Different Causes of Reduced Sensitivity to Thyroid Hormone

Medscape just put this article out which is a reasonable overview. At least they are beginning to realize that there can be different causes. PR



Normal TH metabolism and action require adequate cellular TH signalling. The last decade has witnessed the identification of several novel syndromes resulting from defects in TH transport, deiodination and receptor function. Because the clinical consequences can be severe, it is of utmost important to develop adequate treatment strategies for these different clinical syndromes. These important recent discoveries may hold the promise that the route of TH signalling will turn out to be even more exciting in the near future.

4 Replies

  • Only had a brief read through - and indeed it is good to see papers which actually produce a list of the various known mechanisms.

    I keep thinking that there must be mechanisms which cause mild, possibly temporary (albeit lasting months or years), resistance.

    Imagine if some sort of deficiency, or a virus or other infection, or a small amount of some substance or other, or anything else you can think up, could reduce the transport of thyroid hormone across cell walls, or the effectiveness of a thyroid hormone receptor.


  • Rod, I think we have barely scratched the surface of understanding regarding the total thyroid system. The more I read the more I am amazed at how complex a piece of machinery the human body is. It astounds me that we work as well as we do for as long as we do, especially given the changes in lifestyle, our food supply and the increased chemical toxicity of our environment. I believe those changes are largely responsible for the tremendous increase in autoimmune conditions that we have seen over the last 40-50 years.

    Dr. Hollenberg, a researcher in the CoActivators and CoRepressors arena, quipped at the beginning of his 2012 ATA presentation, "When you look at transport, the deiodinases and the CoActivators and CoRepressors, it almost makes the serum levels irrelevant." That is stretching it a little bit but there is a lot of truth in what he said. As Dr. Derry said, "All control of thyroid is local, in the tissues and organs throughout the human body." Science is a slow tedious process, eventually it will catch up to what thyroid patients have been forced to learn in order to survive, until then dealing with many doctors can be a real pain in the tuckus. PR

  • I just get so angry when i think about how much money and research that some areas of medicin get and how little is spent on Thyroid research. Thyroid is not "sexy". Antiageing medicin have money because it is profitable and some of those findings benefit us but that is about it it seems.


  • Although we see much made of research into cancer, diabetes, and so on, there is actually quite a lot going on in the thyroid world. I get an email every day listing the latest research papers published on PubMed (see below for today's one - which is fairly typical).

    The problem, it seems to me, is getting the research information into clinical practice. Most especially, into GP care (though many endos seem pretty well adrift from research). We still see people being told that they absolutely must take their thyroid hormone in the morning - despite research and the evidence of many here that some do better taking it at other times.

    Items 1 - 22 of 22

    1. Toxicol Sci. 2013 Nov 11. [Epub ahead of print]

    Flame retardant BDE-47 effectively activates nuclear receptor CAR in human primary hepatocytes.

    Sueyoshi T, Li L, Wang H, Moore R, Kodavanti PR, Lehmler HJ, Negishi M, Birnbaum LS.

    Pharmacogenetics section, Laboratory of Reproductive and Developmental Toxicology, Research Triangle Park, NC 27709.


    Polybrominated diphenyl ether BDE-47 (2,2',4,4'-tetrabromodiphenyl ether) is a thyroid hormone disruptor in mice; hepatic induction of various metabolic enzymes and transporters has been suggested as the mechanism for this disruption. Utilizing Car-/- and Pxr -/- mice as well as human primary hepatocytes, here we have demonstrated that BDE-47 activated both mouse and human nuclear receptor constitutive activated/androstane receptor (CAR). In mouse livers, CAR, not PXR, was responsible for Cyp2b10 mRNA induction by BDE-47. In human primary hepatocytes, BDE-47 was able to induce translocation of YFP-tagged human CAR from the cytoplasm to the nucleus andCYP2B6 and CYP3A4 mRNAs expressions. BDE-47 activated human CAR in a manner akin to the human CAR ligand CITCO (6-(4-Chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime) in luciferase-reporter assays using Huh-7 cells. In contrast, mouse CAR was not potently activated by BDE-47 in the same reporter assays. Furthermore, human PXR (pregnane X receptor) was effectively activated by BDE-47 while mouse PXR was weakly activated in luciferase-reporter assays. Our results indicate that BDE-47 induces CYP genes through activation of human CAR in addition to the previously identified pathway through human PXR.

    PMID: 24218150 [PubMed - as supplied by publisher]

    2. Toxicol Sci. 2013 Nov 11. [Epub ahead of print]

    Perinatal Exposure to BDE-99 Causes Decreased Protein Levels of Cyclin D1 via GSK3β Activation and Increased ROS Production in Rat Pup Livers.

    Blanco J, Mulero M, Domingo JL, Sanchez DJ.

    Laboratory of Toxicology and Environmental Health, School of Medicine, IISPV, Universitat Rovira i Virgili, Sant Llorens 21, 43201 Reus, Spain.


    We here examined the potential liver toxicity in rat pups from dams exposed during the gestational and lactation periods to 2,2',4,4',5-pentaBDE (BDE-99). Dams were exposed to 0, 1, and 2 mg/kg/day of BDE-99 from gestation day 6 to post-natal day 21. When the pups were weaning, the liver from one pup of each litter was excised to evaluate oxidative stress markers and the mRNA expression of multiple cytochrome P450 (CYP) isoforms. To determine whether thyroid hormone (TH) was disrupted, the proteins and mRNA expression of several TH receptors (TRs) isoforms were evaluated, as well as the protein levels of cyclin D1 and the phosphorylated protein kinases Akt and GSK3β. Perinatal exposure to BDE-99 produced decreased levels of cyclin D1 in rat pup livers. A decrease in the active form of Akt and an increase in the active form of GSK3β were observed. The decreased Akt pathway may be due to a potential disruption of the non-genomic actions of TH by BDE 99 and its metabolites. This possible TH disruption was noted as a decrease in TR isoforms expression. By contrast, we observed an up-regulation of CYP2B1 gene expression, which is correlated with an increase in ROS production. This outcome indicates activation of the nuclear constitutive androstane receptor, which could induce the expression of other enzymes capable of metabolizing TH. The present findings support the hypothesis that perinatal exposure to PBDEs, at levels found in humans, may have serious implications for metabolic processes in rat pup livers.

    PMID: 24218147 [PubMed - as supplied by publisher]

    3. Chirurg. 2013 Nov 13. [Epub ahead of print]

    [Minimally invasive video-assisted thyroidectomy : Establishment in a thyroid center.]

    [Article in German]

    Piniek A, Schuhmann R, Coerper S.

    Chirurgisches Schilddrüsen- und Nebenschilddrüsenzentrum, Klinik für Allgemein-, Visceral- und Gefäßchirurgie, Krankenhaus Martha-Maria, Stadenstr. 58, 90491, Nürnberg, Deutschland, Stephan.Coerper@Martha-Maria.de.



    This study retrospectively evaluated a series of patients who underwent minimally invasive video-assisted thyroidectomy (MIVAT) during the introduction stage of this surgical technique at the Martha-Maria Hospital in Nuremberg.


    The eligibility criteria for MIVAT were a thyroid volume < 25 ml, nodules < 30 mm, no thyroiditis, no preoperative evidence of carcinoma and no previous neck surgery. A retrospective evaluation was performed together with a control group of patients who underwent conventional thyroid surgery during the same time period and included a follow-up for general patient satisfaction and cosmetic results.


    Between August 2008 and July 2009 a total of 55 patients underwent MIVAT including 8 conversions to open surgery and 45 patients who underwent conventional surgery served as matched controls. No significant differences in terms of perioperative complication rates were found (e.g. recurrent laryngeal nerve palsy, hypocalcemia or secondary hemorrhage). The mean operating time was significantly longer in the MIVAT group (96.8 ± 3.7 min vs. 69.8 ± 2.3 min, p = 0.001) whereas a significant decrease in the mean operating time for hemithyroidectomy after 5 months was observed (98.1 ± 3.77 min vs. 76.0 ± 4.98 min, p = 0.013). Patients in the MIVAT group were more satisfied with the cosmetic outcome (8.5 ± 0.3 vs. 8.2 ± 0.2, p = 0.05) as well as with the overall surgical procedure (9.0 ± 0.3 vs. 8.6 ± 0.2, p = 0.02).


    During introduction of the MIVAT procedure a learning effect can be observed which is hallmarked by a decrease in operating time and conversion rate to open surgery. Moreover, no significant differences in terms of main postoperative complications were found so that MIVAT can be considered a safe and feasible technique under the conditions of correct eligibility criteria.

    PMID: 24218083 [PubMed - as supplied by publisher]

    4. J Clin Endocrinol Metab. 2013 Nov 11. [Epub ahead of print]

    Five-Year Follow-Up for Women With Subclinical Hypothyroidism in Pregnancy.

    Shields BM, Knight BA, Hill AV, Hattersley AT, Vaidya B.

    National Institute for Health Research Exeter Clinical Research Facility (B.M.S., B.A.K., A.V.H., A.T.H., B.V.), University of Exeter Medical School, University of Exeter, Exeter, United Kingdom; and Department of Endocrinology (B.A.K., B.V.), Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom.


    Context:Increasing numbers of women are being treated with l-thyroxine in pregnancy for mild thyroid dysfunction because of its association with impaired neuropsychological development in their offspring and other adverse obstetric outcomes. However, there are limited data to indicate whether treatment should be continued outside of pregnancy.Objectives:We aimed to determine whether subclinical hypothyroidism and maternal hypothyroxinemia resolve postdelivery.Design, Setting, and Participants:A total of 523 pregnant healthy women with no known thyroid disorders were recruited during routine antenatal care and provided blood samples at 28 weeks of pregnancy and at a mean of 4.9 years postpregnancy.Main Outcome Measures:TSH, free T4, free T3, and thyroid peroxidase antibody levels were measured in serum taken in pregnancy and at follow-up.Results:Subclinical hypothyroidism in pregnancy (TSH >3 mIU/L) was present in 65 of 523 (12.4%) women. Of these, 49 (75.4%) women had normal thyroid function postpregnancy; 16 of 65 (24.6%) had persistent high TSH (TSH >4.5 mIU/L postpregnancy) with 3 women receiving l-thyroxine treatment. A total of 44 of 523 (8.4%) women had isolated maternal hypothyroxinemia in pregnancy (free T4 <10th centile and TSH ≤3 mIU/L). Only 2 of 44 (4.5%) had TSH >4.5 mIU/L outside pregnancy. Of the women with subclinical hypothyroidism in pregnancy with antibody measurements available, those with thyroid peroxidase antibodies in pregnancy were more likely to have persistently elevated TSH or be receiving l-thyroxine replacement after pregnancy (6 of 7 [86%] vs 10 of 57 [18%], P < .001).Conclusions:The majority of cases of subclinical hypothyroidism in pregnancy are transient, so treatment with l-thyroxine in these patients should be reviewed because it may not be warranted after pregnancy.

    PMID: 24217906 [PubMed - as supplied by publisher]

    5. J Clin Endocrinol Metab. 2013 Nov 11. [Epub ahead of print]

    Coexistence of Malignant Struma Ovarii and Cervical Papillary Thyroid Carcinoma.

    Leong A, Roche PJ, Paliouras M, Rochon L, Trifiro M, Tamilia M.

    Division of Endocrinology and Metabolism (A.L., M.Tr., M.Ta.), Lady Davis Research Institute (P.J.R.R., M.P., M.Tr.), and Department of Pathology (L.R.), Jewish General Hospital, McGill University, Montreal, Canada QC H3A 1A1.


    Context:Struma ovarii is an uncommon monodermal teratoma in which thyroid tissue is the predominant element. Malignant transformation of struma ovarii is an even rarer occurrence.Case Presentation:We describe a 42-year-old woman who underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy for a symptomatic left pelvic mass. Histology revealed malignant struma ovarii with classical papillary thyroid carcinoma expression. Ultrasonography of the cervical neck showed thyroid micronodules and a dominant 1-cm nodule in the left thyroid lobe. Because the ovarian tumor was large, the patient underwent a total thyroidectomy with the intention of administering 131I therapy in an adjuvant setting. Histology of the cervical thyroid gland revealed bilateral multifocal papillary thyroid carcinoma with extrathyroidal extension and perithyroidal lymph node metastasis.Methods:Morphological (microscopy), immunohistochemical (Hector Battifora mesothelial cell 1, cytokeratin-19, galectin-3), and molecular (BRAF V600E, RAS, RET-PTC) characteristics and clonality analysis of the cervical thyroid and ovarian tumors were explored to distinguish them as separate malignancies.Results:The thyroid-type tumors from the cervical gland and ovary were discordant in terms of tissue histology and level of cytokeratin-19 expression. The clinical features and tumor profile results supported the independent existence of these two embryologically related, although topographically distinct, malignancies.Conclusion:Our findings provided support for synchronous, albeit distinct, primary tumors in the ovary and cervical thyroid. "Field cancerization" and early genomic instability may explain multifocality in all thyroid-type tissue. In this regard, patients with malignant struma ovarii should undergo imaging of their thyroid gland for coexisting disease and thyroidectomy recommended for suspected malignancy or in preparation for radioiodine therapy.

    PMID: 24217901 [PubMed - as supplied by publisher]

    6. Clin Ter. 2013 Sep-Oct;164(5):397-402. doi: 10.7417/CT.2013.1602.

    Classification and comparative study of vitiligo in Southeast of Turkey with biochemical and immunological parameters.

    Kalkanli N, Kalkanli S.

    Department of Dermatology and Venereology, Veni Vidi Hospital; Medicine Faculty, Dicle University, Turkey.


    Objective. To investigate classification and comparative with biochemical and immunological parameters of vitiligo disease in Southeast of Turkey. Patients and Methods. 148 patients who referred to the Department & Dermatology and Venereology with the complaint of vitiligo were selected. All patients gave informed consent for participation in the study. The patients were classified according to types of the skin. The complete blood cell and biochemical laboratory tests, ASO, CRP, RF, ANA, thyroid hormone levels were examined. Results. In the evaluation of 148 vitiligo patients; we didn't observe any significant difference between age and sex groups. We observed the maximum number of patients in the ages of 20-29 years and the most common types of clinical and focal types. We compared the childeren and adult patients according to their skin types, the difference was significant. We viewed that the onset of the disease commonly first in the face area. Koebner phenomenon 17 (11.48%), halo nevus 5 (3.38%) and leucotrichia 5 (3.38%) of patients were positive. Conclusion. Vitiligo is associated with loss of color by the destruction of melanocytes. The incidence of vitiligo is 1-2% and is found in every race. This study is important for the reason of the first research which evaluates vitiligo patients in southeast of Turkey.

    PMID: 24217824 [PubMed - in process]

    7. JAMA Intern Med. 2013 Nov 11. doi: 10.1001/jamainternmed.2013.12188. [Epub ahead of print]

    Thyroid Function Testing in Patients With Newly Diagnosed Hyperlipidemia.

    Willard DL, Leung AM, Pearce EN.

    Department of Medicine, Boston Medical Center, Boston, Massachusetts.

    PMID: 24217672 [PubMed - as supplied by publisher]

    8. Med Sci Monit. 2013 Nov 10;19:960-8. doi: 10.12659/MSM.889621.

    Left and right ventricular structure and function in subclinical hypothyroidism: The effects of one-year levothyroxine treatment.

    Ilic S, Tadic M, Ivanovic B, Caparevic Z, Trbojevic B, Celic V.

    Department of Endocrinology, University Clinical Hospital Center "Dr Dragisa Misovic", Belgrade, Serbia.


    Background The aim of this study was to investigate left ventricular (LV) and right ventricular (RV) structure, function, and mechanics in patients with subclinical hypothyroidism (SHT), and to evaluate the effect of a 1-year levothyroxine treatment. Material and Methods We compared 45 untreated women with subclinical hypothyroidism and 35 healthy control women matched by age. All the subjects underwent laboratory analyses, which included a thyroid hormone levels (free T3, free T4, and TSH) test, and a complete 2-dimensional echocardiographic study. All the SHT patients received levothyroxine therapy and were followed for a year after euthyroid state was achieved. Results The LV mass index in the SHT participants before and after replacement therapy was significantly higher than in controls. In the SHT patients before the treatment, LV diastolic function and global function estimated by the Tei index were significantly impaired, whereas the LV systolic function was decreased. The results show that LV mechanics was significantly impaired in the SHT patients at baseline. Additionally, the SHT participants before levothyroxine substitution had increased RV wall thickness and significantly impaired RV diastolic and global function in comparison with the controls or the SHT subjects after the treatment. Furthermore, RV mechanics was also significantly deteriorated in the SHT patients before the treatment. Conclusions Subclinical hypothyroidism significantly affected LV and RV structure, systolic, diastolic and global function, and LV and RV mechanics. Levothyroxine replacement therapy significantly improved cardiac structure, function, and mechanics in the SHT patients.

    PMID: 24217559 [PubMed - in process]

    9. Clin Nucl Med. 2013 Nov 7. [Epub ahead of print]

    Benign Cystic Mesothelioma: False-Positive Iodine Accumulation in a Patient With Oncocytic Follicular Thyroid Carcinoma.

    Meyer M, Godbert Y, Soubeyran I, Cazeau AL, Bonichon F.

    From the *Departments of Nuclear Medicine; and †Pathology, Institut Bergonié, Bordeaux, France.


    Whole-body (I) scintigraphy (WBS) is used to detect residual or metastatic tissue during treatment of differentiated thyroid carcinoma in combination with thyroglobulin (Tg) and ultrasonography of the neck. It is a highly sensitive method, but there is a high rate of false positives. We report the case of a 52-year-old woman with false-positive iodine accumulation in a benign cystic mesothelioma discovered during treatment for a oncocytic follicular thyroid carcinoma (stage pT2 pNx Mx). This lesion was detected by WBS and confirmed by surgery and histopathologic analysis.

    PMID: 24217550 [PubMed - as supplied by publisher]

    10. Nucl Med Commun. 2013 Nov 8. [Epub ahead of print]

    Dual malignancies in the setting of differentiated thyroid carcinoma: their synchronous or metachronous nature, impact of radioiodine treatment on occurrence of second malignancy and other associated variables.

    Gandhi S, Abhyankar A, Basu S.

    Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Hospital, Mumbai, India.



    The primary objective of the study was to assess the risk for second primary malignancy after radioiodine treatment for differentiated thyroid carcinoma (DTC). Other objectives were to study the different variables associated with the occurrence of synchronous or metachronous dual malignancies in association with DTC.


    The patient population studied comprised patients with histopathologically proven DTC referred for radioactive iodine treatment after thyroidectomy followed up at a single centre during the period from January 1963 to March 2011. The data collected were analysed with respect to different variables associated with two primary tumours in the setting of DTC.


    Out of the total 8614 patients studied from 1963 to March 2011, 44 dual malignancies in association with DTC were detected, showing a prevalence rate of 0.5%. The most common site of second primary malignancy was the head and neck (H&N) in men and the breast in women. Of the 44 dual malignancies, 18 were synchronous in nature and 26 were metachronous. In the metachronous group, thyroid carcinoma was the first primary malignancy in only 5/26 patients, whereas the remaining 21 patients had thyroid carcinoma as the second primary malignancy. In 5/26 patients in whom carcinoma of the thyroid was the first primary malignancy, the second primary malignancy was breast carcinoma in two cases, renal cell carcinoma in one case, colorectal carcinoma in one case and metastatic NET of unknown primary in one case. All these five patients received radioiodine treatment with different activities. In 21/26 patients in whom thyroid carcinoma was the second primary malignancy, the most common first primary malignancy comprised H&N tumours. In this group, 12 patients had a history of external beam radiotherapy (EBRT). Among synchronous malignancies (18/44 patients), H&N tumours were the most commonly associated.


    There was no significant risk for second primary malignancy after radioactive iodine treatment in patients with DTC. There is increased risk for thyroid malignancy after EBRT delivered for other primary tumours, especially in children. Hence, any thyroid abnormality on long-term follow-up of patients after EBRT for other tumours should be considered carefully. H&N malignancies are the most common synchronous, metachronous and overall associated second malignancy with thyroid carcinoma.

    PMID: 24217429 [PubMed - as supplied by publisher]

    11. Aust Fam Physician. 2013 Nov;42(11):801-2.

    Hairy elbows - A case study.

    Serrano PF, Ruiz-Villaverde R, Serrano JL.

    PhD, MD, is a consultant, Department of Dermatology, Hospital Alto Guadalquivir, Andújar, Jaén, Spain.


    Case study A boy aged 6 years was referred to our clinic for evaluation of the presence of fair, thin hair on both of his elbows. This condition had first been observed when he was 2 years of age and the hair had subsequently increased in length and thickness (Figure 1). He had a history of asthma and was being treated by a paediatrician. His family medical record was otherwise unremarkable. This unusual hairiness was symmetrically distributed on the extensor surfaces of both proximal forearms and distal arms. The underlying skin showed no abnormalities. No hypertrichosis was found elsewhere and examination of teeth, skeleton and fingernails was also normal. No other morphological changes were noted. In addition, his height was appropriate for his age. No developmental, mental or physical impairment was observed. The blood cell count and general biochemistry, as well as thyroid and sexual hormonal profiles were all normal. Radiological examination, which was performed on the parents' request, was normal. The boy was diagnosed with hypertrichosis cubiti (HC), and shaving of the areas was recommended.

    PMID: 24217102 [PubMed - in process]

    12. Turk J Pediatr. 2013 May-Jun;55(3):322-7.

    Thyroid Hormone Resistance: A Novel Mutation in Thyroid Hormone Receptor Beta (THRB) Gene - Case Report.

    Işık E, Beck Peccoz P, Campi I, Ozön A, Alikaşifoğlu A, Gönç N, Kandemir N.

    Division of Pediatric Endocrinology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey. dremregul@gmail.com.


    Thyroid hormone resistance (THR) is a dominantly inherited syndrome characterized by reduced sensitivity to thyroid hormones. It is usually caused by mutations in the thyroid hormone receptor beta (THRB) gene. In the present report, we describe the clinical and laboratory characteristics and genetic analysis of patients with a novel THRB gene mutation. The index patient had been misdiagnosed as hyperthyroidism and treated with antithyroid drugs since eight days of age. Thyroid hormone results showed that thyrotropin (thyroid-stimulating hormone, TSH) was never suppressed despite elevated thyroid hormone levels, and there was no symptom suggesting hyperthyroidism. A heterozygous mutation at codon 350 located in exon 9 of the THRB gene was detected in all the affected members of the family. It is important to consider thyroid hormone levels in association with TSH levels to prevent inappropriate treatment and the potential complications, such as clinical hypothyroidism or an increase in goiter size.

    PMID: 24217081 [PubMed - in process]

    13. Free Radic Biol Med. 2013 Nov 8. pii: S0891-5849(13)01487-1. doi: 10.1016/j.freeradbiomed.2013.10.818. [Epub ahead of print]

    Tolfenamic Acid Induces Apoptosis and Growth Inhibition in Anaplastic Thyroid Cancer: Involvement of NAG-1 Expression and Intracellular ROS Generation.

    Won Chang J, Kang SU, Choi JW, Shin YS, Baek SJ, Lee SH, Kim CH.

    Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Korea; Center for Cell Death Regulating Biodrug, School of Medicine, Ajou University, Suwon, Korea.


    Non-steroidal anti-inflammatory drugs (NSAIDs) are usually used for the treatment of inflammatory diseases. However certain NSAIDs also have an antitumor activities on the various cancers including head and neck cancer through cyclooxygenase (COX) dependent or independent pathways. Non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1), a TGF-β superfamily protein is induced by NSAIDs and has been shown to be induced by several anti-tumorigenic compounds and to exhibit pro-apoptotic and anti-tumorigenic activities. In this report, we demonstrate for the first time that tolfenamic acid (TA) transcriptionally induced the expression of NAG-1 during TA-induced apoptosis of anaplastic thyroid cancer (ATC) cells. TA reduced the viability of ATC cells in a dose-dependent manner and induced apoptosis, findings that were coincident with NAG-1 expression. Overexpression of NAG-1 gene using cDNA enhanced the apoptotic effect of TA, whereas suppression of NAG-1 expression by small interfering (si) RNA attenuated TA-induced apoptosis, respectively. Subsequently, we found that intracellular ROS generation plays an important role in activating these pro-apoptotic proteins, NAG-1. Then, we confirmed anti-tumorigenic effect of TA in a nude mice orthotopic ATC model, and this result accompanied the augmentation of NAG-1 expression and ROS generation in tumor tissue. Taken together, these results demonstrate that TA induces apoptosis via NAG-1 expression and ROS generation in in vitro and in vivo ATC models, providing a novel mechanistic explanation and indicating a potential chemotherapeutic approach for treatment of ATC.

    © 2013 Elsevier Inc. All rights reserved.

    PMID: 24216474 [PubMed - as supplied by publisher]

    14. Am J Pathol. 2013 Nov 8. pii: S0002-9440(13)00684-6. doi: 10.1016/j.ajpath.2013.10.006. [Epub ahead of print]

    The Thyroid Hormone Triiodothyronine Controls Macrophage Maturation and Functions: Protective Role during Inflammation.

    Perrotta C, Buldorini M, Assi E, Cazzato D, De Palma C, Clementi E, Cervia D.

    Unit of Clinical Pharmacology, the Department of Biomedical and Clinical Sciences, CNR Institute of Neuroscience, Luigi Sacco University Hospital, Università di Milano, Milano, Italy.


    The endocrine system participates in regulating macrophage maturation, although little is known about the modulating role of the thyroid hormones. In vitro results demonstrate a negative role of one such hormone, triiodothyronine (T 3), in triggering the differentiation of bone marrow-derived monocytes into unpolarized macrophages. T3-induced macrophages displayed a classically activated (M1) signature. A T3-induced M1-priming effect was also observed on polarized macrophages because T3 reverses alternatively activated (M2) activation, whereas it enhances that of M1 cells. In vivo, circulating T3 increased the content of the resident macrophages in the peritoneal cavity, whereas it reduced the content of the recruited monocyte-derived cells. Of interest, T3 significantly protected mice against endotoxemia induced by lipopolysaccharide i.p. injection; in these damaged animals, decreased T3 levels increased the recruited (potentially damaging) cells, whereas restoring T3 levels decreased recruited and increased resident (potentially beneficial) cells. These data suggest that the anti-inflammatory effect of T3 is coupled to the modulation of peritoneal macrophage content, in a context not fully explained by the M1/M2 framework. Thyroid hormone receptor expression analysis and the use of different thyroid hormone receptor antagonists suggest thyroid hormone receptor β1 as the major player mediating T3 effects on macrophages. The novel homeostatic link between thyroid hormones and the pathophysiological role of macrophages opens new perspectives on the interactions between the endocrine and immune systems.

    Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

    PMID: 24215914 [PubMed - as supplied by publisher]

    15. Arch Med Res. 2013 Nov 8. pii: S0188-4409(13)00254-3. doi: 10.1016/j.arcmed.2013.10.009. [Epub ahead of print]

    Chronic Kidney Disease and Hypothalamic-Pituitary-Axis Dysfunction: The Chicken or the Egg?

    Meuwese CL, Carrero JJ.

    Division of Renal Medicine and Baxter Novum, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Epidemiology, Leiden University Medical Centre, Sweden.


    Hormonal derangements at the level of the hypothalamic-pituitary axis are often seen with the worsening of kidney function. This may not be surprising given the role of the kidney in synthesis, metabolism and elimination of many of these hormones. Traditionally, these derangements have been understood as a consequence of kidney failure. Conversely, recent evidence points towards the implication of such hormonal disorders in the genesis of CKD. In this review we present arguments supporting both the role of hypothalamic-pituitary axis dysfunction as a consequence of uremic complications and a culprit in disease incidence and progression. Focus is given to evidence regarding thyroidal, adrenal and gonadal axes.

    Copyright © 2013 IMSS. Published by Elsevier Inc. All rights reserved.

    PMID: 24215784 [PubMed - as supplied by publisher]

    16. Curr Eye Res. 2013 Nov 11. [Epub ahead of print]

    Assessment of Tear Meniscus with Optical Coherence Tomography in Thyroid-Associated Ophtalmopathy.

    Sizmaz S, Altan-Yaycioglu R, Bakiner OS, Bozkirli E, Coban-Karatas M, Ulas B.

    Department of Ophthalmology and.


    Abstract Purpose: To evaluate the tear-film meniscus with optical coherence tomography (OCT) in patients with Graves' disease (GD). Materials and methods: Patients with GD without clinical features of thyroid-associated ophthalmopathy (TAO) (Group 1, n = 35), patients with signs of TAO (Group 2, n = 31) and healthy participants (Group 3, n = 31) were enrolled. Palpebral fissure width, Schirmer test, tear break-up time (TBUT) test and tear-film meniscus height and area obtained with Fourier-domain-OCT were analyzed. Results: TBUT test scores were 8 s (2-25) in Group 1, 8 s (2-15) in Group 2 (p = 0.380); and10 s (5-17) in Group 3 (p = 0.000 Group 1 versus 3, and 0.000 for Group 2 versus 3). Tear-film meniscus height did not significantly differ between Groups 1 and 2 (257.5 µm (86-962) and 258 µm (99-1340), respectively, p = 0.980). In Group 3, tear-film meniscus height was 316 µm (122-720) (p = 0.005 Group 1 versus 3 and 0.004 for Group 2 versus 3). Tear-film meniscus area did not significantly differ between Groups 1 and 2 (0.025 mm2 (0.004-0.250) and 0.024 mm2 (0.003-0.316), respectively, p = 0.850). In Group 3, tear-film meniscus area was 0.048 mm2 (0.006-0.75) (p = 0.000 Group 1 versus 3 and 0.000 for Group 2 versus 3). Conclusion: Tear function is significantly disturbed in GD. OCT is an effective way to assess the tearing function also in patients with GD.

    PMID: 24215623 [PubMed - as supplied by publisher]

    17. Ann Med. 2013 Nov 12. [Epub ahead of print]

    Rosiglitazone may reduce thyroid cancer risk in patients with type 2 diabetes.

    Tseng CH.

    Department of Internal Medicine, National Taiwan University College of Medicine , Taipei , Taiwan , Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital , Taipei , Taiwan , and Division of Environmental Health and Occupational Medicine of the National Health Research Institutes , Taipei , Taiwan.


    Background. Whether rosiglitazone use in patients with type 2 diabetes may affect thyroid cancer risk has not been investigated. Methods. The reimbursement databases of all diabetic patients under oral anti-diabetic agents or insulin from 1996 to 2009 were retrieved from the National Health Insurance of Taiwan. An entry date was set at 1 January 2006, and 887,665 patients with type 2 diabetes were followed for thyroid cancer incidence until the end of 2009 for ever-users, never-users, and subgroups of rosiglitazone exposure using tertile cut-offs for time since starting rosiglitazone, duration of therapy, and cumulative dose. Hazard ratios were estimated by Cox regression. Results. There were 103,224 ever-users and 784,441 never-users, with respective numbers of incident thyroid cancer of 84 (0.08%) and 764 (0.10%), and respective incidence of 23.12 and 28.09 per 100,000 person-years. The overall multivariable-adjusted hazard ratio was not significant. However, in dose-response analyses, the adjusted hazard ratios (95% confidence intervals) were significant for the third tertile of duration of therapy (≥ 14 months) and cumulative dose (≥ 1,800 mg) for age ≥ 50 years: 0.53 (0.31-0.89) and 0.50 (0.29-0.87), respectively. Conclusions. This study suggests that rosiglitazone use in patients with type 2 diabetes may reduce the risk of thyroid cancer.

    PMID: 24215589 [PubMed - as supplied by publisher]

    18. Curr Eye Res. 2013 Nov 11. [Epub ahead of print]

    Vision-Related Quality of Life Tends to be More Severely Impaired in Patients with Dysthyroid Optic Neuropathy.

    Du Y, Ye H, Li K, Xiao X, Chen R, He JF, Yang H.

    State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University , Guangzhou, Guangdong , China .


    Abstract Purpose: Dysthyroid optic neuropathy (DON) is the most severe condition in thyroid eye disease (TED); however, no study has been conducted to assess quality of life in these patients to date. The aim of this study was to evaluate vision-related quality of life in TED patients with DON using a Chinese version of the 25-item National Eye Institute Visual Function Questionnaire (CHI-VFQ-25). Methods: The CHI-VFQ-25 scores were compared for 23 TED patients with DON and 13 TED patients without DON. The correlations between the clinical characteristics and subscale scores on the CHI-VFQ-25 and the floor and ceiling effects of the CHI-VFQ-25 were also assessed. Results: Patients with DON scored significantly lower than patients without DON on the CHI-VFQ-25 (composite score: 54 versus 77, respectively, p = 0.001). Many subscales were significantly correlated with the severity and activity of the disease (p < 0.05). In patients with DON, no floor effects were found, and ceiling effects were only observed for Color vision, Peripheral vision and Social function. Role limitations and Mental health were the lowest scores in all the subscales. Conclusions: The current study showed that vision-related quality of life tended to be more severely impaired in TED patients with DON than in patients without DON. The CHI-VFQ-25 may be a promising tool to estimate the benefits of interventions in patients with DON.

    PMID: 24215175 [PubMed - as supplied by publisher]

    19. Orbit. 2013 Dec;32(6):395-8. doi: 10.3109/01676830.2013.833253.

    Ocular sparganosis mimicking an orbital idiopathic inflammatory syndrome.

    Ho TH, Lin MC, Yu WW, Lai PH, Sheu SJ, Bee YS.

    Department of Ophthalmology, Kaohsiung Veterans General Hospital, Kaohsiung , Taiwan , ROC .


    Abstract Sparganosis is an infection by the parasitic tapeworm larvae of Spirometra species. Ocular sparganosis is a rare disease that is easily misdiagnosed. We reported a rare case of ocular sparganosis mimicking orbital idiopathic inflammatory syndrome at initial presentation. A 34-year-old female presented with rapid progressive swelling of her left eyelid and mild proptosis for the duration of one month. The other ocular examinations were normal and the thyroid function was normal. Magnetic resonance imaging revealed a fusiform enlargement and mild heterogenous enhancement of the superior oblique muscle of the left orbit. First she received prednisolone therapy and the proptosis partially improved. Six months later, a white, flat and wrinkled string like worm wriggled out from the caruncular conjunctiva of the left eye. The pathology results confirmed that the worm was a Spirometra species larva. After removal of the larva and treatment with praziquantel, the proptosis was resolved without recurrence. Ocular sparganosis is a rare disease and only a few case reports have been reported. The drug therapy has not been effective and the surgical removal is the principal therapy. Despite its rarity, ocular sparganosis should be considered as a possible cause of orbital inflammation in patients.

    PMID: 24215169 [PubMed - in process]

    20. Gene. 2013 Oct 25;529(2):300-6. doi: 10.1016/j.gene.2013.07.015. Epub 2013 Jul 31.

    AMOTL2 interaction with TAZ causes the inhibition of surfactant proteins expression in lung cells.

    Lucci V, Di Palma T, D'Ambrosio C, Scaloni A, Zannini M.

    CNR - National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy. Electronic address: valeria.lucci@unina.it.



    TAZ (Transcriptional co-Activator with PDZ-binding motif), is a biologically potent transcriptional coactivator and functions by binding to the PPXY motif present in several transcription factors. Notably, TAZ behaves as a transducer linking cytoplasmic signaling events to transcriptional regulation in the nucleus. Several different factors regulate TAZ expression and/or function. In particular, a major regulation of TAZ activity occurs through the Hippo pathway by a phosphorylation-mediated mechanism that causes its cytoplasmic sequestration or degradation.


    Here we demonstrate that AMOTL2 robustly co-immunoprecipitates with TAZ, and their interaction is dependent on the WW domain of TAZ and the PPXY motif in the N-terminus of AMOTL2. Furthermore, we show that AMOTL2 colocalizes with TAZ in the cytoplasm of H441 human lung cells and regulates TAZ cytoplasm-to-nucleus translocation through direct protein-protein interaction. Interestingly, the overexpression of AMOTL2 inhibits the functional cooperation between the transcription factor TTF-1 and TAZ on the Surfactant C gene promoter, as well as the expression of other known target genes of these regulatory factors.


    Taken together, our results suggest an inhibitory role of AMOTL2 on TAZ ability to co-activate transcription and describe a different mechanism, Hippo pathway-independent, that modulates the activity of TAZ in lung cells through the interaction with Angiomotin-like 2 (AMOTL2).

    © 2013 Elsevier B.V. All rights reserved.

    PMID: 23911299 [PubMed - indexed for MEDLINE]

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    21. Endocrinology. 2013 Sep;154(9):3008-15. doi: 10.1210/en.2013-1576. Epub 2013 Jul 30.

    Cutting edge: retrobulbar inflammation, adipogenesis, and acute orbital congestion in a preclinical female mouse model of Graves' orbitopathy induced by thyrotropin receptor plasmid-in vivo electroporation.

    Moshkelgosha S, So PW, Deasy N, Diaz-Cano S, Banga JP.

    Division of Diabetes and Nutritional Sciences, King's College London School of Medicine, The Rayne Institute, 123 Coldharbour Lane, London, SE5 9NU, United Kingdom.

    Comment in

    News and views: at long last, an animal model of Graves' orbitopathy. [Endocrinology. 2013]


    Graves' orbitopathy (GO) is a complication in Graves' disease (GD) but mechanistic insights into pathogenesis remain unresolved, hampered by lack of animal model. The TSH receptor (TSHR) and perhaps IGF-1 receptor (IGF-1R) are considered relevant antigens. We show that genetic immunization of human TSHR (hTSHR) A-subunit plasmid leads to extensive remodeling of orbital tissue, recapitulating GO. Female BALB/c mice immunized with hTSHR A-subunit or control plasmids by in vivo muscle electroporation were evaluated for orbital remodeling by histopathology and magnetic resonance imaging (MRI). Antibodies to TSHR and IGF-1R were present in animals challenged with hTSHR A-subunit plasmid, with predominantly TSH blocking antibodies and were profoundly hypothyroid. Orbital pathology was characterized by interstitial inflammation of extraocular muscles with CD3+ T cells, F4/80+ macrophages, and mast cells, accompanied by glycosaminoglycan deposition with resultant separation of individual muscle fibers. Some animals showed heterogeneity in orbital pathology with 1) large infiltrate surrounding the optic nerve or 2) extensive adipogenesis with expansion of retrobulbar adipose tissue. A striking finding that underpins the new model were the in vivo MRI scans of mouse orbital region that provided clear and quantifiable evidence of orbital muscle hypertrophy with protrusion (proptosis) of the eye. Additionally, eyelid manifestations of chemosis, including dilated and congested orbital blood vessels, were visually apparent. Immunization with control plasmids failed to show any orbital pathology. Overall, these findings support TSHR as the pathogenic antigen in GO. Development of a new preclinical model will facilitate molecular investigations on GO and evaluation of new therapeutic interventions.

    PMID: 23900776 [PubMed - indexed for MEDLINE]

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    22. Neth J Med. 2012 Nov;70(9):415-9.

    Rapid widening of the mediastinum after coronary angiography.

    Seubert ME, Beurele E, Brandjes DP.

    Department of Intensive Care Medicine, Slotervaartziekenhuis, Amsterdam, the Netherlands. seubert@xs4all.nl

    Free Article

    PMID: 23123538 [PubMed - indexed for MEDLINE]

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