Thyroid International - ETA2019 - Issue 01/2019 - Merck Healthcare Professionals ...
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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. 23 24
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