T4 Replacement Research Articles

High-intensity interval training ameliorates spatial and recognition memory impairments, reduces hippocampal TNF-alpha levels, and amyloid-beta peptide load in male hypothyroid rats

Thyroid hormones are critical for healthy brain functions at every stage of life. Hypothyroidism can cause severe cognitive dysfunction in patients who do not receive adequate treatment. Although thyroid hormone replacement alleviates cognitive decline in hypothyroid patients, there are studies showing that there is no complete recovery. The aim of this study was to investigate the effects of high-intensity interval training (HIIT) in hypothyroid rats on spatial and recognition memory, neuroinflammation, amyloid-beta load and compare these effects with T3 replacement. Hypothyroidism was induced and maintained by administration of 6-n-propyl-2-thiouracil (PTU) with their drinking water to 6-weeks-old male Sprague–Dawley rats for 7 weeks. The animals exercised in the treadmill according to the HIIT protocol for four weeks. T3 was injected intraperitoneally daily during the last two weeks of the study. All animals performed in the elevated plus maze test, Morris water maze test, novel object recognition test, and rotarod motor performance test in the last week of the study and then the animals were sacrificed. Amyloid beta (1−42) and TNFα levels were measured in the prefrontal cortex and hippocampus by ELISA. Anxiety-like behaviors did not significantly differ between groups. T3 replacement with or without HIIT increased motor performance in PTU-treated rats. HIIT and/or T3 replacement increased the exercise performance. HIIT and/or T3 replacement alleviated spatial and recognition memory impairments and normalized TNFα and amyloid-beta levels in the hippocampus in hypothyroid rats. In summary, regular physical exercise may have potential benefits in preserving cognitive functions in hypothyroid patients.

Local modulation of thyroid hormone signaling in the retina affects the development of diabetic retinopathy

Thyroid hormone (TH) dyshomeostasis is associated with poor prognosis in acute and prolonged illness, but its role in diabetic retinopathy (DR) has never been investigated. Here, we characterized the TH system in the retinas of db/db mice and highlighted regulatory processes in MIO-M1 cells. In the db/db retinas, typical functional traits and molecular signatures of DR were paralleled by a tissue-restricted reduction of TH levels. A local condition of low T3 (LT3S) was also demonstrated, which was likely to be induced by deiodinase 3 (DIO3) upregulation, and by decreased expression of DIO2 and of TH receptors. Concurrently, T3-responsive genes, including mitochondrial markers and microRNAs (miR-133-3p, 338-3p and 29c-3p), were downregulated. In MIO-M1 cells, a feedback regulatory circuit was evidenced whereby miR-133-3p triggered the post-transcriptional repression of DIO3 in a T3-dependent manner, while high glucose (HG) led to DIO3 upregulation through a nuclear factor erythroid 2-related factor 2–hypoxia-inducible factor-1 pathway. Finally, an in vitro simulated condition of early LT3S and hyperglycemia correlated with reduced markers of both mitochondrial function and stress response, which was reverted by T3 replacement. Together, the data suggest that, in the early phases of DR, a DIO3-driven LT3S may be protective against retinal stress, while, in the chronic phase, it not only fails to limit HG-induced damage, but also increases cell vulnerability likely due to persistent mitochondrial dysfunction.

The Etiology of Abnormal TSH in Veterans Cared by a VA Medical Center – One High Serum Thyrotropin is Associated with Higher 5-Years Mortality

Objective: By analyzing the etiology of abnormal TSH in randomly selected veteran patients, we set our heart on improving future clinical care/management of the clinical/subclinical hyper- and hypothyroidism in the aging veteran population. Methods: A total of 1100 patients’ charts in alphabetical order were selected. Excluded cases of insufficient information, 897 patients’ charts were reviewed and analyzed for causes of abnormal TSH. Among them, 602 for the cause of low TSH (below 0.55 uU/mL) and 295 for high TSH (above 4.78 uU/mL) were reviewed retrospectively. Findings: Among the 1100 patients selected, 680 (61.8%) were 60 y or older (female=44, 6.8%); 420 were under 60 y (female=80, 19.0%); significantly more female patients were found in the younger age group (P<0.001). After excluding patients with insufficient data, the most common cause of suppressed TSH is iodine-induced, CT iodinated contrast and betadine use caused 35.0% in the older group (n=126) compared to 23.6% in the younger group(n=57) (P = 0.027). The significant difference is that older veterans received more contrast CTs (P < 0.05 compared to the younger group). In both age groups with concurrent FT4 study, we found four high FT4 among 90 studies, 4.4% overt hyperthyroidism. The second most common cause of suppressed TSH is due to thyroid hormone (TH) replacement in the older group (119 patients, 33.1%) with age > 60y, significantly more frequent compared to the younger group, P<0.001. There is significantly more overt hyperthyroidism, 27.8/%, than the iodine-load induced suppression of TSH, P<0.001, due to 17 patients on TSH suppression therapy after total thyroidectomy for thyroid cancer. Among the 295 patients with elevated TSH, the most common cause of high TSH was due to hypothyroidism on T4 replacement: a total of 128 (59.3%) in the older group (N=216) is, similar to 47 (59.5%) in the younger group (N=79). In both age groups, there were 139 patients with concomitant FT4 measurement; 17 overt hypothyroidism were found, 12.2%. No significant difference is seen in the two age groups. The next most common causes of elevated TSH are CT contrast infusion, 23 (10.6%) in the older group and 7 (8.9%) in the younger group. We find high TSH is associated with a higher death rate of 101/238 (42.4%) in a 5-year follow-up (from 2016 to 2021), as compared to low TSH of 68/238 (28.6%), in the older age group, p<0.03； both were significantly higher than the age- and sex-matched general US population, 19.7%, P<0.01. Conclusion: Even though most, ~ 90%, were subclinical, the suppressed and elevated TSH are associated with severe consequences in CV/CNS and immune-suppression complications in aging veterans. Therefore, cautious use (and more frequent check of TSH) of TH replacement and CT contrast in aging veterans is recommended. The alarming increase in the 5-year death rate in older patients with elevated TSH deserves further study.

Van Wyk Grumbach Syndrome and Ovarian Hyperstimulation in Juvenile Primary Hypothyroidism: Lessons From a 30-Case Cohort.

Prolonged hypothyroidism in children commonly causes short stature with delayed bone maturation, and delayed puberty. However, a paradoxical occurrence of peripheral precocious puberty and pituitary enlargement in chronically untreated juvenile hypothyroidism was first reported by Van Wyk and Grumbach in 1960. To create increased awareness and a better understanding of this clinical entity among emergency room physicians, pediatricians, surgeons, gynecologists and oncologists. Case records of children diagnosed with Van Wyk-Grumbach syndrome (VWGS) were analyzed retrospectively. Twenty-six girls and 4 boys were identified (2005-2020). All had profound primary hypothyroidism (total thyroxine [T4]: 2.5-33.5 nmol/L, thyrotropin: > 75-3744μIU/mL). Hypothyroidism was not the referral diagnosis in any of the girls. Among them, 17 were referred for precocious puberty, 5 with a diagnosis of pituitary tumor on magnetic resonance imaging, and others for acute surgical abdomen in 7 girls (painful abdominal mass-2, ovarian tumor-2, ovarian torsion-2, ruptured ovarian cyst-1), acute myelopathy in 1, and menorrhagia with headache in another. All girls were successfully managed with levothyroxine replacement alone, except for the 2 with ovarian torsion, who required surgery. Menstruation ceased promptly with T4 therapy in all girls, occurring at an age-appropriate later date. All boys had testicular enlargement at presentation that regressed partially after T4treatment. Catch-up growth was remarkable during the first treatment year, but the final height was compromised in all. Increased awareness of varied presentations of VWGS is vital among pediatricians to facilitate early diagnosis and targeted investigations, and to help in the initiation of the simple yet highly rewarding T4 replacement therapy to avoid all possible complications.

Thyroxine Replacement Therapy during Ramadan Fasting: Physicians' and Patients' Perceptions and Practices

Abstract Objective Thyroxine (T4) therapy is taken on an empty stomach and no food is taken for a short period. During Ramadan fasting (RF), Muslim patients may face difficulties taking levothyroxine as recommended. Materials and Methods We performed a mixed methods study of an online survey of 218 physicians to explore their perceptions and practices. Also, we interviewed a sample of 172 hypothyroid patients to establish their practices and source of information. Their median age was 46 (17–90) years; they had hypothyroidism for a median of 5 years and took a median thyroxine dose of 100 µg daily. Furthermore, we attempted to explore the effects of RF on available thyroid function tests. Results Consultants were 58.4%, and the most represented specialty was endocrinology, 46.1%. Regarding the impact of RF on T4 therapy, 52.3% thought the RF was not clinically relevant in most patients on T4 replacement. However, 27.5% thought RF affects T4 replacement therapy in a clinically relevant manner. About 77.1% of respondents reported giving advice routinely to all patients on T4 replacement during RF. One hundred sixty-four respondents were split between recommending taking the medications with Iftar, Suhour, or other times. Most respondents (73.9%) do not repeat measurements of thyroid hormone levels after Ramadan unless needed during their scheduled clinic visit. On the other hand, 50.3% of the patients confirmed that their physician advised them to take their thyroxine during Ramadan, whereas 40.4% could not recall receiving any advice. About 59.9% of the patients took thyroxine with Iftar, 23.8% with Suhour, and 16.3% at different times. In those patients where thyroid function tests were available before and after RF, serum thyroid-stimulating hormone and serum-free T4 did not show a specific pattern in the group as a whole and with subgroups. Conclusion There is variation in the advice that hypothyroid patients receive on taking thyroxine during Ramadan and in their practices. Further studies are needed to determine the best timing for thyroxine replacement.

Hypothyroidism Prevalence in the United States: A Retrospective Study Combining National Health and Nutrition Examination Survey and Claims Data, 2009-2019.

Previous estimates determined prevalence of hypothyroidism (HT) to be 4.6% of the US population. This study aimed to update estimates of HT prevalence in the United States by retrospective analysis of 2 datasets. Data on HT type (overt or subclinical HT) and treatment were collected from the 2009-2010 and 2011-2012 National Health and Nutrition Examination Survey (NHANES) cycles. From the Optum administrative claims database, medical and pharmacy claims were collected between January 1, 2012, and December 31, 2019. Patients were defined as having HT if, per given year, they had >1 prescription for HT treatment, >1 claim indicating an HT diagnosis, or thyroid-stimulating hormone levels >4.0 mIU/L (NHANES arm). For both studies, treatment was defined as any evidence of synthetic or natural thyroid hormone replacement, identified by pharmacy claims or patient surveys. Data are reported as percentage of patients with HT and treatments received. Between 2009 and 2012, HT prevalence remained around 9.6% of the US population. The administrative claims dataset showed that HT prevalence grew from 9.5% in 2012 to 11.7% in 2019 and that >78% of patients received thyroxine (T4) monotherapy. Similarly, the NHANES dataset showed that T4 replacement therapy was the most common treatment for HT. From 2012-2019, patients with untreated HT grew from 11.8% to 14.4%. The prevalence of HT in the United States has steadily increased since 2009. Likewise, the percentage of hypothyroid-diagnosed patients not receiving treatment also increased, suggesting that the increased prevalence may be due to increased cases of subclinical HT.

Optimized Replacement T4 and T4+T3 Dosing in Male and Female Hypothyroid Patients With Different BMIs Using a Personalized Mechanistic Model of Thyroid Hormone Regulation Dynamics.

ObjectiveA personalized simulation tool, p-THYROSIM, was developed (1) to better optimize replacement LT4 and LT4+LT3 dosing for hypothyroid patients, based on individual hormone levels, BMIs, and gender; and (2) to better understand how gender and BMI impact thyroid dynamical regulation over time in these patients.Methodsp-THYROSIM was developed by (1) modifying and refining THYROSIM, an established physiologically based mechanistic model of the system regulating serum T3, T4, and TSH level dynamics; (2) incorporating sex and BMI of individual patients into the model; and (3) quantifying it with 3 experimental datasets and validating it with a fourth containing data from distinct male and female patients across a wide range of BMIs. For validation, we compared our optimized predictions with previously published results on optimized LT4 monotherapies. We also optimized combination T3+T4 dosing and computed unmeasured residual thyroid function (RTF) across a wide range of BMIs from male and female patient data.ResultsCompared with 3 other dosing methods, the accuracy of p-THYROSIM optimized dosages for LT4 monotherapy was better overall (53% vs. 44%, 43%, and 38%) and for extreme BMI patients (63% vs. ~51% low BMI, 48% vs. ~36% and 22% for high BMI). Optimal dosing for combination LT4+LT3 therapy and unmeasured RTFs was predictively computed with p-THYROSIM for male and female patients in low, normal, and high BMI ranges, yielding daily T3 doses of 5 to 7.5 μg of LT3 combined with 62.5–100 μg of LT4 for women or 75–125 μg of LT4 for men. Also, graphs of steady-state serum T3, T4, and TSH concentrations vs. RTF (range 0%–50%) for untreated patients showed that neither BMI nor gender had any effect on RTF predictions for our patient cohort data. Notably, the graphs provide a means for estimating unmeasurable RTFs for individual patients from their hormone measurements before treatment.Conclusionsp-THYROSIM can provide accurate monotherapies for male and female hypothyroid patients, personalized with their BMIs. Where combination therapy is warranted, our results predict that not much LT3 is needed in addition to LT4 to restore euthyroid levels, suggesting opportunities for further research exploring combination therapy with lower T3 doses and slow-releasing T3 formulations.

Strategies for improved management of hypothyroidism.

Management is clear-cut-yet many patients don't reach treatment goals. To optimize quality of life, master the fine points of T4 replacement and address the impact of comorbidities.

Myxoedema coma caused by immunotherapy-related thyroiditis and enteritis.

SummaryThyroid dysfunction is among the most common immune-related adverse reactions associated with immune checkpoint inhibitors. It most commonly manifests as painless thyroiditis followed by permanent hypothyroidism. This usually causes mild toxicity that does not interfere with oncological treatment. In rare instances, however, a life-threatening form of decompensated hypothyroidism called myxoedema coma may develop. We present a case of myxoedema coma in a woman in her sixties who was treated with a combination of CTLA-4 and PD-1 immune checkpoint inhibitors; for stage four malignant melanoma. She became hypothyroid and required thyroxine replacement after an episode of painless thyroiditis. Six months after the initial diagnosis of malignant melanoma, she presented to the emergency department with abdominal pain, profuse diarrhoea, lethargy and confusion. She was drowsy, hypotensive with a BP of 60/40 mmHg, hyponatraemic and hypoglycaemic. Thyroid function tests (TFTs) indicated profound hypothyroidism with a TSH of 19 mIU/L, and undetectable fT3 and fT4, despite the patient being compliant with thyroxine. She was diagnosed with a myxoedema coma caused by immune-related enteritis and subsequent thyroxine malabsorption. The patient was treated with i.v. triiodothyronine (T3) and methylprednisolone in the ICU. While her clinical status improved with T3 replacement, her enteritis was refractory to steroid therapy. A thyroxine absorption test confirmed persistent malabsorption. Attempts to revert to oral thyroxine were unsuccessful. Unfortunately, the patient’s malignant melanoma progressed significantly and she passed away four months later. This is the first reported case of myxoedema coma that resulted from two distinct immune-related adverse reactions, namely painless thyroiditis and enterocolitis.Learning pointsMyxoedema coma, a severe form of decompensated hypothyroidism is a rare immunotherapy-related endocrinopathy.Myxedema coma should be treated with either i.v. triiodothyronine (T3) or i.v. thyroxine (T4).Intravenous glucocorticoids should be co-administered with thyroid hormone replacement to avoid precipitating an adrenal crisis.Thyroid function tests (TFTs) should be monitored closely in individuals with hypothyroidism and diarrhoea due to the risk of thyroxine malabsorption.A thyroxine absorption test can be used to confirm thyroxine malabsorption in individuals with persistent hypothyroidism.

Effect of Thyromimetic GC-1 Selective Signaling on Reproductive and Lactational Performance in the Hypothyroid Rat

Introduction: The potential of the thyroid hormone receptor β (TRβ1) selective analog GC-1 has been widely proven in animal models and humans. However, its effect on the reproductive stage of the female rat has not been evaluated. Methods: The effect of the administration of GC-1 or equimolar doses of triiodothyronine (T3) was evaluated on the reproductive performance of the hypothyroid female rat and the indirect effect on pup thyroid status, weight, and survival. Results: Hypothyroidism reduced the number of embryos implanted in the uterus, whereas T3 and GC-1 treatment in hypothyroid females reestablished the number of implanted embryos to normal. Initiation of labor was delayed by hypothyroidism, and T3 replacement treatment reinstated the normal timing of parturition. The administration of GC-1 alone to the lactating mother did not affect pup survival, weight, or thyroidal status. Conclusions: Our findings show the differential effect of thyroid hormone selective signaling during gestation and the indirect exposure of the pups; we also emphasize the plausible use of GC-1 for treatment of hypothyroid mothers during the lactation period.

COVID-19 Induced Myxedema Madness

Background: Corona Virus Disease 2019 (COVID-19) pandemic was first reported in December 31st, 2019 in Wuhan, China. The clinical presentation is variable, including a variety of neuropsychiatric related symptoms. Myxedema Madness is a rare and severe neuropsychiatric complication of hypothyroidism manifested as psychosis. Case Presentation: A 25-year-old female with past medical history significant for treated Papillary Thyroid Cancer, presented with near syncopal event associated with weakness, lower extremity swelling, constipation, cold intolerance and dry skin. The patient was not compliant with her thyroid replacement therapy. Upon collateral history taken from the patient’s mother; the patient became dysphoric and tearful. On examination, patient had slightly decreased blood pressure and non-pitting edema on lower extremities. On neurological evaluation she exhibited forgetfulness and retardation of speech and motoric activity. Lab was remarkable for TSH greater than 100 uU/mL (reference range 0.30-4.20 uU/mL), FT4 0.4 ng/dL (reference range 0.6-1.5 ng/dL), and FT3 0.7 pg/mL (reference range 2.3-4.2 pg/mL). Patient tested negative for COVID-19 PCR. She was started on her home dose of Levothyroxine 150 mcg daily. Patient was discharged home after she was assessed by a psychiatrist, with no further interventions. Three days later, the patient was readmitted for confusion, disorientation and memory loss. Patient was found to be positive for COVID-19 PCR and negative for SARS-CoV-2 antibodies. She was found to be disoriented with paranoid delusions. Laboratory studies showed negative urine drug screen, syphilis and NMDA antibodies. CSF analysis were within normal ranges. Brain Magnetic resonance imaging was only positive for pituitary hyperplasia. Patient was started on T4 and T3 replacement therapy (Levothyroxine 50 mcq Intravenous, Liothyronine 5 mcg daily orally, respectively) followed by Risperdal 1 mg nightly. Aftersignificant improvement in her mood and delusions, patient was discharged home on Levothyroxine 150 mg daily and Risperdal 1mg for two weeks. Patient and family members were counseled on medications compliance. In a two-week follow-up visit, patient reported to be compliant with medications and improvement of mood. She denied hallucination or delusions. Her lab work was significant for TSH 5.57 uU/mL, FT4 1.3 ng/dL and FT3 3.2 pg/mL. Conclusion: Both psychosis secondary to COVID-19 and Myxedema Madness are rare conditions. Appropriate and timely supplementation of thyroid hormone facilitated speedy return of patient’s cognitive and psychiatric functions to appropriate baseline. This case report may increase physician’s awareness for potentially increased susceptibility of patients with severe hypothyroidism to neuropsychiatric manifestations of COVID-19.

Evaluation of the Optimal Thyroxine Levels for Thyroxine Hormone Replacement in Patients With Central Hypothyroidism

Introduction: Central hypothyroidism results from pituitary or hypothalamic dysfunction. The evaluation of the adequacy of thyroxine replacement is difficult, due to the loss of thyrotropin (TSH) as an accurate feedback marker. This study aim to explore the potential metabolic and clinical effects of different free T4 (fT4) replacement targets in patients with central hypothyroidism. Method: This was a single center, prospective open-label crossover-like trial of 51 patients (mean age 56±12.9 years, 27 male) with hypopituitarism with multiple hormonal deficiencies including central hypothyroidism after excluding those with primary thyroid diseases, high risk for cardiovascular diseases (CVD) and known CVD. Dosage of levothyroxine (L-T4) was titrated to a targeted lower, middle and upper fT4 tertile and maintained for 24 weeks before assessment. Anthropometric and physiological measurements, metabolic and peripheral tissue markers, cognitive and quality of life assessments (SF-36 and Hong Kong Montreal Cognitive Assessment-5 [HK-MoCA-5]) were compared before and after each fT4 tertile change. This was followed by another 24-week cycle of L-T4 dosage adjustment to achieve fT4 in another tertile, with the same assessment as above. Results: We demonstrated that raising fT4 target from lower to upper tertile within the normal reference range resulted in significant decrease in body mass index (27.1±6.0 vs 25.7±5.6 kg/m2, P<0.01), waist circumference (89.5±12.7 vs 86.4±12.1 cm, p<0.01), diastolic blood pressure (79.1±12.9 vs 74.5±12.9 mmHg, p<0.05) and low density lipoprotein cholesterol (3.94±0.88 vs 2.90±0.71 mmol/L, p<0.01), apart from expected significant effect on tissue markers such as increased sex-hormone binding globulin (SHBG), increased ferritin and reduced creatinine kinase (CPK). The occurrence of metabolic syndrome (48.2% vs 29.0%, p <0.05) was significantly reduced with increasing fT4 from middle to upper tertile, without significant effect on glycemic indexes, heart rate, SF-36 and HK-MoCA-5. Conclusion: In this study, we demonstrated that raising fT4 target to the upper tertile of normal resulted in a favourable improvement in various metabolic indexes without a significant increase in adverse effects over a period of 48 weeks.

Clinical, diagnostic, and follow-up characteristics of children with ectopic thyroid: An 11-year tertiary referral center experience

Background: Information on the clinical data and follow-up of ectopic thyroid (ET) in pediatric population in India is scanty; hence, this study aims to add more information on this entity. Objective: This study was undertaken to analyze the clinical, biochemical characteristics, and scintigraphy findings at diagnosis and follow-up response to thyroxine (T4) replacement in children with ET. Methods: This study was conducted at the Paediatric Endocrinology Department of Tertiary Center from January 2005 to March 2016. In children with abnormal thyroid function, scintigraphy was done before T4 replacement to establish the diagnosis of permanent congenital hypothyroidism. Thyroid dose modification, growth monitoring was done on follow-up. In infants and children without an etiological diagnosis, at ?3 years of age, thyroid function test, scintigraphy was done after stopping treatment for 4 weeks. The initial clinical, biochemical parameters, follow-up data were analyzed. Results: Among 54 children with ET, 39 (72.2%) were girls. The mean age of presentation was 3.3 years and the average age at diagnosis on the basis of presentation with isolated short stature was 7.3 years. Developmental delay was the predominant symptom (24.9%) in children between age 1 month and 5 years. Among them, 78.5% had initial thyroid-stimulating hormone (TSH) &gt;60 mIU/ml. During the first follow-up visit, high TSH &gt;10 mIU/ml and &gt;60 mIU/ml with normal levels of T4 were found in 29.6% and 7.4%, respectively, who were treatment compliant. TSH levels regressed gradually in the subsequent visits without any increase in T4 dose. Neck masses and externally visible lingual thyroids regressed with oral T4 without any surgical intervention. Conclusions: The assessment of adequacy of T4 replacement at follow-up needs both TSH and T4 levels. The prompt identification, early, and adequate treatment of children with ET can prevent possible surgical intervention.

Effect of hypothyrodism’s medication (T4) on implant osstointegration: A case series and literature search

IntroductionHypothyroidism reduces the recruitment, maturation, and activity of bone cells, decreasing bone resorption and formation. Several investigations have reported that T4 replacement therapy is associated with a significant decrease in bone mineral density in various skeletal parts, while others have failed to corroborate these results. The present study describes both a literature review and our own experience with dental implants in patients with hypothyroidism undergoing T4 replacement therapy. Case presentationThe study included two parts: a literature review and case series. The literature review included 12 articles documenting the success rate of osseointegrated dental implants in patients with hypothyroidism. The clinical cases were chosen from King Saud University Dental College, Riyadh. The patients’ identity was only available to the main researcher. The inclusion criteria for the clinical cases were: T4-treated hypothyroidism, age 20–60 years, and use of dental implants with a follow-up period of 6–12 months after loading. The exclusion criteria were: any other medical condition alongside hypothyroidism, syndromic hypothyroidism, pregnancy, current smoking, bruxism, and hypothyroidism caused by surgical excision combined with radiotherapy. The following parameters were assessed: insertion torque (IT), crestal bone height (CBH), mesial bone width (MBW), and distal bone width (DBW) at different time points, probing depth, and signs of infection. DiscussionSeventeen dental implants placed in patients with T4-treated hypothyroidism showed median IT success (42.4 N⋅cm; range: 35–45 N⋅cm). The median crestal bone loss was measured at 6–12 months after loading was 0.6 mm (range: 0.5–0.7. mm). Conversely, the median bone loss differences in MBW and DBW at 6–12 months after loading were 0.3 mm and 0.2 mm, respectively. ConclusionAfter a 1-year follow-up, patients with T4-treated hypothyroidism who had received dental implants fulfilled the criteria for successful implants.

Effect of thyroxine on the expression of HIF-1α after aneurysmal subarachnoid hemorrhage in rat brain and its mechanism

Objective: To investigate the effect of thyroxine (T4) on the expression of hypoxia inducible factor-1α (HIF-1α) in rat brain after aneurysmal subarachnoid hemorrhage (SAH) and its mechanism. Methods: Seventy-two adult male SD rats were randomly divided into the following 4 groups: subarachnoid hemorrhage model group(SAH), subarachnoid hemorrhage model and T4 group (SAH with T4), subarachnoid hemorrhage model with normal saline group (SAH with vehicle), and sham-operation group, 18 rats in each group. The model of subarachnoid hemorrhage group was established by internal carotid artery puncture. CT plain scan was performed after the modeling immediately, T4 was administrated by intraabdominal injection of 3 μg/100 g every 24 hours for 3 days. SAH with T4 group was treated with thyroxine. SAH with vehicle group was treated with equal volume vehicle, all of them were killed 72 hours after modeling. The brain water content was determined to evaluate the brain edema, the apoptosis of cerebral cortex cells was detected by TUNEL method, and HIF-1α protein and p-Akt protein in cerebral cortex were detected by immunohistochemistry in six SD rats of each group. Results: After the modeling, the brain tissues of SAH group, SAH + T4 group and SAH +vehicle group were swollen obviously, and blood clots were observed in subarachnoid space. The neurobehavioral score,the brain water content, apoptosis index, HIF-1α protein and p-Akt protein in SAH group were significantly higher than those in sham-operation group(P＜0.05).The neurobehavioral score,HIF-1α protein and p-Akt protein in SAH with T4 group were significantly higher than those in SAH group, and the brain water content, apoptosis index were significantly lower than those in SAH group (P＜0.05). Conclusion: The expression of HIF-1α protein in the brain of rats after aneurysm subarachnoid hemorrhage can be upregulated by T4 replacement therapy, which may by activating the signal pathway of inositol triphosphate kinase / protein kinase B (PI3K/Akt). Finally, apoptosis index was decreased, the rat behavior was improved and the brain was protected.

Dietary supplementation of wheatgrass powder to assess somatic response of juvenile grass carp (Ctenopharyngodon idella)

Consequence of dietary fish meal substitution with wheatgrass was evaluated by observing growth response, associated feed cost and survival of grass carp (Ctenopharyngodonidella) fingerlings for sixty days. Sprouted wheatgrass (Triticumaestivum) was prepared for its inexpensively rich nutrients. Four isonitrogenous test diets were formulated and applied as treatments (T) in triplicates (R). In the control (T1), basal inclusion rate of fish meal was 30%, of which 10% was replaced with wheatgrass powder in T2 and in T3 replacement was 20%. In contrast, 30% of basal fishmeal was replaced in T4. Grass carp fingerlings (6.38±0.21 cm and 2.83±0.36 g) were stocked in twelve aquaria (60×40×45 cm³) each containing 75 L water, at 10 fish per aquarium, fed test diets at 5% of body weight twice daily. Prominent effect of wheatgrass supplementation was found on food conversion ratio (FCR) and survival rates. The significantly lowest FCR was observed in T3 (2.13±0.42) followed by T2 (2.89±0.99), T1 (3.01±1.53) and T4 (3.05±0.94). Besides, fish survival rate was significantly improved in T2 (90%), T3 (93.33%) and T4 (93.33%) compared to the lowest survival in T1 (83.33%). In conformity, fish tolerance (LT50) to low pH stressor was also increased with wheatgrass supplementation. The other growth parameters among the treatments were statistically similar with highest specific growth rate and fish production in T3 (1.13±0.12 %/day and 2.28±0.13 tons/ha). Dietary wheatgrass did not affect the fish carcass composition rather gave better result to some extents. The significantly highest carcass protein and lowest moisture was retained in T3 (14.13±0.05% and 74.91±0.25% respectively), whereas comparatively higher lipid and mineral (ash) content was found in T1 (7.69±0.02% and 2.35±0.27% respectively). Importantly, feed formulation cost was reduced by 2.61, 4.89, and 7.71% in T2, T3, and T4 respectively compared to T1. Therefore, wheatgrass could be promising in juvenile grass carp diet.&#x0D; Asian J. Med. Biol. Res. September 2020, 6(3): 482-490

Thyroxine replacement modifies changes in deiodinase and thyroid hormone transporter expression induced by subclinical hypothyroidism in rats.

The potential benefits of treating subclinical hypothyroidism (SCH) are unclear and still controversial. Thus, we surgically induced SCH in rats and evaluated the effects of thyroxine (T4) replacement on the gene expression levels of deiodinases and thyroid hormone (TH) transporters in different tissues. SCH was induced by hemithyroid electrocauterization. The control animals underwent the same surgical procedure but were not subjected to electrocauterization (sham). After 14days, half of the SCH animals were treated with T4 (SCH + T4). At the end of the experimental protocol, all of the rats were euthanized, serum hormone concentrations were measured, and RNA analyses were performed on different tissues and organs. Consistent with previous studies, we observed increased TSH levels, normal TH levels, and reduced hypothalamic TRH expression in the SCH group. Additionally, Dio2 mRNA expression was downregulated in the hippocampus and pituitary, and Dio1 was upregulated in the kidney and pituitary of the SCH animals. The changes in Dio3 expression were tissue-specific. Concerning TH transporters, Mct10 expression was upregulated in the pituitary, kidney, hypothalamus, and hippocampus, and Mct8 expression was downregulated in the kidney of the SCH group. Crym expression was upregulated in the kidney and pituitary. Notably, T4 replacement significantly attenuated serum TSH levels and reverted Dio1, Dio2, Mct10, and Crym expression in the pituitary, hippocampus, and kidney to levels that were similar to the sham group. Tissue-specific responses were also observed in the liver and hypothalamus. Our results indicate that treatment of SCH should be considered before the appearance of clinical symptoms of hypothyroidism.

T3 Critically Affects the Mhrt/Brg1 Axis to Regulate the Cardiac MHC Switch: Role of an Epigenetic Cross-Talk.

The LncRNA my-heart (Mhrt) and the chromatin remodeler Brg1 inhibit each other to respectively prevent or favor the maladaptive α-myosin-heavy-chain (Myh6) to β-myosin-heavy-chain (Myh7) switch, so their balance crucially guides the outcome of cardiac remodeling under stress conditions. Even though triiodothyronine (T3) has long been recognized as a critical regulator of the cardiac Myh isoform composition, its role as a modulator of the Mhrt/Brg1 axis is still unexplored. Here the effect of T3 on the Mhrt/Brg1 regulatory circuit has been analyzed in relation with chromatin remodeling and previously identified T3-dependent miRNAs. The expression levels of Mhrt, Brg1 and Myh6/Myh7 have been assessed in rat models of hyperthyroidism or acute myocardial ischemia/reperfusion (IR) treated with T3 replacement therapy. To gain mechanistic insights, in silico analyses and site-directed mutagenesis have been adopted in combination with gene reporter assays and loss or gain of function strategies in cultured cardiomyocytes. Our results indicate a pivotal role of Mhrt over-expression in the T3-dependent regulation of Myh switch. Mechanistically, T3 activates the Mhrt promoter at two putative thyroid hormone responsive elements (TRE) located in a crucial region that is necessary for both Mhrt activation and Brg1-dependent Mhrt repression. This newly identified T3 mode of action requires DNA chromatinization and is critically involved in mitigating the repressive function of the Brg1 protein on Mhrt promoter. In addition, T3 is also able to prevent the Brg1 over-expression observed in the post-IR setting through a pathway that might entail the T3-mediated up-regulation of miR-208a. Taken together, our data evidence a novel T3-responsive network of cross-talking epigenetic factors that dictates the cardiac Myh composition and could be of great translational relevance.

Congestive Heart Failure and Thyroid Dysfunction: The Role of the Low T3 Syndrome and Therapeutic Aspects.

Both the morbidity and mortality rates from congestive heart failure (CHF) remain elevated despite the medical and non-medical management of the disease, thus suggesting the existence of residual risk factors such as thyroid dysfunction. Particularly, the 15-30% of patients with CHF, especially those with severe ventricular dysfunction, display the so-called low T3 syndrome (LT3S), which seems to negatively affect the cardiovascular prognosis. Only a few clinical trials have been carried out to verify both the safety and the efficacy of thyroid replacement in the LT3S, aiming to ameliorate the prognosis of CHF, and most of the results were controversial. Since the aim of the present review was to briefly overview both the indication and contraindication of triiodothyronine replacement in CHF and LT3S, the authors searched PubMed using the medical subject headings (MeSH) related to the following terms: "congestive heart failure" and "low T3 syndrome" or "euthyroid sick syndrome" or "non-thyroidal sick syndrome". The research study only focused on the narrative and systematic reviews, randomized clinical trials and meta-analysis studies which were conducted before June 2019. Studies conducted in both animal models and humans provided controversial information about the effectiveness and safety of the T3 replacement for improving ventricular dysfunction, particularly in the long-term. Further clinical trials are needed to better explore the role of LT3S in patients with CHF and its consequent therapeutic strategy in this clinical setting.

SAT-458 A Case of Cardiac Arrest Due to Hashimoto’s Thyroiditis Associated Cardiac Tamponade

Introduction: Myxedema coma is currently an uncommon medical emergency. We present a case of undiagnosed Hashimoto’s thyroiditis with myxedema coma and cardiac tamponade leading to cardiac arrest. Case Presentation: A 35 year-old man with no significant past medical history was brought to the emergency department after being found unresponsive. The patient was hypoglycemic (17 mg/dL), hypothermic (34°C), tachypneic (26/min), hypotensive (84/50 mmHg), and hypoxemic (90% on ambient air). Physical exam showed mild anasarca, jugular vein distention, clear lung sounds, and muffled heart sounds. Laboratory findings showed TSH 168.16 uIU/mL (0.45–5.33 uIU/mL), fT4 <0.25 ng/dL (0.58–1.64 ng/dL), fT3 1.33 pg/mL (2.5–3.9 pg/mL), cortisol 5.7 mcg/dL (3–16 mcg/dL). Chest x-ray demonstrated markedly enlarged, globular heart. ECG revealed sinus rhythm and low voltage of QRS complexes. Echocardiogram was significant for a very large pericardial effusion. Resuscitation was started with intravenous thyroxine and hydrocortisone, during which the patient was found to be in a cardiac arrest with pulseless electrical activity. CPR per ACLS protocol was initiated with return of spontaneous circulation. Clear fluid (2000 ml) was evacuated from the pericardial space. He was diagnosed with Hashimoto thyroiditis (thyroid peroxidase antibody level 355 IU/mL, normal <9 IU/mL). He recovered without neurological deficits and was discharged home with thyroid replacement therapy (levothyroxine 100 mcg). Discussion: Myxedema coma occurs as a complication of undiagnosed/untreated thyroid disease. It may be precipitated by an event such as infection, drug overdose, or myocardial infarction. The mainstay of treatment is T4 replacement along with supportive therapy, and glucocorticoids to counter possible underlying adrenal insufficiency. Massive pericardial effusion due to hypothyroidism, especially resulting in cardiac tamponade, is extremely rare. The incidence of pericardial effusion in patients with hypothyroidism has significantly decreased from 30–80% to 3–6%, due to early recognition of this common disorder. Our case highlights the importance of prompt recognition of hypothyroidism as a cause of cardiac tamponade, thus allowing rapid life-saving treatment. In patient populations with limited access to health care, it should be remembered that very late and potentially fatal complications of otherwise easily treatable conditions can occur. Awareness of this may help limit morbidity and mortality.