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Congress Report: Highlights from the 86th Annual Meeting of the American Thyroid Association

Congress Report: Highlights from the 86th Annual Meeting of the American Thyroid Association
  • Endocrinology and metabolism
  • Thyroid disorder

Novel findings in basic, translational and clinical thyroid research were presented at ATA 2016

Thyroid and neoplasia

Basic thyroid research into neoplasia by Rodiger J et al (National Institute of Child Health and Development (NIC), National Institute of Health (NIH), Bethesda, USA) found that the protein arginine N-methyltransferase 1 (PRMT1), a coactivator recruited after thyroid hormone is bound to its nuclear receptor, is upregulated around birth in developing stem cells and is important for thyroid hormone-dependent mouse intestinal maturation. As PRMT1 dysregulation is involved in cancer, these findings provide new insights into the possible role of thyroid hormones in intestinal diseases.

Another basic thyroid study on stem cells looked at thyroid hormone (T3)-dependent frog metamorphosis, which resembles mammalian postembryonic development. This model is useful to study how adult stem cells are formed and how the balance between proliferation (eg., c-Myc expression) and differentiation (eg., Mad expression) are maintained. Okada M et al (NIH, Bethesda, USA) used microarray analysis of intestinal gene expression during metamorphosis to show that Mad expression is induced by T3, just prior to c-Myc expression and adult stem cell formation. High levels of Mad expression are localized to apoptotic cells while c-Myc expression is present in adult stem cells. These findings help to identify novel candidate adult stem cell-related genes in vertebrates.

Antitumour effects were explored by Zhu X et al (NIH, Bethesda, USA) in a mouse model that spontaneously develops anaplastic thyroid cancer. A small molecule, JQ1, was shown to suppress Myc transcription by competing with acetylated histones for binding to bromodomain and extraterminal domain (BET) proteins. This action inhibits BET-activated transcription of the Myc gene.

In the translational field of thyroid cancer, the notion that T1a papillary thyroid carcinomas (PTC) can vary from indolent to aggressive was reinforced. BRAFV600E, TERT and TP53 are oncogenic mutations associated with aggressive behaviour. Buddhdev KB et al (University of Nebraska Medical Center, Omaha, USA) used whole exome sequencing to identify additional mutations predictive of biologic behaviour in T1a tumours. BRAFV600E mutations were present in the majority of T1aN1b tumours, confirming a more aggressive biological behavior. Two novel mutations were identified: SLC25A5 in BRAFV600E positive tumours together with CDC27, a potential germline mutation, in N0 tumours. 

Also in the translational thyroid cancer section was an oral presentation on the challenge of pre-surgical molecular diagnosis of cytologically indeterminate thyroid nodules. A highly accurate, cost efficient matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-TOF) mass spectrometry mutation detection (MassARRAY) was set up by Eszlinger M et al (Department of Oncology and Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Canada and Division of Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany). Its performance was measured using a panel of the 53 most prevalent thyroid cancer specific point mutations from 48 routine air-dried fine needle aspiration (FNA) samples (27 indeterminate, 13 suspicious and 8 malignant). Mutation detection by the MassARRAY 53-mutation-panel detected 74% of cancers in the indeterminate category.

Characterization of the immune infiltrate associated with anaplastic thyroid cancer (ATC) tumours by Dadu R et al (University of Texas MD Anderson Cancer Center, Houston, USA) revealed that tumour cells positive for the immune suppression marker PD-L1 and for tumour infiltrating lymphocytes are present at high frequency in this aggressive kind of tumour. Immunoprofiling of ATC can help find targets for immune-based therapies.

Coexisting TERT promoter and BRAF V600E mutations are synergistically associated with papillary thyroid cancer (PTC) recurrence. However, the single nucleotide polymorphism (SNP), rs2853669, in the TERT promoter was reported to disrupt the ETS2 transcription factor binding site, thereby downregulating TERT. Liu R et al (John Hopkins University School of Medicine, Baltimore, USA) examined genetic variants of PTC in 608 patients and showed that the variant allele of rs2853669 significantly reduces the impact of the TERT promoter mutation, whether alone or in coexistence with the BRAF mutation, reducing the aggressiveness of the PTC. This represents a novel genetic factor that can help refine TERT promoter mutation-based risk stratification of PTC.

Klubo-Gwiezdzinska J et al. (NIH, Bethesda, USA) analyzed the expression of mitochondrial glycerophosphate dehydrogenase (mGPDH), a molecular target of metformin, in 48 human thyroid tissue samples, both benign and malignant. They also used a metastatic mouse model to study the expression of mGPDH in metastases by immunostaining. After 4 weeks of treatment with metformin, the tumour burden was significantly smaller and the intensity of mGPDH staining in metastases was significantly reduced in animals treated with metformin compared with the placebo group. The authors concluded that treatment with metformin delays progression of thyroid cancer metastases in vivo and is associated with downregulation of mGPDH in metastatic lesions. The molecular target of metformin, mGPDH, is overexpressed in thyroid cancer and may serve as a biomarker of response to metformin treatment in thyroid cancer.

Inhibition of both the PI3K-AKT pathway and histone deacetylases (HDAC) induces differentiation of thyroid cancer cells. Kotian S et al (NCI, Bethesda, USA) evaluated the simultaneous targeting of these pathways in thyroid cancer cells with CUDC-907, a dual inhibitor of HDACs and the PI3K-AKT pathway. The authors showed an upregulation of thyroid differentiation markers in thyroid cancer cells and inhibition of growth and metastasis in vivo, suggesting that CUDC-907 may be an agent worth evaluating in a clinical trial for advanced and metastatic thyroid cancer.

In the clinical field of thyroid cancer and nodules, headlining studies included:

The new ATA risk of malignancy assessment based on sonographic pattern of thyroid nodules undergoing ultrasound-guided FNA was validated by Tang M et al (University of Cincinnati, Cincinnati, USA) in a prospective study of 211 thyroid nodules. Remarkably, these authors also confirmed that cytological indeterminate nodules with an ATA high risk sonographic pattern have a high likelihood of being malignant.

Lenvatinib is approved for use in patients with radioactive iodine-resistant (RAIR) differentiated thyroid cancer (DTC). Few data exist regarding early adverse events, impact on quality of life (QOL) and post-approval ‘‘real world’’ lenvatinib outcomes; Jasim S et al (Mayo Clinic, Rochester, USA) reported their initial lenvatinib experience in 25 consecutively-treated patients with progressive, metastatic RAIR DTC. Most patients developed adverse events in the first month of this therapy, including hypertension in 16 (64%). The authors concluded that lenvatinib is a promising therapy in patients with RAIR DTC, but toxicities are great and occur early, and dose reductions are frequent; however, QOL can be maintained on lenvatinib therapy.

Valderrabano P et al  (H. Lee Moffitt Cancer Center and Research Institute, Tampa, USA) challenged the new concept of the ‘‘non-invasive follicular thyroid neoplasms with papillary-like nuclear features’’ (NIFTP) as a benign lesion, fearing removal of the diagnosis of cancer could impact the treatment and follow-up of patients. They compared NIFTP to the invasive follicular variant of papillary thyroid carcinoma (I-FVPTC) and found that a small proportion of NIFTP had nodal and distant metastatic spread. The authors proposed follow up after lobectomy may be justified, and questioned whether these nodules that are now considered benign, are truly benign.

Thyroid hormone action

Grøntved L et al (University of Southern Denmark, Odense, Denmark), in their basic thyroid research oral presentation described thyroid hormone receptor (TR) signaling in mouse liver tissue in hypo- and hyper-thyroid conditions by genome-wide analysis. The observation of the interaction of TR/TR-coregulator complexes with chromatin, provided novel insights into understanding the molecular basis for TR mutations associated with human disease.

Phillips K et al (Baylor College of Medicine, Houston, TX, USA) in an oral presentation, showed that thyroid receptor (TR) activation induced adaptive thermogenesis in white adipocytes, a process called ‘beiging’. The observed mechanisms after TR activation with TR agonists include an increase in Ucp1 protein levels, rapid fat loss and pronounced anti-diabetic effects. TR agonists activate beige fat without increasing the activity of brown fat, thus dissociating beige fat activation from that of canonical brown fat. TR mediated beiging is cell autonomous activation of beige fat and adaptive thermogenesis, independent of β-AR stimulation, which was thought to be the key regulator of adaptive thermogenesis.

Han C et al (NCI, NIH, Bethesda, USA) showed that abnormal erythropoietic parameters characteristic of patients with mutations of thyroid hormone receptor α (THRα) can be reversed with a mutated co repressor (NCOR1DID). NCOR1DID interfered with the mutated THRα to mediate its dominant negative actions.

The translational research oral presentation on thyroid action by Fujisawa H et al. (The University of Chicago, Chicago, USA) described their study to replicate the thyroid phenotype of patients with selenocysteine insertion sequence binding protein 2 (Sbp2) deficiency, a complex syndrome with multi-organ involvement. They used a mouse model of global Sbp2 deficiency (iCKO Sbp2 deficient mice) and showed that the decrease in both 5’ and 5 deiodination, as well as the effect of elevated serum thyroid stimulating hormone (TSH), contributed to the elevated serum T4 characteristic of this syndrome. Reduced liver D1 enzyme activity also resulted in decreased degradation of rT3 and subsequent high serum rT3 levels.

Transport of thyroid hormonesbasic research oral presentations

T3-regulated gene expression in neural cells depends upon transmembrane transporters such as MCT8 or OATP1C1 that facilitate the transfer of T4 and T3 across the blood-brain barrier and the activity of Dio2 which is required to convert T4 to T3 in astrocytes. In order to understand how MCT8-Dio2 and MCT8- OATP1C1 deficiencies resemble the effects of global hypothyroidism on gene expression in the mouse cerebral cortex, Morte B et al (CIBERER, Center for Biomedical Research on Rare Diseases, Madrid, Spain) performed differential gene expression analysis in mice and demonstrated that the combined inactivation of Dio2, MCT8 and OATP1C1 only partially reflects the effects of global hypothyroidism on gene expression.

Mutations in MCT8 results in Allan-Herndon-Dudley Syndrome (AHDS). To explore the pathogenic mechanism of mutations found in AHDS patients, Groeneweg S et al (Erasmus University, Rotterdam, The Netherlands) reported the first MCT8 homology model in outward-open (Ce) conformation, which supports the important role of His192 and Arg445 in thyroid hormone uptake.

Autoimmunity

Faustino L et al (Albert Einstein College of Medicine, New York, USA) in their basic research oral presentation, mentioned that thyroglobulin (TG) is a thyroid-specific susceptibility gene for both Graves’ disease and Hashimoto’s thyroiditis upregulated by interferon alpha (IFNα), a cytokine secreted during viral infections. These authors created a new model whereby IFNα triggers autoimmune thyroid diseases (AITD) by inducing degradation of TG into immunogenic peptides within lysosomes by cathepsins B, D and L, leading to activation of self-reactive T-cells.

Wang Y et al (The First Affiliated Hospital of Xi’an Jiaotong University School of Medicine, Xi’an, China) in their translational research, used next generation sequencing to perform deep quantitative profiling of TCR repertoires from peripheral blood samples of Graves’ disease (GD) patients from disease onset to remission at several time points. Based on their findings, these authors advocate TCR repertoire as a useful biomarker for diagnostic GD and highlight that GD remission is achieved through the ‘‘resetting’’ of the immune balance rather than complete ablation of autoimmune clones.

Th17 lymphocytes and regulatory B lymphocytes (Breg) seem to play a role in the pathogenesis of autoimmune disorders. In isolated Hashimoto’s thyroiditis, increased Th1 and Th17 activation have been described, but little is known about Breg which allegedly suppresses the pro-inflammatory response. Santaguida M et al (‘Sapienza’ University of Rome, Rome, Italy) confirmed activation of the proinflammatory Th17 pathway, but described for the first time an upregulation of IL-10 producing Breg cells in Hashimoto’s thyroiditis, which may oppose the Th17 activation.

In the clinical field, Antonelli A et al (University of Pisa, Pisa, Italy) compared the THAb rate and repertoire in GD patients with ophthalmopathy (TAO), GD patients without TAO, or patients with Hashimoto’s thyroiditis. The authors agreed that development of TAO in GD seems to be associated with a more restricted repertoire, implying autoimmunization against distinct thyroglobulin-iodinated tyrosines (T3-specific or T4-specific).

Iyer P et al (All Children’s Hospital/John Hopkins Medicine, St Petersburg, Florida, USA) reported on a series of clinical cases of immunotherapy-related destructive thyroiditis (irT) occurring with newer immunotherapy (IO) agents. Patients diagnosed with destructive irT while receiving IO developed an early onset of hyperthyroidism, typically followed by subsequent rapid hypothyroidism. The majority of patients were asymptomatic, not thyroid autoantibody positive, and most cases of irT were seen with the anti PD-1 drugs, alone or in combination. Conservative therapy during hyperthyroidism was sufficient.

Thyroid and pregnancy

Wang Y et al (Pharmacy Practice and Pharmaceutical Sciences, University of Minnesota, Duluth, USA) in their basic research, studied iron deficient rats and reported on the effects of gestational and neonatal iron deficiency and the effects of neonatal iron repletion, on circulating and tissue thyroid hormone levels from birth through the first month of neonatal life. They concluded that adequate iron stores are important for maintaining normal levels of circulating thyroid hormones during development.

The translational research by Srichomkwun P et al (The University of Chicago, Chicago, USA) showed that exposure to high TH levels in utero resets the sensitivity of the thyrotrophs to L-T3, producing a phenotype of central resistance to TH, persistent into adulthood. Studies in a mouse model suggest that this epigenetic effect is due to increased T3 degradation by D3.

Ehrenkranz J et al (Intermountain Medical Center, Murray, Utah, USA) in their clinical study assessed whether the diagnosis and treatment of infants with congenital primary hypothyroidism (CPH) in Utah corresponded to AAP Guidelines. TSH measurements were obtained between 2006 and 2015 in 4394 children <2 years of age. They found that 51% of CPH infants were inadequately treated, underscoring the need to follow these patients more closely.

A further clinical study by Korevaar T et al (Erasmus Medical Center, Rotterdam, The Netherlands) investigated the threshold at which TPOAb levels begin to affect thyroid function and the thyroidal response to human chorionic gonadotropin (hCG). They showed that TPOAbs affect maternal thyroid function during pregnancy at levels well below commonly used cut-off values in both early and late pregnancy. Moreover, TPOAbs have a stronger effect on maternal thyroid function during early pregnancy than late pregnancy. This is most likely due to the fact that TPOAbs impair the thyroidal response to hCG, which also occurs at levels below commonly used cut-off values.

Päkkilä F et al (University of Oulu, Oulu, Finland) found a similar prevalence of sensory and linguistic impairments in children from mothers with and without gestational thyroid dysfunction. There was a trend towards a higher prevalence of vision impairment in children of hypothyroid and hypothyroxinemic mothers.

Lee SY et al (Boston University School of Medicine, Boston, USA) performed a retrospective cohort study to assess potential associations between maternal TSH levels in pregnancy and adverse obstetric and perinatal outcomes. Elevated serum TSH levels in any trimester of pregnancy were associated with an increased risk of prematurity compared with normal serum TSH values (b-estimate 0.38, P-value 0.048, odds ratio 1.5)

A clinical study by Heikkinen AE et al (University of Helsinki, Helsinki, Finland) investigated the relationship between maternal TPOAb positivity during pregnancy and any components of metabolic syndrome present in the child during adolescence. Interestingly, mothers with positive TPOAb during pregnancy produced children with greater waist circumference and body mass index and more metabolic syndrome in adolescence than controls.

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