T3 Administration Research Articles

Role of AMPK in the protective effects exerted by triiodothyronine in ischemic-reperfused myocardium.

Recent studies have provided evidence that triiodothyronine (T3) might play an effective role in the recovery of ischemic myocardium, through the preservation of mitochondrial function and the improvement of energy substrate metabolism. To this respect, it has been suggested that T3 could activate AMP-activated protein kinase (AMPK), the cellular 'fuel-gauge' enzyme, although its role has yet to be elucidated. The aim of the present study was to investigate the effects produced by acute treatment with T3 (60 nM) and the pharmacological inhibition of AMPK by compound C on isolated rat left atria subjected to 75 min simulated ischemia-75 min reperfusion. Results showed that T3 increased AMPK activation during simulated ischemia-reperfusion, while compound C prevented it. At the end of simulated reperfusion, acute T3 treatment increased contractile function recovery and cellular viability conservation. Mitochondrial ultrastructure was better preserved in the presence of T3 as well as mitochondrial ATP production rate and tissue ATP content. Calcium retention capacity, a parameter widely used as an indicator of the resistance of mitochondrial permeability transition pore (MPTP) to opening, and GSK-3β phosphorylation, a master switch enzyme that limits MPTP opening, were increased by T3 administration. All these beneficial effects exerted by T3 acute treatment were prevented when compound C was co-administrated. The present study provided original evidence that T3 enhances intrinsic activation of AMPK during myocardial ischemia-reperfusion, being this enzyme involved, at least in part, in the protective effects exerted by T3, contributing to mitochondrial structure and function preservation, post-ischemic contractile recovery and conservation of cellular viability.

Potency of probiotic on broiler growth performance and economics analysis

The study was undertaken to know the economic analysis in broilers fed probiotic containing Lactobacillus casei and Lactobacillus rhamnosus supplementation in lieu of antibiotic growth promoters (AGP) to feed conversion ratio (FCR) and body weight (BW). The treatments were T0: control, T1: 0.01 g AGP/kg feed, T2: 0.05 g/ kg feed, T3: 0.1 g/ kg feed, T4: 0.025 g probiotic/litre drinking water; T5: 0.05 g probiotic/liter drinking water. Data analysis was carried out using the Analysis of Variance (ANOVA) method, business analysis was held out by XLSTAT then analyzing descriptively. The results indicated that there was a significant difference among the treatments. Probiotic administration of T2, T3, T4 and T5 could increase broiler's body weight and improve feed conversion ratio. The higher production performance and most profitable economic analysis was obtained with the addition of 0.025 g probiotic/litre (T4), which had the best results in a Break Even Point and Return Cost Ratio. It could be concluded that supplementation of 0.025 g probiotic/litre drinking water indicates the improve growth performance and profits in broiler.

Thyroid dysfunction and incident heart failure phenotypes among older adults: the atherosclerosis risk in communities (aric) study

Abstract Background/Introduction Abnormal thyroid hormone concentrations have been associated with adverse cardiovascular outcomes, but the relationship between thyroid dysfunction and specific heart failure phenotypes is less clear. Purpose To examine the association of thyroid dysfunction with the risk of incident HF in older adults without pre-existing HF. Methods We analyzed participants enrolled in the Atherosclerosis Risk in Communities (ARIC) study who attended the visit 5 examination (2011–2013). Participants with previous HF history, and participants treated with amiodarone, levothyroxine, and antithyroid medication were excluded. We used Cox regression models to assess the associations between serum thyroid indices (free thyroxine [FT4], total triiodothyronine [TT3], or thyroid stimulating hormone [TSH]) and incident adjudicated HF with reduced (HFrEF) and preserved (HFpEF) left ventricular ejection fraction. Continuous associations between TT3 and outcome were further assessed via Cox model using restricted cubic spline. Results Among 3349 participants (mean age 75±5 years, 56% women, 20% black), subclinical hypothyroidism was prevalent in 12% of participants and low T3 syndrome in 3%. Those with overt hypothyroidism (<1%) or hyperthyroidism (<1%) were not included in the analysis given the low prevalence. Over a median follow-up of 5.5 years, incident HF occurred in 198 subjects (5.9%) at a rate of 11.1 per 1000 person-years. Of these, 86 were HFrEF, 83 HFpEF, and 29 were unclassified HF. We observed an inverse association of TT3 level with risk of incident HFpEF, but not overall incident HF or incident HFrEF, after adjustment for clinical confounders and baseline NT-proBNP levels (HR per 1 SD 0.70, 95% CI 0.54–0.92; P 0.010) (Figure). Similar results were observed for the composite endpoint of incident HFpEF or all-cause death. No statistically significant associations were found between TSH or T4 levels and incident HF. Low T3 syndrome was associated with incident HFpEF, but not overall incident HF or incident HFrEF, after adjustment for clinical confounders (HR 2.71, 95% CI 1.08–6.82; P 0.035); however, its association was significantly attenuated after adjustment with NT-proBNP (HR 2.25, 95% CI 0.87–5.79; P 0.09). No statistically significant association was found between subclinical hypothyroidism and incident HF. Conclusions In a contemporary biracial cohort of older adults, serum T3 level was inversely associated with incident HFpEF hospitalization. T3 administration could be considered as a potential target in future clinical trials preventing HFpEF hospitalization. Figure 1 Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): The Atherosclerosis Risk in Communities Study is performed as a collaborative study supported by National Heart, Lung, and Blood Institute contracts

A Preclinical Safety Study of Thyroid Hormone Instilled into the Lungs of Healthy Rats-an Investigational Therapy for ARDS.

Acute respiratory distress syndrome (ARDS) is a severe, life-threatening form of respiratory failure characterized by pulmonary edema, inflammation, and hypoxemia due to reduced alveolar fluid clearance (AFC). Alveolar fluid clearance is required for recovery and effective gas exchange, and higher rates of AFC are associated with reduced mortality. Thyroid hormones play multiple roles in lung function, and L-3,5,3'-triiodothyronine (T3) has multiple effects on lung alveolar type II cells. T3 enhances AFC in normal adult rat lungs when administered intramuscularly and in normal or hypoxia-injured lungs when given intratracheally. The safety of a commercially available formulation of liothyronine sodium (synthetic T3) administered intratracheally was assessed in an Investigational New Drug Application-enabling toxicology study in healthy rats. Instillation of the commercial formulation of T3 without modification rapidly caused tracheal injury and often mortality. Intratracheal instillation of T3 that was reformulated and brought to a neutral pH at the maximum feasible dose of 2.73 µg T3 in 300 µl for 5 consecutive days had no clinically relevant T3-related adverse clinical, histopathologic, or clinical pathology findings. There were no unscheduled deaths that could be attributed to the reformulated T3 or control articles, no differences in the lung weights, and no macroscopic or microscopic findings considered to be related to treatment with T3. This preclinical safety study has paved the way for a phase I/II study to determine the safety and tolerability of a T3 formulation delivered into the lungs of patients with ARDS, including coronavirus disease 2019-associated ARDS, and to measure the effect on extravascular lung water in these patients. SIGNIFICANCE STATEMENT: There is growing interest in treating lung disease with thyroid hormone [triiodothyronine (T3)] in pulmonary edema and acute respiratory distress syndrome (ARDS). However, there is not any published experience on the impact of direct administration of T3 into the lung. An essential step is to determine the safety of multiple doses of T3 administered in a relevant animal species. This study enabled Food and Drug Administration approval of a phase I/II clinical trial of T3 instillation in patients with ARDS, including coronavirus disease 2019-associated ARDS (T3-ARDS ClinicalTrials.gov Identifier NCT04115514).

Combination therapy of apo-transferrin and thyroid hormones enhances remyelination.

The current study presents two different approaches with a view to elucidating the interaction between thyroid hormones (TH) and apo-transferrin (aTf) and their role in myelination and remyelination. First, in vitro assays were conducted to determine the single and combined effects of aTf and triiodothyronine (T3) on oligodendroglial cell lineage proliferation and oligodendrocyte (OLG) maturation in primary cultures. Results revealed higher proliferation rates upon single aTf treatment but Control values upon T3 and aTf + T3 treatments. In addition, both aTf and T3 accelerated OLG maturation, with the greatest effects being exerted by combined aTf + T3 administration in terms of both myelin basic protein (MBP) expression and morphological complexity. Second, in vivo assays were carried out to establish single and combined effects of aTf and T3, as well as TH receptor (THR) inhibitor I-850, on remyelination following a CPZ-induced demyelination protocol. Results showed an increase in myelin deposition and the number of mature remyelinating OLG upon single treatments, but a synergic effect upon combined aTf + T3 treatment which was prevented by THR inhibition. It may be thus concluded that combined treatment yielded the most beneficial effects on OLG maturation parameters in vitro and remyelinating capacity in vivo when compared to single treatments. These findings may help explore the development of new target molecules in the treatment of demyelinating diseases.

Circulating Thyroid Hormone Profile in Response to a Triiodothyronine Challenge in Familial Longevity.

ContextFamilial longevity is associated with higher circulating levels of thyrotropin (TSH), in the absence of differences in circulating thyroid hormones, and a lower thyroid responsivity to TSH, as previously observed in the Leiden Longevity Study (LLS). Further mechanisms underlying these observations remain unknown.ObjectiveWe hypothesized that members from long-lived families (offspring) have higher thyroid hormone turnover or less negative feedback effect on TSH secretion compared to controls.Methods In a case-control intervention study, 14 offspring and 13 similarly aged controls received 100 µg 3,5,3′-triiodothyronine (T3) orally. Their circulating T3, free T3 (fT3), and TSH levels were measured during 5 consecutive days. We compared profiles of circulating T3, fT3, and TSH between offspring and controls using general linear modeling (GLM) and calculated the percentage decline in TSH following T3 administration.ResultsCirculating T3 and fT3 levels increased to supraphysiologic values and normalized over the course of 5 days. There were no serious adverse events. T3 and fT3 concentration profiles over 5 days were similar between offspring and controls (T3 GLM P = .11, fT3 GLM P = .46). TSH levels decreased in a biphasic manner and started returning to baseline by day 5. The TSH concentration profile over 5 days was similar between offspring and controls (GLM P = .08), as was the relative TSH decline (%).ConclusionsMembers of long-lived families have neither higher T3 turnover nor diminished negative feedback of T3 on TSH secretion. The cause and biological role of elevated TSH levels in familial longevity remain to be elucidated.

SAT-LB83 Amiodarone Induced Myxedema Coma

Introduction Amiodarone is widely used as a rhythm-conversion agent in atrial fibrillation. It’s low negative inotropic activity and low risk of ventricular arrhythmia makes it an advantageous agent for atrial arrhythmia. One of the major limiting factors in the use of amiodarone can be its thyroid toxicity leading to thyroid-dysfunction; ranging from thyrotoxicosis to myxedema coma. Myxedema coma, although rare, is a deadly complication of hypothyroidism with a mortality rate as high as 60%. It is considered an endocrinologic emergency that requires prompt attention and treatment. We present a case of myxedema coma in the setting of chronic amiodarone intake.Case Presentation A 75-year-old female with a past medical history significant for atrial fibrillation, hypothyroidism, end stage renal disease from diabetic nephropathy on hemodialysis, Hepatitis C, hypertension, and hyperlipidemia was admitted to the hospital for evaluation of generalized weakness. Her medications included amiodarone 200mg/day among others. The next day, the rapid response team was called when the patient became hypotensive, bradycardic and unresponsive. She was transferred to the ICU and intubated immediately. On exam, her skin was dry and cold. Her laboratory findings revealed a markedly elevated TSH level of 185uIU/mL. Her most recent TSH level was 9.044uIU/mL from a year back. Other laboratory tests revealed WBC count of 9.0k/mm cu, hemoglobin 13.7 g/dL, platelet count 48 k/mm cu. A diagnosis of myxedema coma was made based on her presentation and lab findings. The patient was started on intravenous levothyroxine 100mg daily with intravenous hydrocortisone 100mg every 8 hours. T4 levels were 0.38ng/dL, T3 levels were 1.83pg/mL and TPO antibodies were negative. A decision was made not to administer intravenous T3 because of the patient’s advanced age and underlying atrial fibrillation. Over the course of the hospitalization, the patient was showing signs of clinical improvement and attempts were being made to wean her off the ventilator. However, later she died due to hemorrhagic shock.Conclusion Myxedema coma may manifest nonspecifically as lethargy and altered mental status and can present without the more specific symptoms of skin changes or myxedematous soft tissue changes. It is therefore, very important for physicians to consider myxedema coma as one of the differential diagnoses in patients on amiodarone with underlying thyroid disease. Administering amiodarone for elderly patients with underlying thyroid problems warrants attention to polypharmacy. The treatment guidelines for myxedema coma are yet to be established. While intravenous levothyroxine with intravenous hydrocortisone remains the mainstay of therapy, there are no consensus on T3 administration.

Control of Adipocyte Thermogenesis and Lipogenesis through β3-Adrenergic and Thyroid Hormone Signal Integration

SUMMARYHere, we show that β adrenergic signaling coordinately upregulates de novo lipogenesis (DNL) and thermogenesis in subcutaneous white adipose tissue (sWAT), and both effects are blocked in mice lacking the cAMP-generating G protein-coupled receptor Gs (Adipo-GsαKO) in adipocytes. However, UCP1 expression but not DNL activation requires rapamycin-sensitive mTORC1. Furthermore, β3-adrenergic agonist CL316243 readily upregulates thermogenic but not lipogenic genes in cultured adipocytes, indicating that additional regulators must operate on DNL in sWAT in vivo. We identify one such factor as thyroid hormone T3, which is elevated locally by adrenergic signaling. T3 administration to wild-type mice enhances both thermogenesis and DNL in sWAT. Mechanistically, T3 action on UCP1 expression in sWAT depends upon cAMP and is blocked in Adipo-GsαKO mice even as elevated DNL persists. Thus, T3 enhances sWAT thermogenesis by amplifying cAMP signaling, while its control of adipocyte DNL can be mediated independently of both cAMP and rapamycin-sensitive mTORC1.

Potential role of two novel agonists of thyroid hormone receptor-β on liver regeneration.

ObjectivesAlthough the hepatomitogenic activity of triiodothyronine (T3) is well established, the wide range of harmful effects exerted by this hormone precludes its use in liver regenerative therapy. Selective agonists of the beta isoform of thyroid hormone receptor (TRβ) do not exhibit T3‐induced cardiotoxicity and show a good safety profile in patients with NASH. The aim of this study was to investigate whether two novel TRβ agonists, the prodrug TG68 and the active compound IS25 could stimulate hepatocyte proliferation without T3/TRα‐dependent side effects.MethodsRats were treated with three different doses (12.5, 25 and 50 μg/100 g body weight) for one week. Hepatocyte proliferation, liver injury and serum biochemical parameters were measured by immunohistochemistry, qRT‐PCR and Western blot.ResultsBoth drugs increased hepatocyte proliferation as assessed by bromodeoxyuridine incorporation (from 14% to 28% vs 5% of controls) and mitotic activity. Enhanced proliferation occurred in the absence of significant signs of liver injury as shown by lack of increased serum transaminase levels or of apoptosis. No cardiac or renal hypertrophy typically associated with treatment with T3 was observed. Importantly, no proliferation of pancreatic acinar cells, such as that seen after administration of T3 or the TRβ agonist GC1 was detected following either TG68 or IS25, demonstrating the hepato‐specificity of these novel TRβ agonists.ConclusionsThe present study shows that TG68 and IS25 induce massive hepatocyte proliferation without overt toxicity. Hence, these agents may have a significant clinical application for regenerative therapies in liver transplantation or other surgical settings.

Seasonal Related Multifactorial Control of Pituitary Gonadotropin and Growth Hormone in Female Goldfish: Influences of Neuropeptides and Thyroid Hormone.

Female reproduction is under multifactorial control of brain-pituitary-peripheral origin. The present study provides information on seasonal changes in circulating LH and GH concentrations, as well as transcript levels for a number of genes involved in the regulation of reproduction and growth in female goldfish. We also provide information on the effects of treatments with GnRH and/or GnIH, and their interaction with T3, at three stages of gonadal recrudescence. Maximum basal concentration of LH was observed at late recrudescence (Spring) while no seasonal changes in basal serum GH levels was detected. Serum LH and GH levels were stimulated by GnRH as expected, depending on the season. GnIH stimulated basal GH concentrations in gonadally regressed fish. GnIH inhibitory action on GnRH-induced LH response was observed in late, but not in mid recrudescence. T3 actions on basal and GnRH- or GnIH-induced GH secretion were generally inhibitory, depending on season. Administration of T3 attenuated GnRH-induced LH responses in mid and late stages of gonadal recrudescence, and the presence of GnIH abolished inhibitory actions of T3 in fish at mid recrudescence. Our results also demonstrated seasonal patterns in basal and GnRH- and/or GnIH-induced transcript levels for ERα, ERβI, FSHR, aromatase, TRαI, TRβ, IGF-I, and Vtg in the liver and ovary. However, there were no clear correlations between changes in transcript levels and circulating levels of LH and GH. The results support the hypothesis that GnRH, GnIH, and T3 are contributing factors in complex reciprocal control of reproduction and growth in goldfish.

Triiodothyronine Improves Morphology and Up-regulates seladin-1 of neurospheres extracted from Subventricular Zone in Streptozotocin-induced rat model of Alzheimer's disease

Objectives: In this study, the effects of triiodothyronine (T3) on neurospheres isolated from SVZ of AD induced rats were examined. Methods: Eighteen male Wistar rats were classified into two groups: Sham (Sh) and STZ (Streptozotocin injected, 1.5 mg/kg in each lateral ventricle on days 1 and 3 after recovery). On day 21, the SVZ was extracted and neurospheres were cultured. T3 (50 nM) was added to the culture medium (STZ+T3 group) and then, the morphology and seladin-1 gene expression of neurospheres were evaluated. Results: The diameter and the number of neurospheres along with the gene expression of seladin-1 were significantly decreased in the STZ group compared to Sh group (P˂0.05) while the administration of T3 significantly (P˂0.05) increased all these parameters in the STZ group. Conclusion: STZ decreases the proliferation of stem cells extracted from SVZ and administration of T3 to the culture media improves the morphology and up-regulates the gene expression of seladin-1 of neurospheres.

Effect of thyroid hormones on rat exocrine pancreas morphology and function

AimThe influence of thyroid hormones on exocrine pancreas function is poorly understood, and limited to the postnatal development period. Here, we evaluated the effects of hypo- and hyperthyroidism on the morphology and enzyme content of this tissue. Main methodsTo induce hypothyroidism male Wistar rats were subjected to a thyroidectomy (Tx) or sham operated (SO). After 40 days, some of the Tx and SO rats were treated with T3 for 7 days. Following euthanization, the pancreas was removed and evaluated for morphology, as well as amylase, lipase and trypsin content, using histological and immunoreactive techniques analyses, respectively. Serum amylase levels were also evaluated. Key findingsThe pancreatic acinar cells of Tx rats were smaller, exhibited reduced Haematoxyllin stained areas, and contained lower amylase and lipase levels, indicative of low cell activity. Tx rats also presented higher collagen levels, and high trypsin content in pancreatic extracts. Interestingly, T3 administration reversed the observed acinar cell alterations and restored pancreatic enzyme content, by augmenting amylase and lipase and attenuating trypsin levels, but failed to change collagen content. Increased levels of lipase and decreased trypsin were also observed in T3-treated SO rats. SignificanceThyroid hormones play an important role in acinar cell morphology and function. In the hypothyroid state there is a decrease in pancreatic enzyme levels that is restored with T3 treatment. In addition to participating in insulin sensitivity and glycemic control, THs also modulate enzyme expression and activity in the exocrine pancreas, consequently, delivering metabolic substrates to specific organs and tissues.

The long-term oral administration of thyroxine: effects on blood hematological and biochemical features in broiler breeder hens

Published data on the beneficial effect of short-term administration of thyroxine (T4) in broiler breeder hens to reduce the ascites incidence in their progeny chicks raises the question as to what extent might the long-term maternal administration of T4 affect the blood hematological and biochemical attributes in breeder hens. A total of 70 broiler breeder hens (47-wk-old) were randomly allotted to control or thyroxine treated (T4) groups. Pure T4 (0.3 mg/bird per day) was orally administered to T4 birds for 14 successive weeks, whereas the control group received the drinking water only. Blood samples were obtained from the brachial vein prior to the initiation of the trial as well as weeks 50, 53, 55, 57, 59, and 61 of age. Body weight was decreased but egg production was not affected by T4 treatment. Plasma concentration of T4, but not triiodothyronine (T3), was increased in T4-treated hens (P < 0.05). The total number of leukocytes and erythrocytes were also higher in T4 birds. A significant effect of time was observed for erythrocyte number and plasma cholesterol concentration (P < 0.05). The long-term administration of T4 did not affect the concentrations of serum calcium and plasma total protein, albumin, globulin, cholesterol, triglyceride, high density lipoprotein, low density lipoprotein, very low density lipoprotein, alanine amino transferase, and aspartate amino transferase (P > 0.05). However, serum concentrations of phosphorus, glucose, and alkaline phosphatase were higher in T4 hens as compared to their control counterparts. In spite of differences in circulatory concentrations of a number of traits between the experimental groups, the recorded values were within their reference ranges. Therefore, the administration of T4 for an extended period of time had no apparent adverse effect on the clinical profile in subjected hens, which may practically support the implementation of this preventative treatment as an approach to decrease the ascites incidence; however, a lower incidence rate in the progeny chicks produced from hens receiving T4 for long-term periods of time remains to be elucidated.

Triiodothyronine modulates neuronal plasticity mechanisms to enhance functional outcome after stroke

The development of new therapeutic approaches for stroke patients requires a detailed understanding of the mechanisms that enhance recovery of lost neurological functions. The efficacy to enhance homeostatic mechanisms during the first weeks after stroke will influence functional outcome. Thyroid hormones (TH) are essential regulators of neuronal plasticity, however, their role in recovery related mechanisms of neuronal plasticity after stroke remains unknown. This study addresses important findings of 3,5,3′-triiodo-L-thyronine (T3) in the regulation of homeostatic mechanisms that adjust excitability – inhibition ratio in the post-ischemic brain. This is valid during the first 2 weeks after experimental stroke induced by photothrombosis (PT) and in cultured neurons subjected to an in vitro model of acute cerebral ischemia. In the human post-stroke brain, we assessed the expression pattern of TH receptors (TR) protein levels, important for mediating T3 actions.Our results show that T3 modulates several plasticity mechanisms that may operate on different temporal and spatial scales as compensatory mechanisms to assure appropriate synaptic neurotransmission. We have shown in vivo that long-term administration of T3 after PT significantly (1) enhances lost sensorimotor function; (2) increases levels of synaptotagmin 1&2 and levels of the post-synaptic GluR2 subunit in AMPA receptors in the peri-infarct area; (3) increases dendritic spine density in the peri-infarct and contralateral region and (4) decreases tonic GABAergic signaling in the peri-infarct area by a reduced number of parvalbumin+ / c-fos+ neurons and glutamic acid decarboxylase 65/67 levels. In addition, we have shown that T3 modulates in vitro neuron membrane properties with the balance of inward glutamate ligand-gated channels currents and decreases synaptotagmin levels in conditions of deprived oxygen and glucose. Interestingly, we found increased levels of TRβ1 in the infarct core of post-mortem human stroke patients, which mediate T3 actions. Summarizing, our data identify T3 as a potential key therapeutic agent to enhance recovery of lost neurological functions after ischemic stroke.

The Swinging Pendulum in Treatment for Hypothyroidism: From (and Toward?) Combination Therapy.

Thyroid hormone replacement for hypothyroidism can be achieved via several approaches utilizing different preparations of thyroid hormones, T3, and/or T4. “Combination therapy” involves administration of both T3 and T4, and was technically the first treatment for hypothyroidism. It was lauded as a cure for the morbidity and mortality associated with myxedema, the most severe presentation of overt hypothyroidism. In the late nineteenth and the early Twentieth centuries, combination therapy per se could consist of thyroid gland transplant, or more commonly, consumption of desiccated animal thyroid, thyroid extract, or thyroglobulin. Combination therapy remained the mainstay of therapy for decades despite development of synthetic formulations of T4 and T3, because it was efficacious and cost effective. However, concerns emerged about the consistency and potency of desiccated thyroid hormone after cases were reported detailing either continued hypothyroidism or iatrogenic thyrotoxicosis. Development of the TSH radioimmunoassay and discovery of conversion of T4-to-T3 in humans led to a major transition in clinical practices away from combination therapy, to adoption of levothyroxine “monotherapy” as the standard of care. Levothyroxine monotherapy has a favorable safety profile and can effectively normalize the serum TSH, the most sensitive marker of hypothyroidism. Whether levothyroxine monotherapy restores thyroid hormone signaling within all tissues remains controversial. Evidence of persistent signs and symptoms of hypothyroidism during levothyroxine monotherapy at doses that normalize serum TSH is mounting. Hence, in the last decade there has been acknowledgment by all thyroid professional societies that there may be a role for the use of combination therapy; this represents a significant shift in the clinical practice guidelines. Further bolstering this trend are the recent findings that the Thr92AlaD2 polymorphism may reduce thyroid hormone signaling, resulting in localized and systemic hypothyroidism. This strengthens the hypothesis that treatment options could be personalized, taking into consideration genotypes and comorbidities. The development of long-acting formulations of liothyronine and continued advancements in development of thyroid regenerative therapy, may propel the field closer to adoption of a physiologic thyroid hormone replacement regimen with combination therapy.

Low Free Triiodothyronine Is Associated with Advanced Fibrosis in Patients at High Risk for Nonalcoholic Steatohepatitis.

Thyroid hormone is critical for tissue-organ development, growth, differentiation, and metabolism. In murine models of advanced nonalcoholic steatohepatitis (NASH), the administration of T3 reduced liver triglyceride, repressed liver inflammation, and attenuated injury. In recent studies of patients with NASH, hypothyroidism was noted to be associated with more advanced NASH. These findings suggest that thyroid hormone function might be a modulator of nonalcoholic fatty liver disease (NAFLD) outcomes. Herein, we evaluated the correlation between plasma TSH/free T3 (fT3)/free T4 (fT4) levels and (non-invasive) surrogate markers of NAFLD fibrosis. We performed a retrospective analysis of 144 patients who were seen in our NASH outpatient clinic between 2015 and 2017. Each patient underwent a standard anthropometric assessment, laboratory and clinical evaluations, and liver stiffness measurements by transient elastography (Fibroscan). Univariate analysis and multivariate linear and logistic regression analysis were used to identify factors independently associated with NASH and advanced fibrosis. Low fT3 values but not TSH and fT4 were associated with higher liver stiffness and higher NAFLD fibrosis score, respectively. fT3 and TSH values correlated significantly with indices of liver disease including INR, albumin, ALT, AST, bilirubin, and platelets. In multivariate analyses, a low fT3 was independently associated with high NFS scores (OR 0.169, CI 0.05-0.54, p = 0.003) and was also associated with high liver stiffness readings (OR 0.326, CI 0.135-0.785, p = 0.001). A low-normal thyroid hormone function is predictive of NASH and advanced fibrosis and may have a pathogenic role in modulating NAFLD outcomes.

A Redox-Inactive Derivative of Tocotrienol Suppresses Tumor Growth of Mesothelioma Cells in a Xenograft Model.

Malignant mesothelioma (MM) is an aggressive cancer with poor prognosis. We focused on the anticancer activity of tocotrienol (T3) and have reported that a new redox-inactive T3 derivative (6-O-carboxypropyl-α-tocotrienol; T3E) exerts stronger inhibitory effects on MM cell growth than that of T3 in vitro. Furthermore, we have revealed some mechanisms of T3E that are involved in anti-MM effects. However, the effect of T3E in vivo remains unclear. In this study, we compared the plasma concentrations of T3E to that of T3 using mice to clarify differences in pharmacokinetics. Blood was sequentially collected after oral administration of T3 or T3E, and plasma concentrations were analyzed by HPLC. The area under the plasma T3 and T3E concentration-time curve from 0 to 24 h (AUC0-24 h) of T3E was two times higher than that of T3. In addition, we evaluated the effect of T3E oral administration on tumor growth using a xenograft model of mice that were transplanted with human MM cells (H2052 cell line). Tumor volume was significantly reduced without body weight loss in mice orally administered 150 mg/kg T3E once per 2 d for 10 d, which suggests that T3E has potential anti-MM effects.

Evaluation of cardiovascular risk by growth-differentiation factor-15 and tissue Doppler imaging in children with subclinical hypothyroidism.

Subclinical hypothyroidism, defined as increased TSH serum levels and normal serum free T4 concentrations, has been associated with an increased risk of heart disease in adults. But, data in children and adolescents are scanty and treatment of subclinical hypothyroidism is controversial. Growth differentiation factor-15 (GDF-15) is a promising biomarker of cardiac remodeling. This study aimed to evaluate the cardiovascular risk factors in children with subclinical hypothyroidism, measured with tissue Doppler echocardiography (TDE), and conventional echocardiography and GDF-15 level. The study comprised a total of 41 pediatric patients with subclinical hypothyroidism (SH) (mean age 9.6 ± 4.7 years) and 31 healthy children (mean age 11.2 ± 3.4 years) as the control group. Subclinical hypothyroidism was defined as a thyroid-stimulating hormone level higher than 4 mIU/l and a normal free-thyroxine level (0.6-1.8 ng/dl). Tissue Doppler echocardiography was performed to all individuals in the control group and patient group at the beginning of the study. Global systolic function as assessed by left ventricular ejection fraction was compared between groups. The serum GDF-15 level was measured. There were no significant differences in demographic parameters between the SH and control groups. The left ventricular internal diameter end systole, interventricular septal end diastole, left ventricular posterior wall end diastole, and tricuspid annular plane systolic excursion values were significantly different between the SH and control groups (p = 0.038, 0.028, 0.005, and 0.000, respectively). The mean mitral isovolumic relaxation time value of the SH group was 57.2 ± 9.3 ms, compared to 44.5 ± 5.6 ms for the control group (p = 0.000). The mean tricuspid isovolumic contraction time value of the SH group was 58.7 ± 9.4 ms, and that of the control group was 45.1 ± 5.3 ms (p = 0.000). The mean tricuspid isovolumic relaxation time value of the SH group was 58.03 ± 9.5 ms, and that of the control group was 45.1 ± 5.3 ms (p = 0.000). There were no significant differences in the other m-mode or pulse Doppler echocardiography values between two groups. The GDF-15 value of the SH group was 382.6 ± 268.2 pg/mL, and that of the control group was 473.6 ± 337.9 pg/mL; this difference was not significant. Patients with subclinical hypothyroidism versus healthy individuals had some changes in echocardiographic parameters that indicate involvement of diastolic function of the left ventricle. They were significantly different when compared SH group and the control group. This study demonstrated ventricle diastolic dysfunction in pediatric patients with hypothyroidism. The results of our study suggest that cardiac follow-up may be useful in patients with subclinical hypothyroidism and clinical trials are needed to explore therapeutic effects of T4 and T3 administration in this patients.

Serum autotaxin levels are associated with Graves' disease.

Graves' Disease is a representative autoimmune thyroid disease that presents with hyperthyroidism. Emerging evidence has shown the involvement of lysophosphatidic acid (LPA) and its producing enzyme, autotaxin (ATX), in the pathogenesis of various diseases; among them, the involvement of the ATX/LPA axis in some immunological disturbances has been proposed. In this study, we investigated the association between serum ATX levels and Graves' disease. We measured the levels of serum total ATX and ATX isoforms (classical ATX and novel ATX) in patients with untreated Graves' disease, Graves' disease treated with anti-thyroid drugs, patients with subacute thyroiditis, silent thyroiditis, Plummer's disease, or Hashimoto's thyroiditis, and patients who had undergone a total thyroidectomy, as well as normal subjects. The serum total ATX and ATX isoform levels were higher in the patients with Graves' disease, compared with the levels in the healthy subjects and the patients with subacute thyroiditis. Treatment with anti-thyroid drugs significantly decreased the serum ATX levels. The serum ATX levels and the changes in serum ATX levels during treatment were moderately or strongly correlated with the serum concentrations or the changes in thyroid hormones. However, the administration of T3 or T4 did not increase the expression or serum levels of ATX in 3T3L1 adipocytes or wild-type mice. In conclusion, the serum ATX levels were higher in subjects with Graves' disease, possibly because of a mechanism that does not involve hyperthyroidism. These results suggest the possible involvement of the ATX/LPA axis in the pathogenesis of Graves' disease.

GABA-A and GABA-B Receptors in Filial Imprinting Linked With Opening and Closing of the Sensitive Period in Domestic Chicks (Gallus gallus domesticus).

Filial imprinting of domestic chicks has a well-defined sensitive (critical) period lasting in the laboratory from hatching to day 3. It is a typical model to investigate the molecular mechanisms underlying memory formation in early learning. We recently found that thyroid hormone 3,5,3′-triiodothyronine (T3) is a determinant of the sensitive period. Rapid increases in cerebral T3 levels are induced by imprinting training, rendering chicks imprintable. Furthermore, the administration of exogenous T3 makes chicks imprintable on days 4 or 6 even after the sensitive period has ended. However, how T3 affects neural transmission to enable imprinting remains mostly unknown. In this study, we demonstrate opposing roles for gamma-aminobutyric acid (GABA)-A and GABA-B receptors in imprinting downstream of T3. Quantitative reverse transcription polymerase chain reaction and immunoblotting showed that the GABA-A receptor expression increases gradually from days 1 to 5, whereas the GABA-B receptor expression gradually decreases. We examined whether neurons in the intermediate medial mesopallium (IMM), the brain region responsible for imprinting, express both types of GABA receptors. Immunostaining showed that morphologically identified putative projection neurons express both GABA-A and GABA-B receptors, suggesting that those GABA receptors interact with each other in these cells to modulate the IMM outputs. The roles of GABA-A and GABA-B receptors were investigated using various agonists and antagonists. Our results show that GABA-B receptor antagonists suppressed imprinting on day 1, while its agonists made day 4 chicks imprintable without administration of exogenous T3. By contrast, GABA-A receptor agonists suppressed imprinting on day 1, while its antagonists induced imprintability on day 4 without exogenous T3. Furthermore, both GABA-A receptor agonists and GABA-B receptor antagonists suppressed T3-induced imprintability on day 4 after the sensitive period has ended. Our data from these pharmacological experiments indicate that GABA-B receptors facilitate imprinting downstream of T3 by initiating the sensitive period, while the GABA-A receptor contributes to the termination of the sensitive period. In conclusion, we propose that opposing roles of GABA-A and GABA-B receptors in the brain during development determine the induction and termination of the sensitive period.