Reduced Thyroid Hormone Research Articles

TMET-26. TARGETING TRANSSULFURATION VIA SUPPRESSION OF THYROID HORMONE SIGNALING: A WINDOW OF OPPORTUNITY TRIAL OF METHIMAZOLE IN PATIENTS WITH PROGRESSIVE WHO GRADE 4 GLIOMAS (NCT05607407)

Abstract BACKGROUND Gaseous hydrogen sulfide (H2S), a by-product of cysteine metabolism, inhibits cancer cell behavior and growth in glioblastoma (GBM) models. H2S production capacity (HPC) is decreased in human GBM specimens compared to non-tumor controls. Thus, boosting HPC is a novel strategy for GBM treatment. Suppression of thyroid hormone signaling increases endogenous production of H2S. Hypothesis: hypothyroidism induced by methimazole will enhance the efficacy of chemotherapy in WHO grade 4 gliomas by increasing HPC within the tumor. Goal: proof of concept that methimazole, by reducing thyroid hormone signaling, can increase HPC in patients with WHO grade 4 gliomas (G4G). METHODS This window of opportunity trial evaluates safety, HPC in plasma and tumor, and efficacy of methimazole + chemotherapy in patients with progressive G4G. MAIN OBJECTIVE 10% increase in HPC and a 1.5-fold increase in peripheral blood sulfhydration signaling. Patients planned for a clinically-indicated resection receive pre-op (5-7 days) and post-op methimazole with the addition of investigator’s choice of chemotherapy 1 month after starting post op methimazole. Patients receive methimazole + chemotherapy until progression. Pre- and post-op plasma and resected tumor tissue are assayed for HPC and proteins relevant to H2S production. Key eligibility: progressive G4G for whom a clinically-indicated resection is planned; normal thyroid function with no history of thyroid dysfunction. Patients may have received unlimited prior regimens including bevacizumab. RESULTS To date 12 patients (8 male) median age 56 years enrolled, 3 of whom are in pre-op phase. Relative to age/sex matched control, post-methimazole plasma at all time points tested but not tumor HPC increased (minimum increase 56%, p 0.041). No grade 3-5 toxicities or significant changes in thyroid function tests. PFS6 0 for first 6 patients. CONCLUSIONS Induction of subclinical hypothyroidism is feasible and safe in recurrent GBM with significant increases in plasma but not tumor HPC. The protocol is being modified to increase methimazole doses and allow earlier addition (10 days) of post-op chemotherapy.

Time-restricted feeding prevents memory impairments induced by obesogenic diet consumption, via hippocampal thyroid hormone signaling

ObjectivesThe early consumption of calorie-rich diet disrupts circadian rhythms and has adverse effects on memory, yet the effects of time-restricted feeding (TRF) and the underlying molecular mechanisms are unknown. Here, we set out to identify the behavioral and molecular circadian rhythms disruptions generated by juvenile obesogenic diet consumption and their restoration by TRF in male mice. MethodsMetabolic rhythms were measured by indirect calorimetry and memory performances by behavioral tasks. Hippocampal translatome (pS6_TRAP), enrichment and co-regulated gene network analyses were conducted to identify the molecular pathways involved in memory impairments and their restoration by TRF. Differential exon usage analyses, mass spectrometry and pharmacological intervention were used to confirm thyroid hormone signaling involvement. ResultsWe show that four weeks of TRF restore the rhythmicity of metabolic parameters and prevents memory impairments in mice fed a high fat-high sucrose (HFS) diet since weaning, independently of body fat levels. Hippocampal translatome and differential exon usage analyses indicate that impaired memory of mice under ad libitum HFS diet is accompanied by reduced thyroid hormone signaling and altered expression of astrocytic genes regulating glutamate neurotransmission. TRF restored the diurnal expression variation of part of these genes and intra-hippocampal infusion of T3, the active form of thyroid hormone, rescues memory performances and astrocytic gene expression of ad libitum HFS diet-fed mice. ConclusionsThus, thyroid hormones contribute to the TRF positive effects on both metabolism and memory in mice fed an obesogenic diet, highlighting this nutritional approach as a powerful tool in addressing obesity brain comorbidities and paving the way for further mechanistic studies on hippocampal thyroid signaling.

Exploring the role of plasmapheresis prior to thyroidectomy in managing thyrotoxicosis: a comprehensive scoping review.

A thyroid storm is the most extreme and life-threatening presentation of thyrotoxicosis. Thyroidectomy can be used for definitive treatment. It should be performed after euthyroidism is accomplished. The use of therapeutic plasma exchange (TPE) is a last resort option in cases where standard pharmacological therapy proves to be ineffective. Due to its rare prevalence, there are limited data evaluating the usefulness and efficacy of TPE as a bridging therapy to thyroidectomy. The absence of relevant literature prompted us to conduct a scoping review. The following bibliographic databases were searched for articles dated 30 November 2023: Medline, EMBASE, Web of Science and Google Scholar. The search identified 1047 records, of which 42 articles were accepted with a total of 234 patients. The dominant indications for TPE were side effects due to conventional treatment. The mean fT4 level decreased 51.9% of baseline after TPE, while the mean fT3 level decreased 66.6% of baseline. The main side effects observed with FFP were allergic reactions, while the use of an albumin solution was associated with perioperative bleeding. Based on the limited data available in the literature, we recognize plasmapheresis as an effective treatment option for reducing thyroid hormone levels prior to thyroidectomy in patients with thyrotoxicosis. Available data suggest that it might be reasonable to limit the number of sessions in favor of an earlier surgical intervention. To reduce the risk of bleeding, FFP may be a better option as a replacement fluid, especially in the session prior to thyroidectomy.

Epigenetic regulation of thyroid hormone action in human metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by inflammation, fibrosis, and accumulation of fatty acids in the liver. MASH disease progression has been associated with reduced thyroid hormone (TH) signaling in the liver, including reduced expression of deiodinase type I (DIO1) and TH receptor beta (THRB). However, the underlying mechanisms mediating these effects remain elusive. Here, we hypothesized that epigenetic mechanisms may be involved in modulating hepatic TH action. Liver samples from patients with and without MASH were analyzed by qRT-PCR and correlated with clinical parameters. Luciferase reporter assays and overexpression of miRNA in HepG2 cells were used to validate the functional binding of miRNA to predicted targets. DNA methylation was analyzed by bisulfite pyrosequencing. miR-34a-5p was upregulated in MASH patients and correlated positively with the clinical parameters of MASH. Using in silico and in vitro analysis, we demonstrate that miR-34a-5p is capable of targeting several modulators of local hepatic TH action, as evidenced by the functional binding of miR-34a-5p to the seed sequence in the THRB and DIO1 genes. Consequently, overexpression of miR-34a-5p in HepG2 cells reduced the expression of THRA, THRB, DIO1, and SLC10A1, thus potentially mediating an acquired hepatic resistance to TH in MASH. As an additional regulatory mechanism, DNA methylation of THRB intron 1 was increased in MASH and negatively correlated with THRB expression. miR-34a-5p constitutes a possible epigenetic master regulator of hepatic TH action, which together with THRB-specific DNA methylation could explain a possible developing TH resistance in the liver during MASH progression on the molecular level.

Graves disease: latest understanding of pathogenesis and treatment options.

Graves disease is the most common cause of hyperthyroidism in iodine-sufficient areas. The main responsible mechanism is related to autoantibodies that bind and activate the thyrotropin receptor (TSHR). Although Graves hyperthyroidism is relatively common, no causal treatment options are available. Established treatment modalities are antithyroid drugs, which reduce thyroid hormone synthesis, radioactive iodine and surgery. However, emerging drugs that target the main autoantigen (monoclonal antibodies, small molecules, peptides) or block the immune pathway have been recently tested in clinical trials. Graves disease can involve the thyroid exclusively or it can be associated with extrathyroidal manifestations, among which Graves orbitopathy is the most common. The presence of Graves orbitopathy can change the management of the disease. An established treatment for moderate-to-severe Graves orbitopathy is intravenous glucocorticoids. However, recent advances in understanding the pathogenesis of Graves orbitopathy have allowed the development of new target-based therapies by blocking pro-inflammatory cytokine receptors, lymphocytic infiltration or the insulin-like growth factor 1 receptor (IGF1R), with several clinical trials providing promising results. This article reviews the new discoveries in the pathogenesis of Graves hyperthyroidism and Graves orbitopathy that offer several important tools in disease management.

비만의 변화된 대사 적응에 대한 기능의학적 이해

The World Health Organization describes obesity as “a chronic complex disease defined by excessive fat deposits that can impair health,” declaring obesity as a major health concern and disease in 1997. In 2013, the American Medical Association recognized the obesity disease condition as one associated with various pathophysiological problems requiring intervention. The global obese population continues to increase, calculated to be greater than 1 billion in 2024, or about 1 in every 8 persons. Likewise, the prevalence of obesity among Korean adults continues to increase. As a significant health risk factor and one of the main causes of chronic disease, obesity is caused by the increased intake of ultra-processed food, excessive nutritional intake, inadequate physical activity, smoking, heavy drinking, sleep disorders, particular chemicals and drugs, environmental toxins, endocrine disruptors, stress and mental illness, genetic and congenital disorders, et cetera. Obesity has detrimental effects on physical, mental, psychological, and sociological well-being, leading to body dysmorphia and image disfiguration, discomfort, disability, disease, and death. Obesity is not simply a risk factor for chronic diseases, rather, it is an epidemic of a complex chronic illness that is difficult to be cured. Obesity is exacerbated in the modern era due to rapidly changing societal lifestyles and its associated multifaceted effects. Due to the difficulty in the management of obesity, the individual causes and societal influence on lifestyle must be tightly controlled. The most decisive pathological process of obesity is inflammatory changes of adipose tissue. Produced by adipose tissue, various hormones and inflammatory agents affect normal tissue to induce an inflammatory response, leading to insulin resistance and a disruption of neuroendocrine homeostasis, particularly the reduction in thyroid hormone and the imbalance of adrenal hormones. In this article, the author will review the functional medicine aspect of altered metabolic adaptation in obesity.

Thyrotoxicosis in Partial Mola Hidatidosa

Thyrotoxicosis is a clinical condition associated with excessive thyroid hormone levels. Symptoms can range from asymptomatic to life-threatening due to thyroid storm. Thyrotoxicosis in hydatidiform moles is a rare condition but has a high mortality rate, so etiological studies are still needed for optimal management. Case Report: Patient Mrs. T, 25 years old Hindu, Balinese, 12 weeks pregnant (Gravida 1 Para 0 abortion 0), came to the obstetrics ER on September 24, 2023 with complaints of discharge from the birth canal since the morning, nausea (+), often shaking, easily tired and often sweaty. physical examination obtained blood pressure 100/60mmHg, pulse 78x/min, respiratory rate 20x/min, axillary temperature 36.80C oxygen saturation 99%. From obstetric examination, fundus uteri height ½ center, vaginal toucher vulva vagina within normal limits, portiono (-) fluxus (+), laboratory examination obtained HCG 387,392.8 mIU/m, FT4 31.05 pmol/L (N: 9-22), TSH <0.01 uIU/mL (N: 0.4-4.2) ultrasound results describe honey comb appearance and histopathology results describe partial mola. Evacuation by curettage was performed, resulting in reduced serum ?-hCG levels and reduced thyroid hormone levels. Discussion: The patient was diagnosed with partial hydatidiform mole and thyrotoxicosis. Hydatidiform moles can cause thyrotoxicosis. This condition is caused by the structure of ?- hCG which resembles TSH so that it can activate TSH receptors. After evacuation of hydatidiform moles, normal TSH and FT4 levels will be obtained. Conclusion: The female patient with thyrotoxicosis due to hydatidiform moles had the moles evacuated, resulting in normal thyroid hormone levels.

Assessment of bidirectional relationships between hypothyroidism and endometrial cancer: a two-sample Mendelian randomization study.

Hypothyroidism, characterized by reduced thyroid hormone levels, and endometrial cancer, a prevalent gynecological malignancy, have been suggested to have a potential association in previous observational studies. However, the causal relationship between them remains uncertain. This study aimed to investigate the causal relationship between hypothyroidism and endometrial cancer using a bilateral Mendelian randomization approach. A bidirectional two-sample Mendelian randomization study was conducted using summary statistics from genome-wide association studies to identify genetic variants associated with hypothyroidism and endometrial cancer. The inverse variance weighting method was used as the main analysis, and sensitivity analyses were conducted to validate the MR results. The results of our analysis did not support a causal effect of hypothyroidism (OR: 0.93, p=0.08) or autoimmune hypothyroidism (OR: 0.98, p=0.39) on endometrial cancer risk. In the reverse MR analysis, we did not find a significant causal effect of endometrial cancer on hypothyroidism (OR: 0.96, p=0.75) or autoimmune hypothyroidism (OR: 0.92, p=0.50). Based on subgroup analysis by pathological subtypes of endometrial cancer, the above findings were further substantiated (all p-value >0.05). Our Mendelian randomization analysis suggests a lack of causal association between hypothyroidism and endometrial cancer. To gain a deeper understanding of this association, it is essential to conduct large-scale randomized controlled trials in the future to validate our findings.

Challenging diagnosis of resistance to thyroid hormone in a patient with COVID-19, pituitary microadenoma and unusual response to octreotide long-acting release test.

The resistance to thyroid hormone syndrome (RTHβ) occurs uncommonly and requires a high level of clinical suspicion and specific investigations to reach a precise diagnosis and to avoid unnecessary and potentially harmful therapies. We report a case of a young male patient referred to our unit for SARS-CoV-2 infection and atrial fibrillation with elevated thyroid hormones and non-suppressed thyroid-stimulating hormone (TSH), for which antithyroid therapy was prescribed. A mood disorder was reported in the medical history. The family history was unknown as the patient was adopted. Thyroid-specific antibodies were undetectable, and thyroid ultrasound revealed a normal thyroid gland without nodules. After the resolution of SARS-CoV-2 infection, the diagnostic workup continued, and the pituitary MRI revealed a small area ascribable to a microadenoma. Due to atrial fibrillation, the execution of the T3 test was contraindicated. The octreotide long-acting release (LAR) test showed an initial reduction of free thyroid hormones levels at first administration, which was consistent with the presence of a TSH-secreting pituitary tumour, although an escape from the response was observed after the following two injections of octreotide LAR. Indeed, the genetic investigation revealed a variant in heterozygosity of the THRβ gene (Pro453Ser), thus leading to an RTHβ diagnosis, and, therefore, medical treatment with triiodothyroacetic acid was initiated. After 2 years from the SARS-CoV-2 infection, the patient continues the follow-up at our outpatient clinic, and no other medical interventions are needed. RTHβ is a rare genetic syndrome characterised by discrepant thyroid function tests and by a dissociation between the observed hormone levels and the expected patient signs and symptoms. Features of thyroid hormone deficiency in TR-ß dependent tissues (pituitary gland, hypothalamus, liver and neurosensitive epithelia), as well as thyroid hormone excess in TR-α-dependent tissues (heart, bone, skeletal muscle and brain), may coexist in the same individual. Clinical pictures can be different even when the same variant occurs, suggesting that other genetic and/or epigenetic factors may play a role in determining the patient's phenotype. Differentiating RTHβ from a TSH-secreting pituitary tumour is very difficult, especially when a concomitant pituitary adenoma is detected during diagnostic workup. The injection of long-acting somatostatin analogues can help differentiate the two conditions, but it is important to detect any interference in the dosage of thyroid hormones to avoid an incorrect diagnosis. Genetic testing is fundamental to prevent unnecessary and potentially harmful therapies. Medical treatment with triiodothyroacetic acid was demonstrated to be effective in reducing thyroid hormone excess and controlling symptoms.

Dynamic Observation in Children and Adolescents Following Management of Differentiated Thyroid Cancer

Differentiated thyroid cancer (DTC) is one of the most common malignancies within the endocrine system, with a progressively increasing incidence over recent decades. In the structure of DTC, occurrence in the pediatric age group is relatively rare and is associated with excellent prognoses in terms of disease-specific survival. However, the prevalence of advanced disease in children and the frequency of recurrences present interdisciplinary teams with questions regarding the optimal management approach for such patients, focusing not on achieving disease eradication but preserving and maintaining quality of life. Notably, the presence of oncological pathology, coupled with fluctuations in thyroid hormone levels due to therapeutic interventions, underscores the importance of maintaining psychological and physiological well-being that are affected by the increased frequency of anxiety and depressive symptoms in children and their parents, as well as cognitive and physical functioning. These symptoms may exacerbate against the backdrop of hypothyroidism and directly correlate with TSH levels. To maintain quality of life during the period of dynamic observation and risk group re-stratification, we proposed a method of reduced thyroid hormone doses as an alternative to discontinuing thyroid hormones to assess stimulated thyroglobulin when reaching a threshold TSH level >30 mIU/L. The method was implemented in 2 pediatric patients, showing positive outcomes in terms of absence of hypothyroidism-related complaints, preservation of free thyroid hormone fractions, achievement of adequate target TSH levels, and informative tumor marker indicators. The results of our study underscore the importance of an individualized approach to the management of children with DTC and demonstrate the potential effectiveness of the reduced dose method in maintaining the quality of life of these patients. Further research and clinical observations are necessary for a deeper understanding of the applicability of this method and its impact on longterm outcomes.

Perinatal maternal exposure to high-dose sodium phenobarbital in the modified Comparative Thyroid Assay: no significant reduction in thyroid hormones in pups despite notable effects in dams.

We propose a modified Comparative Thyroid Assay (CTA, USEPA) utilizing a smaller number of Sprague-Dawley rats (N=10/group) that assesses brain thyroid hormone (TH) concentrations and periventricular heterotopia while maintaining assay sensitivity. Our recent findings demonstrated that a prenatal test cohort of the modified CTA detected a dose-dependent decrease in maternal serum T3 (up to -26%) and T4 (up to -44%) with sodium phenobarbital (NaPB) exposure at 1000 ppm and 1500 ppm, equivalent to intakes of 60 and 84 mg/kg/day, respectively. On gestation day (GD) 20, fetuses exhibited reduced serum (-26%) and brain (-29%) TH concentrations, although these reductions were not dose dependent. The present study expanded the treatment in a postnatal test cohort, with maternal exposure to NaPB (81-93 mg/kg/day) from GD6 to lactation day (LD) 21. We assessed serum and brain TH concentrations, and periventricular heterotopia in pups on postnatal days (PND) 4, 21, and 28. While LD21 dams showed significant reductions in serum T3 (up to -34%) and T4 (up to -54%), the pups did not exhibit significant TH suppression or periventricular heterotopia at any test point. Instead, a compensatory increase in T4 was observed in serum and brain of PND21 pups. The present study confirmed that perinatal maternal exposure to high doses of NaPB leads to a moderate decrease in maternal TH concentrations; however, the exposure of maternal rats to a similar dose of NaPB did not significantly reduce serum or brain TH concentrations in their postnatal offspring.

Maternal and Neonatal Effects of Maternal Oral Exposure to Perfluoro-2-methoxyacetic Acid (PFMOAA) during Pregnancy and Early Lactation in the Sprague-Dawley Rat.

Perfluoro-2-methoxyacetic acid (PFMOAA) is a short-chain perfluoroalkyl ether carboxylic acid that has been detected at high concentrations (∼10 μg/L) in drinking water in eastern North Carolina, USA, and in human serum and breastmilk in China. Despite documented human exposure there are almost no toxicity data available to inform risk assessment of PFMOAA. Here we exposed pregnant Sprague-Dawley rats to a range of PFMOAA doses (10-450 mg/kg/d) via oral gavage from gestation day (GD) 8 to postnatal day (PND) 2 and compared results to those we previously reported for perfluorooctanoic acid (PFOA) and hexafluoropropylene oxide-dimer acid (HFPO-DA or GenX). Newborn pups displayed reduced birthweight (≥30 mg/kg), depleted liver glycogen concentrations (all doses), hypoglycemia (≥125 mg/kg), and numerous significantly altered genes in the liver associated with fatty acid and glucose metabolism similar to gene changes produced by HFPO-DA. Pup survival was significantly reduced at ≥125 mg/kg, and at necropsy on PND2 both maternal and neonatal animals displayed increased liver weights, increased serum aspartate aminotransferase (AST), and reduced serum thyroid hormones at all doses (≥10 mg/kg). Pups also displayed highly elevated serum cholesterol at all doses. PFMOAA concentrations in serum and liver increased with maternal oral dose in both maternal and F1 animals and were similar to those we reported for PFOA but considerably higher than HFPO-DA. We calculated 10% effect levels (ED10 or EC10) and relative potency factors (RPF; PFOA = index chemical) among the three compounds based on maternal oral dose and maternal serum concentration (μM). Reduced pup liver glycogen, increased liver weights and reduced thyroid hormone levels (maternal and pup) were the most sensitive end points modeled. PFMOAA was ∼3-7-fold less potent than PFOA for most end points based on maternal serum RPFs, but slightly more potent for increased maternal and pup liver weights. PFMOAA is a maternal and developmental toxicant in the rat producing a constellation of adverse effects similar to PFOA and HFPO-DA.

Cellular Iron Deficiency Disrupts Thyroid Hormone Regulated Gene Expression in Developing Hippocampal Neurons

BackgroundDeveloping neurons have high thyroid hormone and iron requirements to support their metabolically demanding growth. Early-life iron and thyroid-hormone deficiencies are prevalent and often coexist, and each independently increases risk of permanently impaired neurobehavioral function in children. Early-life dietary iron deficiency reduces thyroid-hormone concentrations and impairs thyroid hormone-responsive gene expression in the neonatal rat brain, but it is unclear whether the effect is cell-intrinsic. ObjectivesThis study determined whether neuronal-specific iron deficiency alters thyroid hormone-regulated gene expression in developing neurons. MethodsIron deficiency was induced in primary mouse embryonic hippocampal neuron cultures with the iron chelator deferoxamine (DFO) beginning at 3 d in vitro (DIV). At 11DIV and 18DIV, thyroid hormone-regulated gene messenger ribonucleic acid (mRNA)concentrations indexing thyroid hormone homeostasis (Hairless, mu-crystallin, Type II deiodinase, solute carrier family member 1c1, and solute carrier family member 16a2) and neurodevelopment (neurogranin, Parvalbumin, and Krüppel-like factor 9) were quantified. To assess the effect of iron repletion, DFO was removed at 14DIV from a subset of DFO-treated cultures, and gene expression and adenosine 5'-triphosphate (ATP) concentrations were quantified at 21DIV. ResultsAt 11DIV and 18DIV, neuronal iron deficiency decreased neurogranin, Parvalbumin, and mu-crystallin, and by 18DIV, solute carrier family member 16a2, solute carrier family member 1c1, Type II deiodinase, and Hairless were increased, suggesting cellular sensing of a functionally abnormal thyroid hormone state. Dimensionality reduction with Principal component analysis reveals that thyroid hormone homeostatic genes strongly correlate with and predict iron status. Iron repletion from 14–21DIV did not restore ATP concentration, and Principal component analysis suggests that, after iron repletion, cultures maintain a gene expression signature indicative of previous iron deficiency. ConclusionsThese novel findings suggest there is an intracellular mechanism coordinating cellular iron/thyroid hormone activities. We speculate this is a part of the homeostatic response to acutely match neuronal energy production and growth signaling. However, the adaptation to iron deficiency may cause permanent deficits in thyroid hormone-dependent neurodevelopmental processes even after recovery from iron deficiency.

Influence of Hypothyroidism on the Variability of Carotenoid Coloration in Amatitlania nigrofasciata Females (Cichlidae)

The study of the effect of thyroid hormones on the development of the pigment pattern, including the expression of sexual dichromatism, contributes to our understanding of the role of endocrine signaling in the evolution of cichlid fishes, one of the most diverse groups of teleosts. This work shows the effect of reduced thyroid hormone signaling on the development of reversed sexual dichromatism in Amatitlania nigrofasciata, a Neotropical cichlid in which females, unlike males, have carotenoid coloration. In hypothyroid fishes, there was a slowdown in the rate of metamorphic transformations of the pigment pattern and an increase in phenotypic variability. The adult pattern based on carotenoids began to develop in females only after the completion of treatment of thiourea, which suppresses the synthesis of endogenous thyroid hormones. The data obtained indicate a potentially important role of thyroid hormone-mediated developmental plasticity in the diversification of carotenoid coloration in Neotropical cichlids.

THU659 Plasmapheresis As A Therapy For Amiodarone-induced Thyrotoxicosis: A Case Report And Literature Review

Abstract Disclosure: C.L. Loughner: None. P.L. Bononi: None. Introduction: Amiodarone-induced thyrotoxicosis (AIT) is a common cause of hyperthyroidism. Treatment consists of stabilizing the thyroid followed by thyroidectomy1. Plasmapheresis has been suggested as a temporary measure when illness severity precludes standard therapy. Here, we review current literature and provide a case of AIT treated with plasmapheresis. Clinical Case: A 71-year-old male was seen for progressive subclinical hyperthyroidism, diagnosed several years prior. Three years ago, he started taking amiodarone for paroxysmal ventricular tachycardia. One month prior to admission, he was admitted for decompensated heart failure and had TSH 0.02 mcU/mL (n 0.4-4.4 mcU/mL), free T4 4.48 ng/dL (n 0.7-1.9 ng/dL), and free T3 2.58 pg/mL (n 2.0-4.4 pg/mL). Amiodarone was halved after being diagnosed with AIT. Methimazole and prednisone were started. He was readmitted one month later. TSH was undetectable at admission and free T4 was 4.04 ng/dL. Amiodarone was discontinued. His hepatic enzymes were elevated, necessitating the discontinuation of methimazole. His heart failure precluded thyroidectomy. Due to the limitation of treatment options, the patient was given three rounds of plasmapheresis to reduce thyroid hormone levels. His free T4 dropped to 2.81 ng/dL. The patient underwent total thyroidectomy once stable. His free T4 was 1.73 after and was started on levothyroxine. Clinical Lesson: When patients are unable to have standard treatment of AIT, other options must be considered. While there are some case reports3,4, there are currently no RCTs for plasmapheresis for AIT. In the case of this patient with cardiac complications from AIT and concurrent hepatic impairment, plasmapheresis provided stability of thyroid hormones until surgical correction could be achieved.

The Impact of Metformin on the Development of Hypothyroidism and Cardiotoxicity Induced by Cyclophosphamide, Methotrexate, and Fluorouracil in Rats.

Cyclophosphamide (CYP), methotrexate (MTX), and 5-fluorouracil (5-FU) are extensively utilized in the therapeutic management of various malignancies. It is noteworthy, however, that potential chemotherapy-related complications include the occurrence of hypothyroidism and cardiotoxicity. Metformin (MET) is a pharmacological agent for managing type 2 diabetes. It has been reported to mitigate certain toxic manifestations associated with chemotherapy. This study's primary objective is to investigate MET's protective effects against hypothyroidism and cardiotoxicity induced by CMF treatment. A total of forty male rats were allocated into four distinct groups, each consisting of ten rats per group. These groups were categorized as follows: saline, MET, CMF, and CMF + MET. The experimental group of rats were administered CMF via intraperitoneal injection, receiving two doses of CMF, and fed MET in their daily drinking water, with a 2.5 mg/mL concentration. Blood samples were collected into EDTA tubes for assessment of TSH, free and total (T4 and T3), troponin I, CK, and CK-MB levels utilizing Electrochemiluminescence Immunoassays (ECI). The saline and MET groups did not exhibit significant alterations in thyroid hormones or cardiotoxic biomarkers. In contrast, in the CMF group, there was a notable reduction in T4, FT4, T3, and FT3 levels but no significant changes in TSH levels; however, troponin I, CK, and CK-MB levels were notably elevated. MET co-treatment with CMF did not ameliorate these effects caused by CMF. In conclusion, CMF treatment induced hypothyroidism and cardiotoxicity in rats, but MET co-treatment did not rescue the reduction of thyroid hormones or the elevation of cardiotoxic biomarkers.

Exogenous corticosterone administration during pregnancy in mice alters placental and fetal thyroid hormone availability in females

IntroductionMaternal prenatal psychological stress is associated with adverse pregnancy outcomes and increased risk of adverse health outcomes in children. While the molecular mechanisms that govern these associations has not been fully teased apart, stress-induced changes in placental function can drive sex-specific phenotypes in offspring. We sought to identify and examine molecular pathways in the placenta that are altered in response to maternal prenatal stress. MethodsWe previously employed a mouse model of maternal prenatal stress where pregnant dams were treated with stress hormone (CORT) beginning in mid-gestation. Using this model, we conducted RNAseq analysis of whole placenta at E18.5. We used qRT-PCR to validate gene expression changes in the placenta and in a trophoblast cell line. ELISAs were used to measure the abundance of thyroid hormones in maternal and fetal serum and in the placenta. ResultsDio2 was amongst the top differentially expressed genes in response to exogenous stress hormone. Dio2 expression was more downregulated in placenta of female fetuses from CORT-treated dams than both control placenta from females and placenta from male fetuses. Consistent with Dio2's role in production of bioactive thyroid hormone (T3), we found that there was a reduction of T3 in placenta and serum of female embryos from CORT-treated dams at E18.5. Both T3 and T4 were reduced in the fetal compartment of the placenta of female fetuses from CORT-treated dams at E16.5. Exogenous stress hormone induced reduction in thyroid hormone in females was independent of circulating levels of TH in the dams. DiscussionThe placental thyroid hormone synthesis pathway may be a target of elevated maternal stress hormone and modulate fetal programming of health and disease of offspring in a sex-specific fashion.

Comparative evaluation of doxorubicin, cyclophosphamide, 5-fluorouracil, and cisplatin on cognitive dysfunction in rats: Delineating the role of inflammation of hippocampal neurons and hypothyroidism

Chemotherapeutic agents such as doxorubicin, cyclophosphamide, fluorouracil, and cisplatin are commonly used to treat a variety of cancers and often result in chemobrain, which manifests as difficulties in learning and memory processes that can persist in the years following treatment. The current study aims to evaluate the cognitive function following treatment with these agents and the underlying mechanisms using a rat model of neuroinflammation and possible implication of thyroid toxicity in chemotherapy induced cognitive dysfunction. Wistar female rats were treated with a single dose of doxorubicin (DOX, 25 mg/kg), 5-fluorouracil (5-FU, 100 mg/kg), cisplatin (8 mg/kg), and cyclophosphamide (CYP, 200 mg/kg) by intraperitoneal injection. The cognitive performance of rats was then evaluated in spatial memory tasks using the Y-maze, novel object recognition (NOR), and elevated plus maze (EPM) tests. Serum levels of thyroid hormones (T3, T4, FT3, and FT4) and thyroid stimulating hormone (TSH) were measured, followed by estimation of TNFα, IL-6, and IL-1β in the hippocampal tissue. Results revealed that all the chemotherapeutic agents produced impairment of cognitive function, and significant increase of pro-inflammatory cytokines such as TNFα, IL-6 and IL-1β in the hippocampal tissues. There was a significant reduction in thyroid hormones (T3, FT3, and T4) and an increase in thyroid stimulating hormone (TSH) in serum, which may also have contributed to the decline in cognitive function. In conclusion, DOX, 5-FU, CYP, and cisplatin produces impairment of spatial memory possibly by inflammation of hippocampal neurons and endocrine disruption (hypothyroidism) in rats.

Sensitivity to thyroid hormone and risk of components of metabolic syndrome in a Chinese euthyroid population.

To evaluate the association of sensitivity to thyroid hormone with metabolic syndrome (MetS) and its components in a Chinese euthyroid population. A total of 3573 participants from Pinggu Metabolic Disease Study were analyzed. Serum-free triiodothyronine (FT3), free thyroxine (FT4), thyrotropin (TSH), total adipose tissue (TAT), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) area of abdominal, and lumbar skeletal muscle area (SMA) were measured. Central thyroid hormone resistance was calculated by the Thyroid Feedback Quantile-based Index (TFQI) and Chinese-referenced Parametric TFQI (PTFQI), Thyrotroph T4 Resistance Index (TT4RI) and TSH Index (TSHI). Peripheral thyroid hormone resistance was assessed by FT3/FT4 ratio. Higher values of TSHI (odds ratio [OR] = 1.167, 95% confidence interval [CI]: 1.079-1.262, p < .001), TT4RI (OR = 1.115, 95% CI: 1.031-1.206, p = .006), TFQI (OR = 1.196, 95% CI: 1.106-1.294, p < .001), PTFQI (OR = 1.194, 95% CI: 1.104-1.292, p < .001), and lower values of FT3/FT4 ratio (OR = 0.914, 95% CI: 0.845-0.990, p = .026) were associated with MetS. Increased levels of TFQI and PTFQI were associated with abdominal obesity, hypertriglyceridemia, and hypertension. Increased levels of TSHI and TT4RI were associated with hypertriglyceridemia, abdominal obesity, low high-density lipoprotein cholesterol. Reduced levels of FT3/FT4 ratio were associated with hyperglycemia, hypertension, and hypertriglyceridemia. The levels of TSHI, TFQI, and PTFQI were negatively related to SMA and positively related to VAT, SAT, and TAT (all p < .05). Reduced thyroid hormone sensitivity was associated with MetS and its components. Impaired thyroid hormone sensitivity might affect the distribution of adipose tissue and muscle.

Thyroid storm and hypercalcemic crisis as a result of unconventional treatment of Graves’ disease

We present a case of severe thyroid storm with simultaneous hypercalcemic crisis resulting from excessive intake of 5% Lugol’s iodine solution (5% iodine, 15% potassium iodide, 85% water; 10 drops/day) and vitamin D3 (10000 IU/day) during 2 months of unconventional treatment in a 78-year-old female with a history of hyperthyroidism in course of Graves’ disease. Supplements were prescribed by herbalist/healer before admission to the hospital. At the clinic, we started therapy with antithyroid drugs, inorganic iodide and corticosteroids but without positive effect. Patient’s condition kept deteriorating with loss of consciousness. Plasmapheresis (4 procedures) was required to successfully reduce thyroid hormone levels and finally total thyroidectomy was performed resulting in postoperative hypothyroidism and transient hypoparathyroidism. Additionally, patient suffered from serious complications such as Takotsubo cardiomyopathy and sepsis requiring intensive care unit. Treatment with corticosteroids led to secondary adrenal insufficiency. Following 2-month hospitalization, patient was discharged in stable condition.