Hyperthyroidism caused by Graves’ disease (GD) is a relatively rare disease in children. Treatment options are the same as in adults - anti-thyroid drugs (ATD), radio-active iodine (RAI) or thyroid surgery, but the risks and benefits of each modality are different. This European Thyroid Association guideline provides new recommendations for the management of pediatric GD with and without orbitopathy. Clinicians should be alert that GD may present with behavioral changes or declining academic performance in children. Measurement of serum TSH receptor antibodies is recommended for all pediatric patients with hyperthyroidism. Management recommendations include the first-line use of a prolonged course of methimazole/carbimazole ATD treatment (three years or more), a preference for dose titration instead of block and replace ATD, and to avoid propylthiouracil use. Where definitive treatment is required either total thyroidectomy or RAI is recommended, aiming for complete thyroid ablation with a personalized RAI activity. We recommend avoiding RAI in children under 10 years of age but favor surgery in patients with large goiter. Pediatric endocrinologists should be involved in all cases.
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Christiaan F Mooij, Timothy D. Cheetham, Frederik A. Verburg, Anja Eckstein, Simon H.s Pearce, Juliane Leger, and A. S. Paul van Trotsenburg
Joanna Boguslawska, Marlena Godlewska, Ewa Gajda, and Agnieszka Piekiełko-Witkowska
Autoimmune thyroid disease (AITD) is the most common human autoimmune disease. The two major clinical manifestations of AITD are Graves’ disease (GD) and Hashimoto’s thyroiditis (HT). AITD is characterized by lymphocytic infiltration of the thyroid gland, leading either to follicular cell damage, thyroid gland destruction, and development of hypothyroidism (in HT) or thyroid hyperplasia, induced by thyroid antibodies which activate TSHR on thyrocytes, leading to hyperthyroidism. The aim of this review is to present up-to-date picture of the molecular and cellular mechanisms that underlie the pathology of AITD. Based on studies involving patients, animal AITD models, and thyroid cell lines, we discuss the key events leading to the loss of immune tolerance to thyroid autoantigens as well as the signaling cascades leading to the destruction of thyroid gland. Special focus is given on the interplay between the environmental and genetic factors, as well as non-coding RNAs (ncRNAs) and microbiome contributing to AITD development. In particular, we describe mechanistic models by which single nucleotide polymorphisms (SNPs) in genes involved in immune regulation and thyroid function, such as CD40, TSHR, FLT3, and PTPN22 underlie AITD predisposition. The clinical significance of novel diagnostic and prognostic biomarkers based on ncRNAs, and microbiome composition is also underscored. Finally, we discuss the possible significance of probiotic supplementation on thyroid function in AITD.
Jorge Tapia-Martinez, Margarita Franco-Colin, Vanessa Blas-Valdivia, and Edgar Cano-Europa
Introduction: Congenital hypothyroidism affects metabolic and thyroid programming, having a deleterious effect on body weight regulation promoting metabolic diseases. This work aimed to demonstrate the development of type 2 diabetes mellitus (T2D) in animals with congenital hypothyroidism, only by the consumption of a mild hypercaloric diet in the extrauterine stage.
Methods: Two groups of female Wistar rats (n = 9): euthyroid and hypothyroid were used. Hypothyroidism was induced by a thyroidectomy with parathyroid reimplantation. Males offsprings post-weaning were divided into four groups (n = 10): euthyroid, hypothyroid, euthyroid + hypercaloric diet, and hypothyroid + hypercaloric diet. The hypercaloric diet consisted of ground commercial feed plus 20% lard and was administered until postnatal week 40th. Bodyweight and energy intake were monitored weekly. Also, analyzed metabolic and hormonal markers related to cardiovascular risk, insulin resistance, and glucose tolerance at week 40th. Then, animals were euthanized to perform the morphometric analysis of the pancreas and adipose tissue.
Results: T2D was developed in animals fed a hypercaloric diet denoted by the presence of central obesity, hyperphagia, hyperglycemia, dyslipidemia, glucose tolerance, insulin resistance, and hypertension. As well as changes in the cytoarchitecture of the pancreas and adipose tissue related to T2D.The results show that congenital hypothyroid animals had an increase
Conclusions: Congenital hypothyroid animals develop T2D, having the highest metabolic disturbances and a worsened clinical prognosis than euthyroid animals.
David Shaki, Marina Eskin-Schwartz, Noam Hadar, Emily Bosin, Lior Carmon, Samuel Refetoff, Eli Hershkovitz, Ohad S. Birk, and Alon Haim
Objective: Bi-allelic loss-of-function mutations in TSHB, encoding the beta-subunit of TSH, cause congenital non-goiterous hypothyroidism. Homozygosity for the TSHB p.R75G variant, previously described in South Asian individuals, does not alter TSH function, but abrogates its detection by some immune-detection-based platforms, leading to erroneous diagnosis of hyperthyroidism. We set out to identify and determine carrier rate of the p.R75G variant among clinically euthyroid Bene Israel Indian Jews, to examine possible founder origin of this variant worldwide and to determine phenotypic effects of its heterozygosity.
Design: Molecular genetic studies of Bene Israel Jews and comparative studies with South Asian cohort.
Methods: TSHB p.R75G variant tested by Sanger sequencing and RFLP. Haplotype analysis in the vicinity of the TSHB gene performed using SNP arrays.
Results: Clinically euthyroid individuals with low or undetectable TSH levels from three apparently unrelated Israeli Jewish families of Bene Israel ethnicity, originating from the Mumbai region of India, were found heterozygous or homozygous for the p.R75G TSHB variant. Extremely high carrier rate of p.R75G TSHB in Bene Israel Indian Jews (~4%) was observed. A haplotype block of 239.7kB in the vicinity of TSHB shared by Bene Israel and individuals of South Asian origin was detected.
Conclusions: Our findings highlight the high prevalence of the R75G TSHB variant in euthyroid Bene Israel Indian Jews, demonstrate that heterozygosity of this variant can cause erroneous detection of subnormal TSH levels, and show that R75G TSHB is an ancient founder variant, delineating shared ancestry of its carriers.
Furio Pacini, Gagmar Fuehrer-Sake, Rossella Elisei, Daria Handkiewicz-Junak, Sophie Leboulleux, Markus Luster, Martin Schlumberger, and Johannes W Smit
Modern use of postoperative radioactive iodine (RAI) treatment for differentiated thyroid cancer (DTC) should be implemented in line with patients' risk stratification. Although beneficial effects of radioiodine are undisputed in high-risk patients, controversy remains in intermediate-risk and some low-risk patients. Since the last consensus on post-surgical use of RAI in DTC patients, new retrospective data and results of prospective randomized trials have been published, which have allowed the development of a new European Thyroid Association statement for the indications of post-surgical RAI therapy in DTC. Questions about which patients are candidates for RAI therapy, which activities of RAI can be used, and which modalities of pre-treatment patient preparation should be used are addressed in the present guidelines.
Takaaki Konishi, Michimasa Fujiogi, Nobuaki Michihata, Takayoshi Niwa, Kojiro Morita, Hiroki Matsui, Kiyohide Fushimi, Masahiko Tanabe, Yasuyuki Seto, and Hideo Yasunaga
Introduction: Recent studies have shown worse postoperative outcomes following several surgeries in underweight or obese patients. However, the association between body mass index (BMI) and short-term outcomes following thyroid cancer surgery remains unclear because of the small number of patients, deficits in background data known as risk factors (e.g., cancer stage, operative procedure, intraoperative device use and hospital volume) and categorisation of BMI.
Methods: We identified patients who underwent thyroidectomy for differentiated thyroid cancer from July 2010 to March 2017 using a Japanese nationwide inpatient database. We used restricted cubic spline (RCS) analyses to investigate potential nonlinear associations between BMI (without categorisation) and outcomes: postoperative complications (local and general), duration of anaesthesia, postoperative length of hospital stay and hospitalisation costs. The analyses were adjusted for demographic and clinical backgrounds including above-stated factors. We also performed multivariable regression analyses for the outcomes with categorisation of BMI.
Results: Among 59,671 eligible patients, the median BMI was 22.9 kg/m2 (interquartile range [IQR], 20.7–25.6 kg/m2). In total, 3860 patients (6.5%) had local complications and 787 patients (1.3%) had general complications. Although there were no significant associations with local complications, such as bleeding, recurrent laryngeal nerve paralysis and surgical site infection, the occurrence of general complications was significantly associated with higher BMI. BMI showed a linear association with duration of anaesthesia and U-shaped associations with postoperative length of stay and hospitalisation costs. The lowest points of the U-shaped curves occurred at a BMI of approximately 24 kg/m2. The multivariate regression analyses showed consistent results with the RCS analyses.
Discussion/conclusion: Whereas RCS analyses revealed no significant associations between BMI and postoperative local complications, obese was significantly associated with the occurrence of general complications. The linear association between BMI and duration of anaesthesia corresponds with previous studies. Although postoperative length of stay and total hospitalisation costs demonstrated U-shaped associations, the slight differences would not be clinically important. Even if surgeons must pay attention to general complications in obese patients undergoing thyroid cancer surgery as well as other surgeries, underweight and overweight patients can undergo thyroidectomy as safely as patients with normal B
Claire L Wood, Niamh Morrison, Michael Cole, Malcolm Donaldson, David B Dunger, Ruth Wood, Simon H.s Pearce, and Tim D Cheetham
Objective: Patients with thyrotoxicosis are treated with antithyroid drug (ATD) using block and replace (BR) or a smaller, titrated dose of ATD (dose titration, DT).
Design: A multi-centre, phase III, open-label trial of newly diagnosed paediatric thyrotoxicosis patients randomised to BR/DT. We compared the biochemical response to BR/DT in the first 6 months of therapy.
Methods: Patients commenced 0.75mg/kg carbimazole (CBZ) daily with randomisation to BR/DT. We examined baseline patient characteristics, CBZ dose, time to serum TSH/FT4 normalisation and BMI Z-score change.
Results: There were 80 patients (baseline) and 78 patients (61 female) at 6 months. Mean CBZ dose was 0.9mg/kg/day (BR) and 0.5mg/kg/day (DT). There was no difference in time to non-suppressed TSH concentration; 16 of 39 patients (BR) and 11 of 39 (DT) had suppressed TSH at 6 months. Patients with suppressed TSH had higher mean baseline FT4 levels (72.7 v 51.7 pmol/l; 95% CI for difference 1.73,31.7; p=0.029). Time to normalise FT4 levels was reduced in DT (log rank test, p=0.049) with 50% attaining normal FT4 at 28 days (95% CI 25, 32) versus 35 days in BR (95% CI 28, 58). Mean BMI Z-score increased from 0.10 to 0.81 at 6 months (95% CI for difference 0.57,0.86; p<0.001) and was greatest in patients with higher baseline FT4 concentrations.
Conclusions: DT-treated patients normalised FT4 concentrations more quickly than BR. 94% of patients overall have normal FT4 levels after six months but 33% still have TSH suppression. Excessive weight gain occurs with both BR and DT therapy.
Laure Felix, Peggy Jacon, Maxime Lugosi, Justine Cristante, Julie Roux, and Olivier Chabre
Background: It has recently been reported in a cross sectional study that patients with amiodarone induced thyrotoxicosis (AIT) showed a “white” thyroid on unenhanced computed tomography. However the link and time-course between increase in thyroid radiographic density and thyrotoxicosis remain unknown
Methods: We present the case of a 34-year-old patient with severe sarcoidosis-related hypertrophic cardiomyopathy who was followed with successive unenhanced CT scans integrated to FDG PET. After the first CT scan the patient was exposed to amiodarone during 23 months and developed AIT, very likely by thyroiditis (AIT type 2).
Results: Analysis of the successive enhanced CT scans revealed that thyroid density and volume increased before revelation of AIT before rapidly returning to normal as thyrotoxicosis receded
Conclusion: Evolution of thyroid radiographic density on unenhanced CT scan is correlated with the evolution of thyroid function during the development of AIT, and shows a very large increase in thyroid iodine content before occurence of thyrotoxicosis. This suggests that in AIT type 2 thyrotoxicosis might be the consequence of an enormous accumulation of iodinated compounds in the follicles and that unenhanced CT scan might be used to predict the development and remission of AIT.
Maria Lopes Pereira, Anna Quialheiro, Patrício Costa, Susana Roque, Nadine Correia Santos, Margarida Correia-Neves, Ana Goios, Ivone Carvalho, T. Korevaar, Laura Vilarinho, and Joana Almeida Palha
Objectives: Over 1.9 billion people worldwide are living in areas estimated to be iodine insufficient. Strategies for iodine supplementation include campaigns targeting vulnerable groups, such as women in pre-conception, pregnancy and lactation. Portuguese women of childbearing age and pregnant women were shown to be mildly-to-moderately iodine deficient. As a response, in 2013, the National Health Authority issued a recommendation that all women considering pregnancy, pregnant or breastfeeding, take a daily supplement of 150-200 μg iodine. This study explored how the iodine supplementation recommendation has been fulfilled among pregnant and lactating women in Portugal, and whether reported iodine supplements intake impacted on adverse obstetric and neonatal outcomes.
Design and Methods: Observational retrospective study on pregnant women who delivered or had a fetal loss in the Braga Hospital and had their pregnancies followed in Family Health Units.
Results: The use of iodine supplements increased from 25% (before the recommendation) to 81% after the recommendation. This was mostly due to an increase in the use of supplements containing iodine only. Iodine supplementation was protective for the number of adverse obstetric outcomes (OR=0.791, p=0.018) and for neonatal morbidities (OR=0.528, p=0.024) after controlling for relevant confounding variables.
Conclusion: The recommendation seems to have succeeded in implementing iodine supplementation during pregnancy. National prospective studies are now needed to evaluate the impact of iodine supplementation on maternal thyroid homeostasis and offspring psychomotor development and on whether the time of the beginning of iodine supplementation (how early during preconception or pregnancy) is relevant to consider.
J L Reverter, L Ferrer-Estopiñan, F Vazquez, S Ballesta, S Batule, A Perez-Montes de Oca, C Puig-Jove, and M Puig-Domingo
Introduction: Computer-aided diagnostic (CAD) programs for malignancy risk stratification from ultrasound imaging of thyroid nodules are being validated both experimentally and in real-world practice. However, they have not been tested for reliability in analyzing difficult or unclear images.
Methods: Ultrasound images with indeterminate characteristics were evaluated by five observers with different experience in ultrasound examination and by a commercial CAD program. The nodules, on which the observers widely agreed, were considered concordant and, if there was little agreement, not concordant or difficult to assess. The diagnostic performance of the readers and the CAD program was calculated and compared in both groups of nodule images.
Results: In the group of concordant thyroid nodules (n= 37), the clinicians and the CAD system obtained similar levels of accuracy (77.0% vs 74.2%, respectively; p=0.7) and no differences were found in sensitivity (SEN) (95.0% vs 87.5%, p=0.2), specificity (SPE) (45.5 vs 49.4, respectively; p=0.7), positive predictive value (PPV) (75.2% vs 77.7%, respectively; p=0.8) nor negative predictive value (NPV) (85.6 vs 77.7, respectively; p=0.3). When analyzing the non-concordant nodules (n= 43), the CAD system presented a decrease in accuracy of 4.2%, which was significantly lower than that observed by the experts (19.9%, p= 0.02).
Conclusions: Clinical observers are similar to the CAD system in the ultrasound assessment of the risk of thyroid nodules. However, the AI system for thyroid nodules CAD-AmUT showed more reliability in the analysis of unclear or misleading images.