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Thyroid International - ETA2019 - Issue 01/2019 - Merck Healthcare Professionals ...
Thyroid
International
                                      Issue 01/2019

ETA2019

41st Annual Meeting of the European
Thyroid Association
Disclaimer                                                                                                  Contents
                                                     Thyroid International                                  41st Annual Meeting of the European Thyroid                                        The ETA Industry-Sponsored Satellite
This scientific publication is published by
                                                                                                            Association................................................................... 1
and with financial support from Merck KGaA,                                                                                                                                                    SYMPOSIUM (Sanofi Genzyme)................................... 17

Darmstadt, Germany subject to the requirement                                                               In Remembrance.......................................................... 2           Latest Developments in Thyroid Cancer Management
                                                     Editor-in-Chief: Peter PA Smyth, UCD, Dublin
that article(s) published are of a scientific                                                               Topic Highlights............................................................ 3       Chair Rosella Elisei (Italy).                                        17
                                                     This is the title of a publication series published
nature. The views expressed by the author(s) do      by and with financial support from Merck KGaA,           Pearce, Newcastle                                                           3         Bournaud, France                                                  17
not necessarily reflect the views, ideas or policy   Darmstadt, Germany.                                      Nemeth, Budapest                                                            3         Wadsley, United Kingdom                                           17
of Merck KGaA.                                                                                                Puxeddu, Perugia and Pisa                                                   3    ETA Industry sponsored (Bayer)
                                                     The Editor-in-Chief is publishing papers from
This publication is provided for general                                                                      Luongo, Paris and Essen                                                     4    Satellite Symposium................................................... 18
                                                     renowned international thyroid experts in order
reference only and is intended solely for                                                                     Oczko-Wojciechowska, Gliwice                                                4      Experience in action: RAI-R DTC in 2018                              18
                                                     to pass on the extensive experience which the
healthcare professionals. As a result of ongoing                                                              Groeneweg, Rotterdam                                                        5         Sophie Leboulleux, France                                         18
                                                     authors possess in their field to a wide range
medical advances and developments, the               of physicians dealing with the diagnosis and           Special Lectures........................................................... 6           Smit, The Netherlands                                             18
information in this material may not always          therapy of thyroid diseases. Please refer to the                                                                                               Brose, USA                                                        18
                                                                                                              E uropean Thyroid Journal (ETJ) Lecture                                    6
be completely up to date and, for this reason,       full disclaimer on the inside front cover.
                                                                                                                 Wilmar Wiersinga, The Netherlands                                        6    Selected Abstracts..................................................... 19
such information is provided on an “as is”
                                                                                                                 Harrington-de Visscher Prize Lecture                                     6      Muller and colleagues, Cardiff                                       19
and “as available” basis. Merck KGaA makes           Responsible at Merck KGaA, Darmstadt,
                                                                                                                                                                                                 Davies, New York                                                     19
no warranties, representations or gives any          Germany: Renato P. Oliveira                            Pinchera Prize Lecture.................................................. 8
                                                                                                                                                                                                 Folkestad, Odense                                                    20
undertakings either express or implied about                                                                   hair(s): Pilar Santisteban (Spain) & Colin Dayan (United
                                                                                                              C
                                                     Thyroid International · 1-2019                           Kingdom)                                                   8                       Wang et al, Shenyang                                                 20
any content of this publication.
                                                                                                                                                                                                 Leenhardt, Villejuif                                                 21
                                                     Merck KGaA, Darmstadt, Germany, D-64271                ETA Symposium (Basic)................................................ 9
It may refer to pharmaceutical products,                                                                                                                                                         Morillo, Madrid                                                      21
                                                                                                              Thyroid Hormone Action through Time                                         9
therapeutics or indications not registered or        ISSN 0946-5464                                                                                                                              Diana et al, Mainz                                                   22
                                                                                                                 Vincent Laudet, France                                                   9
approved in a given country.                                                                                                                                                                     Lillevang-Johansen, Odense                                           22
                                                     Full text versions of previous Thyroid International        Remaud, France                                                           9
                                                                                                                                                                                                 Zøylner Swan, Aarhus                                                 22
Please always refer to the full prescribing          editions are available at:                                  Hollenberg, USA                                                        10
information applicable in your country for any                                                                                                                                                   Bliddal, Copenhagen                                                  23
                                                     hcp.merckgroup.com/en/thyroid                          ETA Symposium (Translational): The future is in vivo. 11
pharmaceutical product.                                                                                                                                                                          Biscarini, Cardiff                                                   23
                                                                                                              Chair(s): Monica Dentice (Italy) & Jens Mittag (Germany) 11                        Wasniewska, Messina                                                  24
Registration conditions, warnings and                                                                            Marelli, Italy                                                         11       Leng et al, Newcastle                                                24
precautions for pharmaceutical products differ                                                                   Heuer, Germany                                                         11       Centanni, Latina                                                     24
from country to country.                                                                                         Bassett, UK                                                            12       Kim et al, Seoul                                                     25

Copyright in this publication is expressly owned                                                            ETA Industry Sponsored Satellite Symposia............... 13                        Previous Editions of Thyroid International................. 26
by Merck KGaA and/or its Affiliates (except                                                                    erck Symposium: Pharmacokinetics & Bioequivalence
                                                                                                              M
                                                                                                              of L-T4 compounds                                                         13
for any third party content which has been
                                                                                                                 Lipp, Tubingen                                                         13
identified as such).
                                                                                                              Bioequivalence of L-T4                                                    14
All rights reserved.                                                                                             Ravzi, Newcastle                                                       14

Production Date: June 2019                                                                                  ETA Industry Sponsored (Berlin Chemie)
                                                                                                            Satellite Symposium................................................... 15
                                                                                                              Thyroid Update                                                            15
                                                                                                                 Santisteban, Madrid                                                    15
                                                                                                                 Dayan, Cardiff                                                         15
                                                                                                                 Bednarczuk, Warsaw                                                     16

2                                                                                                                                                                                                                                                                     3
41st Annual Meeting of the                                                                              In remembrance...
European Thyroid Association
                                                                                                                                           It was with great sadness that the meeting
                                                                                                                                           acknowledged the recent death of former
Newcastle, England, September 15-18, 2018
                                                                                                                                           President and distinguished thyroidologist
Peter PA Smyth, Dublin, Ireland
                                                                                                                                           Theo Visser, Rotterdam, whose memory
                                                                                                                                           was celebrated in a talk by Robin Peeters,
The 41st Annual Meeting of the European             Newcastle was a particularly appropriate site                                          The Netherlands. Another distinguished
Thyroid Association (ETA) was held in               for a thyroid conference as it was the location                                        thyroidologist Reginald Hall, much of whose
the dramatic setting of Sage, Gateshead,            of the first use of thyroid hormone replacement                                        career was spent in Newcastle, was honored in
overlooking the River Tyne from 15-18               therapy in 1891, when Dr. George Murray                                                a lecture by Tony Weetman, UK.
September 2018. The well-attended meeting           treated the first hypothyroid patients with sheep
attracted 961 full participants and 11 one day      thyroid extract. The location had particular                                           Further, it is with deep regret that we at
attendees. The program, organized by the            resonance for older members as the city had                                            Thyroid International learned of the death of
Executive Committee under ETA President Pilar       hosted the 10 th ETA Annual Meeting in 1979.                                           Georg Hennemann on 27 December 2018.
Santisteban, consisted of 13 oral sessions with                                                                                            Together with his Rotterdam colleague Eric
98 individual presentations. These included         The opening ceremony took place in the Sage                                            Krenning, Georg edited Thyroid International
the now very successful Topic Highlights and        Conference Centre with an ETA Network Dinner                                           from its inception until 2005. He was a highly
Short Call Abstracts. Daily poster sessions         in ‘The Biscuit Factory.’ The ETA Program                                              distinguished thyroidologist both as a clinician
included 203 posters with leader-chaired poster     Committee and Local Organizing Committee                                               and basic researcher. A past President of the
discussion sessions. The six ETA Symposia were      under Simon Pearce worked extremely hard                                               European Thyroid Association, Georg was one of
evenly divided between clinical and basic topics.   to fit so much activity so successfully into                                           the giants of European and world thyroidology
In addition, there were six Industry Sponsored      four days.                                                                             who will be sorely missed.
Satellite Symposia. Also included were the          This is not intended to be a comprehensive
                                                                                                        Georg Hennemann                    May he rest in peace.
customary Iodine Global Network (formerly           report of all the meeting activities but
ICCIDD) and ETA-CRN satellite meetings.                                                                 (1 July 1932 - 27 December 2018)
                                                    represents my subjective preferences. The
Educational needs were serviced by eight Meet       text of all the accepted abstracts for ETA 2016
the Expert sessions and two Updates, Clinical                                                                                              Peter Smyth - Editor in Chief
                                                    can be viewed at www.eta2018.com or on the
and Basic, as well as the customary                 ETA website: www.eurothyroid.com. ETA 2018
ultrasound course.                                  Abstracts are published as a supplement to the
                                                    European Thyroid Journal Vol. 7, Suppl. 1, 2018.

                                                    Peter Smyth - Editor in Chief, October 2018

1                                                                                                                                                                                        2
Topic Highlights                                                                             The authors concluded that ATC, PTC and PDTC each showed a peculiar and specific
                                                                                             pattern of interaction with the immune system compared to normal tissue; in this
                                                                                             regard, PDTCs appear to have only a modest deregulation of immune-related pathways.
Pearce, Newcastle reported on ‘Antigen-Specific Immune-Modulation Using TSH
Receptor Peptides (ATX-GD-59) for Graves’ Hyperthyroidism: Results Of A First-In-            Luongo, Paris and Essen presented data on ‘Local control of thyroid hormone
Human Study’. In this study, antigen specific immunotherapy via intradermal injections       availability determines cell fate decisions in the adult neural stem niche’. They examined
of ATX-GD-59 in a gradually escalating dose to a maximum of 800 μg followed by five          how neural stem cell (NSC) fate, to either a neuronal or an oligodendroglial progenitor,
further injections of 800 μg were administered to 12 patients with mild untreated            is modified by thyroid hormone (TH) availability. She explained that TH availability is
Graves’ hyperthyroidism. Three subjects were subsequently excluded. Following ten            regulated by expression of thyroid hormone transporters (THTs) and deiodinases. As
doses of ATX-GD-59, six of the nine subjects (67%) had made a full or partial response,      MCT8 and OATP1C1 knockout (KO) mice display reduced SVZ (Subventricular Zone)
with four having both Free T3 (FT3) and Free T4 (FT4) within reference range (means          derived neurogenesis, they hypothesized that in the murine adult SVZ, neuron-glia
5.1 pmol/l and 15.8 pmol/l, respectively; full response). The remaining three subjects       lineage fate decisions involve a tight regulation of TH availability. THTs expression was
had FT3 above the reference range. No subjects had to be rescued with carbimazole            analyzed using immunohistochemistry and reverse transcription polymerase chain
during the 20 weeks of dosing, but three subjects had higher FT3 or FT4 concentrations       reaction (RT-qPCR) performed on NSCs and their progeny isolated by flow cytometry.
at the end of the treatment than at baseline. He questioned whether the observed             THTs, deiodinases and TH receptors were differentially expressed in NSC/progenitors
improvement could be spontaneous remission as improvement exceeded other studies.            cells and neuroblasts: MCT8 and OATP1C1 highly expressed in NSCs and neuronal
He concluded that as no new treatments for Graves’ hyperthyroidism had appeared in           progenitors (NPCs), but not in oligodendrocyte progenitors (OPCs). In contrast, OPCs,
60 years, his study shows a first signal for the efficacy of ATX-GD-59 in patients with      but not NPCs, express high levels of the T3-inactivating deiodinase, D3, thus protecting
untreated Graves’ hyperthyroidism.                                                           OPCs from the neutralizing effects of T3. In the adult double knockout (DKO) SVZ, they
                                                                                             observed a dramatic reduction in the numbers of NSCs and NPCs, while OPCs number
Nemeth, Budapest talked about the ‘Development of a recombinant Fluorescence
                                                                                             was unaffected. She concluded that in NPCs, high intracellular TH availability is favored
resonance energy transfer (FRET)-based biosensor to assess compartment-specific
                                                                                             by the expression of THTs and effects of TH by the presence of human thyroid hormone
Triiodothyronine (T3) levels in live cells’. She described the development of a tool to
                                                                                             receptor alpha (TRα1). In contrast, in OPCs, D3 expression reduces T3 availability
allow the detection of T3 movement into cells. The group generated a recombinant
                                                                                             thereby promoting glial determination. The absence of THTs induces a strong reduction
biosensor undergoing T3-evoked conformational changes that is manifested in increased
                                                                                             of SVZ-derived NSCs and NPCs.
energy transfer that can be measured by FRET in live cells. The sensor consisted of
the human thyroid hormone receptor beta (TRβ) ligand binding domain (LBD) inserted           Oczko-Wojciechowska, Gliwice discussed whole-genome methylation profiling of
between well characterized FRET pair, mTurquoise2 and YPet. Using optimal conditions         Medullary Thyroid Cancer (MTC). She pointed out that while genetic events in MTC such
in which the biosensor was transfected into HEK293 cells, an increased FRET signal was       as RET and RAS mutations are well characterized; the epigenetic basis of this disease
observed selectively in the nucleus after ten minutes followed by the T3 addition. The       is still poorly understood. The aim of the study was a description of MTC methylome
findings indicate that the FRET-based T3-biosensor can assess compartment-specific T3        and its relationship with genotype and phenotype of the tumor (MTC clinical course
availability in live cells and will be especially useful for studies in polarized cells      and outcome). Methylation profiles were performed on 60 post-operative fresh frozen
e.g. neurons.                                                                                MTC tissue samples (30 RET positive, 18 RAS positive, three with co-existence of RET
                                                                                             and RAS mutation and nine with no detectable RET and RAS mutations) using Human
Puxeddu, Perugia and Pisa described ‘The use of nanostring technology to define
                                                                                             Methylation 450 K BeadChips. The most distinct differences in methylation pattern
the immune profile of thyroid carcinoma’. Understanding mechanisms such as
                                                                                             were observed among samples carrying mutations in RAS genes and samples with
immunodeleting and oncogenesis underlying thyroid cancer immune escape can lead
                                                                                             no detectable somatic RAS and RET mutations. The differences in methylation profile
to the identification of new molecular targets and/or efficacy biomarkers, possibly
                                                                                             between RET positive samples and samples with no detectable somatic RAS and RET
translatable to other cancer models. Immune expression profiling was performed in
                                                                                             mutations were also significant, and 422 probes demonstrated distinct methylation
thyroid cancers to obtain a comprehensive view on immune mechanisms activated in
                                                                                             status. In terms of MTC clinical outcome, significant differences in tumor methylation
the microenvironment of the tumors during cancer progression. Studies were conducted
                                                                                             pattern were noticed between the group of patients, who achieved complete remission
retrospectively in 25 papillary thyroid carcinomas (PTC), 14 poorly differentiated thyroid
                                                                                             and those with persistent biochemical or structural disease. The findings suggest that
carcinomas (PDTC), 13 anaplastic thyroid carcinomas (ATC), and seven normal thyroid
                                                                                             MTC methylation status may be considered as a prognostic factor of MTC outcome.
tissue samples (NT). Using the Kyoto Encyclopedia of Genes and Genomes (KEGG)
pathway enrichment analysis, ATC, and to a lower extent PTC, showed a significant
enrichment of up-regulated genes in the cell adhesion (including PD-L1, PD-L2, LAG-
3, TIGIT and their receptors) and cytokine-cytokine receptor pathways. There was a
correlation between histological type and immune presentation with 57% ATC, 43% PTC
but only 30% in PDTC showing correlation.

3                                                                                                                                                                                    4
Groeneweg, Rotterdam described ‘Thyroid hormone analog therapy in patients with              Special Lectures
MCT8 deficiency: The TRIAC trial’. This communication was dedicated to the memory
of the late Theo Visser. The author reviewed how mutations in the thyroid hormone
                                                                                             European Thyroid Journal (ETJ) Lecture
(TH) transporter MCT8 result in MCT8 deficiency, which is characterized by severe
intellectual and motor disability and high serum T3 concentrations inducing thyrotoxicity
in peripheral tissues. The objective was to study the effect of 3,5,3,’-Triiodothyroacetic   Wilmar Wiersinga, The Netherlands, Editor of the ETJ, introduced the ETJ Prize
acid (TRIAC) on serum T3 concentrations and signs of thyrotoxicosis in patients with         Lecturer for 2018, Miguel Lopez, Spain. The title of his lecture was ‘Energy balance
MCT8 deficiency. He pointed out that in hyperthyroidism, transporters other than             regulation of thyroid hormones at central level’. He explained how current thinking
MCT8 predominate. A trial was conducted in which 40 patients with MCT8 deficiency            was directed at how TH affects food intake, energy expenditure, and metabolism by
received TRIAC treatment for one year. The primary endpoint was the reduction of             acting to a large extent at the central level. His example was how hyperthyroidism
serum T3 concentrations, and secondary endpoints included normalization of heart             induces leanness despite stimulating increased appetite. He explained how effects of
rate (HR), improvement of body weight (BW), and serum parameters that reflect TH             THs are interrelated with global energy sensors in the central nervous system (CNS),
action in peripheral tissues. Interim analysis of findings indicates that TRIAC treatment    such as uncoupling protein 2 (UCP2), AMP-activated protein kinase (AMPK; the ‘AMPK–
effectively normalizes serum T3 concentrations in patients with MCT8 deficiency. Both        BAT axis’), and mechanistic target of rapamycin (mTOR) which serves as a whole-body
clinical outcomes (BW, BMI, and HR) and biochemical markers representing the thyroid         nuclear sensor. The TH receptor Trα co-locates with mTOR in the arcuate nucleus of the
state in different tissues improved on TRIAC treatment.                                      hypothalamus (ARC). T3 in the ARC induces mTOR signaling and induces feeding through
                                                                                             mTOR signaling. Central T3 promotes hepatic lipogenesis with parallel stimulation of
                                                                                             the thermogenic program in brown adipose tissue (BAT). Central action of T3 regulates
                                                                                             de novo lipogenesis in liver and lipid oxidation in BAT through the parasympathetic
                                                                                             (PSNS) and sympathetic nervous system (SNS), respectively. The action of T3
                                                                                             depends on AMP-activated protein kinase (AMPK)-induced regulation of two signaling
                                                                                             pathways in the ventromedial nucleus of the hypothalamus (VMH), which promotes BAT
                                                                                             thermogenesis, and increased c-Jun N-terminal kinase (JNK) activation, which controls
                                                                                             hepatic lipid metabolism. He defined AMPK as nature’s energy sensor. Hyperthyroidism
                                                                                             i.e. excess T3, inhibits hypothalamic AMPK. T3 in the VMH decreased ceramide-induced
                                                                                             endoplasmic reticulum (ER) stress while T3 in the VMH increases hepatic lipogenesis
                                                                                             through JNK1 which controls hepatic lipid metabolism. Finally, he described a strategy
                                                                                             for targeting hypothalamic AMPK by analyzing its phosphorylated protein levels in
                                                                                             specific neuronal subsets as AMPK is activated when it is phosphorylated at Thr-172.

                                                                                             Harrington-de Visscher Prize Lecture entitled ‘Winter is coming (the role of Thyroid
                                                                                             Hormone Receptor α1 in adaptation to cold) was delivered by Jens Mittag, Lubeck.

                                                                                             Speaking of the importance of the Thyroid Hormone Receptor (TRα1) Mittag
                                                                                             demonstrated how mice became disoriented in the presence of a (TRα1) mutation.
                                                                                             Addition of T3 resulted in a significant improvement. He explained how activation of
                                                                                             TRα1 in mice by binding T3 increases metabolic heat production to maintain the core
                                                                                             body temperature, followed by shivering. However, body temperature can remain low.
                                                                                             He used the analogy of how a house, when heated, gets warm but loses heat through
                                                                                             the roof and windows. In the TRα1 mutant mouse, impaired acetylcholine-mediated
                                                                                             vascular relaxation as well as phenylephrine-induced vasoconstriction results in heat
                                                                                             loss through the tail arteries which in turn leads to compensatory alterations in brown
                                                                                             fat activity. The administration of T3 reverses the vasodilation defect and allows for
                                                                                             heat retention. When the defect in mice heterozygous for a point mutation in thyroid
                                                                                             hormone receptor α1 was reversed with the selective α1-adrenergic agonist midodrine,
                                                                                             the inappropriate heat loss over their tail surface was reduced, normalizing brown fat
                                                                                             activity and energy expenditure. The impaired TRα1 signaling leading to tail heat loss
                                                                                             in the mouse may be related to the cold sensitivity observed in hypothyroid patients.
                                                                                             Mutation of TRα1 in heart tissue causes bradycardia. He described how thyroid hormone
                                                                                             in addition to its profound direct effects on cardiovascular function and metabolism also
                                                                                             regulates these systems indirectly through the Central Nervous System

5                                                                                                                                                                                   6
He also described how parvalbuminergic neurons in the anterior hypothalamus require        Pinchera Prize Lecture
thyroid hormone receptor signaling for proper development. Defects in autonomic
innervation are observed in TRα1 mutant mice. Impaired TRα1 signaling leads to a
                                                                                           Chair(s): Pilar Santisteban (Spain) & Colin Dayan (United Kingdom)
reduced number of hypothalamic parvalbuminergic neurons which control heart and
blood pressure in a temperature dependent manner. Neuronal ablation in the mouse
resulted in hypertension and temperature-dependent tachycardia, indicating a role          The Pinchera Prize Lecturer for 2018 was Rosella Elisei, Pisa. She outlined her
in the central autonomic control of blood pressure and heart rate. Parvalbuminergic        long association with Aldo Pinchera and his influence on her career. The title of her
neurons are dependent on maternal TH and link maternal endocrinology to                    lecture was ‘Medullary Thyroid Cancer: From Genetics to Therapy’. She explained that
cardiovascular function in the offspring. He concluded that the data suggest that the      Medullary thyroid carcinoma (MTC) is a rare endocrine tumor that accounts for 5-8%
offspring of a hypothyroid mother may have a defect in central control of cardiovascular   of all thyroid carcinomas, but represents up to 13.4% of thyroid cancer-related deaths.
function and might be hypertensive, suggesting that measurement of blood pressure          It occurs as a sporadic tumor in about 75-80% of those treated and as a hereditary
should be included in assessment of such individuals.                                      tumor in others (20-25%). Hereditary MTC can be associated with other endocrine
                                                                                           tumors, in a syndrome termed Multiple Endocrine Neoplasia Syndrome (MEN 2A and
                                                                                           2B) with a ten-year disease-specific survival rate of about 75%. The defect responsible
                                                                                           for hereditary MTC is found on chromosome 10 with germ-line point mutations in the
                                                                                           RET protooncogene responsible for tumor growth and for the heritage setting of MEN
                                                                                           2A and 2B. She reported on 1,160 patients with sporadic MTC and 166 with hereditary
                                                                                           MEN 2. All were submitted to genetic screening. In contrast to the alterations found
                                                                                           in PTC, the activation of RET in MTC is mainly due to activating point mutations. RET
                                                                                           mutations are a very strong factor for poor prognosis in medullary thyroid cancer. One
                                                                                           or more somatic RET mutations are found in 86% of advanced sporadic MTC. Mutations
                                                                                           in MTC included 10.1% RAS; 41.5% RET but 47.4% with no mutations. Of those with a
                                                                                           mutation, approximately 90% had exclusively those of RAS and RET. There was a low
                                                                                           heterogeneity with respect to other cancers as 80% had one mutation or the other.
                                                                                           She then described the search for gene mutations in those tumors who were RET or
                                                                                           RAS negative using analysis of circulating tumoral DNA. Of 165 families examined, 667
                                                                                           relatives were screened for RET gene deletion. Some 42% were RET+ with 58% showing
                                                                                           mixed genetic screening. RET genetic screening can determine the reclassification
                                                                                           of apparently sporadic MTC. She noted that not all RET mutations are transforming
                                                                                           with no MTC being observed in heterozygotes. Several RET mutations are not of the
                                                                                           transforming variety. On the subject of serum calcitonin measurement in management
                                                                                           of MTC, she noted that the area remained controversial.

                                                                                           The use of genetics in MTC therapy was mainly directed at the P13 Kinase pathway
                                                                                           which is activated in RET mutations. She discussed the use of multikinase inhibitors,
                                                                                           in particular vandetanib and cabozantanib. They both showed a significant increase in
                                                                                           prognosis with the latter having more side effects. She advised that while both drugs
                                                                                           gave similar results, they should be utilized according to the type of tumor. Vandetanib
                                                                                           targets the epidermal growth factor (EGF) and vascular endothelial growth factor
                                                                                           (VEGF) receptors while cabozantanib is a multikinase inhibitor. The adverse side effects
                                                                                           of both compounds are due to their activity against otherwise beneficial biological
                                                                                           inhibitors. She concluded that long-term studies for the clinical evaluation of RET
                                                                                           specific inhibitors are currently under way.

7                                                                                                                                                                                 8
ETA Symposium (Basic)                                                                       Hollenberg, USA discussed ‘Thyroid hormone and eternal life’ and explained that while
                                                                                            TH affected many tissues, there was a shortage of biomarkers for TH action. The most
                                                                                            commonly used biomarker, serum Thyroid Stimulating Hormone (TSH), only reflected
Thyroid Hormone Action through Time
                                                                                            action at the pituitary level and not other tissues. Intracellular T3 levels determine
                                                                                            TH action on peripheral tissues and CNS control of the intracellular availability of TH,
Vincent Laudet, France presented data on ‘Evolution of thyroid hormone action’ and          with the result that circulating concentrations of TH are not fully representative of
explained how thyroid hormones control a complex hierarchical cascade of target genes       what each cell type sees. TH transporters, deiodinases and thyroid hormone receptor
by binding to specific receptors, TRα and TRβ, ligand-activated transcription factors       coregulators can strongly control tissue-specific sensitivity to a set amount of TH.
belonging to the nuclear receptor superfamily. Metamorphosis is actually widespread         Recently, hypothyroidism has been associated with both neurological disease and a
in vertebrates, though quite diverse in the way it manifests in a particular species.       longer life span. Levels of TSH have been associated with longevity, schizophrenia,
THs are key coordinators of post-embryonic development, allowing its coupling with          or bipolar disorder in two independent studies, suggesting that octogenarians and/or
external conditions and the adjustment of the internal physiology of the organism. In       patients with schizophrenia have higher concentrations of circulating TSH. He postulated
studying the predation effect in fish, he demonstrated that TH increased survivability.     that increasing TSH may be a physiological response to aging and that lower TH
He explained how most fish found on coral reefs actually spend the first part of their      signaling might play a role in longevity. In the case of lower thyroid function and its
life as free-swimming larvae out in the ocean. Thyroid hormones controlled the changes      benefits, he postulated that the T3:T4 ratio might be more important than individual TH
that enabled the juveniles to efficiently graze on algae growing on the reef such as        levels. He posed the question as to how a TH response in tissues might be evaluated.
an elongated gut. Thus, herbivorous fish play a major role in supporting coral reef         Some TH metabolites can serve as markers by changes observed in hypothyroidism
ecosystems by reducing algal cover and therefore promoting coral recruitment.               and hyperthyroidism using the techniques of metabolomics. The metabolism of fat and
                                                                                            methionine are well known markers of TH action. Dietary restriction (DR) encompasses
Remaud, France discussed ‘Regulation of Thyroid hormone action during neuronal
                                                                                            a variety of nutritional interventions with overlapping functional benefits, including
progenitor development’ and asked the question, how does TH control the fate of
                                                                                            increased stress resistance and extended longevity in a number of organisms across
neural stem cells (NSC) in the young adult subventricular zone (SVZ)? The cellular
                                                                                            evolutionary boundaries. Restriction of sulfur amino acids (SAA), methionine (Met)
basis for neuronal vs glial determination in progenitors involves asymmetric
                                                                                            and cysteine (Cys) is common to numerous DR regimens and is thus a potential
partitioning of epidermal growth factor receptor (EGFR) and TRα1, expression of
                                                                                            shared nutritional trigger of DR benefits. DR post-surgery results in increased survival
which favor glio- and neurogenesis, respectively. TRα1 is expressed in the neuronal
                                                                                            via stimulation of the methionine cycle resulting in increased hydrogen sulfide
but not in the oligodendrocytic lineage cells and is asymmetrically distributed in
                                                                                            (H2S) production. While toxic at high levels, H2S produced at low concentrations by
mitosis in the adult SVZ. MCT8 and organic-anion-transporting polypeptide (OATP)
                                                                                            degradation of cysteine or homocysteine acts on the vasculature and the brain as
TH transporters are strongly expressed in NSCs and in progenitor cells within the
                                                                                            a signaling molecule to reduce blood pressure and prevent neurodegeneration. H2S
adult SVZ. These transporters occur principally in committed neuronal cells but not
                                                                                            induces a state of suspended animation and is a powerful indicator of longevity. TH
in progenitors. Oligodendrocyte progenitors, but not neuroblasts, express high levels
                                                                                            regulates hepatic H2S with T3 inhibiting H2S production. Thus, increased TH production
of a T3-inactivating deiodinase, DiO3. Thus, TRα1 absence with high levels of DiO3
                                                                                            as in hyperthyroidism decreases while hypothyroidism increases H2S production.
provides double-pronged blockage of T3 action during glial lineage commitment.
                                                                                            Although diet can impact H2S production, neither the dietary requirements for increased
TH favors NSC fate towards a neuronal phenotype. Expression of the deiodinase
                                                                                            H2S production nor the potential role of H2S in the benefits of DR are currently known.
Thyroxine 5-deiodinase (DiO3) in the adult excludes TH signaling from proliferating
                                                                                            The possible importance of the T3:T4 ratio is emphasized by the effect of TH on the
oligodendrocyte progenitor cells but not from neuroblasts. Loss of DiO3 function
                                                                                            methionine cycle whereby switching from levothyroxine (L-T4) to liothyronine (L-T3)
reduces both proliferation and oligodendrocytes in the adult SVZ. She asked how does a
                                                                                            results in negative repression of H2S production, probably acting autonomously through
reduction in TH availability, as in hypothyroidism, impact neurogenesis in the adult SVZ.
                                                                                            regulation of the hepatic methionine cycle. He concluded that both TH and also growth
A thyroid hormone T3-free window, with or without a demyelinating insult, provides a
                                                                                            hormone/insulin-like growth factor 1 (GH/IGF-1) negatively regulate hepatic H2S
favorable environment for SVZ-derived oligodendrocyte progenitor generation. Thus,
                                                                                            production through distinct mechanisms, with functional consequences on feedback
after demyelination, oligodendrocytes derived from these newly-formed progenitors
                                                                                            control of hepatic IGF-1 and TH production. Together, these data point to H2S as a
provide functional remyelination, restoring normal conduction. She concluded that
                                                                                            potential downstream mediator of benefits shared between decreased GH/TH signaling
taken together, the data provide evidence that transient hypothyroidism favors lineage
                                                                                            and DR.
determination of adult multipotential SVZ-progenitors towards an oligodendroglial fate
and promotes functional brain remyelination in vivo.

9                                                                                                                                                                               10
ETA Symposium (Translational):                                                                Bassett, UK talked about ‘Cell specific targeting of thyroid hormone metabolism’. He
                                                                                              started by reminding the audience that the unliganded TH receptor repressed gene
The future is in vivo                                                                         transcription. He also stressed the importance of the deiodinases D1O2 and D1O3 in
                                                                                              regulating T3 target gene expression during development. In their absence, there
Chair(s): Monica Dentice (Italy) & Jens Mittag (Germany)                                      is a repression of transcription with a need for added T3. D1O2 undergoes substrate
                                                                                              dependent degradation; low levels of T4, high D1O2; high T4, lower D1O2. These
Marelli, Italy presented data on ‘Cell specific targeting of thyroid hormone receptors        processes are necessary to maintain T3 equilibrium. He described advantages and
in zebrafish model’. She described her experience using a zebrafish model supplied            disadvantages of targeting activation enzymes D1O2 and D1O3. Overexpression of D1O2
by the Karolinska Institute, Sweden (TKI). Zebrafish with its rapid external embryonic        in mice results in no great increase in T3, but increased heart rate. The effect may be
development has been extensively used in developmental biology. In zebrafish, TH              limited by a compensatory increase in D1O3. D1O2 deficiency impairs hypothyroid-like
action is mediated by different receptors (TRα1 and TRα2, TRβ1 and TRβ2) encoded by           TSH response. Deletion of D1O3 in mice results in impaired muscle degeneration with
two genes, thyroid hormone receptor alpha and beta (THRα and THRβ), with differing            exposure of activated satellite cells to excess T3 with increased apoptosis. In the liver,
tissue distribution e.g. TRα1 in brain, heart, liver, kidney, and TRβ1 in muscle, liver,      no effect on hepatocyte regeneration is observed, but faster recovery from low T3
kidney, ovary, and testis. T3 signaling in the zebrafish is well developed with contrasting   syndrome. He concluded by observing that in bone, deiodinase activity is restricted
function of different isoforms. Overexpression of TR mutant isoforms suggests that            to mature osteoblasts. Recent studies have shown an essential physiological role for
isoform specific function cannot only be explained by their relative abundance in target      D1O2 in the optimization of bone mineralization and strength. Emerging population
tissues. Alterations in TH are a distinct feature of thyroid hormone receptor alpha α         studies have also identified the genes encoding D1O2 and D1O3 as susceptibility loci
(THRα) embryology. Reduced sensitivity to TSH suppression is a distinct feature of THRβ       for osteoarthritis. Local control of T3 availability via D1O2 and D1O3 in osteoblasts and
KD embryos. She described studies aimed at dissecting isoform specific properties             chondrocytes is necessary during maintenance and repair of bone and cartilage.
of TRs in zebrafish. TRα1-specific cardiac phenotype was revealed in zebrafish (KI)
embryos. TRβ1 had specific hypothalamic–pituitary–thyroid (HPT) axis phenotype; TRβ2
regulation of cone photoreceptors. Both TRα1 and TRβ1 mutants resulted in delayed
cartilage development. She concluded that the respective functions of TRα1, TRβ1, and
TRβ2 probably results from their different expression patterns and different intrinsic
properties. Specific genetic models of zebrafish embryos will be suitable for phenotypic
characterization of novel candidate genes.

Heuer, Germany described ‘Cell specific targeting of thyroid hormone transporters’.
The action of TH requires understanding of transport, binding, and action. The TH
transporter MCT8 is present in different cell types in the brain. Patients with MCT8
mutations suffer profound neurological complications. She posed the question why does
MCT8 result in such changes and can such patients be treated? KO mice have the same
disorder as most human patients. They display an abnormal TH profile resulting from a
disordered HPT axis and also have hyperthyroid peripheral tissues.

In KO mice, the absence of MCT8 results in the forebrain neurons not affecting
intraneuronal TH status as demonstrated by normal thyrotropin-releasing hormone
(TRH). In contrast, the absence of MCT8 in OATPC1 expressing cells results in TH
deficient CNS (elevated TRH). She explained how MCT8 was not critical for T3 uptake
but was important for the solar plexus. The role of tanycytes in the regulation of the
HPT axis has been more recently recognized. Absence of MCT8 in tancytes shows
increased TSH. In contrast, hyperthyroidism results in upregulation of tanycyte
Pyroglutamyl Peptidase II (PPII), contributing to inhibition of TSH secretion by reducing
the amount of TRH reaching the portal system. Absence of MCT8 in the thyroid gland
results in decreased T4 export while absence of MCT8 in liver does not affect TH status.
Therefore, additional transporters must be present. She concluded by suggesting
that MCT8 deletion studies in pituitary and kidney may provide further answers to
understanding pathways of TH transport.

11                                                                                                                                                                                  12
ETA Industry Sponsored                                                                         Bioequivalence of L-T4

Satellite Symposia
                                                                                               Ravzi, Newcastle substituting for Hennessey, Boston discussed the bioequivalence
                                                                                               of L-T4 preparations. He explained that in 2017 the UK Medicines & Healthcare products
Merck Symposium: Pharmacokinetics & Bioequivalence of L-T4 compounds
                                                                                               Regulatory Agency (MHRA) began to see an increased level of reports of serum
                                                                                               TSH being elevated when T4 brands were changed, despite dosage levels remaining
The speakers were introduced by the Chairman George Kahaly, Mainz who                          constant. He stressed that a two-fold increase in serum T4 levels was equivalent to a
explained that Salman Razvi, UK would be deputizing for James Hennessey who was                100-fold increase in TSH. These findings were consistent with equivalent reports from
unable to attend.                                                                              Denmark, USA, and The Netherlands in all of whom, changes in L-T4 preparations were
                                                                                               implicated. In France there was a formulation change whereby lactose was removed
Lipp, Tubingen explained the difficulties encountered when drug formulations
                                                                                               from the preparation and replaced by citric acid/mannitol. This change was aimed at
were changed or when patients substituted different formulations of the same drug.
                                                                                               increasing stability of the product and improving tolerance. Following complaints, the
He explained that after loss of patent, the drug itself becomes available for other
                                                                                               original formulation was restored. Ravzi emphasized that bioequivalence does not
companies whereas, the process of formulation remains hidden. This leads to difficulties
                                                                                               mean similar bioavailability in target populations and urged that care be taken when
in comparing products from different companies, particularly in terms of measured
                                                                                               discordant results are observed in patients whose T4 preparations have been changed.
plasma levels of the drug. He outlined the different stages in substituting a drug. Firstly,
                                                                                               This is supported by American Thyroid Association (ATA) and European Thyroid
the pharmacokinetics (PK) definition, derived from data obtained in healthy volunteers
                                                                                               Association (ETA) guidelines which urge caution when switching from one L-T4 product
when the generic drug has to be tested against the reference brand with defined PK
                                                                                               to another.
boundaries for the 90% confidence limit of 80-125% or 90-111% as appropriate. Various
factors influence T4 absorption that lead to the narrower confidence limits being applied.
These tests are covered by the four-letter acronym ADME, for absorption, distribution,
metabolism, and excretion. In the case of L-T4, bioequivalence trials are particularly
difficult as dosage regimes vary and washout times are lengthy (6-9 days). Shelf life has
to be taken into account with potency being kept between 95-105% over time. He
posed the question does 10% loss of potency raise clinical concerns? Patients very
quickly detect changes requiring new bioequivalence trials. These require about 36
months of testing. The potency specifications (95-105%) have been applied to L-T4
preparations with the new formulation of L-T4 meeting the most stringent potency
specification guidelines, and has been demonstrated to be bioequivalent to the current
formulation and to show dosage form. He concluded by invoking the NOCEBO effect
(when a patient anticipates a side effect of a medication, they can suffer that effect
even if the ‘medication’ is actually an inert substance), and urged caution when
switching medications.

13                                                                                                                                                                                14
ETA Industry Sponsored (Berlin Chemie)                                                       Bednarczuk, Warsaw looked at the thyroid side effects of using iodinated contrast
                                                                                             media (ICM) in radiological practice. ICM exposure is associated with subsequent
Satellite Symposium                                                                          development of incident hyperthyroidism or hypothyroidism. Hyperthyroidism is more
                                                                                             frequent in patients living in an area of current or previous iodine deficiency. Patients
Thyroid Update                                                                               with functioning thyroid nodules with or without suppressed TSH are particularly at risk.
                                                                                             Treatment guidelines are of little benefit as in most individuals the risk of developing
The Symposium was opened by George Kahaly, Mainz who in introducing the                      thyroid disorders is very low. However, it is important that patients with a history of
speakers, commented on the power of the panel of presenters who included the                 thyroid disease should undergo thyroid function tests before having ICM administered.
President of the ETA, Pilar Santisteban, the Secretary Colin Dayan, and the Treasurer        ICM-induced hyperthyroidism is usually self-limiting, but vigilance is required in older
Tomasz Bednarczuk.                                                                           patients, particularly those with underlying heart disease. He concluded that in areas
                                                                                             of iodine deficiency preventive therapy with thionamides or perchlorate prior to ICM
Santisteban, Madrid discussed the current state of the Thyroid Cancer Genome Atlas           administration to at-risk patients should be considered.
(TCGA). The genetic landscape of papillary thyroid cancer (PTC) was derived from 500
patients. The majority (~80%) of oncogenes involved in PTC were BRAF, NRAS and
KRAS. The rest were distributed over 31 genes. Newer genes TERT, CHEK 2, and PPMID
have also been described and have been associated with metastasis. Many cancer genes
belong to the so-called long tail distribution. The molecular classification of thyroid
cancer takes into account that many genes act together or in mRNA clusters. Classes
include BRAF-like and RAS-like mutations. They can be identified by differing properties
such as MAPK signaling, high in BRAF-like and low in RAS-like histology, and degree of
differentiation.

Commenting on mitogen-activated protein kinase (MAPK) inhibitors she explained
that the MEK tyrosine kinase inhibitor (TKI) selumetinib, enhanced radioactive iodine
(RAI) uptake in a subset of RAI refractory thyroid cancers. Selumetinib causes the
sustained inhibition of extracellular signal-regulated kinases (ERK) phosphorylation. The
mechanism seemed to be re-differentiation of the cancer toward a more normal state,
most like the tissue from which the cancer arose. The mechanism of action may be
that selumetinib restores iodide uptake by NIS, by the inhibition of its related targeting
microRNAs (miRNAs), in particular MiRNA146. She concluded by emphasizing the role of
miRNAs in thyroid cancer and their clinical utility as prognostic or diagnostic markers.

Dayan, Cardiff addressed the management of thyroid dysfunction following immune
reconstitution therapy. He explained how alemtuzumab (ALTZ), a highly-effective
treatment for multiple sclerosis (MS), depletes T lymphocytes with its therapeutic
effect, mediated by the alteration in immune repertoire that accompanies subsequent
lymphocyte reconstitution. The principal adverse effect of ALTZ is development of
autoimmunity, occurring most frequently at 16 months following last date of drug
administration. Graves’ disease is the most common autoimmune disease, being
observed in about 30% of ALTZ treated patients. Measurements of TSH receptor
autoantibodies (TRAb) bioactivity, documenting the presence of both TSH receptor
autoantibodies (TSAb) and TSH-blocking autoantibodies (TBAb)/TRAb activities in ALTZ
treated patients, support the notion that changes in the circulating proportions of TSAb
and TBAb species over time, with resultant stimulation or inhibition of thyroid hormone
production, lead to fluctuation in thyroid status. The responses to antithyroid drug
therapy also varied with delayed responses being observed in 73% of Graves’ patients.
A further 34% had remission. Interestingly, 14% developed blocking (TBAb) antibodies.
He concluded that Graves’ disease may develop several years after ALTZ treatment
and exhibit a fluctuating course (likely related to changing repertoire of stimulating vs
blocking TRAb), with a need for definitive, RAI or surgery, or long-term ATD treatment
that exceeds that in conventional Graves’ disease.

15                                                                                                                                                                                16
The ETA Industry-Sponsored Satellite                                                       ETA Industry sponsored (Bayer)
SYMPOSIUM (Sanofi Genzyme)                                                                 Satellite Symposium

Latest Developments in Thyroid Cancer Management.                                          Experience in action: RAI-R DTC in 2018
Chair Rosella Elisei (Italy).
                                                                                           The Chair: Sophie Leboulleux, France discussed ‘RAI-R DTC: the current state of
The first speaker Bournaud, France talked about ‘Radioactive Iodine Therapy of             play’. She defined RAI refractoriness as the absence of significant thyroidal RAI uptake
Thyroid Cancer Patients with Lymph Node Involvement’. She outlined the history of          in a tumor which progressed after one or two treatments with RAI within 16 months.
RAI treatment for thyroid cancer following T4 withdrawal. Next, she described the ATA
criteria for RAI treatment and how patients were stratified by age
Selected Abstracts                                                                           Folkestad, Odense described how ‘Hyperthyroidism Increases The Risk of Dementia,
                                                                                             Which Partially Relates to Pre-Existing Morbidity – A Register Based Cohort Study of Two
                                                                                             Large Cohorts’. They hypothesized that patients with hyperthyroidism have increased
Muller and colleagues, Cardiff looked at the long-term cardiometabolic effects of
                                                                                             risk of developing dementia. The study consisted of two groups of hyperthyroid patients.
treating maternal sub-optimal thyroid function in subjects participating in the Controlled
                                                                                             Cohort A comprised of patients registered with a hyperthyroid diagnosis (ICD-10) in the
Antenatal Thyroid Screening (CATS) study. 336 mothers were evaluated 7-10 years after
                                                                                             Danish National Patient Register (DNPR) from 1995-2014. Each patient was matched
pregnancy: 203 with normal gestational thyroid function (NGTF), 56 with untreated
                                                                                             according to age and sex with four reference individuals, without known thyroid disease.
suboptimal gestational thyroid function (SGTF: untreated) and 77 SGTF who received
                                                                                             Cohort B comprised of individuals who in the period 1995-2011 had at least one TSH
levothyroxine (150 μg daily) during pregnancy (SGTF treated); 334 paired children were
                                                                                             measurement from general practices or hospitals in Funen, Denmark. Dementia was
also evaluated. They concluded that thyroxine supplementation of women with SGTF
                                                                                             identified with a relevant ICD-10 diagnosis in DNPR or treatment with relevant drugs
during pregnancy did not benefit children’s BMI or other cardiometabolic parameters.
                                                                                             according to the ATC-classification in The National Prescription Register (DNPrR). Cohort
However, screening for SGTF during pregnancy identified women that would benefit
                                                                                             A: 56,624 patients with a hyperthyroid diagnosis (median follow-up 7.3 yr), of whom
from levothyroxine replacement: absence of such treatment resulted in sustained long-
                                                                                             2,120 (3.7%) were subsequently diagnosed with dementia. In the reference population,
term BMI increase.
                                                                                             7,547 (3.3%) out of 226,496 (median follow-up 8.1 yr) were diagnosed with dementia
Davies, New York reported on ‘Epigenetic Changes During Human Thyroid Cell                   during follow-up. HR for dementia was 1.17 [95% confidence interval (CI): 1.12-1.23],
Differentiation’. He described how the transcriptional co-activator known as TAZ             but was nonsignificant when correcting for pre-existing morbidity HR 0.99 [95% CI:
(transcriptional co-activator with PDZ-binding motif) regulates the activity of several      0.94-1.04]. Cohort B: 234,218 patients; 2,772 with hyperthyroidism (median follow-up
transcription factors including PAX8 and NKX2-1 and plays a central role in tissue-          7.2 yr) and 231,446 reference individuals (median follow-up 8.6 yr). 192 hyperthyroid
specific transcription. It has been shown that TAZ, together with PAX8 and NKX2-1 are        patients (7.1%) and 6,431 reference individuals (2.8%) were diagnosed with dementia
co-expressed in the nucleus of thyroid cells and that TAZ interacts directly with both       HR 1.21 [95% CI: 1.05-1.40], which persisted after correcting for pre-existing morbidity
PAX8 and NKX2-1. A potential role for TAZ in the control of genes involved in thyroid        HR 1.21 [95% CI: 1.04-1.40]. The cumulative HR for dementia, per six months of low
differentiation has been suggested. The authors reported on the epigenetic changes in        TSH, was 1.17 [95% CI: 1.13-1.21]. They concluded that by employing two hyperthyroid
methylation and acetylation in the promoter region of selected thyroid transcriptional       cohorts, an approximately 20% increased risk of being diagnosed with dementia is
factors and thyroid specific genes in human embryonic cells (hES) treated with the           demonstrated but that this is partially explained by pre-existing non-thyroid morbidity.
TAZ activator ethacridine. The promoter activity of NKX2-1, PAX8, and TG was highly
                                                                                             Wang et al, Shenyang reported on the ‘Dual Effects of Thyroid-Stimulating
induced in ethacridine and Activin A hES cells as measured by acetyl-histone H4
                                                                                             Hormone on Metabolic Syndrome (MetS) and its Components in Euthyroid Adults: A
immunoprecipitation (ChIP) assay (64-fold, 4-fold, and 6-fold respectively). They
                                                                                             Population-Based Thyroid Study’. A total of 48,355 adults (25,981 males and 22,374
concluded that acetyl-histone H4 is involved in the differentiation of thyroid follicular
                                                                                             females) without thyroid disease were recruited and received a comprehensive health
cells from hES cells.
                                                                                             examination including height, weight, waist circumference, blood pressure, and lipid
                                                                                             profile. Furthermore, all participants underwent a 75 g oral glucose tolerance test. MetS
                                                                                             was identified using the 2009 International Diabetes Federation criteria. All participants
                                                                                             were divided into three groups based on the tertiles of TSH levels. Generally, 30.5%
                                                                                             males and 20.5% females suffered from MetS in the euthyroid population. However,
                                                                                             there was no significant difference between TSH tertiles in the prevalence of MetS.
                                                                                             After multivariable adjustment, there was a positive correlation between TSH and
                                                                                             MetS risk (OR = 1.13 [1.03-1.25], p=0.014 for males; OR = 1.39 [1.24-1.57], p
Leenhardt, Villejuif reported on ‘Recombinant Human Thyrotropin vs Thyroid                Diana et al, Mainz presented data that ‘Dilution Analysis of Thyroid Stimulating
Hormone Withdrawal In Radioactive Iodine Therapy of Thyroid Cancer Patients With          Antibodies Differentiates between Graves’ Thyroidal And Orbital Disease’. The authors
Nodal Metastatic Disease: A Large Multicenter Retrospective Matched Cohort Study’.        aimed to demonstrate if there was a highly significant differentiation between patients
The primary objective of the study was to demonstrate noninferiority of recombinant       with GD versus GD+GO by analyzing TSAb levels in serially diluted serum samples.
human thyrotropin (rhTSH) vs thyroid hormone withdrawal (THW) in terms of disease-        All undiluted samples of hyperthyroid patients with GD were only positive in the TSAb
free status [basal ultrasensitive Tg
Bliddal, Copenhagen presented data on ‘Thyroid Peroxidase Antibodies and Anti-            Wasniewska, Messina presented data on ‘Differences In Levothyroxine Dosages
müllerian Hormone (AMH) in 470 Women with Unexplained Recurrent Pregnancy Loss’.          For Replacement In Children With Distinct Causes Of Permanent Hypothyroidism’.
The mechanism is unknown, but TPOAbs have been shown to be present in ovaries of          The study population consisted of 22 children affected by congenital hypothroidism
women with pregnancy loss. Anti-Müllerian Hormone (AMH) is currently debated as a         (CoH), (14 by thyroid dysgenesis- CoH1, eight by dyshormonogenesis genesis- CoH2),
marker of egg reserve (and egg quality), and low AMH has been suggested as a risk         23 by autoimmune hypothyroidism (AH), and 22 by central hypothroidism (CH);
factor for pregnancy loss. The authors investigated if TPOAbs were associated with        (13 by idiopathic hypopituitarism- CH1, nine secondary to pituitary tumors- CH2).
AMH levels in women with unexplained recurrent pregnancy loss (RPL). A total of 565       The objective was to find the mean L-T4 doses for CoH, AH, and CH in pediatric age
women with RPL had attended the unit, of which 470 (83.5%) had measurements of            necessary to maintain optimal hormone replacement. In AH children, mean L-T4
both TPOAbs and AMH. Of these, 72 (15.3%) were TPOAb-positive and 54 (11.5%) had          maintenance euthyroid doses were significantly lower than in the CoH and CH groups
AMH-levels ≤5 pmol/L. There was no difference in median AMH-levels between TPOAb-         (p=0.02 and p=0.008 respectively), while no differences were found between CoH and
positive and TPOAb-negative women and only 4 of 72 (5.6%) TPOAb-positive women had        CH groups (p=0.1) (Table 1). Mean L-T4 doses to maintain euthyroidism were similar
AMH-levels ≤5 pmol. Compared to 50 of 398 (12.6%) TPOAb-negative women. Among             in patients with athyreosis vs dyshormonogenesis (p=0.1) and in those with idiopathic
TPOAb-positive women, 10.8% had low levels of AMH, 14.8% had normal levels, and           and secondary CH (p=0.4). There was no statistically significant correlation between
19.8% had high levels if applying method- and age-specific reference ranges. Excluding    LT4-dosage and serum FT4 levels or chronological age in all forms of permanent
all women with high AMH-levels, TPOAbs were still not significantly associated with low   hypothyroidism in the study population. They concluded that CH children need (weight-
AMH. The authors concluded the association between TPOAbs and pregnancy loss is           based daily) L-T4 dosages similar to CoH ones, while significantly lower doses are
unlikely to be explained by reduced AMH levels and vice versa. However, women who         sufficient to maintain clinical and biochemical euthyroid status in those with AH.
smoked had a four times higher risk of having a low AMH-level.
                                                                                          Leng et al, Newcastle described the ‘Effect Of Sample Timing On The Diagnosis Of
Biscarini, Cardiff in a multicenter study, reported on the ‘Investigation Of Novel        Subclinical Thyroid Diseases In Patients With Acute Myocardial Infarction: The ThyrAMI
Biomarkers, Definition of Role Of Microbiome in Graves’ Orbitopathy (GO) INDIGO:          1 Study’. They investigated whether the diurnal pattern for TSH secretion observed
Microbiota Analysis of Patients at Recruitment’. The authors tested the hypothesis        in healthy individuals is retained in acute myocardial infarction (AMI) and if it impacts
that in Graves’ disease (GD)/Graves’ Orbitopathy (GO), bacteria inducing tolerance        on the diagnosis of subclinical thyroid diseases (SCTDs). The multicenter Thyroxine in
(Treg) are under-represented or those promoting inflammation (Th17) are over-             Acute Myocardial Infarction (ThyrAMI) study prospectively recruited patients aged >18
represented. Fecal samples were obtained from untreated patients, or within six weeks     years presenting with AMI (n=1,569). Serum TSH maintained its diurnal rhythm with
of commencing treatment at recruitment; GD (n=65) with no or minimal eye signs; GO        a peak in the early hours of the morning (02:40am) and nadir in the afternoon. Serum
(n=56), mild or moderate-severe (as defined by EUGOGO) and healthy controls (n=42)        FT4 also exhibited a diurnal rhythmicity with a peak approximately 2.5 hours after TSH
from four European countries. Total DNA was extracted for microbiota analysis, using      (05:09am) while serum FT3 had no significant diurnal variation. Thus, the prevalence
V1-V2 region primers of the 16S rRNA gene, to generate 10,000 paired-ends reads per       of subclinical hypothyroidism (SCH) was more than double in the period of 00:00-05:59
sample (Miseq Illumina). Data were processed using the QIIME bioinformatics pipeline      vs 12:00-17:59 (23.9% vs 10.6%). These findings were similar to the published data for
for analyzing microbial communities. A subset was also evaluated using traditional        healthy individuals resulting in almost one quarter of AMI patients meeting the criteria
microbiology methodology. Bacteroidetes were significantly more abundant in controls      for SCH in the early hours of the morning compared to a tenth of patients presenting in
(38.5%) than in GD (24.2%) and GO (27.3%) patients, while firmicutes were more            the afternoon. The authors stressed the potential confounding factor of sample timing
abundant in GD (59%) and GO patients (60.5%) than controls (53.2%). Consequently          on the diagnostic classification of SCTD in patients with AMI.
the firmicutes:bacteroidetes ratio was significantly higher in GD/GO than controls, but
                                                                                          Centanni, Latina presented data on ‘Ulcerative Colitis: A Novel Cause Of Increased
similar between GD and GO. The data illustrate substantial perturbation of the gut
                                                                                          Need For Thyroxine’. A total of 43 patients bearing an inflammatory bowel disease
microbiota composition in GD/GO, which may be driven by hyperthyroidism.
                                                                                          were recruited. All patients were taking thyroxine in fasting conditions, abstaining
                                                                                          from eating or drinking for at least one hour. To calculate the possible excess of T4
                                                                                          required in our patients, the individual requirement of T4 was compared to the one
                                                                                          observed in 115 similarly treated age and BMI matched patients, clearly devoid from
                                                                                          gastrointestinal and/or pharmacological interference. The T4 dose required in ulcerative
                                                                                          colitis patients was higher than in the reference group in 13/15 patients (87%) and the
                                                                                          median thyroxine dose needed was 1.72 μg/kg/day. A median dose excess of 22% has
                                                                                          been observed as compared to the minimal effective dose in control group. The authors
                                                                                          concluded that the data support the hypothesis that ulcerative colitis may represent a
                                                                                          novel cause of increased need for thyroxine.

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