38-year-old Asian male presented with sudden onset diffuse weakness, numbness, and tingling. The weakness was so severe that he could barely walk more than a few steps. However, his symptoms resolved in less than 24 hours without any intervention. Five months later, the patient experienced a recurrent episode of this similar constellation of diffuse muscle weakness and paresthesia. The patient was taken to a nearby hospital, where he was provided with intravenous fluid resuscitation. Initial laboratory workup was notable for hypokalemia to 1.4 mmol/L (n: 3.6 - 5.3 mmol/L), hypophosphatemia to 0.6 mmol/L (n: 2.4 – 4.8 mmol/L), and elevated creatinine kinase to 807 U/L (n: 22 – 198 U/L). Additionally, TSH was <0.001 mU/L (n: 0.45 – 4.5 mU/L) along with free T4 3.4 ng/dL (n: 0.80 – 1.70 ng/dL. The patient denied any other symptoms or a family history of similar symptoms. Lumbar puncture and brain/spine MRIs were unremarkable. Symptoms gradually improved throughout hospitalization with fluid and electrolyte repletion. Hyperthyroidism was treated with methimazole 5mg twice daily, later changed to PTU 50mg every eight hours due to recurrent headaches. Thyroid uptake scan showed diffuse bilateral uptake to 39.11% at 4 hours and 61.8% at 24 hours. Follow up labs revealed: TSH 0.3 mU/L, free T4 1.44 ng/dL, free T3 3.5 pg/mL (n: 2.3 – 4.1 pg/mL). Patient denied recurrent episodes of weakness or paresthesia. Definitive hyperthyroidism treatment with RAI was planned. Conclusions: The prevalence of TPP is higher in Asian males compared to other ethnic groups. TPP manifests as a sporadic onset of muscle weakness ranging from mild weakness to flaccid paralysis. It has been described that thyroid hormone itself augments the activity of the Na-K-ATPase channel and increases its responsiveness to beta-adrenergic stimulation. In addition, hyperthyroidism is associated with insulin resistance leading to hyperinsulinemia. Both beta-agonism and insulin promote potassium to be driven into cells resulting in hypokalemia. As such, activities which increase beta adrenergic stimulation, like stress and exercise, and promote the secretion of insulin, such as heavy carbohydrate intake, are well described triggers of TPP. Treatment revolves around acutely treating hypokalemia followed by preventing subsequent attacks via regulation of the altered thyroid state.

Pro-Arrhythmic Signaling of Thyroid Hormones and Its Relevance in Subclinical Hyperthyroidism.

A perennial task is to prevent the occurrence and/or recurrence of most frequent or life-threatening cardiac arrhythmias such as atrial fibrillation (AF) and ventricular fibrillation (VF). VF may be lethal in cases without an implantable cardioverter defibrillator or with failure of this device. Incidences of AF, even the asymptomatic ones, jeopardize the patient’s life due to its complication, notably the high risk of embolic stroke. Therefore, there has been a growing interest in subclinical AF screening and searching for novel electrophysiological and molecular markers. Considering the worldwide increase in cases of thyroid dysfunction and diseases, including thyroid carcinoma, we aimed to explore the implication of thyroid hormones in pro-arrhythmic signaling in the pathophysiological setting. The present review provides updated information about the impact of altered thyroid status on both the occurrence and recurrence of cardiac arrhythmias, predominantly AF. Moreover, it emphasizes the importance of both thyroid status monitoring and AF screening in the general population, as well as in patients with thyroid dysfunction and malignancies. Real-world data on early AF identification in relation to thyroid function are scarce. Even though symptomatic AF is rare in patients with thyroid malignancies, who are under thyroid suppressive therapy, clinicians should be aware of potential interaction with asymptomatic AF. It may prevent adverse consequences and improve the quality of life. This issue may be challenging for an updated registry of AF in clinical practice. Thyroid hormones should be considered a biomarker for cardiac arrhythmias screening and their tailored management because of their multifaceted cellular actions.

Role of thyroid hormones in craniofacial development.

The development of the craniofacial skeleton relies on complex temporospatial organization of diverse cell types by key signalling molecules. Even minor disruptions to these processes can result in deleterious consequences for the structure and function of the skull. Thyroid hormone deficiency causes delayed craniofacial and tooth development, dysplastic facial features and delayed development of the ossicles in the middle ear. Thyroid hormone excess, by contrast, accelerates development of the skull and, in severe cases, might lead to craniosynostosis with neurological sequelae and facial hypoplasia. The pathogenesis of these important abnormalities remains poorly understood and underinvestigated. The orchestration of craniofacial development and regulation of suture and synchondrosis growth is dependent on several critical signalling pathways. The underlying mechanisms by which these key pathways regulate craniofacial growth and maturation are largely unclear, but studies of single-gene disorders resulting in craniofacial malformations have identified a number of critical signalling molecules and receptors. The craniofacial consequences resulting from gain-of-function and loss-of-function mutations affecting insulin-like growth factor 1, fibroblast growth factor receptor and WNT signalling are similar to the effects of altered thyroid status and mutations affecting thyroid hormone action, suggesting that these critical pathways interact in the regulation of craniofacial development.

Alterations of thyroidal status in brain regions and hypothalamo-pituitary-blood-thyroid-axis associated with dopaminergic depletion in substantia nigra and ROS formation in different brain regions after MPTP treatment in adult male mice

MPTP produces oxidative stress, damages niagrostriatal dopaminergic neurons and develops Parkinsonism in rodents. Due to paucity of information, the thyroidal status in brain regions and peripheral tissues during different post-treatment days in MPTP-induced mice had been executed in the present study. MPTP depleted tyrosine hydroxylase protein expressions that signify the dopaminergic neuronal damage in substantia nigra. MPTP elevated ROS formation differentially in brain regions (cerebral cortex, hippocampus, substantia nigra) with maximal elevation at hippocampus. The changes in thyroid hormone (T4 and T3) levels indicate that brain regions might combat the adverse situation by keeping the levels of thyroid hormones either unchanged or in the elevated conditions in the latter phases (day-3 and day-7), apart from the depletion of thyroid hormones in certain brain regions (T4 in SN and hippocampus, T3 in hippocampus) as the immediate (day-1) effects after MPTP treatment. MPTP caused alterations of cellular morphology, RNA:Protein ratio and TPO protein expression, concomitantly depleted TPO mRNA expression and elevated TSH levels in the thyroid gland. Although T4 levels changed differentially, T3 levels remained unaltered in thyroid gland throughout the post-treatment days. Results have been discussed mentioning the putative role of T4 and TSH in apoptosis and/or proliferation/differentiation of thyrocytes. In blood, T4 levels remained unchanged while the changes in T3 and TSH levels did not signify the clinical feature of hypo/hyperthyroidism of animals. In the pituitary, both T4 and T3 levels remained elevated where TSH differentially altered (elevated followed by depletion) during post-treatment days. Notably, T4, T3 and TSH levels did not alter in hypothalamus except initial (day-1) depletion of the T4 level. Therefore, the feedback control mechanism of hypothalamo-pituitary-blood-thyroid-axis failed to occur after MPTP treatment. Overall, MPTP altered thyroidal status in the brain and peripheral tissues while both events might occur in isolation as well.

Effect of altered thyroid status on the incidence of colon tumors induced by methylnitrosourea in rats

Aim. The present study was designed to determine whether medically induced hyper- and hypothyroidism effect on incidence of colon tumors induced by methylnitrosourea (MNU) burden in rats.&#x0D; Methods. Female rats (n = 88) were randomly divided into four groups: I (euthyroid-control), II (hyperthyroid caused by liothyronine), III (hyperthyroid caused by L-thyroxine) and IV (hypothyroid caused by propylthiouracil (PTU), also 11 rats were intact control. Colon carcinogenesis was induced with a four intrarectal instillation of MNU (4 mg in 0.5 ml saline solution) one time per week. Liothyronine (100 ± 10 µg per 100 g of animal weight 1 time per day), L-thyroxin (100 ± 10 µg per 100 g of animal weight 1 time per day) and propylthiouracil (PTU, 2,0 ± 0,15 mg per 100 g of animal weight 1 time per day) were administered intragastrically through an atraumatic probe daily, starting from the day of the last intrarectal instillation of MNU. Rats were sacrificed at 216 days after experiment beginning, and the total colon were excised, fixed for histology and analyzed.&#x0D; Results. Drug inhibition of thyroid hormone function by PTU resulted in a decrease in the incidence of MNU-induced colon tumors and amounted to 27.3%. The incidence of colon tumors in the hyperthyroid group caused by L-thyroxine was 70.0% (F-test – 0.012, χ2 – 7.67; p &lt; 0.05 compared with the hypothyroid group).

Cardiac Cx43 and ECM Responses to Altered Thyroid Status Are Blunted in Spontaneously Hypertensive versus Normotensive Rats.

Heart function and its susceptibility to arrhythmias are modulated by thyroid hormones (THs) but the responsiveness of hypertensive individuals to thyroid dysfunction is elusive. We aimed to explore the effect of altered thyroid status on crucial factors affecting synchronized heart function, i.e., connexin-43 (Cx43) and extracellular matrix proteins (ECM), in spontaneously hypertensive rats (SHRs) compared to normotensive Wistar Kyoto rats (WKRs). Basal levels of circulating THs were similar in both strains. Hyperthyroid state (HT) was induced by injection of T3 (0.15 mg/kg b.w. for eight weeks) and hypothyroid state (HY) by the administration of methimazol (0.05% for eight weeks). The possible benefit of omega-3 polyunsaturated fatty acids (Omacor, 200 mg/kg for eight weeks) intake was examined as well. Reduced levels of Cx43 in SHRs were unaffected by alterations in THs, unlike WKRs, in which levels of Cx43 and its phosphorylated form at serine368 were decreased in the HT state and increased in the HY state. This specific Cx43 phosphorylation, attributed to enhanced protein kinase C-epsilon signaling, was also increased in HY SHRs. Altered thyroid status did not show significant differences in markers of ECM or collagen deposition in SHRs. WKRs exhibited a decrease in levels of profibrotic transforming growth factor β1 and SMAD2/3 in HT and an increase in HY, along with enhanced interstitial collagen. Short-term intake of omega-3 polyunsaturated fatty acids did not affect any targeted proteins significantly. Key findings suggest that myocardial Cx43 and ECM responses to altered thyroid status are blunted in SHRs compared to WKRs. However, enhanced phosphorylation of Cx43 at serine368 in hypothyroid SHRs might be associated with preservation of intercellular coupling and alleviation of the propensity of the heart to malignant arrhythmias.

Possible activation of NRF2 by Vitamin E/Curcumin against altered thyroid hormone induced oxidative stress via NF\u0138B/AKT/mTOR/KEAP1 signalling in rat heart

Oxidative stress is implicated in both hypo- and hyper-thyroid conditions. In the present study an attempt has been made to elucidate possible interaction between vitamin E or/and curcumin (two established antioxidants) with active portion (redox signaling intervening region) of nuclear factor erythroid 2-related factor 2 (NRF2) as a mechanism to alleviate oxidative stress in rat heart under altered thyroid states. Fifty Wistar strain rats were divided into two clusters (Cluster A: hypothyroidism; Cluster B: hyperthyroidism). The hypo- (0.05% (w/v) propylthiouracil in drinking water) and hyper- (0.0012% (w/v) T4 in drinking water) thyroid rats in both clusters were supplemented orally with antioxidants (vitamin E or/and curcumin) for 30 days. Interactive least count difference and principal component analyses indicated increase in lipid peroxidation, reduced glutathione level, alteration in the activities and protein expression of antioxidant enzymes like superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase under altered thyroid states. However, the expression of stress survival molecules; nuclear factor κB (NFκB) and the serine-threonine kinase B (Akt), in hyper-thyroidism only points towards different mechanisms responsible for either condition. Co-administration of vitamin E and curcumin showed better result in attenuating expression of mammalian target for rapamycin (mTOR), restoration of total protein content and biological activity of Ca2+ ATPase in hyperthyroid rats, whereas, their individual treatment showed partial restoration. Since NRF2 is responsible for activation of antioxidant response element and subsequent expression of antioxidant enzymes, possible interactions of both vitamin E or/and curcumin with the antioxidant enzymes, NRF2 and its regulator Kelch ECH associating protein (KEAP1) were studied in silico. For the first time, a modeled active portion of the zipped protein NRF2 indicated its interaction with both vitamin E and curcumin. Further, curcumin and vitamin E complex showed in silico interaction with KEAP1. Reduction of oxidative stress by curcumin and/or vitamin E may be due to modulation of NRF2 and KEAP1 function in rat heart under altered thyroid states.

Glycosylated Hemoglobin among Non-diabetic Patients Diagnosed as Benign Thyroid Lesions on Cytology: A Cross Sectional Study from a Tertiary Care Centre in India

Background: Hypothyroidism and diabetes usually coexist and are the most common endocrine disorders seen in India (1). Glycosylated Hb (HbA1c) is used for assessment of glycemia and American Diabetic Association (ADA) has recommended its use in diabetes and prediabetes (2). A value between 5.7% and 6.5% represents prediabetes while a value ≥6.5% is considered as diabetes mellitus (3). Glycosylated hemoglobin is a fraction of hemoglobin that undergoes non-enzymatic glycation over the circulatory life span of erythrocytes (4). Several studies have shown glycosylated Hb varies in different conditions like hemoglobinopathies, pregnancy and chronic kidney disease (5). Thyroid hormone plays an important role in glucose homeostasis (6). TSH regulates hematopoiesis in bone marrow (7). Hypothyroidism depresses the marrow which causes decreased erythrocyte production which alters the life span of erythrocytes. Altered life span causes spurious elevation of HbA1C (8, 9, 10). Hence, glycosylated Hb not only depends on glycemia but also on life span of RBC (11). Conditions which effect erythrocyte turnover or survival lead to falsely high or low Hb A1C levels (12). RBC turnover is increased in thyrotoxic states whereas hypothyroidism has the opposite effect (3). In the present study, we hypothesise that glycosylated hemoglobin shows variation in individuals with altered thyroid status. It also aim to establish if a correlation exits between fasting plasma glucose level and hemoglobin with glycosylated hemoglobin in patients with altered thyroid status. Aims and Objectives: To find a correlation between thyroid profile and glycosylated Hb in non-diabetic patients who have been diagnosed on cytology as benign thyroid lesions and Compare the fasting blood glucose and hemoglobin with glycosylated Hb in these patients. Material and Methods: A cross sectional study on 50 cases cytologically diagnosed as benign thyroid lesions in the Department of Pathology in ESIC Medical College and Hospital Faridabad were included in the study with consent of ethical committee. Data Analysis: Pearson’s coefficient was applied to test the association between variables. The significance level was set at 5%. Results: Out of 50 patients (n=25) 50% were hypothyroid, (n=13) 26% were hyperthyroid and (n=12) 24% were euthyroid and (n=22) 88% hypothyroid patients presented with HbA1C >6.5% and were labeled as Diabetic, (n=3) 12% hypothyroid patients were labelled as prediabetic and none was nondiabetic. Most of the euthyroid (n=11) 92% and all of the hyperthyroid patients (n=13) 100% had HbA1C in the nondiabetic range of 6.5%). The correlation of HbA1C with TSH, Hb and MCH of these patients showed statistical significance (p 6.5%) or prediabetic (HbAIc between 5.7 to 6.5%).

A10789 Effect of omega-3 fatty acids on the extracellular matrix and intercellular communication in the heart of hypertensive rats with altered thyroid status

A10789 Effect of omega-3 fatty acids on the extracellular matrix and intercellular communication in the heart of hypertensive rats with altered thyroid status

Thyroid Hormone Receptors Regulate the Expression of microRNAs with Key Roles in Skin Homeostasis.

MicroRNAs (miRNAs) play a unique role in posttranscriptional regulation of gene expression and control different aspects of skin development, homeostasis, and disease. Although it is generally accepted that thyroid hormone signaling is important in skin pathophysiology, the role of their nuclear receptors (TRs) in cutaneous miRNA expression has yet to be explored. RNAseq was used to compare the skin miRnome of wild-type mice and genetically modified mice lacking both TRα1 and TRβ, the main thyroid hormone binding isoforms. Changes in miRNAs with a crucial role in skin physiopathology were confirmed by stem-loop quantitative polymerase chain reaction in both total skin and isolated keratinocytes, and the levels of their target mRNAs were evaluated by real-time polymerase chain reaction. The skin of TRα1/TRβ knockout mice displays altered levels of >50 miRNAs. Among the downregulated species are several miRNAs, including miR-21, miR-31, miR-34, and miR-203, with crucial roles in skin homeostasis. TRα1 appears to be the main isoform responsible for their regulation. Increased levels of gene transcripts previously shown to be bona fide targets of these miRNAs are also found in the skin and keratinocytes of TR-deficient mice. This suggests that multiple miRNAs that are downregulated in the absence of TRs cooperate to regulate gene expression in the skin. The miRNAs reduced in TRα1/TRβ knockout mice are known to play crucial roles in epidermal proliferation, hair cycling, wound healing, stem-cell function, and tumor development, all processes altered in the absence of TRs. These results suggest that their regulation could contribute to the skin defects found in these mice and to the skin disorders associated with altered thyroid status in humans.