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Scientific Highlights from the 2015 International Thyroid Association Congress

Scientific Highlights from the 2015 International Thyroid Association Congress

Progress in thyroid research over the past decade was showcased at this meeting in Lake Buena Vista, Florida, USA (18–23 October). Gabriela Brenta presents the highlights.

Hashimoto’s disease and Graves’ disease represent both ends of the spectrum of thyroid autoimmunity, according to Dr Sandra McLachlan (Cedars-Sinai Medical Center, USA).

Hashimoto’s disease is first characterized by the presence of thyroperoxidase antibodies, thyroglobulin antibodies, and in some rare patients, blocking type thyrotropin receptor (TSHR) antibodies. Thyroid lymphocytic infiltration may be extensive. However, in Graves’ disease, where stimulating TSHR autoantibodies are the hallmark, thyroid lymphocytic infiltration is minor.

The past decade has seen major advances in four main areas of autoimmunity research:

  1. Genetic susceptibility for thyroid autoimmunity: An association has been reported between a single nucleotide polymorphism with intrathymic transcription of TSHR and Graves’ disease, suggesting the single nucleotide polymorphism may be responsible for defective thymic tolerance.1 Further, Stefan et al 2 showed that genetic-epigenetic dysregulation of thymic TSHR gene expression may facilitate the escape of TSHR-reactive T cells from central tolerance and trigger Graves’ disease.
  2. Pathogenesis of the disease: New strategies to understand and control TSHR activation and the autoimmune response to the TSHR are based on finding a thyroid messenger RNA fingerprint in Graves’ disease. Consisting of an over-expression of immune system genes involved in antigen presentation, this fingerprint reflects an active immune defence in Graves’ disease. 3 Epitopes recognized by antibodies on the TSHR were also revealed by studying its crystal structure. 4,5
  3. Animal models of Graves’ disease: The first model of Graves’ orbitopathy 6 further implicates TSHR as the pathogenic antigen and provides a pre-clinical model for the development of new therapeutic interventions for Graves’ orbitopathy. A mouse model of animals spontaneously producing thyroid-stimulating antibodies has been created 7 – an advantage compared with a previous model where TSHR antibodies had to be induced by immunization.
  4. Novel therapies: These include small molecule inhibitors, immunotherapy (B cell depletion) and, in the future, autoantigen specific therapy. Small molecule inhibitors, such as low molecular weight TSHR antagonists can completely abolish recombinant thyroid stimulating hormone, Graves’ disease immunoglobulin G and M22-induced cAMP production in differentiated orbital fibroblasts. 8 Similarly, selective TSHR antagonists inhibit stimulation of thyroid function in female mice. 9 B cell depletion with rituximab, an anti-CD20 agent, proved efficacious in one randomized controlled trial (RCT) of patients with moderate-to-severe Graves’ orbitopathy, 10 but had no additional benefit over placebo in another. 11 Rituximab may act early in Graves’ orbitopathy, but show no benefit if started in more advanced disease, possibly explaining the disparity between the results of these two trials. In the future, autoantigen-specific therapy might be the answer, perhaps inducing neonatal tolerance against Graves’ disease using a recombinant adenovirus expressing the TSHR A-subunit.12

In concluding, Dr McLachlan stressed the importance of genetic susceptibility studies for prediction or early diagnosis of Graves’ disease that will allow for TSHR-specific intervention.

Dr Martin Schlumberger (Gustave Roussy-Université Paris Sus, Villeuif, France) spoke about the progress in thyroid cancer during the past decade, new therapies, and the importance of biological characterization of tumour tissues to identify affected signal transduction pathways, as highlighted in the current American Thyroid Association (ATA) Guidelines (2015).13

Screening has increased the identification of thyroid cancer over the past decade,14 and the vast majority of patients identified have a low-to-intermediate risk, allowing for less aggressive treatments. The advanced cancer rate has remained stable, and standard therapy, levothyroxine (LT4) and systemic treatment (radioiodine) is now joined by focal treatments such as surgery for the metastases, external beam radiotherapy, radiofrequency and cryoablation with cement injection. Treatment of advanced disease in patients with distant metastases showed an overall survival at 10 years after initiation of (131)I treatment of 92% in patients who achieved a negative imaging study and 19% in those who did not.15

In addition, (131)I treatment was highly effective in younger patients with (131)I uptake and with small metastases. Durante et al15 recommended treating patients until the disappearance of any uptake or until a cumulative activity of 22 GBq had been administered. However, for patients with tumour progression, other treatment modalities should be considered.

For patients with radioiodine refractory thyroid cancer, the size of the metastases (more than 1 or 2 cm in diameter) and their progression rate in 1 year should be measured. Tyrosine kinase inhibitors are a treatment option.

Several RCTs have been performed for tyrosine kinase inhibitors since 2005. Cabozantinib, lenvatinib and pazopanib have shown the highest response rate compared with other tyrosine kinase inhibitors. However, response rate is not a good predictor of overall survival; a better measure is progression free survival. Both sorafenib and lenvatinib have shown improvement of progression free survival rates in phase three trials. The SELECT study found significant improvements in progression free survival in those treated with lenvatinib compared with placebo,16 but also a very frequent occurrence of adverse effects such as fatigue, diarrhoea, hypertension, anorexia and skin toxicities. This may lead to dose reduction in about two-thirds of patients and definitive withdrawal in 15–20%. So far, there are two labelled drugs for radioiodine refractory differentiated thyroid cancer with target lesions and documented progression: sorafenib and lenvatinib. However, a large proportion of patients do not respond to these drugs, highlighting the need for other treatment modalities such as other anti-angiogenic drugs (pazopanib, cabozantinib), with other targets such as BRAF, PI3 kinase, and immunotherapy such as anti-PD1 or anti-PD-L1 antibodies.

Drug treatment of advanced thyroid cancer with drugs such as selumetinib, a MEK inhibitor, has shown beneficial effects in 20 patients with iodine refractory tumours, with results better in those with RAS mutations than in those with tumors with BRAF mutations.17

Spotlighting the new guidelines for thyroid cancer,13 Dr Schlumberger explained that the American Joint Committee on Cancer TNM staging system for initial survival risk and the risk of structural disease recurrence is still used. It has three categories for risk of disease recurrence: low (<5%), intermediate (5–20%) and high (>20%). However, the new ATA guidelines have amplified the spectrum of each of these categories according mainly to lymph node presentation, molecular markers and vascular invasion. The guidelines also allow for an on-going risk re-assessment at each follow-up visit. The response to initial treatment is categorized as excellent, biochemically incomplete, structurally incomplete or indeterminate, according to various parameters. Those patients with an excellent response, regardless of their initial risk of recurrence, will fare well and will not need intensified treatment.

Dr. Schlumberger reviewed other points from the ATA guidelines:

  • Before surgery, a fine needle aspiration biopsy and a neck ultrasonogram is recommended. After surgery, the follow-up strategy includes serial serum thyroglobulin levels and a neck ultrasound.
  • For successful thyroid cancer treatment, radioiodine and surgery should be used selectively. For initial surgery, total thyroidectomy has to be considered for nodules >1 cm. Therapeutic compartment-based dissection is indicated in case of N1 (clinical or ultrasound) disease. However, further RCTs are needed for consensus on the need for unilateral lobectomy in T1–T2 and prophylactic neck dissection.
  • There are three objectives of post-surgical radioiodine administration: remnant ablation, destruction of neoplastic foci (known foci [treatment] or remote foci [adjuvant]) and post radioiodine thyroid body scans (single-photon emission computed tomography/computed tomography is a major advance in this area). Two studies have demonstrated that lower dose (30 mci) radioiodine and the use of recombinant thyroid stimulating hormone to stimulate thyroglobulin levels are as good as the traditional 100 mci radioiodine dose or deprivation of LT4 in low risk thyroid cancer patients (HI-LO and ESTIMABL). Higher radioiodine doses are needed for pT1–3 and N1a–N1b patients.
  • Follow-up involves assessing disease status by measuring thyroglobulin levels either after recombinant human thyroid stimulating hormone or during LT4 treatment (using a sensitive and reliable method) and neck ultrasound 12 months after surgery. Response to initial therapy has to be defined (excellent, biochemically incomplete, structurally incomplete or indeterminate) to help predict prognosis and modify treatment accordingly.

The guidelines can be improved by data from new RCTs. Currently ongoing are RCTs to explore if radioiodine is needed in patients with T1bN0, and if central dissection is needed in T2 N0 patients.

Dr Douglas Forrest (Laboratory of Endocrinology and Receptor Biology, NIDDK, NIH, USA) gave his personal view on key thyroid hormone findings during the past decade.

The whole concept of thyroid hormone action has evolved as more parts of the thyroid puzzle have been discovered. Key findings include elucidation of the thyroid receptor system and T3 regulated transcription factors, the discovery of the deiodinases that convert T4 into T3 and the transporters that help these hormones into cells.

Furthermore, mutations of the T3 receptor (THR) has revealed much of the mechanisms of action of the thyroid system. Mice models with THR mutations have helped us to understand that the different isoforms mediate different tissue-specific functions. Two families with mutations in the THRalpha gene were first identified in 2012 by two research groups, one from Cambridge,UK,18 the other from Rotterdam, the Netherlands.19 These groups characterized the clinical phenotype associated with THRalpha mutations as growth, motor and mental retardation, constipation and anaemia with paradoxical minimal changes of the thyroid serum profile. Similar to THRbeta resistance, THRalpha resistance is a very rare autosomal dominant disease and both share a similar trait where the mutated allele has a dominant negative effect over the wild type allele. The aberrant recruitment of nuclear receptor corepressor (NCOR1) by THRalpha mutants could explain the clinical hypothyroidism present in individuals with this mutation. Therefore, therapies aimed at the THRalpha-NCOR1 interaction or its downstream actions could be tested as potential targets in treating THRalpha mutant-mediated hypothyroidism in patients.20

Genome-wide analysis of THR binding sites in the liver21 and neural tissue22 have helped to determine how THR regulates genes in different ways and has opened up new avenues for selective modulation of thyroid hormone action.

Deiodinases (Dio), found and elucidated during the past decade, can amplify or deplete levels of thyroid hormones in target tissues. The different types of Dio are differentially expressed in tissues, with type 2 deiodinase, Dio2, the most studied, whilst studies of Dio3 are scarce. Dio2 deficient mice have brittle bones and are prone to fractures.23 Dio3 mice are smaller, are glucose intolerant and have multiple defects showing the importance of the tight regulatory system controlled by the thyroid hormones according to physiological needs.24 Dio3 participates in intracellular inactivation of thyroid hormone which is key to the process of survival of multiple cell systems.25

Mutations in the thyroid hormone transporter MCT8 have also been reported in Allan–Herndon-Dudley syndrome; symptoms of which are cognitive impairment, hypotonia, spasticity, speech defects and high T3 low T4 and normal thyroid stimulating hormone levels.26–28 In mice, deletion of both MCT8 and T4-selective organic anion transporting polypeptide provides a basis to study the pathogenic mechanisms underlying Allan–Herndon-Dudley syndrome-associated endocrine abnormalities.27

Dr Forrest concluded with the discovery by Mittag J et al29 of the need for parvalbuminergic neurons in the anterior hypothalamus for THRalpha1 signaling to control blood pressure and heart rate, emphasizing the fact that there is still a lot to learn about the expression of THR and T3 action in the body.

Dr David S Cooper, Johns Hopkins University School of Medicine, USA, was asked to comment on the most influential papers of the past decade. For this task he used a bibliometric analysis.

He divided the term ‘clinical thyroid disease’ into several topics and used Scopus database to reveal the top articles published in each field. ‘Thyroid cancer’ had the highest number of papers.

For papers published between 2004 and 2012, those cited most frequently for each of six areas are:

  1. Iodine deficiency and iodine nutrition
    Vermiglio F, et al (J Clin Endocrinol Metab. 2004;89:6054–60); reflecting on the association of attention-deficit/hyperactivity disorder and iodine deficiency.

    De Benoist B, et al (Food and Nutr Bull. 2008;29:195–202); discussing global progress in this topic.
  2. Thyroiditis:
    Negro R, et al (J Clin Endocrinol Metab. 2006;91:2587–91); reflecting that treatment of thyroid peroxidase antibody positive pregnant women with LT4 might reduce miscarriage.

    Castillo P, et al (Arch Neurol. 2006;63:197–202); describing Hashimoto encephalopathy.
  3. Hyperthyroidism:
    Velaga MR, et al (J Clin Endocrinol Metab. 2004;89:5862–5); reporting a polymorphism in the lymphoid tyrosine phosphatase-22 gene associated with Graves’ disease.

    Eckstein AK, et al (J Clin Endocrinol Metab. 2006;91:3464–70); reporting the association of TRAb with Graves’ ophthalmopathy.

    Casey BM, et al (Obstet Gynecol. 2006;107 [2 pt 1]:337–41); reflecting on the lack of detrimental effect of subclinical hyperthyroidism in pregnancy. [Anchor]
    Salvi M, et al (Eur J Endocrinol. 2007;156:33–40); describing the efficacy of rituximab in Graves’ ophthalmopathy.
  4. Hypothyroidism:
    Casey BM, et al (Obstet Gynecol. 2005;105:239–45); finding that subclinical hypothyroidism in pregnancy is associated with miscarriage.

    Alexander EK, et al (N Engl J Med. 2004;351:241–9); documenting that the need for levothyroxine in pregnancy increases by 45% and should be fulfilled as early as possible.
  5. Thyroid nodules:
    Moon WJ, et al (Radiology. 2008;247:762–70); describing sonographic features to distinguish between benign and malignant nodules.

    Nikiforov YE, et al (J Clin Endocrinol Metab. 2009;94:2092–8); describing a prospective study of mutational analysis of fine needle aspiration biopsy specimens.
  6. Thyroid cancer:
    Davies L, et al (JAMA. 2006;295:2164–7); the first paper to describe the epidemic of small papillary thyroid cancer.

    He H, et al (Proc Natl Acad Sci USA. 2005;102:19075–80); describing the transcriptional regulation of certain miRNAs in papillary thyroid cancer.

    Xing M, et al (J Clin Endocrinol Metab. 2005;90:6373–9); reporting that the BRAF mutation predicts a poorer prognosis in papillary thyroid cancer.

Owing to the time bias of the above list, Dr. Cooper also looked at the top cited article per single year, covering 2010 to 2014. The results are as follows:  

In 2010, Rodondi N, et al (JAMA. 2010:304:1365–74); describing the higher risk of coronary heart disease and mortality in patients with subclinical hypothyroidism (269 citations).

In 2011, Nikiforov YE, et al (J Clin Endocrinol Metab. 2011;96:3390–7); describing the impact of molecular testing in indeterminate thyroid nodules (269 citations).

In 2012, Wells SA Jr, et al (J Clin Oncol. 2012;30:134–41); concerning vandetanib in an RCT of locally advanced medullary thyroid cancer patients (322 citations).

In 2013, Xing M, et al (J Clin Endocrinol Metab. 2005;90:6373–9); showing that the BRAF mutation predicts a poorer prognosis in papillary thyroid cancer (147 citations).

In 2014, Brose MS, et al (Lancet. 2014;384:319–28); with an RCT of sorafenib in radioactive iodine refractory thyroid cancer (73 citations).

Dr. Cooper concluded his presentation with the fact that the field of thyroid cancer has yielded more publications in thyroidology in the past decade than any other field. As the number of citations apply to the number of researchers in that field, the citation numbers can only be applied to papers within the same field.


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Gabriela Brenta

Department of Endocrinology and Metabolism
Milstein Hospital
Buenos Aires University
Buenos Aires, Argentina
thyroid cancer
scientific meeting