Thyroid hormones (TH) are of crucial importance for the physiological function of almost all organs. In cases of abnormal TH signaling, pathophysiological consequences may arise. The routine assessment of a healthy or diseased thyroid function state is currently based on the determination of serum concentrations of thyroid-stimulating hormone (TSH), and the TH T<sub>3</sub> and T<sub>4</sub>. However, the definition of a ‘normal' TSH range and similarly ‘normal' T<sub>3</sub> and T<sub>4</sub> concentrations remains the subject of debate in different countries worldwide and has important implications on patient treatment in clinics. Not surprisingly, a significant number of patients whose thyroid function tests are biochemically determined to be within the normal range complain of impaired well-being. The reasons for this are so far not fully understood, but it has been recognized that thyroid function status needs to be ‘individualized' and extended beyond simple TSH measurement. Thus, more precise and reliable parameters are required in order to optimally define the healthy thyroid status of an individual, and as a perspective to employ these in clinical routine. With the recent identification of new key players in TH action, a more accurate assessment of a patient's thyroid status may in the future become possible. Recently described distinct TH derivatives and metabolites, TH transporters, nongenomic TH effects (either through membrane-bound or cytosolic signaling), and classical nuclear TH action allow for insights into molecular and cellular preconditions of a healthy thyroid state. This will be a prerequisite to improve management of thyroid dysfunction, and additionally to prevent and target TH-related nonthyroid disease.
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- Author: Dagmar Fuhrer x
Dagmar Führer, Klaudia Brix, and Heike Biebermann
Denise Zwanziger, Helena Rakov, Kathrin Engels, Lars C. Moeller, and Dagmar Führer
Background: In the liver the tight junction protein claudin-1 plays an important role in bile secretion by maintaining the paracellular barrier of bile canaliculi and the bile duct. A diminished bile excretion has been found in hypothyroid patients, and the prevalence of gallstones is increased in hypothyroidism. This association, however, only applies for men and is in contrast to the well-established female preponderance of biliary disease in the general population. Objectives: We hypothesized that hypothyroidism could lead to altered claudin-1 expression in the liver, and that this effect may be sex specific. Methods: We characterized claudin-1 expression and localization in livers of euthyroid and hypothyroid male and female C57BL/6NTac mice by real-time PCR, Western blot and immunofluorescence. Results: Claudin-1 is expressed in canalicular regions and the bile ducts of the murine liver. Livers of female mice showed lower claudin-1 expression than male livers. In hypothyroid livers, female animals showed an elevated claudin-1 expression, whereas reduced claudin-1 expression was found in male animals compared to the euthyroid controls. Conclusion: We demonstrate a correlation between claudin-1 expression and hypothyroidism in the murine liver. Furthermore, a sex-dependent alteration of claudin-1 expression was found.
Tim Brandenburg, Philipp Muchalla, Sarah Theurer, Kurt Werner Schmid, and Dagmar Führer
Introduction: Primary squamous cell carcinoma (PSCC) of the thyroid is an exceptionally rare malignancy accounting for <1% of all primary thyroid cancers. Therapy is multimodal including surgery, radiotherapy, and chemotherapy but with no consensus for management and therapy. Here, we describe a case of a male patient who presented with a BRAF V600E-mutated PSCC of the thyroid gland showing response to combined dabrafenib and trametinib therapy over a period of >12 months. Case Presentation: A 78-year-old male patient presented with a 3-week history of dysphonia and dyspnoea. Laryngoscopy revealed a mechanical obstruction by a right-sided, subglottical mass, which on cervical ultrasound was highly suggestive of anaplastic thyroid carcinoma. Additional workup including esophagogastroduodenoscopy showed compression of the oesophagus but no oesophageal infiltration by the tumour. Immunohistochemistry displayed CK19-positive cells indicating epithelial origin of the tumour. CK5/6 and P40 immunohistochemistry confirmed the morphological impression of squamous cell differentiation while staining with thyroid markers TTF-1 and TPO was negative and PAX8 showed a nuclear positive signal. Based on immunohistopathology, presence of TP53 and BRAF V600E mutations, and exclusion of metastatic squamous cell carcinoma of other origin, the diagnosis of a PSCC of the thyroid was established. As an individualized treatment concept, we decided to advocate combined BRAF V600E targeting by the multikinase inhibitors dabrafenib and trametinib. This led to drastic improvement in patient’s quality of life without severe side effects over a period of >12 months. Conclusion: In this case, molecular diagnosis allowed a highly individualized treatment concept with combined dabrafenib and trametinib therapy.
Joanna Szumska, Maria Qatato, Maren Rehders, Dagmar Führer, Heike Biebermann, David K. Grandy, Josef Köhrle, and Klaudia Brix
Background: The trace amine-associated receptor 1 (Taar1) is one member of the Taar family of G-protein-coupled receptors (GPCR) accepting various biogenic amines as ligands. It has been proposed that Taar1 mediates rapid, membrane-initiated effects of thyronamines, the endogenous decarboxylated and deiodinated relatives of the classical thyroid hormones T<sub>4</sub> and T<sub>3</sub>. Objectives: Although the physiological actions of thyronamines in general and 3-iodothyronamine (T<sub>1</sub>AM) in particular are incompletely understood, studies published to date suggest that synthetic T<sub>1</sub>AM-activated Taar1 signaling antagonizes thyromimetic effects exerted by T<sub>3</sub>. However, the location of Taar1 is currently unknown. Methods: To fill this gap in our knowledge we employed immunofluorescence microscopy and a polyclonal antibody to detect Taar1 protein expression in thyroid tissue from Fisher rats, wild-type and taar1-deficient mice, and in the polarized FRT cells. Results: With this approach we found that Taar1 is expressed in the membranes of subcellular compartments of the secretory pathway and on the apical plasma membrane of FRT cells. Three-dimensional analyses further revealed Taar1 immunoreactivity in cilial extensions of postconfluent FRT cell cultures that had formed follicle-like structures. Conclusions: The results suggest Taar1 transport along the secretory pathway and its accumulation in the primary cilium of thyrocytes. These findings are of significance considering the increasing interest in the role of cilia in harboring functional GPCR. We hypothesize that thyronamines can reach and activate Taar1 in thyroid follicular epithelia by acting from within the thyroid follicle lumen, their potential site of synthesis, as part of a nonclassical mechanism of thyroid autoregulation.
Lars C. Moeller, Yaw Appiagyei-Dankah, Birgit Köhler, Heike Biebermann, Onno E. Janssen, and Dagmar Führer
Background: Thyroxine-binding globulin (TBG) is the main transport protein for T<sub>4</sub> in blood. Until now, 22 mutations leading to complete TBG deficiency (TBG-CD) have been reported. Objective: We report two mutations associated with TBG-CD found in patients from Andrews, S.C., USA (TBG-CD-Andrews), and Berlin, Germany (TBG-CD-Berlin). Methods: Automated chemiluminescence immunoassays were used for the determination of TSH, free and total T<sub>4</sub> and T<sub>3</sub> (fT<sub>4</sub>, TT<sub>4</sub>, TT<sub>3</sub>) and TBG. Direct DNA sequencing was used to identify the TBG mutations in the propositi. Results: TBG-CD-Andrews was found in a 1-month-old boy who was euthyroid with normal TSH and fT<sub>4</sub>, but reduced TT<sub>4</sub>, indicating TBG deficiency. TBG was not detectable, confirming TBG-CD. No mutation in the coding region and the promoter of the TBG gene was found, but a single nucleotide substitution in intron 1 disrupts the donor splice site of exon 0 (IVS1+2T>C). Another mutation was found in an 11-year-old boy. He was also euthyroid with normal fT<sub>4</sub> and TSH. However, TT<sub>4</sub> and TT<sub>3</sub> were low, suggesting TBG-CD. Sequencing revealed a 79-nucleotide deletion, ranging from intron 3 into exon 3. Conclusion: We report two novel mutations of the TBG gene associated with TBG-CD. Whereas most TBG-CDs are caused by small deletions, in TBG-CD-Andrews the disruption of a donor splice site was detected, whilst in TBG-CD-Berlin the largest deletion in the Serpina7 gene to date was found.
Furio Pacini, Dagmar Fuhrer, Rossella Elisei, Daria Handkiewicz-Junak, Sophie Leboulleux, Markus Luster, Martin Schlumberger, and Johannes W Smit
Modern use of post-operative radioactive iodine (RAI) treatment for differentiated thyroid cancer (DTC) should be implemented in line with patients’ risk stratification. Although beneficial effects of radioiodine are undisputed in high-risk patients, controversy remains in intermediate-risk and some low-risk patients. Since the last consensus on post-surgical use of RAI in DTC patients, new retrospective data and results of prospective randomized trials have been published, which have allowed the development of a new European Thyroid Association (ETA) statement for the indications of post-surgical RAI therapy in DTC. Questions about which patients are candidates for RAI therapy, which activities of RAI can be used, and which modalities of pre-treatment patient preparation should be used are addressed in the present guidelines.
Kathrin Engels, Helena Rakov, Denise Zwanziger, Lars C. Moeller, Georg Homuth, Josef Köhrle, Klaudia Brix, and Dagmar Führer
Background: Clinical features of thyroid dysfunction vary with age, and an oligosymptomatic presentation of hyperthyroidism is frequently observed in the elderly. This suggests age modulation of thyroid hormone (TH) action, which may occur, for example, by alterations in TH production, metabolism and/or TH action in target organs. Objectives: In this paper, we address possible changes in TH transporter expression in liver tissues as a mechanism of age-dependent variation in TH action. Methods: Chronic hyperthyroidism was induced in 4- and 20-month-old C57BL6/NTac male mice (n = 8-10) by intraperitoneal injections of 1 µg/g body weight <smlcap>L</smlcap>-thyroxine (T<sub>4</sub>) every 48 h over 7 weeks. Control animals were injected with PBS. Total RNA was isolated from liver samples for analysis of the TH transporter and TH-responsive gene expression. TH concentrations were determined in mice sera. Results: Baseline serum free T<sub>4</sub> (fT<sub>4</sub>) concentrations were significantly higher in euthyroid young compared to old mice. T<sub>4</sub> treatment increased total T<sub>4</sub>, fT<sub>4</sub> and free triiodothyronine to comparable concentrations in young and old mice. In the euthyroid state, TH transporter expression was significantly higher in old than in young mice, except for Mct8 and Oatp1a1 expression levels. Hyperthyroidism resulted in upregulation of Mct10, Lat1 and Lat2 in liver tissue, while Oatp1a1, Oatp1b2 and Oatp1a4 expression was downregulated. This effect was preserved in old animals. Conclusion: Here, we show age-dependent differences in TH transporter mRNA expression in the euthyroid and hyperthyroid state of mice focusing on the liver as a classical TH target organ.
Laura Fugazzola, Rossella Elisei, Dagmar Fuhrer, Barbara Jarzab, Sophie Leboulleux, Kate Newbold, and Jan Smit
The vast majority of thyroid cancers of follicular origin (TC) have a very favourable outcome, but 5–10% of cases will develop metastatic disease. Around 60–70% of this subset, hence less than 5% of all patients with TC, will become radioiodine refractory (RAI-R), with a significant negative impact on prognosis and a mean life expectancy of 3–5 years. Since no European expert consensus or guidance for this challenging condition is currently available, a task force of TC experts was nominated by the European Thyroid Association (ETA) to prepare this document based on the principles of clinical evidence. The task force started to work in September 2018 and after several revision rounds, prepared a list of recommendations to support the treatment and follow-up of patients with advanced TC. Criteria for advanced RAI-R TC were proposed, and the most appropriate diagnostic tools and the local, systemic and palliative treatments are described. Systemic therapy with multikinase inhibitors is fully discussed, including recommendations on how to start it and at which dosage, on the duration of treatment, and on the management of side effects. The appropriate relationship between the specialist and the patient/family as well as ethical issues are covered. Based on the available studies and on personal experience, the experts provided 39 recommendations aimed to improve the management of advanced RAI-R TCs. Above all of them is the indication to treat and follow these patients in a specialized setting which allows the interaction between several specialists in a multidisciplinary team.
Lars Bastholt, Michael C. Kreissl, Dagmar Führer, Ana L. Maia, Laura D. Locati, Léa Maciel, Yi Wu, Kevin N. Heller, Alan Webster, and Rossella Elisei
Objectives: Effective management of adverse events (AEs) following vandetanib treatment is important to maximize clinical benefits. We examined whether more frequent contact with vandetanib-treated patients reduced AEs of CTCAE grade 2 or higher. Study Design: In this open-label, multicentre, phase III study, patients with locally advanced or metastatic medullary thyroid cancer were randomized to a patient outreach programme (outreach) or a standard AE monitoring schedule (vandetanib control) for 52 weeks. In addition to standard AE monitoring, patients in the outreach arm were contacted every 2 weeks by telephone/during their clinic visit for specific AE questioning related to diarrhoea, nausea, vomiting, fatigue, headache and rash. Patients received vandetanib at 200 or 300 mg/day, depending on the creatinine levels at screening. Results: Altogether, 205 patients were randomized (outreach, n = 103; vandetanib control, n = 102). This study did not meet its primary objective; the mean percentage of time patients experienced at least one AE of grade 2 or higher was higher for the outreach group (51.65%) than for the vandetanib control group (45.19%); the difference was not statistically significant (t statistic: 1.29; 95% CI -3.44 to 16.37%; p = 0.199). The most frequently reported AEs were diarrhoea (56.9% for the outreach group vs. 46.6% for the vandetanib controls), hypertension (36.3 vs. 31.1%), rash (25.5 vs. 24.3%) and nausea (25.5% vs. 18.4%), and the most frequently reported AEs of grade 2 or higher were hypertension (33.3 vs. 23.3%), diarrhoea (26.5 vs. 24.3%) and dermatitis acneiform (11.8 vs. 9.7%). Conclusions: Additional outreach to patients treated with vandetanib had no impact on the rate or severity of AEs compared to the standard AE monitoring schedule. AEs were consistent with the known safety profile of vandetanib.
Beatrice Engelmann, Julia Bischof, Anne-Luise Dirk, Nele Friedrich, Elke Hammer, Thomas Thiele, Dagmar Führer, Georg Homuth, Georg Brabant, and Uwe Völker
Background: Hyperthyroidism is known to induce a hypercoagulable state. It stimulates plasma levels of procoagulative factors and reduces fibrinolytic activity. So far most of the data have been derived from patients with endogenous hyperthyroidism with a wide variability in the underlying pathogenesis and severity of the disease. Objectives: In this study we experimentally induced thyrotoxicosis in healthy volunteers to explore the effects of thyroxine excess on the plasma proteome. Using a shotgun proteomics approach, the abundance of plasma proteins was monitored before, during and after thyrotoxicosis. Methods: Sixteen healthy male subjects were sampled at baseline, 4 and 8 weeks under 250 µg/day thyroxine p.o., as well as 4 and 8 weeks after stopping the application. Plasma proteins were analyzed after depletion of 6 high-abundance proteins (MARS6) by LC-ESI-MS/MS mass spectrometry. Mass spectrometric raw data were processed using a label-free, intensity-based workflow. Subsequently, the linear dependence between protein abundances and fT<sub>4</sub> levels were calculated using a Pearson correlation. Results: All subjects developed biochemical thyrotoxicosis, and this effect was reversed within the first 4 weeks of follow-up. None of the volunteers noticed any subjective symptoms. Levels of 10 proteins involved in the coagulation cascade specifically correlated with fT<sub>4</sub>, supporting an influence of thyroid hormone levels on blood coagulation even at nonpathological levels. Conclusions: The results suggest that experimental thyrotoxicosis exerts selective and specific thyroxine-induced effects on coagulation markers. Our study design allows assessment of thyroid hormone effects on plasma protein levels without secondary effects of other diseases or therapies.