Stichting Schildklieronderzoek Nederland
Research

ACADEMIC MEDICAL CENTER,  UNIVERSITY OF AMSTERDAM

The Academic Medical Center (AMC) of the University of Amsterdam has a longstanding tradition in clinical and referral thyroid patient care and thyroid research. The thyroid research has a strong translational approach, with appointments for both basic and clinical researchers within one department. As a unique feature, the AMC hosts the core facility of the neonatal screening program for congenital hypothyroidism in the northwest part of The Netherlands. Current thyroid research of the department of Endocrinology AMC is focused on two themes: thyroid hormone metabolism and action during illness (1) and clinical aspects and novel genetic causes of congenital central hypothyroidism (2).  

Thyroid hormone metabolism and action during illness

                  Illness of any cause is known to be associated with decreased serum thyroid hormone concentrations and paradoxically low serum TSH, together known as nonthyroidal illness syndrome (NTIS). The  functional meaning of NTIS  has remained  enigmatic. Although the common view was that NTIS results in overall downregulation of metabolism in order to save energy, recent work has shown a more complex picture. Local T3 tissue concentrations in NTIS may be decreased, unaltered or even increased. This differential picture results from marked variation in transcriptional and translational activity of genes involved in thyroid hormone metabolism, ranging from inhibition to activation, dependent on the organ or tissue studied. In addition, the illness induced changes appear to be very different during acute or chronic inflammation.

                  We recently published that type 2 deiodinase, the main T3 activating enzyme, is expressed in macrophages and serves  as a local determinant of  macrophage function during inflammation.  Type 3 deiodinase (D3) is the main T3 inactivating enzyme, converting the thyroid hormones T3 and T4 to their inactive metabolites. Our lab discovered that D3 is expressed in infiltrating murine neutrophils, a type of white blood cell that  is key to  the innate immune system. As D3 knockout mice show impaired bacterial killing compared to wildtype mice, D3 expression in neutrophils is likely a novel player in the innate immune response. To further unravel these novel roles of deiodinating enzymes in immune functions we will use mouse models, primary cultures and cell lines. 

                  Our previous studies in postmortem human hypothalamus in NTIS showed decreased hypothalamic TRH expression in critical illness, while work by others showed clear effects of iv TRH administration in ICU patients, restoring the HPT axis to a large extent. We aim to perform clinical studies in ICU patients in order to address the clinical relevance of interventions that restore serum thyroid hormone concentrations in protracted critical illness.

PRINCIPAL INVESTIGATORS:

Dr. Anita Boelen,  a.boelen@amc.uva.nl

Prof. dr. Eric Flierse.fliers@amc.uva.nl

Clinical aspects and novel genetic causes of congenital central hypothyroidism

                  Central hypothyroidism (CeH) is characterized by thyroid hormone (TH) deficiency due to insufficient stimulation of an otherwise normal thyroid gland by thyroid-stimulating hormone (TSH). Central hypothyroidism occurs either isolated, or in combination with other pituitary hormone deficiencies. Well-known genetic causes of isolated central hypothyroidism include mutations in TSHB, TRHR and IGSF1. Using whole-exome sequencing in patients with isolated central hypothyroidism of unknown origin we recently identified two additional and novel genetic causes for CeH. One of these mutations is associated with a unique syndrome of CeH and sensorineural hearing loss. We are now assessing  clinical, biochemical and radiological characteristics of the probands and the carriers. Additionally, we focus on the mechanisms involved using cell systems and transgenic mice models.

                  The laboratory of Endocrinology has hosted  the Neonatal Screening Laboratory Amsterdam since the start of the neonatal screening in the Netherlands (1981). A blood sample is taken from every newborn between 72 – 168 hours after birth. The blood is tested in the laboratory for 17 rare diseases. Early detection and treatment of these diseases can prevent or limit serious impairment of the physical and mental development of the child. Congenital hypothyroidism was the first disease to be taken up in the programme.

PRINCIPAL INVESTIGATORS:

Dr. Anita Boelen,  a.boelen@amc.uva.nl

Prof. dr. Eric Flierse.fliers@amc.uva.nl

Dr. Paul van Trotsenburg,  a.s.vantrotsenburg@amc.uva.nl 

KEY PUBLICATIONS:

  1. Fliers E, Bianco A, Langouche L, and Boelen A. Thyroid (dys)function in critically ill patients. Invited review Lancet Diabetes Endocrinol 2015; 3: 816-25
  2. Kwakkel J, Surovtseva OV, De Vries M, Stap J, Fliers F, Boelen A. A novel role for the thyroid hormone activating enzyme type 2 deiodinase in the inflammatory response of macrophages. Endocrinology 2014; 155(7), 2725-34
  3. de Vries EM, Kwakkel J, Eggels E, Kalsbeek A, Barrett P, Fliers E, Boelen A. NFκB signaling is essential for the lipopolysaccharide-induced increase of type 2 deiodinase in tanycytes. Endocrinology 2014; 155(5), 2000-8
  4. Sun Y, Bak B, Schoenmakers N, van Trotsenburg AS, Oostdijk W, Voshol P, Cambridge E, White JK, le Tissier P, Gharavy SN, Martinez-Barbera JP, Stokvis-Brantsma WH, Vulsma T, Kempers MJ, Persani L, Campi I, Bonomi M, Beck-Peccoz P, Zhu H, Davis TM, Hokken-Koelega AC, Del Blanco DG, Rangasami JJ, Ruivenkamp CA, Laros JF, Kriek M, Kant SG, Bosch CA, Biermasz NR, Appelman-Dijkstra NM, Corssmit EP, Hovens GC, Pereira AM, den Dunnen JT, Wade MG, Breuning MH, Hennekam RC, Chatterjee K, Dattani MT, Wit JM, Bernard DJ. Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement. Nat Genet. 2012 Dec;44(12):1375-81. doi: 10.1038/ng.2453. Epub 2012 Nov 11.
  5. Boelen A, Kwakkel J, Fliers E. Beyond low plasma T3: local thyroid hormone metabolism during inflammation and infection.  Endocr Rev. 2011 32(5):670-93. Review.
  6. Boelen A, Kwakkel J, Wieland CW, St.Germain DL, Fliers E and Hernandez A. Impaired bacterial clearance in type 3 deiodinase deficient mice infected with Streptococcus pneumoniae. Endocrinology 2009 150 (4): 1984-1990 

 

FREE UNIVERSITY MEDICAL CENTER, Amsterdam

                  Myocardial infarction (MI), aortic stenosis, valvular disease or pulmonary hypertension, all result in chronic hemodynamic overload of the heart which induces remodeling of the left or right ventricle. Although initially compensatory, this process often progresses to cardiac dysfunction and chronic heart failure. Changes in gene expression that affect contractile properties of the cardiomyocyte underlie this pathological form of ventricular remodeling. Numerous interacting signal-transduction pathways have been shown to play a role in this process, but the underlying mechanisms are still poorly understood. Heart failure is one of the major causes of morbidity and mortality in developed countries, yet therapeutic options are limited and novel approaches are therefore needed.

                  Cardiac gene expression is particularly sensitive to thyroid hormone (T3).  Nuclear T3 receptors mediate the transcriptional regulation of T3-responsive genes and the cardiac responsiveness is illustrated by marked differences in ventricular contractility and energy metabolism in the absence of T3 (hypothyroidism) and presence of excess levels (hyperthyroidism). The similar changes in expression of key cardiac genes in hypothyroidism and in chronic heart failure suggest involvement of reduced cardiac activity of T3 in pathological remodeling. We tested this hypothesis in different rodent models of right- and left-ventricular failure and found a 50% reduction of both T3-dependent gene transcription and T3 content in remodeling cardiomyocytes. This was associated with persistent induction in the heart of the enzyme deiodinase type 3 (Dio3), which converts T3 to the inactive metabolite T2. This finding was unexpected since Dio3 activity is present in the fetal heart, but negligible in the healthy myocardium. Analysis of Dio3 expression in left-ventricular tissue from non-failing donor hearts and explanted hearts of patients suffering from chronic heart failure caused by ischemic heart disease, also showed increased Dio3 levels, which correlated with changes in T3-dependent gene expression.

                  We now focus on establishing firstly whether the induction of Dio3 activity is responsible for the reduction of cardiac T3 levels, and secondly, how Dio3 expression is regulated in the hemodynamically overloaded heart. In collaboration with the group of dr. Salvatore (Naples, Italy) we have developed a conditional, cardiomyocyte-specific Dio3 knock-out mouse model. Given the clinical relevance of chronic heart failure following MI, we will use this mouse in our established model of post-MI cardiac remodeling to assess the role of Dio3 activity in impairment of T3 signaling and cardiac dysfunction. If such a role exists, it may provide novel options for the treatment or prevention of chronic heart failure.

PRINCIPAL INVESTIGATOR

Dr. Warner S. Simonides,  ws.simonides@vumc.nl

KEY PUBLICATIONS

  1. Wassen WJS, Schiel AE, Kuiper GJGM, Kaptein E, Bakker O, Visser TJ, Simonides WS.  Induction of thyroid hormone-degrading deiodinase in cardiac hypertrophy and failure. Endocrinology 143. 2812-2815, 2002.
  2. Simonides WS, Mulcahey MA, Redout EM, Muller A, Zuidwijk MJ, Visser TJ, Wassen FWJS, Crescenzi A, da-Silva WS, Harney J, Engel FB, Obregon MJ, Larsen PR, Bianco AC, Huang SA. Hypoxia-inducible factor induces local thyroid hormone inactivation in hypoxic-ischemic disease in rats. J. Clin. Invest. 118, 975-983, 2008.
  3. Pol CJ, Muller A, Simonides WS. Cardiomyocyte-specific inactivation of thyroid hormone in pathologic ventricular hypertrophy: an adaptative response or part of the problem? Heart Failure Rev. 15: 133-142, 2010.
  4. Pol CJ,  Muller A, Zuidwijk MJ, van Deel ED, Kaptein E, Saba A,  Marchini M, Zucchi R, Visser TJ, Paulus WJ, Duncker DJ, Simonides WS. Left-ventricular remodeling following myocardial infarction is associated with a cardiomyocyte-specific hypothyroid condition. Endocrinology 152: 669-679, 2011.
  5. Janssen R, Zuidwijk MJ, Muller A, Mulders J, Oudejans CBM, Simonides WS. Cardiac expression of deiodinase type 3 (Dio3) following myocardial infarction is associated with the induction of a pluripotency microRNA signature from the Dlk1-Dio3 genomic region. Endocrinology 154, 1973-1978, 2013.
  6. Janssen R, Zuidwijk MJ, Kuster DWD, Muller A, Simonides WS. Thyroid hormone-regulated cardiac microRNAs are predicted to suppress pathological hypertrophic signaling. Front Endocrinol doi: 10.3389/fendo.2014.00171, 2014.

 

UNIVERSITY MEDICAL CENTER GRONINGEN, Groningen              

                  Thyroid cancer is the most common malignancy of the endocrine organs, with an estimated 750 new cases in the  Netherlands in 2015. Differentiated thyroid carcinoma (DTC) is the most frequent histological subtype consisting of the papillary and follicular carcinoma and accounts for approximately 90% of the thyroid malignancies. The prognosis is favorable for the majority of DTC patients  with a 5-year relative survival of 95%. The incidence of DTC has doubled over the last 15 years in The Netherlands. This  is mainly due to an increased diagnosis of patients with low-risk DTC. Medullary (MTC) and anaplastic thyroid cancer (ATC) are the other – mostly rare occurring - types of thyroid cancer. These types often behave more aggressively.

                  Treatment for patients with DTC consists of a total thyroidectomy accompanied by a central and/or lateral neck lymph node dissection when lymph node metastases are present. Postoperatively radioiodine 131I therapy is administered. According to the risk classification  patients are supplied with supraphysiological doses of thyroid hormone (thyroid hormone suppression therapy (THST).  The long-term adverse effects of 131I therapy and THST are increasingly. For MTC patients, surgery is the primary initial treatment modality and for ATC treatment options are still very limited.

The UMCG is a expertise center for thyroid cancer  and covers the whole spectrum of diagnostic and treatment modalities for thyroid cancer including studies with new drugs.

Research on thyroid at the University Medical Center Groningen covers several topics

  • to assess long-term effects of treatment in patients with DTC, with a focus on damage on the cardiovascular system  and salivary glands
  • to optimize diagnostic modalities like 18F-FDG PET and 18F-DOPA PET
  • to improve therapeutic outcome based on preclinical and clinical studies on targeted therapies

Thyroid cancer in children is rare and data on treatment and outcome. With the support of  a grants of the Stichting Kinderen Kankervrij (KiKa) the UMCG has started a nationwide study in the Netherlands to evaluate presentation, treatment-related complications, and long-term outcome in patients with pediatric differentiated thyroid cancer in the Netherlands. All university hospitals cooperate in this study.

PRINCIPAL INVESTIGATOR

Prof. dr. T.P  Links, t.p.links@umcg.nl

Prof. dr J.T.M.Plukker  j.t.m.plukker@umcg.nl 

KEY PUBLICATIONS

  1. Verbeek HH, Plukker JT, Koopmans KP, de Groot JW, Hofstra RM, Muller Kobold AC, van der Horst-Schrivers AN, Brouwers AH, Links TP. Clinical Relevance of 18F-FDG PET and 18F-DOPA PET in Recurrent Medullary Thyroid Carcinoma. J Nucl Med. 2012;53:1863-71.
  2. van Dijk D, Plukker JT, Phan HT, Muller Kobold AC, van der Horst-Schrivers AN,Jansen L, Sluiter WJ, Brouwers AH, Links TP. 18-fluorodeoxyglucose positron emission tomography in the early diagnostic workup of differentiated thyroid cancer patients with a negative post-therapeutic iodine scan and detectable thyroglobulin. Thyroid. 2013;23:1003-9.
  3. Klein Hesselink EN, Klein Hesselink MS, de Bock GH, Gansevoort RT, Bakker SJ, Vredeveld EJ, van der Horst-Schrivers AN, van der Horst IC, Kamphuisen PW, Plukker JT, Links TP, Lefrandt JD. Long-term cardiovascular mortality in patients with differentiated thyroid carcinoma: an observational study.  J Clin Oncol. 2013 ;31:4046-53.
  4. Links TP, Verbeek HH, Hofstra RM, Plukker J. ENDOCRINE TUMOURS: Progressive metastatic medullary thyroid carcinoma: first and second line strategies. Eur J Endocrinol. 2015 Jun;172(6):R241-51
  5. Prinsen HT, Klein Hesselink EN, Brouwers AH, Plukker JT, Sluiter W1, van der Horst-Schrivers AN, van Imhoff GW, Links TP.  Bone marrow function after 131I therapy in patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab. 2015 Oct;100(10):3911-7.
  6. Hesselink EN, Lefrandt JD, Schuurmans EP, Burgerhof JG, Groen B, Gansevoort RT, van der Horst-Schrivers AN,  Dullaart RP, Van Gelder IC, Brouwers AH, Rienstra M, Links TP.Increased Risk of Atrial Fibrillation After Treatment for Differentiated Thyroid Carcinoma. J Clin Endocrinol Metab. 2015 Dec; Epub 2015 Oct 19.

 

ANIMAL ECOLOGY AND PHYSIOLOGY, RADBOUD UNIVERSITY, Nijmegen                

                  One of the main research topics of the department of Animal Ecology and Physiology (Institute for Water and Wetland Research, Radboud University) is stress physiology in fishes, i.e.: how do fish respond to stressors and ecological challenges. This forms the context of thyroidological research in Nijmegen.

                  Fishes, the earliest vertebrates, comprise a group of more than 30,000 species that are adapted to a wide range of different environments. We find fish at -2°C in supercooled (ant)arctic waters and at >30° in tropical seas, in acid and basic waters, in virtually anoxic conditions, and sometimes even on land. Fish, therefore, are excellent models to study adaptation and acclimation processes.

                  Comparative thyroidological research in Nijmegen is fundamental in principle: we aim to understand the piscine thyroid system (from basic histology to thyroid hormone metabolism). We try to define the role of the thyroid system in the stress response, and to integrate thyroid hormones’ functions with those of other “stress hormones”, cortisol in particular. We relate the fundamental insights we obtain to issues such as sustainable aquaculture, fish welfare, and toxicology and endocrine disruption.                  

PRINCIPAL INVESTIGATOR

Dr. Peter Klaren, p.klaren@fnwi.ru.nl

More information at: http://www.ru.nl/animal/ep/staff/klaren/.

KEY PUBLICATIONS

  1. de Vrieze E, van de Wiel SMW, Zethof J, Flik G, Klaren PHM, Arjona FJ 2014 Knockdown of Monocarboxylate transporter 8 (mct8) disturbs brain development and locomotion in zebrafish. Endocrinology 155:2320-2330
  2. Klaren PHM, Geven EJW, Nagelkerke A, Flik G 2012 Kinetics and thiol requirements of iodothyronine 5'-deiodination are tissue-specific in common carp (Cyprinus carpio L.). Comp Biochem Physiol B 161:275-282
  3. Arjona FJ, de Vrieze E, Visser TJ, Flik G, Klaren PHM 2011 Identification and functional characterization of zebrafish solute carrier slc16a2 (mct8) as a thyroid hormone membrane transporter. Endocrinology 152:5065-5073
  4. Bernier NJ, Flik G, Klaren PHM 2009 Regulation and contribution of the corticotropic, melanotropic and thyrotropic axes to the stress response in fishes. In: Bernier NJ, Van Der Kraak G, Farrell AP, Brauner CJ, eds. Fish Neuroendocrinology. New York: Academic Press; 235-311
  5. Geven EJW, Nguyen N-K, van den Boogaart M, Spanings FAT, Flik G, Klaren PHM 2007 Comparative thyroidology: thyroid gland location and iodothyronine dynamics in Mozambique tilapia (Oreochromis mossambicus Peters) and common carp (Cyprinus carpio L.). J Exp Biol 210:4005-4015

 

UNIVERSITY MEDICAL CENTER NIJMEGEN, RADBOUD UNIVERSITY, Nijmegen

The basic and translational research focusing on thyroid carcinoma at the Radboud UMC Expertise Center for Thyroid Carcinoma are embedded in the Radboud Institute for Molecular Life Sciences (RIMLS), which has a prominent international standing.

The main themes of our translational and clinical research are:

  1. Understanding the molecular pathogenesis of (non-medullary) thyroid carcinoma
  2. Improvement of patient care (diagnosis, therapy, long term consequences and quality of life).

Understanding the molecular pathogenesis of (non-medullary) tyroid carcinoma:

                  In our translational research we focus mainly on the role of inflammation in the pathogenesis of non-medullary thyroid carcinoma. Our research aims to generate basic knowledge from molecular medical research and to translate it into potential targets for translational research and improved approaches towards diagnosis and treatment of the disease. In particular, we investigate the role of the interplay between autophagy and inflammation in cell survival, proliferation and dedifferentiation in thyroid carcinoma. In addition we investigate the role of genetic variation in autophagy, inflammasome and cytokine genes in susceptibility for thyroid carcinoma, response to treatment and clinical outcome of thyroid carcinoma patients. The main purpose of these studies is to unravel novel pathophysiological mechanisms that may enhance or restore iodide uptake in malignant thyroid cells, which may help developing therapeutic applications for effective tumour ablation. Another research interest is the development of TSHR targeted therapies in differentiated thyroid carcinoma.

                  Our group has made important contributions in understanding the pathophysiology of the malignant process in thyroid cancer, as well as on the genetic and immunological determinants of the disease.

Improvement of patient care:

                  In our clinical research we focus on improving the diagnosis, treatment and quality of life of patients with thyroid carcinoma as well as the long-term consequences of the disease.

In collaboration with the Department of Radiology and Nuclear Medicine of our institution we conduct multicentre national studies on the on the role of FDG-PET for the diagnosis of thyroid cancer. In collaboration with the Department of Pathology of our institution we perform multicentre studies on the role of molecular markers in the improvement of the diagnostic value of the fine needle aspiration cytology of thyroid nodules.

                  In addition we participate in the national multicentre studies on the quality of care for the patients with medullary thyroid carcinoma and on the long-term outcome of children with thyroid carcinoma. Furthermore, in collaboration with the Department of Psychology of our institution we have investigated the distress experienced by patients treated for thyroid carcinoma and focus on development of decision aids to improve the shared decision-making.

                  Throughout our participation in the EORTC Task Force for Endocrine Tumors, our center participates in (interventional and observational) international multicenter clinical trials for treatment of advanced thyroid carcinoma.

PRINCIPAL INVESTIGATOR

Dr. Romana Netea-Maier, romana.netea-maier@radboudumc.nl

Dr. Theo Plantinga, theo.plantinga@radboudumc.nl

Prof. Dr. Jan Smit, jan.smit@radboudumc.nl 

KEY PUBLICATIONS

  1. RT Netea-Maier, SW Hunsucker, B Hoevenaars, SM Helmke, P Slootweg, A Hermus, BR Haugen, MW Duncan. Discovery and validation of protein abundance differences between follicular thyroid neoplasms. Cancer Res. 2008 1;68(5):1572-80.
  2. Gudmundsson J, Sulem P, Gudbjartsson DF, Jonasson JG, Masson G, He H, Jonasdottir A, Sigurdsson A, Stacey SN, Johannsdottir H, Helgadottir HT, Li W, Nagy R, Ringel MD, Kloos RT, de Visser MC, Plantinga TS, den Heijer M, Aguillo E, Panadero A, Prats E, Garcia-Castaño A, De Juan A, Rivera F, Walters GB, Bjarnason H, Tryggvadottir L, Eyjolfsson GI, Bjornsdottir US, Holm H, Olafsson I, Kristjansson K, Kristvinsson H, Magnusson OT, Thorleifsson G, Gulcher JR, Kong A, Kiemeney LA, Jonsson T, Hjartarson H, Mayordomo JI, Netea-Maier RT, de la Chapelle A, Hrafnkelsson J, Thorsteinsdottir U, Rafnar T, Stefansson K. Discovery of common variants associated with low TSH levels and thyroid cancer risk. Nat Genet. 2012 Jan 22;44(3):319-22.
  3. Plantinga TS, Heinhuis B, Gerrits D, Netea MG, Joosten LA, Hermus AR, Oyen WJ, Schweppe RE, Haugen BR, Boerman OC, Smit JW, Netea-Maier RT. mTOR Inhibition promotes TTF1-dependent redifferentiation and restores iodine uptake in thyroid carcinoma cell lines. J Clin Endocrinol Metab. 2014 Jul;99(7):E1368-72.
  4. Plantinga TS, Costantini I, Heinhuis B, Huijbers A, Semango G, Kusters B, Netea MG, Hermus AR, Smit JW, Dinarello CA, Joosten LA, Netea-Maier RT.A promoter polymorphism in human interleukin-32 modulates its expression and influences the risk and the outcome of epithelial cell-derived thyroid carcinoma. Carcinogenesis. 2013 Jul;34(7):1529-35.
  5. Vriens D, Adang EM, Netea-Maier RT, Smit JW, de Wilt JH, Oyen WJ, de Geus-Oei LF. Cost-effectiveness of FDG-PET/CT for cytologically indeterminate thyroid nodules: a decision analytic approach. J Clin Endocrinol Metab. 2014 Sep;99(9):3263-74
  6. Petrulea MS, Plantinga TS, Smit JW, Georgescu CE, Netea-Maier RT. PI3K/Akt/mTOR: A promising therapeutic target for non-medullary thyroid carcinoma. Cancer Treat Rev. 2015 Sep;41(8):707-13
  7. Netea-Maier RT, Plantinga TS, Van De Veerdonk FL, Smit JW, Netea MG. Modulation of inflammation by autophagy: consequences for human disease. Autophagy. 2015; Feb;12(2):245-260.
  8. Heinhuis B, Plantinga TS, Semango G, Küsters B, Netea MG, Dinarello CA, Smit JW, Netea-Maier RT, Joosten LA. Alternatively spliced isoforms of IL-32 differentially influence cell death pathways in cancer cell lines. Carcinogenesis. 2015 Dec 17. pii: bgv172. [Epub ahead of print]

 

ERASMUS MEDICAL CENTER, ERASMUS UNIVERSITY, Rotterdam

Erasmus MC (www.erasmusmc.nl) is the largest university medical centre of the Netherlands covering all specialties and is known for its high quality research. The Department of Internal Medicine has a strong background in studying endocrine determinants of disease, both clinically and experimentally. The Thyroid Laboratory as part of the Rotterdam Thyroid Center combines basic molecular biology studies on regulation of thyroid hormone action with epidemiological studies analyzing consequences of thyroid dysfunction in large cohorts and international collaborations. Members of the laboratory have a broad range of expertise, ranging from biochemistry and clinical endocrinology to genetic and clinical epidemiology.  Current thyroid research within Erasmus MC focuses on different themes:

 Department of Internal Medicine:

1) Rare defects in thyroid hormone signaling

Thyroid hormone (TH) is essential for the development of virtually all tissues. The prohormone T4 is converted by outer ring deiodination to the active hormone T3 and by inner ring deiodination to the inactive metabolite rT3. The three deiodinases (D1-3) involved are expressed in different tissues, where they play different roles in systemic and local control of T3 levels. The deiodinases are located in cell membranes with their active site exposed to the cytoplasm, while the T3 receptors reside in the nucleus. Uptake of TH across the plasma membrane is thus required for TH action and metabolism, and is mediated by specific transporters. Our group identified an important T3 transporter (MCT8), mutation of which results in severe intellectual disability and grossly elevated serum T3 levels. In addition, the laboratory is currently leading an international multicentre therapeutic clinical trial in which patients with a defective thyroid hormone transporter MCT8 are treated with a thyroid hormone analogue (Triac) that does not depend on MCT8 to enter the cell (NCT02060474). Recently, we also discovered mutations in the alpha-type T3 receptor (TRa) in patients with marked delays in bone development and mild delays in mental and motor development, as well as increased serum T3 levels. In addition, we follow patients with defective SBP2, which comprises a multisystem disease including abnormal thyroid function tests (high T4, low T3 levels).

KEY PUBLICATIONS

  1. van Mullem AA, Chrysis D, Eythimiadou A, Chroni E, Tsatsoulis A, de Rijke YB, Visser WE, Visser TJ, Peeters RP. Clinical phenotype of a new type of thyroid hormone resistance caused by a mutation of the TRα1 receptor: consequences of LT4 treatment. J Clin Endocrinol Metab. 2013 Jul;98(7):3029-38.
  2. Kersseboom S, Kremers GJ, Friesema EC, Visser WE, Klootwijk W, Peeters RP, Visser TJ. Mutations in MCT8 in patients with Allan-Herndon-Dudley-syndrome affecting its cellular distribution. Mol Endocrinol. 2013 May;27(5):801-13.
  3. van Mullem A, van Heerebeek R, Chrysis D, Visser E, Medici M, Andrikoula M, Tsatsoulis A, Peeters R, Visser TJ. Clinical phenotype and mutant TRα1. N Engl J Med. 2012 Apr 12;366(15):1451-3.

 

PRINCIPAL INVESTIGATOR

Prof.dr. T.J. Visser (t.j.visser@erasmusmc.nl)

Dr. W.E. Visser (w.e.visser@erasmusmc.nl)

Prof.dr. R.P. Peeters (r.peeters@erasmusmc.nl)

Dr. M.E. Meima (m.meima@erasmusmc.nl)

 

2) Determination of the Thyroid Hormone Setpoint

Over the last few years, we analyzed multiple polymorphisms in TH pathway genes in vivo and in vitro, showing consequences for the individual thyroid setpoint. This setpoint likely explains why ~15% of hypothyroid patients have persistent complaints despite treatment. As chair of the Thyroid Working Group of the cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) –consortium, we collaborate with 29 cohorts from around the world, and we have genetic data and information on thyroid function in over 50,000 subjects. Among other things, this resulted in two large genome wide association study (GWAS) meta-analyses for thyroid function and thyroid autoimmunity.

KEY PUBLICATIONS

  1. Medici M, Visser WE, Visser TJ, Peeters RP. Genetic determination of the hypothalamic-pituitary-thyroid axis: where do we stand? Endocr Rev. 2015 Apr;36(2):214-44.
  2. Medici M, Porcu E, Pistis G, Teumer A, Brown SJ, Jensen RA, Rawal R, Roef GL, Plantinga TS, Vermeulen SH, de la Chapelle A, Netea-Maier RT, Gough SC, Meyer Zu Schwabedissen H, Frayling TM, Kaufman JM, Linneberg A, Räikkönen K, Smit JW, Kiemeney LA, Rivadeneira F, Uitterlinden AG, Walsh JP, Meisinger C, den Heijer M, Visser TJ, Spector TD, Wilson SG, Völzke H, Cappola A, Toniolo D, Sanna S, Naitza S, Peeters RP. Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease. PLoS Genet. 2014 Feb 27;10(2):e1004123. doi: 10.1371/journal.pgen.1004123.
  3. Porcu E, Medici M, Pistis G, Volpato CB, Wilson SG, Cappola AR, Bos SD, Deelen J, den Heijer M, Freathy RM, Lahti J, Schlessinger D, Shuldiner AR, Slagboom EP, Uitterlinden AG, Vaidya B, Visser TJ, Wolffenbuttel BH, Meulenbelt I, Rotter JI, Spector TD, Hicks AA, Toniolo D, Sanna S, Peeters RP, Naitza S. A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. PLoS Genet. 2013;9(2):e1003266.

 PRINCIPAL INVESTIGATOR

Prof. dr. R.P. Peeters (r.peeters@erasmusmc.nl)

Dr. M. Medici (m.medici@erasmusmc.nl)

 

3) Subclinical thyroid disorders and various clinical endpoints (including pregnancy and aging).

 The Thyroid Laboratory also plays a prominent international role in studies focusing on the effects of (subclinical) thyroid dysfunction. Via the Rotterdam Study (ERGO), the group is involved in the Thyroid Studies Collaboration, an international collaboration between 17 cohort studies using individual data from more than 70,000 people. In addition, the group is involved in different international guidelines. In recent years, we have demonstrated that minor changes in thyroid status can result in a higher risk of diseases such as cardiovascular disease and depression. We are currently studying consequences of mild changes of thyroid function on several other TH related clinical endpoints. Using various models of aging, we seek to further understand the role of thyroid hormone signaling during aging.

Via the Generation R study, the group is also studying the consequences of subtle changes in thyroid and iodine status on pregnancy, but also on the development of the child. Whereas initial studies have focused on defining reference ranges fro thyroid hormone during pregnancy, we are currently focusing on the consequences of both high and low thyroid hormone levels for neurocognitive development.  

KEY PUBLICATIONS

  1. Korevaar TI, Muetzel R, Medici M, Chaker L, Jaddoe VW, de Rijke YB, Steegers EA, Visser TJ, White T, Tiemeier H, Peeters RP. Association of maternal thyroid function during early pregnancy with offspring IQ and brain morphology in childhood: a population-based prospective cohort study. Lancet Diabetes Endocrinol. 2016 Jan;4(1):35-43.
  2. Korevaar TI, Medici M, Peeters RP. Subclinical Hypothyroidism Overdiagnosis in Pregnant Women. JAMA Intern Med. 2015 Nov;175(11):1872-3
  3. Visser WE, Bombardieri CR, Zevenbergen C, Barnhoorn S, Ottaviani A, van der Pluijm I, Brandt R, Kaptein E, van Heerebeek R, van Toor H, Garinis GA, Peeters RP, Medici M, van Ham W, Vermeij WP, de Waard MC, de Krijger RR, Boelen A, Kwakkel J, Kopchick JJ, List EO, Melis JP, Darras VM, Dollé ME, van der Horst GT, Hoeijmakers JH, Visser TJ. Tissue-Specific Suppression of Thyroid Hormone Signaling in Various Mouse Models of Aging. PLoS One. 2016 Mar 8;11(3):e0149941

PRINCIPAL INVESTIGATOR

Prof.dr. R.P. Peeters (r.peeters@erasmusmc.nl)

Dr. W.E. Visser (w.e.visser@erasmusmc.nl)

Dr. L. Chaker (l.chaker@erasmusmc.nl)

Dr. T.I.M. Korevaar (t.korevaar@erasmusmc.nl)

Department of pathology:

4) Improving FNA diagnostics in patients with (suspicion of) thyroid cancer

Thyroid nodules are very common, with an estimated prevalence of 5-8% in the adult population, of which approximately 5% is malignant. Currently, fine needle aspiration (FNA) cytology is the first step in diagnosing thyroid cancer, but in 15-30% of FNAs no definite diagnosis can be made. Consequently, these patients undergo a hemithyroidectomy to enable a histological diagnosis. If a tumor is diagnosed, total thyroidectomy is performed with subsequent radioiodine therapy. Since thyroid cancer generally has a good prognosis, there is an overtreatment for the majority of patients. Hence, two important clinical problems remain unsolved in patients with thyroid nodules: 1) a high rate of invasive diagnostic surgical procedures which turn out benign, 2) the absence of reliable markers indicative of aggressive behavior. Recently, “The Cancer Genome Atlas” (TCGA) reported that there are three mutually exclusive events that drive the tumorigenesis of thyroid tumors: 1) gene mutations, translocations, and somatic copy number alterations.3 Therefore, our research has focused on the creation of a next-generation sequencing (NGS) molecular test for FNA cytology that covers the most frequently mutated genes, gene-fusions, and chromosomal altered areas. Currently, we aim to distinguish benign from malignant thyroid lesions and identify tumors with aggressive behavior using this NGS test.

PRINCIPAL INVESTIGATOR

Prof. dr. F.J. van Kemenade (f.vankemenade@erasmusmc.nl

Dr. W.N.M. Dinjens (w.dinjens@erasmusmc.nl)

Dr. E. Korpershoek (e.korpershoek.1@erasmusmc.nl)