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.

Objective: A 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. Methods: p-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. Results: Compared 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. Conclusions: p-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.

Orally Induced Hyperthyroidism Regulates Hypothalamic AMP-Activated Protein Kinase.

Besides their direct effects on peripheral metabolic tissues, thyroid hormones (TH) act on the hypothalamus to modulate energy homeostasis. However, since most of the hypothalamic actions of TH have been addressed in studies with direct central administration, the estimation of the relative contribution of the central vs. peripheral effects in physiologic conditions of peripheral release (or administration) of TH remains unclear. In this study we used two different models of peripherally induced hyperthyroidism (i.e., T4 and T3 oral administration) to assess and compare the serum and hypothalamic TH status and relate them to the metabolic effects of the treatment. Peripheral TH treatment affected feeding behavior, overall growth, core body temperature, body composition, brown adipose tissue (BAT) morphology and uncoupling protein 1 (UCP1) levels and metabolic activity, white adipose tissue (WAT) browning and liver metabolism. This resulted in an increased overall uncoupling capacity and a shift of the lipid metabolism from WAT accumulation to BAT fueling. Both peripheral treatment protocols induced significant changes in TH concentrations within the hypothalamus, with T3 eliciting a downregulation of hypothalamic AMP-activated protein kinase (AMPK), supporting the existence of a central action of peripheral TH. Altogether, these data suggest that peripherally administered TH modulate energy balance by various mechanisms; they also provide a unifying vision of the centrally mediated and the direct local metabolic effect of TH in the context of hyperthyroidism.

[De-escalation strategies in differentiated thyroid cancer]. / Les stratégies de désescalade pour les cancers différenciés de la thyroïde.

Thyroid cancer runs the gamut from indolent micropapillary carcinoma to highly aggressive metastatic disease. Today, using prognostic algorithms, treatment and follow-up can be tailored to each patient in order to decrease overtreatment and over-medicalization of indolent disease. Active surveillance of papillary thyroid carcinoma less than 1cm avoids surgery and thyroid hormone replacement in a large proportion of patient whose tumors remain stable for years. Total thyroidectomy, once a dogma in the treatment of all thyroid cancer, is being supplanted by thyroid lobectomy for low-risk cancers, thereby decreasing the surgical risks involved and improving patients' quality of life. Indications for prophylactic central neck dissection, once mandatory, are now being adapted to the risk of cancer recurrence. Radioactive iodine therapy, also previously mandatory for all, is now only employed according to risk factors and expected outcomes. Follow-up is also being tailored to risk factors for recurrence, with less frequent visits and less use of ultrasound and scintigraphy. For more advanced disease, molecular therapies tailored to somatic mutations are opening opportunities for redifferentiation of aggressive tumors which become amenable to radioactive iodine therapy which carries fewer side effects than other systemic therapies. These advances in the management of thyroid cancer with a personalized approach and de-escalation of treatment and follow-up are improving the way we treat thyroid cancer, avoiding overtreatment and improving patients' quality of life.

Use of thyroid hormones in hypothyroid and euthyroid patients: A 2020 THESIS questionnaire survey of members of the Danish Endocrine Society.

PURPOSE: The standard treatment of hypothyroidism is levothyroxine (LT4), which is available as tablets or soft-gel capsules in Denmark. This study aimed to investigate Danish endocrinologists' use of thyroid hormones in hypothyroid and euthyroid patients. METHODS: An e-mail with an invitation to participate in an online survey investigating practices about substitution with thyroid hormones was sent to all members of the Danish Endocrine Society (DES). RESULTS: Out of 488 eligible DES members, a total of 152 (31.2%) respondents were included in the analysis. The majority (94.1%) of responding DES members use LT4 as the treatment of choice. Other treatment options for hypothyroidism are also used, as 58.6% prescribe combination therapy with liothyronine (LT3) + LT4 in their clinical practice. LT4 + LT3 combination is preferred in patients with persistent symptoms of hypothyroidism despite biochemical euthyroidism on LT4 treatment. Over half of the respondents answered that thyroid hormone therapy is never indicated for euthyroid patients, but 42.1% will consider it for euthyroid infertile women with high antibody levels. In various conditions that could interfere with the absorption of LT4, most responding Danish endocrinologists prefer tablets and do not expect a significant difference when switching from one type of tablet formulation to another. CONCLUSION: The treatment of choice for hypothyroidism is LT4. Combination therapy with LT4 + LT3 is considered for patients with persistent symptoms. Even in the presence of conditions affecting bioavailability, responding Danish endocrinologists prefer LT4 tablets rather than newer LT4 formulations, such as soft-gel capsules.

Thyroid hormones modulate irisin concentrations in patients with recently onset hypothyroidism following total thyroidectomy.

PURPOSE: Irisin is a newly discovered adipo-myokine known for having significant effects on body metabolism. Currently, there is a discussion regarding the relation between thyroid function and irisin concentration. This study was designed to evaluate the influential role of levothyroxine replacement therapy on circulating levels of irisin in patients with recently onset hypothyroidism following total thyroidectomy. METHODS: Circulating levels of thyroid hormones, irisin and other metabolic parameters, were assessed in 40 recently thyroidectomized patients (34 females, mean age 50.1 ± 15.2 years) at baseline (5-7 day after surgery) and after 2 months under replacement therapy with levothyroxine. RESULTS: At baseline, circulating levels of thyroid hormones were indicative of hypothyroidism (TSH 12.7 ± 5.0 µU/mL, FT3 1.9 ± 0.7 pg/mL, FT4 8.7 ± 3.6 pg/mL). Mean serum irisin concentrations significantly increased after 2 months under replacement therapy with levothyroxine (from 2.2 ± 0.6 to 2.9 ± 0.6 µg/mL, p < 0.0001). Variations of circulating levels of irisin under levothyroxine replacement therapy were directly correlated with those of FT3 (Rho = 0.454, p = 0.0033) and FT4 (Rho = 0.451, p = 0.0035). Multivariate regression analysis revealed that changes in thyroid hormones concentrations explained up to 10% of the variations of serum irisin levels under levothyroxine replacement therapy (FT3 R2 = 0.098, FT4 R2 = 0.103). CONCLUSION: Our study suggests that levothyroxine replacement therapy mildly influences irisin metabolism in patients with recently onset hypothyroidism following total thyroidectomy.

Postoperative thyroid hormone supplementation rates following thyroid lobectomy.

BACKGROUND: Thyroid lobectomy is performed for symptomatic benign nodules, indeterminate nodules, or low-risk well differentiated thyroid cancer. We aimed to determine factors associated with thyroid stimulating hormone over goal (TH) following lobectomy. METHODS: We performed a retrospective single-institution cohort study of patients undergoing thyroid lobectomy from January 2016 to December 2017. TH was defined as need for thyroid hormone in accordance with guidelines. Univariate and multivariate logistic regression analysis was performed. RESULTS: One hundred patients were included and 47% developed. TH: 73% of those with cancer, 38% with benign pathology (p = 0.002). Patients with TH were more likely to have thyroiditis 26% versus 3.8% (p = 0.002); higher preoperative TSH: mean 1.88mIU/L (SD 1.17) versus 1.16mIU/L (SD 0.77) (p = 0.0002), and smaller remnant thyroid lobe adjusted for body surface area 2.99ml/m2 versus 3.72ml/m2 (p = 0.003). CONCLUSIONS: After thyroid lobectomy, TH is associated with preoperative TSH level, thyroiditis, remnant thyroid volume, and malignancy. The majority of patients with final pathology of carcinoma will require thyroid hormone supplementation to achieve TSH goal.

Impact of pharmacist-managed immune checkpoint inhibitor toxicities.

BACKGROUND: Immune checkpoint inhibitors are associated with unique autoimmune side effects that differ from traditional cytotoxic chemotherapy. Pharmacists may play an important role in providing key supportive care measures necessary to aid patients and oncologists through immune-related adverse events (irAEs). This study aims to evaluate the impact of a pharmacist-managed irAE protocol in an oncology clinic. METHODS: This study is a retrospective chart review of the implementation of a pilot irAE pharmacy protocol. Patients treated with an immune checkpoint inhibitor and subsequently identified to have dermatologic, gastrointestinal, hepatic, or thyroid toxicities and managed under the pilot irAE pharmacy protocol from 1 October 2018 to 28 February 2019 were enrolled. Study endpoints included number of pharmacist interventions and physician satisfaction. Additional endpoints included pharmacotherapy initiated, dose adjustments, and patient follow-ups. RESULTS: From 1 October 2018, to 28 February 2019, 17 patients were referred and approved by their primary oncologists for pharmacy management under the pilot irAE protocol. During the pilot period, pharmacists initiated 21 new medications for the treatment of irAEs, including thyroid hormone replacement in 7 patients (41%) and oral corticosteroids in 6 patients (35%) with a total of 28 dose adjustments. In addition, the pilot protocol included an assessment of physician satisfaction, which showed a reduced number of physician hours per month managing irAEs, increased physician confidence in irAE management, and a desire for continued pharmacist-management of irAEs. CONCLUSIONS: Oncology pharmacists had an impact on management of toxicities in our oncology clinic as indicated by the pharmacist interventions and physician satisfaction.

Current surgical treatment of intermediate risk differentiated thyroid cancer: a systematic review.

Introduction: Surgical treatment of thyroid cancer has become less aggressive but for many patients, the threshold for performing total thyroidectomy (TT), as opposed to thyroid lobectomy (TL), has remained unclear. Current American Thyroid Association (ATA) guidelines encourage more individualization of treatment options, which necessitates explicit review of the pros and cons of the different options with patients.Areas covered: This review focuses on the extent of surgery for treatment of intermediate-risk differentiated thyroid cancer, restricted to relevant literature available after publication of the 2015 ATA guidelines.Expert opinion: Dynamic risk-stratification facilitates a tailored approach when deciding on the extent of surgery for thyroid cancer. Treatment with TT allows for a lower recurrence risk, a simpler follow-up regimen, and treatment with adjuvant post-operative radioactive iodine. Treatment with TL has a lower associated risk of complications and avoidance of lifelong thyroid hormone replacement but has a significant risk of requiring a completion thyroid lobectomy (CT). Overall, treatment with TL and TT have comparable survival outcomes, but TL is the more cost-effective option. Larger cancer size is correlated with worse clinical outcomes, and numerous subgroup analyses have shown poorer outcomes for cancers with a diameter that is 2-4 cm compared to 1-2 cm.

No change in the consumption of thyroid hormones after starting low dose naltrexone (LDN): a quasi-experimental before-after study.

BACKGROUND: Low dose naltrexone (LDN) is reported to have beneficial effects in several autoimmune diseases. The purpose of this study was to examine whether starting LDN was followed by changes in the dispensing of thyroid hormones to patients with hypothyroidism. METHODS: We performed a quasi-experimental before-after study based on the Norwegian Prescription Database. Study participants were identified by using reimbursement codes for hypothyroidism. Cumulative dispensed Defined Daily Doses and the number of users of triiodothyronine (T3) and levothyroxine (LT4) 1 year before and after the first LDN prescription was compared in three groups based on LDN exposure. RESULTS: We identified 898 patients that met the inclusion criteria. There was no association between starting LDN and the subsequent dispensing of thyroid hormones. If anything, there was a tendency towards increasing LT4 consumption with increasing LDN exposure. CONCLUSION: The results of this study do not support claims of efficacy of LDN in hypothyroidism.

Thyroid Hormone Supplementation Therapy for Differentiated Thyroid Cancer After Lobectomy: 5 Years of Follow-Up.

Background: Lobectomy with preservation of the contralateral lobe has already become the most preferred surgical method for patients with low-risk thyroid cancer. The incidence of and risk factors for the development of hypothyroidism after lobectomy for thyroid cancer remains unclear. The previous practice of levothyroxine supplementation post-thyroidectomy, to bring about thyroid stimulating hormone (TSH) suppression, had some serious side effects. This study aimed to evaluate the incidence of hypothyroidism and to identify the factors associated with hypothyroidism requiring thyroid hormone replacement. Methods: We retrospectively reviewed the charts of 256 consecutive patients with differentiated thyroid cancer treated with lobectomy at the Gangnam Severance Hospital between April and December 2014 who were followed-up for more than 5 years. Patients were evaluated using a thyroid function test at the time of outpatient visit every 6 months for the 1st year, with an annual follow-up thereafter. Results: After 5 years, 66.0% (169) of the patients needed levothyroxine supplementation to maintain euthyroid status. The incidence of hypothyroidism requiring levothyroxine supplementation increased until 3 years but showed no significant change in the 4 and 5th year. Recurrence showed no difference between the group with and without levothyroxine supplementation. The presence of thyroiditis and preoperative TSH levels were correlated with postoperative levothyroxine supplementation to maintain euthyroid status, in univariate and multivariate analyses. Conclusion: High preoperative TSH levels and/or thyroiditis indicate a significantly increased likelihood of developing hypothyroidism requiring thyroid hormone supplementation after a thyroid lobectomy. Patients with an increased risk of postoperative hypothyroidism must be aware of their risk factors and should undergo more intensive follow-ups.

Intranasal delivery of Thyroid hormones in MCT8 deficiency.

Loss of function mutations in the gene encoding the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to severe neurodevelopmental defects in humans associated with a specific thyroid hormone phenotype manifesting high serum 3,5,3'-triiodothyronine (T3) and low thyroxine (T4) levels. Patients present a paradoxical state of peripheral hyperthyroidism and brain hypothyroidism, this last one most likely arising from impaired thyroid hormone transport across the brain barriers. The administration of thyroid hormones by delivery pathways that bypass the brain barriers, such as the intranasal delivery route, offers the possibility to improve the neurological defects of MCT8-deficient patients. In this study, the thyroid hormones T4 and T3 were administrated intranasally in different mouse models of MCT8 deficiency. We have found that, under the present formulation, intranasal administration of thyroid hormones does not increase the content of thyroid hormones in the brain and further raises the peripheral thyroid hormone levels. Our data suggests intranasal delivery of thyroid hormones is not a suitable therapeutic strategy for MCT8 deficiency, although alternative formulations could be considered in the future to improve the nose-to-brain transport.

Manipulation of Prenatal Thyroid Hormones Does Not Affect Growth or Physiology in Nestling Pied Flycatchers.

Hormones transferred from mothers to their offspring are thought to be a tool for mothers to prepare their progeny for expected environmental conditions, thus increasing fitness. Thyroid hormones (THs) are crucial across vertebrates for embryonic and postnatal development and metabolism. Yet yolk THs have mostly been ignored in the context of hormone-mediated maternal effects. In addition, the few studies on maternal THs have yielded contrasting results that could be attributed to either species or environmental differences. In this study, we experimentally elevated yolk THs (within the natural range) in a wild population of a migratory passerine, the European pied flycatcher (Ficedula hypoleuca), and assessed the effects on hatching success, nestling survival, growth, and oxidative status (lipid peroxidation, antioxidant enzyme activity, and oxidative balance). We also sought to compare our results with those of a closely related species, the collared flycatcher (Ficedula albicolis), that has strong ecological and life-history similarities with our species. We found no effects of yolk THs on any of the responses measured. We could detect only a weak trend on growth: elevated yolk THs tended to increase growth during the second week after hatching. Our results contradict the findings of previous studies, including those of the collared flycatcher. However, differences in fledging success and nestling growth between both species in the same year suggest a context-dependent influence of the treatment. This study should stimulate more research on maternal effects mediated by THs and their potential context-dependent effects.

[Thyroid hormone therapy in old age]. / Therapie mit Schilddrüsenhormonen im Alter.

BACKGROUND: There is evidence that the treatment of overt hyperthyroidism with thyroid hormones is able to reduce mortality as well as cardiovascular and musculoskeletal morbidity. It remains unclear whether these data can be extrapolated to the mildest form of hypothyroidism, subclinical hypothyroidism. Furthermore, it is uncertain whether and to what extent the threshold for therapeutic intervention needs to be modified in the elderly, in whom hypothalamo-pituitary regulation is increasingly insensitive to the negative feedback by thyroid hormones and the patients' response to thyroid hormones changes. OBJECTIVE: The aim of this review is to evaluate the current evidence on the treatment of hypothyroidism in old age with regard to the initiation of therapy and the therapeutic goals. RESULTS AND CONCLUSIONS: According to new original data and meta-analyses, therapy with thyroid hormones does not alter morbidity and mortality in patients with subclinical hypothyroidism with thyroid stimulating hormone (TSH) below the range of 7-10 mU/l. These data support the TSH threshold of 10 mU/l recommended in guidelines, particularly in elderly patients over the age of 65 years, in whom TSH serum levels increase with age. In contrast to the recommendations, the prescription of thyroxine more than doubled in a large study from Denmark and TSH levels decreased from 10 mU/l to under 7 mU/l between 2001 and 2015. As (the primarily unspecific) symptoms and quality of life are not altered by thyroxine replacement in studies on subclinical hypothyroidism and elderly patients are more susceptible to side effects, thyroid hormone substitution should generally not be started at TSH levels <10 mU/l.

Expression profiles of types 2 and 3 iodothyronine deiodinase genes in relation to vitellogenesis in a tropical damselfish, Chrysiptera cyanea.

Thyroid hormone (TH) is involved in regulating the reproduction of vertebrates. Its physiological action in the target tissues is due to the conversion of TH by iodothyronine deiodinases. In this study, we aimed to clone and characterize type 2 (sdDio2) and type 3 (sdDio3) of the sapphire devil Chrysiptera cyanea, a tropical damselfish that undergoes active reproduction under long-day conditions, and to study the involvement of THs in the ovarian development of this species. When the cDNAs of sdDio2 and sdDio3 were partially cloned, they had deduced amino acid sequences of lengths 271 and 267, respectively, both of which were characterized by one selenocysteine residue. Real-time quantitative PCR (qPCR) revealed that both genes are highly expressed in the whole brain, and sdDio2 and sdDio3 are highly transcribed in the liver and ovary, respectively. In situ hybridization analyses showed positive signals of sdDio2 and sdDio3 transcripts in the hypothalamic area of the brain. Little change in mRNA abundance of sdDio2 and sdDio3 in the brain was observed during the vitellogenic phases. It is assumed that simultaneous activation and inactivation of THs occur in this area because oral administration of triiodothyronine (T3), but not of thyroxine (T4), upregulated mRNA abundance of both genes in the brain. The transcript levels of sdDio2 in the liver and sdDio3 in the ovary increased as vitellogenesis progressed, suggesting that, through the metabolism of THs, sdDio2 and sdDio3 play a role in vitellogenin synthesis in the liver and yolk accumulation/E2 synthesis in the ovary. Taken together, these results suggest that iodothyronine deiodinases act as a driver for vitellogenesis in tropical damselfish by conversion of THs in certain peripheral tissues.

Thyroid hormone therapy in differentiated thyroid cancer.

Surgery-with or without postoperative radioiodine-is the standard of care for most patients with differentiated thyroid carcinoma (DTC). Thyroid hormone replacement therapy is the mainstay of long-term medical management. Patients treated with total thyroidectomy and some who undergo lobectomy alone require thyroid hormone therapy to restore euthyroidism with normal serum thyroid-stimulating hormone (TSH) levels. Because TSH acts as a growth factor for thyroid follicular cells (including those that are neoplastic), it can potentially affect the onset and/or progression of follicular-cell derived thyroid cancer. For this reason, some patients are placed on thyroid hormone therapy at doses that suppress secretion of TSH (suppression therapy). This mini-review looks at the potential benefits and risks of this practice in patients diagnosed with DTC. Aggressive TSH-suppressive therapy is of little or no benefit to the vast majority of patients with DTC. Practice guidelines, therefore, recommend a graded algorithm in which the potential benefits of suppression are weighed against the associated cardiovascular and skeletal risks. Large randomized controlled studies are needed to confirm the presumed oncological benefits of TSH-suppression and its causal role in adverse cardiac, skeletal, and quality of life effects and to assess the efficacy of TSH normalization in reversing or reducing these effects.

Myelin repair stimulated by CNS-selective thyroid hormone action.

Oligodendrocyte processes wrap axons to form neuroprotective myelin sheaths, and damage to myelin in disorders, such as multiple sclerosis (MS), leads to neurodegeneration and disability. There are currently no approved treatments for MS that stimulate myelin repair. During development, thyroid hormone (TH) promotes myelination through enhancing oligodendrocyte differentiation; however, TH itself is unsuitable as a remyelination therapy due to adverse systemic effects. This problem is overcome with selective TH agonists, sobetirome and a CNS-selective prodrug of sobetirome called Sob-AM2. We show here that TH and sobetirome stimulated remyelination in standard gliotoxin models of demyelination. We then utilized a genetic mouse model of demyelination and remyelination, in which we employed motor function tests, histology, and MRI to demonstrate that chronic treatment with sobetirome or Sob-AM2 leads to significant improvement in both clinical signs and remyelination. In contrast, chronic treatment with TH in this model inhibited the endogenous myelin repair and exacerbated disease. These results support the clinical investigation of selective CNS-penetrating TH agonists, but not TH, for myelin repair.

Stage-dependent cardiac regeneration in Xenopus is regulated by thyroid hormone availability.

Despite therapeutic advances, heart failure is the major cause of morbidity and mortality worldwide, but why cardiac regenerative capacity is lost in adult humans remains an enigma. Cardiac regenerative capacity widely varies across vertebrates. Zebrafish and newt hearts regenerate throughout life. In mice, this ability is lost in the first postnatal week, a period physiologically similar to thyroid hormone (TH)-regulated metamorphosis in anuran amphibians. We thus assessed heart regeneration in Xenopus laevis before, during, and after TH-dependent metamorphosis. We found that tadpoles display efficient cardiac regeneration, but this capacity is abrogated during the metamorphic larval-to-adult switch. Therefore, we examined the consequence of TH excess and deprivation on the efficiently regenerating tadpole heart. We found that either acute TH treatment or blocking TH production before resection significantly but differentially altered gene expression and kinetics of extracellular matrix components deposition, and negatively impacted myocardial wall closure, both resulting in an impeded regenerative process. However, neither treatment significantly influenced DNA synthesis or mitosis in cardiac tissue after amputation. Overall, our data highlight an unexplored role of TH availability in modulating the cardiac regenerative outcome, and present X. laevis as an alternative model to decipher the developmental switches underlying stage-dependent constraint on cardiac regeneration.

Therapeutic challenges in the application of serum thyroid stimulating hormone testing in the management of patients with hypothyroidism on replacement thyroid hormone therapy: a review.

Normalizing serum thyroid stimulating hormone (TSH) levels by lifelong treatment with levothyroxine (LT4) remains the primary goal of therapy for patients with hypothyroidism. The reference ranges for TSH are derived from populations with (supposedly) normal thyroid function. But, TSH results are affected by a number of factors including alterations in TSH levels with age, concurrent illnesses, circadian rhythm, inter- and intra-assay differences, and some commonly used medications that interfere with thyroid function or the TSH test. Furthermore, some patients are complex to manage and bringing serum TSH to within its reference range does not always resolve their symptoms of hypothyroidism. Furthermore, changes in TSH within the reference range may provoke symptoms in some sensitive patients, and others may have a personal "set point" for thyroid hormone levels that represents normal function for that individual, but which is outside the population reference range. The introduction of updated LT4 formulations, with better dosing accuracy and stability compared with older versions, should, in theory at least, provide better stability and accuracy of dosing over time. However, the new LT4 formulations are associated with manifold increases in the number of self-reported adverse events. Therefore, patients with hypothyroidism as well as the clinicians managing them need to better understand the utility as well as the limitations of the widely used TSH measurement. In addition, both pharmaceutical companies and the prescribing clinician need to take greater care when patients are switched from older to newer formulations.

Case of nasogastric tube dysfunction.

CLINICAL PRESENTATION: An elderly female patient was admitted to intensive care for prolonged vasopressor therapy and mechanical ventilation after cardiac arrest and acute percutaneous coronary intervention. Antiplatelet, thyroid hormone replacement and statin therapies were administered through a 14-French nasogastric tube (Nestlé Health Science) and enteral feeding was initiated. Correct position of the nasogastric tube was confirmed radiologically. On the seventh day in the intensive care, our patient was seen to regurgitate soft crumbs into her mouth. The blocked nasogastric tube was removed, but attempts to reinsert another tube failed.Upper GI endoscopy revealed an obstruction of the oesophagus with a milky-yellowish caseous substance 20 cm from the incisors (figure 1). The proximal part of the mass showed a central hole and ring-shaped layers resembling the cut face of a tree trunk.gutjnl;68/2/206/F1F1F1Figure 1Obstruction of the oesophagus with a milky-yellowish caseous substance. QUESTIONS: What caused the obstruction?How should we manage such a problem?

Proteomic variation in metamorphosing Paralichthys olivaceus induced by exogenous thyroid hormone.

Thyroid hormone (TH) is essential for Paralichthys olivaceus metamorphosis. Exogenous TH treatment induces premature metamorphosis in P. olivaceus larvae and a series of studies have been conducted to identify thyroid hormone-regulated functional genes and microRNAs involved in the metamorphosis of P. olivaceus; however, the proteins involved in this process remain to be fully clarified. In this study, the differential proteomic responses of P. olivaceus larvae to exogenous TH treatment were examined using tandem mass tags (TMT) for quantitation labeling followed by liquid chromatography tandem mass spectrometry (LC-MS/MS). The expression levels of 629 cellular proteins were identified to be significantly affected by TH treatment. The reliability of our TMT-labeled LC-MS/MS analysis was verified by examining the mRNA and protein levels of four selected proteins using quantitative real-time reverse-transcription PCR and western blot analyses. The possible biological significance of these proteins was further investigated by Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein-protein interaction analyses. Notably, we identified and described five groups of proteins involved in different important life events that were significantly regulated by exogenous TH treatment. Our study provides an improved understanding of the molecular mechanisms by which TH regulates the metamorphosis of P. olivaceus.