Circulating Thyroid Hormone Research Articles

Triiodothyronine Supplementation in Infants Undergoing Cardiopulmonary Bypass: A Randomized Controlled Trial

Cardiopulmonary bypass (CPB) profoundly suppresses circulating thyroid hormone levels in infants. We performed a multicenter randomized placebo controlled trial to determine if triiodothyronine (T3) supplementation improves reduces time to extubation (TTE) in infants after CPB. Infants (n=220) undergoing cardiac surgery with CPB and stratified into 2 age cohorts: ≤30 days and >30 days to <152 days were randomization to receive either intravenous triiodothyronine or placebo bolus followed by study drug infusion until extubated or at 48 hours, whichever preceded. T3 did not significantly alter the primary endpoint, TTE (hazard ratio for chance of extubation (1.08, 95% CI: 0.82-1.43, P = 0.575) in the entire randomized population with censoring at 21 days. T3 showed no significant effect on TTE (HR 0.82, 95% CI:0.55-1.23, P = 0.341) in the younger subgroup or in the older (HR 1.38, 95% CI:0.95-2.2, P = 0.095). T3 also did not significantly impact TTE during the first 48 hours while T3 levels were maintained (HR 1.371, 95% CI:0.942-1.95, P = 0.099) No significant differences occurred for arrhythmias or other sentinel adverse events in the entire cohort or in the subgroups. This trial showed no significant benefit on TTE in the entire cohort. T3 supplementation appears safe as it did not cause an increase in adverse events. The study implementation and analysis were complicated by marked variability in surgical risk, although risk categories were balanced between treatment groups.

The TSH/Thyroid Hormones Axis and Breast Cancer.

Breast cancer, the most prevalent female carcinoma, is characterized by the expression of steroid nuclear receptors in a subset of cases. The most important nuclear receptor with prognostic and therapeutic implications is the Estrogen Receptor (ER), which is expressed in about three out of four breast cancers. The Progesterone Receptor (PR) and the Androgen Receptor (AR) are also commonly expressed. Moreover, non-steroid nuclear receptors, including the vitamin D receptor (VDR) and the thyroid receptors (TRs), are also present in breast cancers and have pathophysiologic implications. Circulating thyroid hormones may influence breast cancer risk and breast cancer cell survival, through ligating their canonical receptors TRα and TRβ but also through additional membrane receptors that are expressed in breast cancer. The expression of TR subtypes and their respective isotypes have diverse effects in breast cancers through co-operation with ER and influence on other cancer-associated pathways. Other components of the TSH/thyroid hormone axis, such as TSH and selenoiodinase enzymes, have putative effects in breast cancer pathophysiology. This paper reviews the pathophysiologic and prognostic implications of the thyroid axis in breast cancer and provides a brief therapeutic perspective.

Thyroidectomy and uncontrolled graves' disease - Multidisciplinary approach prevents unnecessary cancellation.

Dear Editor, Thyroidectomy is the definitive treatment for thyrotoxicosis for patients resistant to medical treatment and performed preferably when the patient is euthyroid.[1] Sometimes it may not be possible to render a patient euthyroid for various reasons leading to postponement or deferment of surgery.[2] A 35-year-old woman, was suffering from Graves’ disease, confirmed by a low thyroid-stimulating hormone (<0.005 miliunits/L), markedly elevated free thyroxine (>100 nanograms/dL), and positive thyroid receptor antibodies. Thionamide (carbimazole) therapy was started to lower the circulating thyroid hormone levels and beta-blockers added to reduce her hyper-adrenergic symptoms. She developed adverse drug effects resulting in agranulocytosis which necessitated discontinuing thionamide therapy. A multidisciplinary team consisting of an endocrinologist, endocrine surgeon, and anaesthetist was convened and a consensus view emerged for urgent total thyroidectomy. In preparation for surgery Lugol’s iodine and oral propranolol 20 mg 8 hourly administered to control tachycardia. Intravenous hydrocortisone 100 mg 8 hourly was started 1 week prior to planned operation to reduce peripheral conversion of free thyroxine to free triiodothyronine. General anaesthesia was administered with target-controlled infusion (TCI) of propofol and remifentanil with intubating dose of atracurium. Neural integrity monitor (NIM) electromyogram tracheal tube was used for intraoperative recurrent laryngeal nerve function monitoring. No further dose of atracurium was used. Anaesthesia was maintained with total intravenous anaesthesia (TIVA) using TCI devices and depth of anaesthesia was monitored with bispectral index (BIS monitor). Total thyroidectomy with parathyroid preservation was uneventful. After a brief observation in the post-anaesthesia recovery unit, she was transferred to the high dependency unit for monitoring. The postoperative course was complicated by severe hypocalcaemia (0.82 mg/dL) due to transient postsurgical hypoparathyroidism. This was confirmed by inappropriately normal parathyroid hormone levels post-surgery despite severe hypocalcaemia. Prolonged and severe stimulation of thyroid hormone is known to induce a high bone turnover state described as thyrotoxic osteodystrophy.[34] The high incidence of hypocalcaemia after thyroidectomy in thyrotoxic patients suggests that rapid loss and sudden removal of T3 and T4 hormone stimulation and inadequate parathyroid hormone response resulting in transient post-thyroidectomy hypocalcaemia. The calcium levels stabilized over the next 3 days with intravenous calcium replacement; subsequently, she was discharged with oral calcium and vitamin D supplements. Thyroidectomy may be the last option in some patients with Graves’ thyrotoxicosis refractory to medical treatment who cannot be optimized by medical treatment. A multidisciplinary team approach may help in appropriate preparation of patients prior to thyroidectomy avoiding unnecessary cancellation or postponement of surgery. Close postoperative monitoring of serum-ionized calcium is also recommended. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Hashimoto’s Disease: Associated Thyroid Gland Disorders, Pharmacological, and Nutritional Interventions

Hashimoto’s disease is a condition that occurs when an affected person’s immune system attacks their thyroid gland and produces an immune response that results in low levels of thyroid hormones in the blood. These hormones are important in maintaining the body’s metabolic processes and the lack of thyroid hormones causes the symptoms of Hashimoto’s disease that include weight gain, paleness, coldness, birth defect, infertility, menorrhagia, and even death in rare cases of uncontrolled hypothyroidism. The disease requires a blood test to determine the levels of circulating thyroid hormones in the blood or the presence of specific antibodies. Thyroid hormone replacement is used to raise the levels of thyroid hormones in the body, if the hormone test shows that they are deficient. People who are middle aged, female, and have or are predisposed to an autoimmune disorder are most at risk for developing the disease. In recent times, the notion that the antidote for managing Hashimoto’s disease may be found in common food and supplements has grown among endocrinologists and caregivers. This review is intended to investigate the various aspects of the disease that include its pathogenesis, associated disorders, pharmacological and nutritional interventions.

A Study of Thyroid Profile (FT3, FT4, TSH) in Liver Cirrhosis in Jharkhand - A Hospital based Study

in people with liver disorders. Aim: To determine the prevalence of thyroid dysfunction in liver cirrhosis patients. Materials and Methods: This case-control study was carried out in a group of randomly selected liver cirrhosis patients in the Department of Medicine at Rajendra Institute of Medical Sciences (R.I.M.S), Ranchi, Jharkhand (India) between September 2017 to August 2018. The equal number of age (&gt;18 years) and sex-matched cases &amp;controls were included in this study. Radioimmunoassays were used to evaluate early morning fasting blood thyroid-stimulating hormone (TSH), serum total free thyroxine (FT4), and free triiodothyronine (FT3) in 100 index patients with liver cirrhosis who had no history of thyroid disorders. Results: In the cases that were studied, which consisted of cirrhotic patients, males (80%) outnumbered females (20%). The mean age of cases was 47.9 years, and the maximum numbers of the patient were between 41-55 years of age group (47%). Among the cirrhotic patients, the commonest etiology was alcoholic liver disease which contributed to 78% of the total cases studied. The rest of the cases included cirrhotics from other etiologies, which included NAFLD (22%), HBsAg positive individuals (07%), and other cases of cryptogenic origin. The mean FT3, FT4, and TSH values in cases were 2.29±0.83; 1.20±0.55 &amp; 3.76±2.43 respectively &amp; the mean FT3, FT4, and TSH of the control group were 2.95±0.52; 1.40±0.25 &amp; 2.70±0.94 respectively. From these data, we can say that there is significant derangement of thyroid function in liver cirrhosis in favor of hypothyroidism (p&lt;0.05). Conclusion: Hypothyroidism, or abnormalities in circulating thyroid hormone concentrations, is seen in people with alcoholrelated liver cirrhosis and is linked to more severe liver disease

Serum Thyrotropin Elevation and Coronary Artery Calcification in Hemodialysis Patients

Introduction: Hypothyroidism is highly prevalent in end-stage kidney disease patients, and emerging data show that lower circulating thyroid hormone levels lead to downregulation of vascular calcification inhibitors and coronary artery calcification (CAC) in this population. To date, no studies have examined the association of serum thyrotropin (TSH), the most sensitive and specific single biochemical metric of thyroid function, with CAC risk in hemodialysis patients. Methods: In secondary analyses of patients from the Anti-Inflammatory and Anti-Oxidative Nutrition in Hypoalbuminemic Dialysis Patients trial, we examined serum TSH levels and CAC risk assessed by cardiac computed tomography scans collected within a 90-day period. We evaluated the relationship between serum TSH with CAC Volume (VS) and Agatston score (AS) (defined as >100 mm³ and >100 Houndsfield Units, respectively) using multivariable logistic regression. Results: Among 104 patients who met eligibility criteria, higher TSH levels in the highest tertile were associated with moderately elevated CAC VS and AS in case-mix-adjusted analyses (ref: lowest tertile): adjusted ORs (95% CIs) 4.26 (1.18, 15.40) and 5.53 (1.44, 21.30), respectively. TSH levels >3.0 mIU/L (ref: ≤3.0 mIU/L) were also associated with moderately elevated CAC VS and AS. In secondary analyses, point estimates of incrementally lower direct free thyroxine levels trended toward elevated CAC VS and AS, although associations did not achieve statistical significance. Conclusions: In hemodialysis patients, higher serum TSH was associated with elevated CAC VS and AS. Further studies are needed to determine if thyroid hormone supplementation can attenuate CAC burden in this population.

Impaired physiological thermoregulation in postweaning obese female LA/Ntul//-cp (corpulent) rats

Groups of lean and obese female lean, and obese LA/Ntul//cp (corpulent) rats were subjected to measures of thermic responses to feeding, noradrenaline administration, and responses to 14 hours of cold exposure to access their capacity for thermoregulation beginning at 6 to 8 weeks of age. Body weights and adipose tissue mass were greater in the obese than the lean phenotype (p=&lt;0.05). RMR and the dose related thermic responses to norepinephrine (NE) in lean were greater than in obese. Cold exposure at 4°C resulted in decreases in rectal but not core temperature in obese rats, and the thermic responses to 45 minutes of 4°C cold exposure on VO2 were typical but were significantly greater in lean than obese animals at all points measured. Circulating thyroid hormone concentrations were similar in lean and obese rats and T3 but not T4 increased dramatically in both phenotypes following the cold exposure, consistent with phenotype- and IBAT-linked changes in T4-5’ deiodinase and thyroidal activity in this strain. These thermoregulatory changes are consistent with previous studies and may contribute to phenotype mediated aspects of energy metabolism, storage, and adipose tissue deposition and to a phenotype specific selective epigenetic propensity for the expression of obesity during the early postweaning period

Human Genetic Disorders Resulting in Systemic Selenoprotein Deficiency.

Selenium, a trace element fundamental to human health, is incorporated as the amino acid selenocysteine (Sec) into more than 25 proteins, referred to as selenoproteins. Human mutations in SECISBP2, SEPSECS and TRU-TCA1-1, three genes essential in the selenocysteine incorporation pathway, affect the expression of most if not all selenoproteins. Systemic selenoprotein deficiency results in a complex, multifactorial disorder, reflecting loss of selenoprotein function in specific tissues and/or long-term impaired selenoenzyme-mediated defence against oxidative and endoplasmic reticulum stress. SEPSECS mutations are associated with a predominantly neurological phenotype with progressive cerebello-cerebral atrophy. Selenoprotein deficiency due to SECISBP2 and TRU-TCA1-1 defects are characterized by abnormal circulating thyroid hormones due to lack of Sec-containing deiodinases, low serum selenium levels (low SELENOP, GPX3), with additional features (myopathy due to low SELENON; photosensitivity, hearing loss, increased adipose mass and function due to reduced antioxidant and endoplasmic reticulum stress defence) in SECISBP2 cases. Antioxidant therapy ameliorates oxidative damage in cells and tissues of patients, but its longer term benefits remain undefined. Ongoing surveillance of patients enables ascertainment of additional phenotypes which may provide further insights into the role of selenoproteins in human biological processes.

Thyroid Profile in Idiopathic Childhood Steroid-Sensitive Nephrotic Syndrome

Background: Nephrotic syndrome (NS), the most common glomerular disease of childhood, characterized by massive proteinuria which may have a negative impact on the circulating thyroid hormone status necessitating thyroid hormone supplementation in these children. Aim: The aim was to determine the thyroid status in steroid-sensitive NS during the time of relapse and remission. Materials and Methods: In this single-center prospective observational study, we documented thyroid hormone profile (thyroid-stimulating hormone [TSH], thyroxine, and triiodothyronine) in fifty children at presentation (first attack or relapse) and again 4 weeks after remission. Baseline characteristics were noted in the prestructured proforma. Results: Out of the total fifty children analyzed, 29 were male and 21 females. Although both T3 and T4 levels were within the normal range in all participants during attack/relapse and in remission, there was a statistically significant difference in absolute levels of both T3 and T4 at relapse and remission (P = 0.001). There was a significant rise of TSH levels during attack/relapse which normalized to normal values after 4 weeks of remission (13.08 ± 7.9 vs. 2.43 ± 1.00 mIU/L,P = 0.0001). None required thyroid hormone replacement therapy. Conclusion: The rise of TSH level during relapse is mostly transient and usually does not require thyroid hormone supplementation.

Therapeutic plasmapheresis for the treatment of thyrotoxicosis: A retrospective multi-center study.

Thyroid storm and severe thyrotoxicosis remain among the most frequent endocrine emergencies, and first-line hyperthyroidism treatment is not always an option. Since the first report in 1970, plasmapheresis is a second-line treatment for severe or otherwise untreatable thyrotoxicosis when rapid euthyroidism is desired. We present a retrospective study of the experience in treating thyrotoxicosis with plasmapheresis between 2012 and 2020 in two specialized centers in Colombia. We register the demographic and clinical characteristic and compare the thyroid hormones and other biochemical measurements before and after treatment. Data from 19 patients was obtained, 58% female with a median age of 35 years (IQR 23.5), and most of them with Graves' disease. The most frequent indication for plasmapheresis was thyroid storm. A median of 4 (IQR 2) sessions lead to a significant reduction in FT4 (P .0001) and TT3 (P < .0003) with a nonsignificant decrease in beta-blocker (P .7353) dose, no change in hepatic enzymes, and no adverse events. After plasmapheresis, thyroidectomy was performed in 10 patients. Plasmapheresis is an effective and safe treatment option for reducing circulating thyroid hormones in severe thyrotoxicosis when other forms of treatment are contraindicated or in case of urgent thyroid and non-thyroid surgery. It is limited by its cost and the need for highly specialized resources.

Thyroid Disorders in Type 2 Diabetics in India: A Real-world Evidence-based Study

Background: In Type 2 diabetes mellitus (T2DM), both hypothyroidism and hyperthyroidism are commonly seen. The circulating thyroid hormones have a significant effect on the metabolism of glucose, lipid, and protein. In the case of T2DM, glycaemic control can worsen due to this effect. In T2DM patients, hyperglycemia can occur due to worsening diabetes mellitus because of hyperthyroidism and thyrotoxicosis and can increase the risk of complications of diabetes. T2DM also affects the levels of thyroid stimulating hormone by reducing it. It also impairs triiodothyronine (T3) conversion from thyroxine (T4) in the peripheral tissues. If T2DM is poorly managed, it can lead to insulin resistance and hyperinsulinemia. It is important to carry out more studies to clarify the relationship between thyroid disorders and T2DM. Objective: To understand the interdependent relationship between TD, T2DM, and hypertension. Material and methods: Retrospective, single-center, observational study conducted on anonymized patient data captured from electronic medical records (EMR). The demographic and clinical profile of T2DM patients were noted along with the thyroid test lab values available for the diabetic patients in the records. Results: A high prevalence of thyroid dysfunction was found in T2DM diabetics than found in the normal population. In the present study, hypothyroidism was found to be more in T2DM patients as compared to hypothyroidism. Conclusion: An increased prevalence of TD is being seen in T2DM patients and can worsen each other's function. A more systematic approach is needed for thyroid testing considering the clinical implications of the coexistence of TD and T2DM.

Reference Intervals for Total T4 and Free T4 in Cynomolgus Macaques (Macaca fascicularis) and Rhesus Macaques (Macaca mulatta).

Thyroid diseases, associated with either increased or decreased concentrations of circulating thyroid hormones, are prevalent in both human and veterinary populations. Hypothyroidism is a differential diagnosis for many medical problems as the disease presents with nonspecific clinical signs that can include lethargy, weight gain, cold intolerance, and dermatologic manifestations such as alopecia. Alopecia is a frequently reported problem in captive nonhuman primates (NHP), and hypothyroidism is considered to be a differential diagnosis. However, thyroid function test results in NHP using total T4 (TT4) and free T4 (FT4) assays are difficult to interpret without accurate reference intervals (RI) for comparison. As a consequence, hypothyroidism may be underdiagnosed in these species. The objective of this study was to establish RI for TT4 and FT4 in healthy populations of cynomolgus macaques ( n = 133; age range 2.6 to 24.7 y) and rhesus macaques ( n = 172; age range 0.8 to 31.0 y). Serum samples were collected across a 14-y period during routine anesthetic events in clinically healthy animals, and TT4 and FT4 concentrations were measured using commercially available immunoassays. The RI established for TT4 and FT4 were 5.1 to 14.9 ug/dL and 0.48 to 1.17 ng/dL for cynomolgus macaques, and 3.9 to 14.7 ug/dL and 0.36 to 1.12 ng/dL for rhesus macaques. Significant differences in thyroid hormone concentrations were found between Indian and Chinese origin rhesus, and between Mauritian and other origin cynomolgus. In addition, juvenile and subadult rhesus exhibited significantly higher FT4 and TT4 concentrations than did older animals. Individual RI were established for subgroups with adequately different thyroid hormone concentrations. These results will allow a more thorough diagnostic evaluation of cynomolgus and rhesus macaques with clinical signs consistent with thyroid disease and will ultimately be a refinement in NHP medicine.

Calm before the Storm: Contrast-induced Thyroid Storm

Hyperthyroidism is a state of excess circulating thyroid hormone. These hormones control many of the body’s most important functions such as breathing, heart rate, weight, digestion, and moods. The extreme manifestation of thyrotoxicosis is referred to as thyroid storm. Thyroid storm manifests as an acute, severe, life-threatening hypermetabolic state caused by either excess release of thyroid hormones or an altered peripheral response to thyroid hormone following the presence of one or more precipitants. Thyroid storm is an uncommon but potentially fatal endocrine emergency. Mortality reaching between 80 – 100% without treatment in thyroid storm with multiple organ failure as the most common cause of death. During thyroid storm, precipitants multiply the effect of thyroid hormones by freeing thyroid hormones from binding sites, increased sensitivity in tissue receptors, or post-receptor modifications in signaling pathways. The most common precipitating factor is infection along with a host of other causes. Of interest, iodinated contrast is an important precipitating factor to consider as it is commonly used in the hospital setting through imaging modalities. Elderly patients are at higher risk due to the increased prevalence of nodular thyroid disease. Care must be taken to quickly recognize and treat this potentially fatal illness.

Urine Proteomic Analysis of Differences Between Patients With Hyperthyroidism Before and After Carbimazole Treatment

Abstract Background: Hyperthyroidism, characterised by increased circulating thyroid hormone (TH) levels, alters the body’s metabolic and systemic haemodynamic balance and directly influences renal function However, the underlying mechanisms and metabolic implications of these changes are not well understood. Objective: In the present study we aimed to study the changes occurring in the urinary proteome of patients with hyperthyroidism before and after treatment. The levels of the excreted proteins in the urine were studied using an untargeted 2D DIGE MALDI TOF proteomic approach with network analysis. Methods: The study included 9 age matched patients with mean age 38.6 ± 12.1 years with newly diagnosed hyperthyroidism. The patients were evaluated at baseline and after receiving treatment with carbimazole. Urine samples were obtained from the same patient at baseline (hyperthyroid state) with serum FT4 levels of 35.4 + 9.9 pmol/L and TSH 0.014 + 0.014 mIU/L (mean + SD), and post treatment with anti-thyroid drugs (euthyroid state) with levels of FT4 17.0 + 2.8 pmol/L and TSH 0.6 + 0.5 mIU/L (mean + SD). Results: Alterations in the abundance of urinary proteins, analyzed by Progenesis software, revealed statistically significant differential abundance in a total of 40 spots corresponding to 33 proteins, 26 up and 7 down (≥1.5-fold change, ANOVA, p ≤ 0.05). The proteins identified in the study are known to regulate processes related to cellular metabolism, transport, acute phase response. The urinary proteins upregulated with hyperthyroidism included serotransferrin, transthyretin, serum albumin, ceruloplasmin, α1B glycoprotein, syntenin-1, nesprin, and glutamilnyl peptide cyclotransferase while the 3 notable down regulated proteins were plasma kallikrein, protein glutamine gamma-glutamyl transferase and serpin B3. Bioinformatic analysis using Ingenuity Pathway Analysis (IPA) identified dysregulation of pathways related to cellular compromise, inflammatory response, cellular assembly and organization and identified the involvement of the APP and AKT signaling pathways via their interactions with interleukins as the central nodes. Conclusion: The urine proteomic profiling between the hyperthyroid and euthyroid states demonstrates alteration in the protein levels involved in acute phase response and in maintaining an individual’s haemodynamic state.

A Randomised, Controlled Trial of Adjunctive Cholestyramine or Prednisolone Compared to Standard Therapy for the Treatment of Uncontrolled Graves’ Disease (the Chops Study)

Introduction: Antithyroid drugs (ATDs) are recommended effective treatment for uncontrolled Graves’ disease but achieves maximal antithyroid effects between 6 to 12 weeks. Cholestyramine sequesters thyroid hormones in the intestine and enhances its fecal excretion. Steroids inhibits the conversion of thyroxine to triiodothyronine peripherally and blocks thyroid hormone production. We hypothesize that adjunctive cholestyramine or prednisolone to ATDs may reduce circulating thyroid hormones and improve biochemical control. Methods: In this multicenter, open labelled, parallel-group trial, we randomly assigned in a 1:1:1 ratio, adult Graves’ disease patients with moderate to severe hyperthyroidism (FT4 levels > 40 pmol/L) to receive either adjunctive cholestyramine 4g twice daily or prednisolone 30 mg daily in tapering down doses in addition to standard treatment or standard treatment alone for 4 weeks. Standard treatment was carbimazole 30mg daily and propanolol 40mg BD for 4 weeks. The primary endpoint was change from baseline for FT4 and FT3 levels at the end of 2 and 4 weeks of intervention. Safety endpoints including gastrointestinal adverse events, hypokalemia, hypothyroid and hyperglycemia were recorded. Results: A total of 107 patients were screened and 97 patients randomised. Baseline demographics, clinical and biochemical characteristics were similar between thegroups. The baseline median FT4 levels were 51.6 pmol/L (42.2-71.1) and FT3 levels 22.5 pmol/L (5.7-30.8). Both FT4 and FT3 declined at two and four weeks from baseline but were no different between the three groups. At week 2, median FT4 levels declined by 43.3% (25.8-53.3), 39.8% (19.1-55.1) and 33.4% (20.1-62.0) (p=0.988) and at 4 weeks, 50.9% (33.3-63.8), 57.8% (39-70.9), 55.8% (36.2-72.0) (p =0.362) in the cholestyramine, prednisolone and standard treatment group respectively. Median FT3 levels reduced by 51.2% (22.8- 58.9), 59.9% (38.9-69.3) and 50.9% (26.9-63.9) (p=0.084) at week 2 and 60% (39.2-67.9), 67.5% (38.4-78.4), 63.1% (45.7-69.3) (p=0.387) in the corresponding cholestyramine, prednisolone and standard treatment only group. A higher number of gastrointestinal adverse events: constipation, bloating, diarrhea, abdominal pain and vomiting were observed in the cholestyramine group in the first 2 weeks of treatment and no difference in the incidence of hypokalemia between groups. Conclusion: Adjunctive cholestyramine or prednisolone did not improve the biochemical control of uncontrolled moderate to severe Graves’ disease when added to ATDs. The additional use of cholestyramine resulted in a higher number of gastrointestinal adverse events but were mild and self-limiting.

Thyroid Storm: A Diagnostic Conundrum

Thyroid storm is a life threatening complication of hyperthyroidism which comes with multi-system involvement and is associated with a mortality of 8-25% despite modern advancements in treatment and supportive measures.A 47 year old woman with past medical history of hypertension and morbid obesity presented to the emergency room with 3 week history of shortness of breath and chest pain associated with productive cough, bilateral leg swelling, orthopnea and palpitations. Upon evaluation, she was in moderate respiratory distress, restless, tachypneic and tachycardic. She had bilateral proptosis and visible jugular venous pulsation along-with bibasilar crackles and pitting edema bilaterally. Lab tests revealed BNP 539 pg/ml and D-Dimer 6401 ng/ml. ECG showed atrial flutter, Chest X-Ray showed bilateral pleural effusions, and CT Chest was negative for pulmonary embolism but revealed anterior mediastinal mass, differential of which included thymoma or teratoma. She was admitted to CCU for aggressive diuresis, control of heart rate and was started on anticoagulation. A review of medical records from outside hospital revealed patient was hyperthyroid 8 months ago, however, was not on any medications. Given a Burch-Wartofsky score >70, she was started on IV hydrocortisone and cholestyramine for severe thyrotoxicosis. Endocrinology was consulted and added PTU to management. TFTs revealed a TSH 0.006 IU/ml, FT4 4 ng/dL and T3 2.5 ng/ml. Bedside ECHO showed LVEF of 14% with global hypokinesis and thyroid ultrasound revealed an enlarged, heterogenous thyroid with a solid, isoechoic, calcified left lobe nodule measuring 0.8 x 0.4 x 0.5 cm. Her serum TSI and thyrotropin receptor antibodies were elevated at 17.20 IU/L and 20.20 IU/L, respectively. She responded to treatment and was discharged on metoprolol, losartan, spironolactone, and furosemide for new-onset heart failure, apixaban for atrial flutter, and PTU and cholestyramine for hyperthyroidism, with Cardiology and Endocrinology follow-ups.Thyroid disease is a common illness affecting 9 to 15 percent of the adults. Thyrotoxicosis refers to the clinical syndrome of hyper-metabolism due to excessive amount of circulating thyroid hormones. The incidence of thyroid storm is 0.57 to 0.76 per 100,000 people per year in the US. It most commonly occurs in women and is more common in patients with underlying Grave’s Disease. The exact underlying mechanism that leads to thyroid storm is not well understood but adrenergic activation seems to have a major role. Our patient had long standing untreated hyperthyroidism with a solid nodule which led to the crisis. The most common cause of death is cardiopulmonary failure and hence treatment should be initiated as soon as diagnosis is suspected owing to high mortality.Awareness of thyroid pathology affecting the heart is important to remember in evaluating the etiology of heart failure in patients.

Proteomics Profiling of the Urine of Patients with Hyperthyroidism after Anti-Thyroid Treatment.

Hyperthyroidism, which is characterized by increased circulating thyroid hormone levels, alters the body’s metabolic and systemic hemodynamic balance and directly influences renal function. In this study, the urinary proteome of patients with hyperthyroidism was characterized using an untargeted proteomic approach with network analysis. Urine samples were collected from nine age-matched patients before and after carbimazole treatment. Differences in the abundance of urinary proteins between hyperthyroid and euthyroid states were determined using a 2D-DIGE coupled to MALDI-TOF mass spectrometry. Alterations in the abundance of urinary proteins, analyzed via Progenesis software, revealed a statistically significant difference in abundance in a total of 40 spots corresponding to 32 proteins, 25 up and 7 down (≥1.5-fold change, ANOVA, p ≤ 0.05). The proteins identified in the study are known to regulate processes associated with cellular metabolism, transport, and acute phase response. The notable upregulated urinary proteins were serotransferrin, transthyretin, serum albumin, ceruloplasmin, alpha-1B-glycoprotein, syntenin-1, and glutaminyl peptide cyclotransferase, whereas the three notable downregulated proteins were plasma kallikrein, protein glutamine gamma-glutamyl transferase, and serpin B3 (SERPINB3). Bioinformatic analysis using ingenuity pathway analysis (IPA) identified the dysregulation of pathways associated with cellular compromise, inflammatory response, cellular assembly, and organization and identified the involvement of the APP and AKT signaling pathways via their interactions with interleukins as the central nodes.

Predicting consequences of POP-induced disruption of blubber glucose uptake, mass gain rate and thyroid hormone levels for weaning mass in grey seal pups

Persistent organic pollutants (POPs) are endocrine disruptors that alter adipose tissue development, regulation and function. Top marine predators are particularly vulnerable because they possess large fat stores that accumulate POPs. However, links between endocrine or adipose tissue function disruption and whole animal energetics have rarely been investigated. We predicted the impact of alterations to blubber metabolic characteristics and circulating thyroid hormone (TH) levels associated with polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and organochlorine pesticides (OCPs) on suckling mass gain and weaning mass in wild grey seal pups. Glucose uptake by inner blubber was a strong predictor of whole animal mass gain rate, which in turn, resulted in heavier weaning mass. Weaning mass was predicted to increase by 3.7 ± 1.59 (sem) %, through increased mass gain rate, in the absence of the previously reported suppressive effect of dioxin-like PCB (DL-PCBs) on blubber glucose uptake. PBDEs were, conversely, associated with faster mass gain. Alleviation of this effect was predicted to reduce weaning mass by 6.02 ± 1.86% (sem). To better predict POPs effects on energy balance, it is crucial to determine if and how PBDEs promote mass gain in grey seal pups. Weaning mass was negatively related to total T3 (TT3) levels. A 20% (range = 9.3–31.7%) reduction in TT3 by DL-PCBs partially overcame the effect of DL-PCB -mediated reduction in blubber glucose uptake. Overall, DL-PCBs were thus predicted to reduce weaning mass by 1.86 ± 1.60%. Organohalogen impacts on whole-animal energy balance in grey seal pups appear to partially offset each other through opposing effects on different mechanisms. POP effects were generally minor, but the largest POP-induced reductions in weaning mass were predicted to occur in pups that were already small. Since weaning mass is positively related to first-year survival, POPs may disproportionately affect smaller individuals, and could continue to have population-level impacts even when levels are relatively low compared to historical values. Our findings show how in vitro experiments combined with measurements in vivo can help elucidate mechanisms that underpin energy balance regulation and help to quantify the magnitude of disruptive effects by contaminants and other stressors in wildlife.

Expanded high-throughput screening and chemotype-enrichment analysis of the phase II: e1k ToxCast library for human sodium-iodide symporter (NIS) inhibition.

The sodium-iodide symporter (NIS) mediates the uptake of iodide into the thyroid. Inhibition of NIS function by xenobiotics has been demonstrated to suppress circulating thyroid hormones and perturb related physiological functions. Until recently, few environmental chemicals had been screened for NIS inhibition activity. We previously screened over 1000 chemicals from the ToxCast Phase II (ph1v2 and ph2) libraries using an in vitro radioactive iodide uptake (RAIU) with the hNIS-HEK293T cell line to identify NIS inhibitors. Here, we broaden the chemical space by expanding screening to include the ToxCast e1k library (804 unique chemicals) with initial screening for RAIU at 1 × 10-4M. Then 209 chemicals demonstrating > 20% RAIU inhibition were further tested in multiple-concentration, parallel RAIU and cell viability assays. This identified 55 chemicals as active, noncytotoxic RAIU inhibitors. Further cytotoxicity-adjusted potency scoring (with NaClO4 having a reference score of 200) revealed five chemicals with moderate to strong RAIU inhibition (scored > 100). These data were combined with our previous PhII screening data to produce binary hit-calls for ~ 1800 unique chemicals (PhII + e1k) with and without cytotoxicity filtering. Results were analyzed with a ToxPrint chemotype-enrichment workflow to identify substructural features significantly enriched in the NIS inhibition hit-call space. We assessed the applicability of enriched PhII chemotypes to prospectively predict NIS inhibition in the e1k dataset. Chemotype enrichments derived for the combined ~ 1800 dataset also identified additional enriched features, as well as chemotypes affiliated with cytotoxicity. These enriched chemotypes provide important new information that can support future data interpretation, structure-activity relationship, chemical use, and regulation.

Per- and Polyfluoroalkyl Substances Are Positively Associated with Thyroid Hormones in an Arctic Seabird.

Per- and polyfluoroalkyl substances (PFAS) are associated with several disrupted physiological and endocrine parameters. Regarding endocrine mechanisms, laboratory studies suggest that PFAS could disrupt the thyroid hormone system and alter circulating thyroid hormone concentrations. Thyroid hormones play a ubiquitous role-controlling thermoregulation, metabolism, and reproduction. However, evidence for disruption of thyroid hormones by PFAS remains scarce in wildlife. The present study investigated the associations between concentrations of PFAS, thyroid hormones, and body condition in an arctic seabird, the black-legged kittiwake (Rissa tridactyla). We collected blood from kittiwakes sampled in Svalbard, Norway (2013 and 2014). Plasma samples were analyzed for total thyroxine (TT4) and total triiodothyronine (TT3) concentrations; detected PFAS included branched and linear (lin) C8 perfluoroalkyl sulfonates (i.e., perfluoroctane sulfonate [PFOS]) and C9 -C14 perfluoroalkyl carboxylates (PFCAs). The dominant PFAS in the kittiwakes were linPFOS and C11 - and C13 -PFCAs. Generally, male kittiwakes had higher concentrations of PFAS than females. We observed positive correlations between linPFOS, C10 -PFCA, and TT4 in males, whereas in females C12-14 -PFCAs were positively correlated to TT3. Interestingly, we observed contrasted correlations between PFAS and body condition; the direction of the relationship was sex-dependent. Although these results show relationships between PFAS and circulating thyroid hormone concentrations in kittiwakes, the study design does not allow for concluding on causal relationships related to effects of PFAS on the thyroid hormone system. Future experimental research is required to quantify this impact of PFAS on the biology of kittiwakes. The apparently different associations among PFAS and body condition for males and females are puzzling, and more research is required. Environ Toxicol Chem 2021;40:820-831. © 2020 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.