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27. october 2011.Belgrade

Thyroid disorders are common in women of childbearing age and in pre-gnancy.

Globally, iodine deficiency and autoimmune thyroiditis are the major causes of ma-

ternal hypothyroxinemia, which even if subtle may have negative effects on the fetal brain.

During pregnancy maternal thyroid hormone turnover increases substantially. This is

due to several mechanisms: an increase in plasma thyroid hormone-binding capacity, thyroidal

stimulation by chorionic gonadotropin, and metabolism of thyroid hormone in the placenta and

transport to the fetus. Consequently, reference values of thyroid hormones change during preg-

nancy. Knowledge of these changes is mandatory. The dosis of thyroxin in hypothyroid women

who become pregnant have to be increased guided by the reference ranges of pregnancy.

These patients cannot adapt to the increased demand of thyroid hormone during pregnancy.

Before pregnancy, thyroid dysfunction may result in menstrual disturbances and infertility.

Autoimmune thyroiditis is associated with spontaneous and recurrent abortion.

Thyroid dysfunction during pregnancy is associated with obstetric and fetal complica-

tions. Iodine deficiency during pregnancy can lead to a spectrum of neurodevelopmental de-

fects in the progeny; this can be prevented by iodine supplementation. Overt hypothyroidism

due to autoimmune thyroiditis in pregnancy should be treated without delay. Whether women

with subclinical hypothyroidism should be treated with thyroxin is not sure. The results of inter-

vention studies are under way, but preliminary data suggest that there are no major advantages

of treatment on maternal and neonatal outcomes.

Thyrotoxicosis in pregnancy is rare, but requires specialist input for optimal manage-

ment.

In the postpartum period thyroid dysfunction is common and due to auto-immune thy-

roiditis.

Most guidelines of professional societies do not advocate universal screening on thyroid

disorders before or during pregnancy but recommend case finding in women with high risk:

those with a family or personal history of thyroid disorders or type 1 diabetes mellitus or other

autoimmune disorders.

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12.00 – 12.30 A.M.Pereira - Clinical Factors Involved in the Recurrence

of Pituitary Adenomas after Surgical Remission:

A Structured Review and Meta-Analysis

12.30 – 13.00 J.W.A. Smit - Kinase Inhibitors in Differentiated Thyroid

Carcinoma

13.00 – 13.30 N.M.Lalić – Incretin based therapy, the role in type 2

diabetes mellitus and beyond

13.30 – 14.00 S.S.Damjanović – Medulary thyroid carcinoma

14.00 – 14.15 Diskusija

14.15-15.15 Pauza

15.15-15.45 A.Berghout – The thyroid and pregnancy

15.45-16.15 D. Pavlović – Hashimoto encephalopathy

16.15-16.45 J.A.Romijn - Headpieces

16.45-17.15 M.Žarković – TSH reference range: what to do, the data

show?

17.15-17.30 Diskusija

Program:

A. M. Pereira; Depart-ment of Endocrinology and Metabolic Diseases, Leiden University Medi-cal Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands

Aim: to study the cur-rently available data of recurrence rates of

functioning and nonfunctioning pituitary adenomas following surgical cure and to analyze

associated predisposing fac-tors, which are not well estab-lished. Methods: A systematic literature search was conducted using Medline, Embase, Web of Sci-ence and the Cochran Library for studies reporting data on re-currence of pituitary adenoma after surgery, in nonfunctioning adenoma (NF), prolactinoma (PRL) acromegaly (ACRO) and Cushing’s disease (CUSH). Of 557 initially retrieved potential relevant studies 143 were se-

lected. Recurrence in NFA was defined as reappearance of tu-mor on MRI or CT. Increase of hormone levels above normal limits as set by the authors af-ter initial remission was used to indicate recurrence in the func-tioning tumor types. Results: Remission percent-age was lowest in NFA com-pared with other tumor types (P <0.001). Surgery-related hypopituitarism was more fre-quent in CUSH than in the other tumors (P <0.001). Recurrence,

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A. M. PEREIRA

Clinical Factors Involved in the Recurrence of Pituitary Adenomas after Surgical Remission: A Structured Review and Meta-Analysis

expressed as percentage of the cured population or as ratio of recurrence and total patient years of follow-up was highest in PRL (P <0.001). The remis-sion percentage did not im-prove over 3 decades of publi-cations, but there was a modest decrease in recurrence rate (P = 0.04). Recurrences peaked between 1 and 5 years after surgery. Most of the studies with a sufficient number of recur-rences did not apply multivari-ate statistics, and mentioned at

best associated factors. Age, gender, tumor size and inva-sion were generally unrelated to recurrence. For functioning adenomas a low postoperative hormone concentration was aprognostically favorable factor. In NFA no specific factor pre-dicted recurrence. Conclusion: Recurrence rate differs between pituitary ad-enomas, being highest in pa-tients with prolactinoma, with the highest incidence of recur-rence between 1 and 5 years

after surgery in all adenomas. Patients with NFA have a lower chance of remission than pa-tients with functioning adeno-mas. The postoperative basal hormone level is the most im-portant predictor for recurrence in functioning adenomas, while in NFA no single convincing factor could be identified.

Curriculum Vitae

Name Smit, J.W.A. First Name JohannesDegree MD, PhDDate of birth January 29th 1962Nationality Dutch

Training and positions:1980 - 1988 Medical school, Utrecht University (cum laude)1989 - 1995 Residency Internal Medicine, University Medical Center Utrecht1995 Ph.D. Thesis: “Clinical consequences of cholesterol synthesis inhibitors”, Utrecht University, The Netherlands1997 - present Staff member Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center2002 – 2003 Visiting scientist, Albert Einstein College of Medicine, Department of Molecular Pharamcology, New York

J.W.A. SMIT

Although the role of ra-dioiodine (RaI) in recur-rent or metastatic thy-

roid cancer is beyond dispute, the efficacy of this therapy is hampered by the decreased ex-pression of the sodium iodide symporter (NIS) in DTC during the process of dedifferentiation. At present, there are no effec-tive therapies available for RaI non-avid DTC. Conventional chemotherapy is hardly ef-

fective in DTC, and no longer recommended in international guidelines. In DTC, many ge-netic alterations have been identified, involving tyrosine kinase signaling pathways. In nearly all cases of PTC, genetic defects involving the RET, RAS, RAF protein kinase signaling cascade are identified. The BRAFV600E mutation has been found in 29% to 69% of PTC and has been associated with

aggressive features including extrathyroidal extension and advanced stage. Translocations of RET observed in PTC result in a chimeric protein consisting of an activated RET tyrosine ki-nase domain. Follicular thyroid carcinomas (FTC) frequently harbor mutations in one of the three RAS genes. The RET-RAS-RAF pathway is interconnected with the EFGR activated cas-cade that among others leads

Kinase Inhibitors in Differentiated Thyroid Carcinoma2nd Serbian Dutch Endocrine Meeting

Prof.dr. J.W.A. SmitLeiden University Medical CenterLeiden, The Netherlands

2007 Chairman Endocrinology Section, Netherlands Society for Internal Medicine2007 Full professorship2009 - present Chairman of the Department of Endocrinology and Internal Medicine

Awards and grants:The group members have in the past years obtained several grants from the Netherlands Association for Scientific Research, the Netherlands Cancer Foundation and the European Union. He has obtained a career development grant from the Netherlands Cancer Foundation and a clinical fellowship from the Netherlands Association for Scientific Research. He has received the 2004 Netherlands Thyroid Award.

International activities:He is reviewer for many journals in the fields of endocrinology, diabetes and metabolism and member of several national and European guideline committees on endocrine diseases. Publications:He is (co)author of >200 publications in peer reviewed journals and chapters in textbooks in the field of clinical endocrinology and endocrine oncology.

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to VEGF and VEGFR synthesis. Therefore, compounds target-ing the activated RET-RAS-RAF pathway and beyond may be effective in non-RaI avid DTC. The anti EGFR compound ge-fitinib was not successful in 27 patients with DTC, medullary or anaplastic thyroid carcinoma. In a phase II study in 60 thyroid carcinoma patients with vari-ous histologies, the VEGFR in-hibitor axitinib showed a partial

response of 30% (median PFS 18 months). Recently, phase II studies have been published, using multi-kinase inhibi-tors, including motesanib and sorafenib. Especially promis-ing results have been reported for Sorafenib (BAY 43-9006), which is an inhibitor of RET, CRAF, wild-type and mutant (V600E) BRAF, VEGFR1, -2, -3, Flt3 and c-KIT, although no complete remissions are report-

ed. Questions to be addressed are the relationship between genetic profile and therapy response, selection of patients for particular drugs, the com-bination of treatment strategies rather than using monotherapy, the response of bone metasta-ses and the reinduction of RaI uptake and the organization of multinational clinical trials.

SVETOZAR S. DAMJANOVIC M.D., Ph.D.

CURRICULUM VITAE

SVETOZAR S. DAMJANOVIC M.D., Ph.D. Professor of Internal Medicine,Medical School, University of Belgrade

Address: Center of Endocrine Oncology and Hereditary Cancer Syndromes, Institute of Endocrinology, Diabetes and Metabolic Diseases, Medical School of Belgrade, Dr Subotica 13, 11000 Belgrade, SerbiaProfessional Interests:

Neuroendocrinology: Pituitary tumors, heart disease, body composition in acromegaly and insulin resistance

MEN 1 and 2: Multiple Endocrine Neoplasia (MEN) syndromes, genetic screening of hereditary tumors in endocrinology, neuroendocrine carcinomas HPA axis: Glucocorticoid receptor (GR) gene and adrenal tumors, HPA axis and GR gene with body composition in surgical stress and physical activities (dynamic and static sports)

Current Position:

• Director of Institute of Endocrinology Diabetes & Metabolic Diseases, Medical School of Belgrade• Head of Department Endocrine Oncology & Hereditary Cancer Syndromes, Institute of Endocrinology, Diabetes & Metabolic Diseases, Medical School of Belgrade• Head of Laboratory for Hereditary Malignant Tumors, Institute of Endocrinology, Diabetes & Metabolic Diseases, Medical School of Belgrade

Education:

M.D.: Medical School, University of Belgrade 1978M.S.: Molecular Biology with Biochemistry, University of Belgrade 1986Ph.D.: Medical School, University of Belgrade 1993

Training: Department of Endocrinology St Bartholomew's Hospital, London 1987, UKDepartment of Endocrinology, Royal Victoria Hospital, Newcastle upon Tyne, 1991, UK

Membership: Serbian Medical Association 1987, President of Endocrine Section of Serbian Medical Association 2004-ENEA (European Neuroendocrine Association) 1993ENETS 2006-

Professional Experience:

Specialist of Internal Medicine, Internal Clinic B, Medical Scholl, University of Belgrade 1985-Subspecialist of Endocrinology, Institute of Endocrinology, Diabetes and Metabolic Diseases, Medi-cal School, University of Belgrade 1987-

Academic carrier:

Professor of Internal Medicine, Medical School of Belgrade, University of Belgrade, 1999-

Projects:

1. Participant in project “New Molecules in the Control of Growth Hormone (GH) Secretion and Energy Homeostasis in Humans” and leader investigator in project: “Molecular Basis of MEN syndromes and Endocrine Dependent Tumors”, financed by Serbian Ministry of Science (M1717).2. Participant in project “Stress Induced Modulation of Glucocorticoid Receptor Function” financed by Serbian Ministry of Science (Bio1654).3. Participant and consortium member in project: “Psychobiology of Posttraumatic Stress Disorder” financed by Sixth Framework Program Priority Inco – WBC– 509213.

Publications:

More than 70 publications in pair reviewed journals (some of them are listed).

1. Popovic V, Damjanovic S, Micic D, Djurovic M, Diguez C, Casanueva F: BLOCKED GROWTH HORMONE-RELEASING PEPTIDE (GHRP-6)-INDUCED GH SECRETION AND ABSCENCE OF THE SYNERGIC ACTION OF GHRP-6 PLUS GH-RELEASING HORMONE IN PATIENTS WITH HYPOTHALAMO-PITUITARY DISCONNECTION; EVIDENCE THAT GHRP-6 MAIN ACTION IS EX-ERTED AT THE HYPOTHALAMIC LEVEL, J Clin Endocrinol Metab 80: 942-947, 1995.2. Damjanović SS, Petakov M., Raicević S., Micić D., Marinković J, Diguez C, Casanueva FF, Popović V: SERUM LEPTIN LEVELS IN PATIENTS WITH ACROMEGALY BEFORE AND AFTER COR-RECTION OF HYPERSOMATOTROPISM BY TRANS-SPHENOIDAL SURGERY. J Clin Endocrinol Metab 85:147-154, 2000.3. Damjanović SS, Nešković A, Petakov M, Popović V, Vujisić B, Petrović M, Đurović M, Simić M, Pekić S, Marinković J. HIGH OUTPUT HEART FAILURE IN PATIENTS WITH NEWLY DIAGNOSED ACROMEGALY. Am J Med 112:610-16, 2002.

4. Damjanovic SS, Neskovic AN, Petakov M, Popovic V, Macut D, Vukojevic P, Joksimovic M: CLINICAL INDICATORS OF BIOCHEMICAL REMISSION IN ACROMEGALY: DOES INCOMPLETE DISEASE CONTROL ALWAYS MEAN THERAPEUTIC FAILURE? Clin Endocrinol (Oxf) 62:410-417, 2005.

5. Damjanović SS, Lalic N, Peško PM, Petakov MS, Jotić A, Miljić D, Lalić KS, Lukić Lj, Djurović M, Djukić VB: ACUTE EFFECTS OF GHRELIN ON INSULIN SECRETION AND GLUCOSE DISPOSAL RATE IN GASTRECTOMIZED PATIENTS. J Clin Endocrinol Metab, 91:2574-2581, 2006.

6. Damjanovic SS, Stojic RV, Lalic NM, Jotic AZ, Macut DP, Ognjanovic SI, Petakov MS, Popovic BM: RELATIONSHIP BETWEEN BASAL METABOLIC RATE AND CORTISOL SECRETION THROUGHOUT PREGNANCY. Endocrine, 35:262-268, 2009.

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LALIĆ

CURRICULUM VITAE DR ARIE BERGHOUT FRCP 2008 Director Teaching Hospital Maasstad Ziekenhuis Rotterdam 1992-2008 Head of the Department of Medicine Maasstad Ziekenhuis Rotterdam

Subspecialties endocrinology, diabetes and vascular medicine 1990-1991 University of Newcastle-upon-Tyne First assistant Department of Medicine (Endocrinology) Royal Victoria Infirmary, Newcastle-upon-Tyne, United Kingdom1990 Academic thesis ‘Sporadic Nontoxic Goitre’1989 Postgraduate course Clinical Epidemiology and Biostatistics, MacMaster University, Hamilton, Ontario, Canada1984-1990 Department of Endocrinology Academic Medical Centre Amsterdam1977-1984 Training Internal Medicine Haarlem and The Hague1967- 1976 Study of Medicine University of Amsterdam

DR ARIE BERGHOUT

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ABSTRACTHashimoto encepha-

lopathy (HE) is still not well understood autoimmune disease with neurological and/or psychiatric manifes-tations and elevated titers of antithyroid antibodies in se-rum and cerebrospinal fluid. Pathogenesis of HE is still not well understood but autoim-mune mechanism with an-tibodies against antigens in brain cortex are suspected. This disease accompanies some cases of Hashimoto thyroiditis but can occure by itself. The main characteris-tic of HE is the presence of two types of autoantibod-

ies: thyroglobulin (TGAb) and/or thyroxin peroxidase (TPOAb). Patients are mostly women. Age vary from 8 to 86 years (mean 46 years). Prevalence of HE is esti-mated to be 2.1/100 000 in general population. There are two main types of HE: occurrences of stroke-like episodes and the clinical pic-ture mimicking Creutzfeldt-Jakob disease but there are also monosymptomatic psychiatric illness, demen-tia, seizures, myelopathy, myoclonus, various types of tremor, peripheral nervous system disturbances and cerebellar symptoms. Dis-

ease course can be acute, subacute, chronic or relaps-ing-remitting. Thyroid func-tion does not influence sig-nificantly the clnical picture of HE and patients can be hypothyroid (63%), hyper-thyroid (5%) and euthyroid (22%). HE responds well to corticosteroid therapy but sometimes other immuno-modulatory therapies must be tried. Some patients im-prove spontaneously but a few die in spite of intensive therapy.

Key words: Hashimo-to encephalopathy, Hashi-moto thyroiditis, autoimmu-nity, anti-TPO antibodies.

BIОGRАFIЈА PRЕDАVАČА Drаgаn Pаvlоvić је vаnrеdni prоfеsоr nа Fаkultеtu zа spеciјаlnu еdukаciјu i rеhаbilitаciјu Univеrzitеtа u Bеоgrаdu. Prеdаvаč sе bаvi bihеviоrаlnоm nеurоlоgiјоm i nеurоpsihоlоgiјоm i оbјаviо је vеći brој rаdоvа, pоglаvlја i mоnоgrаfiја iz оvih оblаsti. Dr Pаvlоvić sе usаvršаvао

u vоdеćim cеntrimа zа nеurоlоgiјu, bihеviоrаlnu nеurоlоgiјu, nеurоpsihоlоgiјu i psihоgеriјаtriјu u svеtu. Dr Pаvlоvić је оdržао vеliki brој prеdаvаnjа pо pоzivu iz оblаsti nеurоlоgiје, bihеviоrаlnе nеurоlоgiје, nеurоpsihоlоgiје, dеmеnciја, trаumаtskih pоvrеdа glаvе, nеurоеndоkrinоlоgiје, nеurоinfеkciја i drugih оblаsti.

DRAGAN PAVLOVIĆ

CURRICULUM VITAE Name: Johannes Anthonius Romijn

Address: Dept. of Medicine, F4 Academic Medical Center University of AmsterdamMeibergdreef 9 1105 AZ AmsterdamThe Netherlands Tel +31 20 5662171 Fax +31 206919658 e-mail: j.a.romijn@amc.uva.nl 1077 WD Amsterdam

Education and positions:1981 M.D., University of Amsterdam1981-1986 Residency training in internal medicine, AMC, University of Amsterdam1986-1998 Internist, AMC, University of Amsterdam, The Netherlands1990 Ph D Thesis: “On metabolic regulation by starvation and disease”, University of Amsterdam.1993-1996 Vice Chairman, Dept of Intensive Care, AMC, Amsterdam1996-1998 Professor in Clinical Nutrition, Leiden University Medical Center, Leiden,The Netherlands1999-present Professor of Medicine and of Endocrinology, Leiden University Medical Center1999-2010 Chairman Depts of Medicine and Endocrinology, Leiden University Medical Center2004-2010 Director, Residency Program in Internal Medicine, LUMC2010-present Professor of Medicine, Chairman of the Departments and Division of Medicine, Academic Medical Center, University of Amsterdam, The Netherlands Publications: 500 publications in peer-reviewed international journals cited in PubMed, and chapters in books on metabolic and endocrine regulation in both clinical and experimental studies.

JOHANNES ANTHONIUS ROMIJN

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MILOŠ ŽARKOVIĆ

During the last few years, establishing the upper limit of TSH reference range has been the subject of numerous discussions

and considerable research. The key question is whether the upper limit should be reduced from about 4 mU/l to 3 or 2.5 mU/l. The reference ranges reported by Hollowel from the NHANES III study which included 13344 refer-ence subjects were 0.45 to 4.12 mU/l. Hamilton

et all, in a carefully defined reference population (766 reference subjects) reported TSH reference limits between 0.54 and 3.37 mU/l, using ELISA to measure TSH. However, using the immuno-chemiluminometric assay, the upper reference range in this study was 4.11 mU/l. Kratzsch et al. reported TSH reference limits between 0.40 and 3.77 mU/l. Friis-Hansen and Hilsted re-ported reference intervals for TSH between 0.64

Žarković MilošClinic of Endocrinology, Dr Subotića 13, 11000 Belgrade; SerbiaTel: +381-11-3639-724 (W), Fax: +381-3639-776E-mail: milos.zarkovic@gmail.comsmzarkov@med.bg.ac.rs

EducationMedical Faculty, University of Belgrade 1984Belgrade, SerbiaGRADUATED.Medical Faculty, University of Belgrade 1990Belgrade, SerbiaMA DEGREE IN MEDICAL SCIENCES, ENDOCRINOLOGY FOR THE WORK ENTITLED

”CONCENTRATIONS OF GLUCOSE, INSULIN, C PEPTIDE, GLUCAGON AND CATECHOLAMINES IN HUMAN BLOOD DURING TRH TEST“.

Medical Faculty, University of Belgrade 1992Belgrade, SerbiaPH.D. DEGREE IN MEDICAL SCIENCES, ENDOCRINOLOGY FOR THE WORK ENTITLED

“DETECTION OF EPISODIC HORMONE SECRETION”.Medical Faculty, University of Belgrade 1993Belgrade, SerbiaBECAME A SPECIALIST IN INTERNAL MEDICINE.Medical Faculty, University of Belgrade 1999

TSH reference range: What do the data show?Miloš ŽarkovićSchool of Medicine, University of Belgrade Clinic of Endocrinology, Clinical Center of Serbia, Belgrade

Belgrade, SerbiaBECAME A SUBSPECIALIST IN ENDOCRINOLOGY.

PROFESSIONAL EXPERIENCEMedical Faculty, University of Belgrade from 2000 up to nowBelgrade, SerbiaASSOCIATE PROFESSOR OF INTERNAL MEDICINE.Medical Faculty, University of Belgrade from 1994 up to 1999Belgrade, SerbiaASSISTANT PROFESSOR OF INTERNAL MEDICINE.Institute of Endocrinology from 1987 up to nowBelgrade, SerbiaEMPLOYED AS A PHYSICIAN.

PROFESSIONAL MEMBERSHIPSTHE SERBIAN MEDICAL ASSOCIATION – ENDOCRINE SOCIETYTHE SEBIAN THYROID ASSOCIATIONSOCIETY FOR ENDOCRINOLOGY (UNITED KINGDOM)THE ENDOCRINE SOCIETY (US)THE EUROPEAN THYROID ASSOCIATION (ETA)THE SERBIAN STATISTICS SOCIETY

and 4.7 mU/l. In the carefully defined reference Serbian population TSH reference range is 0.45 to 3.43 mU/l.TSH data distribution is always right skewed. In some of the studies, the TSH distribution is con-sidered to be lognormal, but that could not be proven in all studies. In the study by Zarkovic et al, smoothed density plots of TSH distribu-tion showed a robust pattern of multiple peaks.

However, interpretation of data depends on the theoretical framework. It could be a lognormal distribution, or a mixture of multiple normal dis-tributions caused by different factors (sex, age, genetics, disease, etc.). It should be noted that if we are dealing with the multimodal distribution descriptive statistics intended for unimodal distri-bution would be misleading.