Thyroid Growth Research Articles

Enhanced pediatric thyroid ultrasound image segmentation using DC-Contrast U-Net

Early screening methods for the thyroid gland include palpation and imaging. Although palpation is relatively simple, its effectiveness in detecting early clinical signs of the thyroid gland may be limited, especially in children, due to the shorter thyroid growth time. Therefore, this constitutes a crucial foundational work. However, accurately determining the location and size of the thyroid gland in children is a challenging task. Accuracy depends on the experience of the ultrasound operator in current clinical practice, leading to subjective results. Even among experts, there is poor agreement on thyroid identification. In addition, the effective use of ultrasound machines also relies on the experience of the ultrasound operator in current clinical practice. In order to extract sufficient texture information from pediatric thyroid ultrasound images while reducing the computational complexity and number of parameters, this paper designs a novel U-Net-based network called DC-Contrast U-Net, which aims to achieve better segmentation performance with lower complexity in medical image segmentation. The results show that compared with other U-Net-related segmentation models, the proposed DC-Contrast U-Net model achieves higher segmentation accuracy while improving the inference speed, making it a promising candidate for deployment in medical edge devices in clinical applications in the future.

Pregnancy-related hormonal changes and thyroid growth: do they have an impact on the higher incidence of differentiated thyroid cancer in women?

To analyze whether pregnancy could play a role in the higher prevalence of differentiated thyroid carcinoma (DTC) in women. Estrogens strongly modify thyroid economy by increasing iodine clearance, thyroid hormone requirement and production. Human chorionic gonadotropin (hCG) contributes to the increased thyroid hormone synthesis. Both estrogens and hCG can interfere with the regulation of thyroid volume and with thyroid nodule development and progression. The potential effect of hCG is exclusively related to its weak agonistic activity on TSH receptor. Estrogen implication on normal and nodule-derived thyrocyte growth has been demonstrated in vitro and in animal models. Furthermore, there is solid clinical evidence showing a promoting effect of pregnancy on thyroid volume and nodule development. Two metanalysis, one including retrospective and another prospective observational studies, failed to show an association between pregnancy and DTC. A large pooled prospective analysis using multivariable-adjusted Cox proportional hazard models did not demonstrate an association between DTC and parity. Similarly, no association between PTC occurrence and parity was observed in a prospective cohort analysis by linkage to the statewide Surveillance, Epidemiology, and End Results (SEER). The presently available evidence does not support an involvement of pregnancy in DTC etiology.

6770 Graves’ disease induced by COVID-19 infection in a 49 year old male

Abstract Disclosure: N. Al-hosainat: None. A. Al Najada: None. T. Salar: None. S. Iqbal: None. K. Abdel Gadir: None. Introduction: Graves’ disease is an autoimmune disease causing hyperthyroidism, characterized by elevated thyrotropin-receptor antibodies. COVID-19 infection has been increasingly reported as a trigger of thyroid illness including Graves’ disease. We present a unique case of 49-year-old patient who was diagnosed with Graves’ disease after COVID-19 infection. Case description: A 49-year-old male patient with history of prediabetes presented with complaints of tremor, fatigue, generalized itching, and unintentional weight loss (30 Ibs in 6 months). He had COVID-19 infection 3 months prior. The remainder of review of systems was negative. No family history of thyroid disease. On exam, the patient had sinus tachycardia with otherwise normal vital signs. Diffuse thyromegaly was noted along with an intermittent fine tremor of the extremities. Blood work was notable for low TSH <0.01 uIU/mL, elevated free T4 (3.4 ng/dL), free T3 (17.6ng/dL), and TSH receptor antibody (12 IU/L). Thyroid ultrasound showed mild goiter with 2 nodules, one of which was TIRADS 4 and 1.5cm. This nodule was biopsied and found to be benign. Radioactive iodine uptake scan revealed homogeneous diffuse increased thyroid uptake. The diagnosis of Graves’ disease was made, and the patient was started on propranolol and methimazole with significant improvement of his symptoms and his laboratory tests normalizing. Discussion: Graves' disease is an autoimmune disease, characterized by hyperthyroidism, goiter, occasional orbitopathy and dermopathy. Caused by antibodies against thyroid-stimulating hormone receptors which stimulate thyroid hormone secretion and thyroid growth. Treatment is aimed to decrease thyroid hormone synthesis by either a Thionamide, radioiodine ablation, or surgery. Remission rates with antithyroid drugs average under 40 percent after one to two years of treatment and could exceed 80 percent after 5 to 10 years of treatment. COVID-19 is a multi-system disease, caused by SARS-CoV-2 virus, transmitted by large droplets and small particle aerosols, was declared a pandemic in 2020 and affected millions of people worldwide. There is emerging data showing the association of COVID-19 with various thyroid diseases including thyroiditis and relapse of known Graves' disease after the infection. We present a case of newly diagnosed Graves’ disease after COVID-19 infection in a patient with no personal or family history of such disease which raises the concern of autoimmune pathway activation induced by the infection. The onset of Graves’ disease after COVID-19 infection does not depend on the presence of pre-existing thyroid pathology and in this case responded well to antithyroid medication. Conclusion: COVID-19 can lead to the development of a range of medical illnesses. In patients who develop symptoms of thyrotoxicosis, Graves’ disease should be suspected, investigated, and treated appropriately Presentation: 6/3/2024

8751 Radiofrequency Thermal Ablation in 32 Patients with Toxic Adenomas with Resolution of Hyperthyroidism in All Cases

Abstract Disclosure: L.G. Amato: None. E.M. Volpi: None. L.D. Volpi: None. P.M. Carani: None. A. Rahal: None. Introduction: In the general population, thyroid nodules are found in 3-7% of individuals on physical examination and in 20-76% on ultrasound. Around 8-10% of benign nodules may present autonomous behavior, being called hot nodules, causing symptoms of hyperthyroidism and being called toxic adenomas (TA). In TAs, autonomous hormone production can be caused by somatic activating mutations of genes regulating thyroid growth and hormone synthesis caused by somatic activating mutations of genes regulating thyroid growth and hormone synthesis. Classically, the proposed treatment for autonomous nodules was surgical resection or radioiodine ablation (RAI). In this context, the prevalence of hypothyroidism after the procedure varies from 2% to 3% following lobectomy, and lower after isthmusectomy in the unique circumstance in which the TA is confined to the thyroid isthmus. A study following 684 patients with TA treated with RAI reported a progressive increase in overt and sub-clinical hypothyroidism. Potential complications following near-total/total thyroidectomy include the risk of permanent hypoparathyroidism (< 2.0%) or recurrent laryngeal nerve injury (RLN) (< 2.0%). A small risk of permanent RLN injury exists with surgery for TA. Following RAI therapy, there have been reports of new-onset Graves Disease (up to 4% prevalence) as well as concern for thyroid malignancy and a very minimal increase in late non thyroid malignancy. Radiofrequency ablation (RFA) has been a precise and effective alternative for the treatment of many benign thyroid nodules over the past ten years, including hot nodules. RFA could preserves normal thyroid function compared to surgery or RAI. Clinical case: We evaluated the effectiveness of a single session of RFA in 32 patients with TA, through hormonal status, achieving normalization of thyroid and volumetric reduction of the nodule. Among the 32 patients included in this study, aged between 25 and 88 years, of these, 31 were women and 1 was a man, all of whom underwent a single RFA procedure (“moving shot” technique associated with hydrodissection). We had a single case of a reversible complication: a patient who had transient vocal cord paralysis, with total reversal. There was a reduction in the volume of all nodules as well as all patients progressed to a state of euthyroidism within 60 days of follow-up. Conclusion: A single session of RFA was effective in treating autonomous nodules, restoring euthyroidism in all patients. Presentation: 6/3/2024

Targeting Thyroid-Stimulating Hormone Receptor: A Perspective on Small-Molecule Modulators and Their Therapeutic Potential.

TSHR is a member of the glycoprotein hormone receptors, a subfamily of class A G-protein-coupled receptors and plays pivotal roles in various physiological and pathological processes, particularly in thyroid growth and hormone production. The aberrant TSHR function has been implicated in several human diseases including Graves' disease and orbitopathy, nonautoimmune hyperthyroidism, hypothyroidism, cancer, neurological disorders, and osteoporosis. Consequently, TSHR is recognized as an attractive therapeutic target, and targeting TSHR with small-molecule modulators including agonists, antagonists, and inverse agonists offers great potential for drug discovery. In this perspective, we summarize the structures and biological functions of TSHR as well as the recent advances in the development of small-molecule TSHR modulators, highlighting their chemotypes, mode of actions, structure-activity relationships, characterizations, in vitro/in vivo activities, and therapeutic potential. The challenges, new opportunities, and future directions in this area are also discussed.

STR mutations on chromosome 15q cause thyrotropin resistance by activating a primate-specific enhancer of MIR7-2/MIR1179.

Thyrotropin (TSH) is the master regulator of thyroid gland growth and function. Resistance to TSH (RTSH) describes conditions with reduced sensitivity to TSH. Dominantly inherited RTSH has been linked to a locus on chromosome 15q, but its genetic basis has remained elusive. Here we show that non-coding mutations in a (TTTG)4 short tandem repeat (STR) underlie dominantly inherited RTSH in all 82 affected participants from 12 unrelated families. The STR is contained in a primate-specific Alu retrotransposon with thyroid-specific cis-regulatory chromatin features. Fiber-seq and RNA-seq studies revealed that the mutant STR activates a thyroid-specific enhancer cluster, leading to haplotype-specific upregulation of the bicistronic MIR7-2/MIR1179 locus 35 kb downstream and overexpression of its microRNA products in the participants' thyrocytes. An imbalance in signaling pathways targeted by these micro-RNAs provides a working model for this cause of RTSH. This finding broadens our current knowledge of genetic defects altering pituitary-thyroid feedback regulation.

FRI489 The Interplay Between Thyroid Nodular Disease And Insulin Resistance Indices In Pregnant Women

Abstract Disclosure: A.J. Nowak: None. M. Trofimiuk-Muldner: None. J. Podlewski: None. A. Hubalewska-Dydejczyk: None. Thyroid cells proliferation and function is regulated by TSH. Other factor, such as insulin/insulin-like growth factors (IGF), through their mitogenic effects, may affect thyroid growth and nodules formation [1].This study evaluated the interplay between insulin resistance indices and thyroid structure in pregnant women. The study group was recruited from the Polish National Program for Elimination of Iodine Deficiency, conducted between 2007-2017. We assessed the fasting glucose, insulin levels, TSH in 1069 pregnant women (median age 29 years, IQR 6 years). Thyroid ultrasound was performed in each study participant. Based on calculated HOMA-IR, pregnant women were stratified into three subgroups HOMA1 (324 women with HOMA-IR < 1), HOMA 2 (570 women with HOMA-IR ≥1& <2.5) and HOMA3 (175 women with HOMA-IR ≥ 2.5). Results: Median (IQR) TSH concentrations were 1.42 (1.33) mIU/L, 1.65 (1.31) mIU/L, and 1.77 (1.29) mIU/L in HOMA1, HOMA2, and HOMA3 subgroups, respectively. The mean (±SD) thyroid volume was 12.36 (4.27) mL, 12.71 (5.37) mL, and 13.70 (4.92) mL in HOMA1, HOMA2, HOMA3 subgroups respectively.33 (10.2%) of women in HOMA1, 53 (9.3%) in HOMA2 and 11 (6.3%) in HOMA3 subgroup had at least one thyroid nodule - there was no significant difference between the subgroups (P = 0.4724)Fasting insulin >10 mIU/mL was found in 27.53% of pregnant women (286 out of 1039) with thyroid volume <25 mL, and in 36.67% women (11 out of 30) with thyroid volume ≥25mL (P=0.27). Conclusions: We have not found any significant relationship between the thyroid volume or structure and insulin or insulin resistance indices in pregnant women. 1. Kimura T., Van Keymeulen A., Golstein J., Fusco A., Dumont J.E., Roger P.P. Regulation of thyroid cell proliferation by TSH and other factors: A critical evaluation of in vitro models. Endocr. Rev. 2001;22:631–656. doi: 10.1210/edrv.22.5.0444. Presentation: Friday, June 16, 2023

Abstract 3068: CREBBP/EP300 disruption promotes tumor progression and confers synthetic lethality in anaplastic thyroid cancers

Abstract Anaplastic thyroid cancers (ATC) are fast-growing, undifferentiated tumors and almost invariably fatal, primarily due to the lack of effective therapeutic options. The recent approval of dabrafenib plus trametinib for the treatment of BRAFV600E-mutant ATCs improved the prognosis of a subset of patients, but ineligibility and acquired resistance still limit their use. Overall, ATC patients remain in great need of tailored therapeutic options. We previously showed that loss-of-function alterations targeting histone acetyltransferase (HAT) genes, namely CREBBP and EP300, occur in 15-20% of ATCs, but only in <1% of their well-differentiated counterparts. What remains unknown are the specific mechanisms by which HAT disruptions perturb chromatin architecture, impact gene homeostasis, and unleash cellular processes in these aggressive tumors. We are assessing the HAT-mediated thyroid cancer progression. CREBBP/EP300 knockouts enhanced thyroid cancer cell proliferation in vitro and induced thyroid gland growth in a thyroid-specific mouse model of HAT loss. We are leveraging these animals to characterize the in vivo effects of Crebbp/Ep300 knockout, alone or in combination with BrafV600E, in thyroid cancer phenotypes and epigenetic reconfiguration. In addition, we are exploiting the molecular consequences of HAT loss to explore tailored treatments. CRISPR/Cas9 screens identified a mutual CREBBP/EP300-dependency of HAT-mutant human cancer cell models. Our experiments in thyroid cancer cells employing CREBBP/EP300-targeting proteolysis-targeting chimera (PROTAC) compounds specifically degraded these proteins and decreased histone acetylation. Our findings prove the oncogenicity of HAT loss in thyroid cancer progression and support exploring synthetic lethality dependencies in CREBBP/EP300-mutant ATCs. In summary, we provide pre-clinical basis to inform genomics-driven and mechanism-oriented decisions for the clinical management of patients with HAT-altered ATC. Citation Format: Jacob Haase, Talia A. Gebhard, Qi Liu, Sara G. Bernabé, Jingzhu Hao, Chisom Unegbu, Athanasios Bikas, Jun Qi, Iñigo Landa. CREBBP/EP300 disruption promotes tumor progression and confers synthetic lethality in anaplastic thyroid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3068.

Abstract 1219: Establishment and characterization of amitrole-induced mouse thyroid adenoma-derived cell lines

Abstract Some types of thyroid cancers are known to arise from thyroid adenomas, as a malignant transition from benign adenoma, as proposed in the multi-step carcinogenesis model. Thyroid cancer studies using human thyroid cancer cell lines have been intensely performed by many researchers. However, mouse thyroid adenoma cell lines have not been well established and characterized. In order to obtain further insights into thyroid carcinogenesis process, we established five cell lines from thyroid adenomas developed in mice treated with goitrogen amitrole. Among them, two cell lines, CAT458/458s (CAT: cells from amitrole treated thyroids; CAT458s: a sub-line from CAT458) and CAT459 were found to be positive for E-cadherin and Claudin-1, representative epithelial markers, and negative for Vimentin, a mesenchymal marker, suggesting that they originated from thyroid epithelial cells. We found higher expression of DUOX1, a member of NADPH oxidase involved in thyroid hormone synthesis, in both CAT458s and 459 cells than normal mouse thyroids, presumably due to an unknown mechanism caused by amitrole treatment. NKX2-1, a master regulator of thyroid development, is not expressed in CAT458s cells while NKX2-1 is abundantly expressed in CAT459 cells. Consistent with this finding, NKX2-1-positive CAT459 cells showed higher mRNA expression of thyroid differentiation markers including Tg, Duox1, and Duox2. NKX2-1 overexpression in NKX2-1-negative CAT458s cells using a lentiviral infection system induced mRNA expressions of these thyroid differentiation marker genes, suggesting that partial thyroid differentiation of the adenoma cells is induced by NKX2-1. TSH and IGF-I are known to work synergistically for thyroid growth. However, Tshr mRNA expression is not detected in either CAT458s or 459 cells, suggesting that TSH signal is not responsible for their growth. On the other hand, IGF-IR protein is expressed and IGF-I induces AKT and S6 phosphorylation in both cells. We further tried to assess somatic gene mutations involved in adenoma development by whole-genome sequencing (WGS). WGS analysis revealed that somatic missense mutations are not found in genes known to be involved in thyroid carcinogenesis and cancer progression, such as Braf, Trp53, Ret, Tert, Hras, Kras, and Nras. This finding suggests that prominent oncogenic mutations are not required for thyroid adenoma development that may later progress to carcinoma. Currently we are validating several missense mutations, including mutations in tumor suppressor genes Atm and Tgfb1, found in these cell lines. In conclusion, we established mouse thyroid adenoma cell lines with different differentiation and molecular profiles. CAT458s and 459 cells would provide a tool to further clarify the process of thyroid adenoma development and thyroid differentiation. Citation Format: Yo-Taro Shirai, Nobuo Hoshi, Huaitian Liu, Maxwell P. Lee, Shioko Kimura. Establishment and characterization of amitrole-induced mouse thyroid adenoma-derived cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1219.

Morphometry and Histology of Thyroid Gland in Developing Human Foetuses: A Cross-sectional Study

Introduction: The thyroid gland regulates the basal metabolic rate, somatic growth, and physical growth. The thyroid gland plays a major role in the normal growth of a foetus during the prenatal period. There are few literatures on foetal thyroid gland. Aim: To study the various morphometric and histological changes during intrauterine life in both gender of human foetuses. Materials and Methods: This cross-sectional study was carried out in the Department of Obstetrics and Gynaecology, Dr. Sushila Tiwari Hospital Government Medical College, Haldwani (UK) and Saraswati Medical College, Unnao in the period of August 2015-2022. Government Medical College, Haldwani for duration of three years on medically terminated 70 foetus of both sexes of known gestational age ranging from 10 to 40 weeks. These foetuses were divided among three groups as group 1 (10-20 weeks), group 2 (21-30 weeks), group 3 (31- 40 week). Midline dissection of neck was done to expose the thyroid gland. Morphometric parameters like length, width, and thickness of each lobe and the isthmus were measured by digital Vernier caliper, weight was also taken by digital weighing machine, then tissue processing was done and paraffin blocks were prepared. All sections were stained with Haematoxylin and Eosin stain (H&E) and studied under the microscope aided camera. By using Analysis of Variance (ANOVA) test and Independent sample test (t-test) comparison among different age groups and gender has been done. Results: There was a significant increase in foetal thyroid weight, length and widths of the right and left lobes, and length of the isthmus with increase in gestational age, while no significant relation was found between male and female foetuses of measured morphometric parameter. The histological features revealed that development of thyroid gland starts earlier and thin capsule was seen at 12 week and it became thicker and more vascular till 35 weeks. Follicles started to form at 14 week and matured follicle were seen at the age of 24 weeks, at 25th week, the lining epithelium of follicles was low columnar to cuboidal, colloid material was seen almost in every follicle. C cells were found at 22 weeks. At the 36 weeks, the follicles were seen spherical and reached to maturity level. Conclusion: As the gestational age increases, the morphometric parameters must increase, if not so, it means the growth of gland is hampered. The knowledge of the growth and differentiation of foetal thyroid will be helpful for clinicians, to judge the thyroid structure prenatally.

Case report: pituitary macroadenoma with thyroid stimulating hormone (TSH) and growth hormone (GH) co-secretion

Case report: pituitary macroadenoma with thyroid stimulating hormone (TSH) and growth hormone (GH) co-secretion

Thyroidal Transcriptomic Profiles of Pathoadaptive Responses to Congenital Hypothyroidism in XB130 Knockout Mice.

Congenital hypothyroidism is a genetic condition in which the thyroid gland fails to produce sufficient thyroid hormone (TH), resulting in metabolic dysfunction and growth retardation. Xb130−/− mice exhibit perturbations of thyrocyte cytoskeleton and polarity, and develop postnatal transient growth retardation due to congenital hypothyroidism, leading ultimately to multinodular goiter. To determine the underlying mechanisms, we performed transcriptomic analyses on thyroid glands of mice at three age points: week 2 (W2, before visible growth retardation), W4 (at the nadir of growth); and W12 (immediately before full growth recovery). Using gene set enrichment analysis, we compared a defined set of thyroidal genes between Xb130+/+ and Xb130−/− mice to identify differentially enriched gene clusters. At the earliest postnatal stage (W2), the thyroid glands of Xb130−/− mice exhibited significantly downregulated gene clusters related to cellular metabolism, which continued to W4. Additionally, mutant thyroids at W4 and W12 showed upregulated gene clusters related to extracellular matrix, angiogenesis, and cell proliferation. At W12, despite nearly normal levels of serum TH and TSH and body size, a significantly large number of gene clusters related to inflammatory response were upregulated. Early postnatal TH deficiency may suppress cellular metabolism within the thyroid gland itself. Upregulation of genes related to extracellular matrix and angiogenesis may promote subsequent thyroid growth. Chronic inflammatory responses may contribute to the pathogenesis of multinodular goiter in later life. Some of the pathoadaptive responses of Xb130−/− mice may overlap with those from other mutations causing congenital hypothyroidism.

Thyrotropin receptor antagonists and inverse agonists, and their potential application to thyroid diseases.

The thyrotropin receptor (TSHR) plays critical roles in thyroid growth and function and in the pathogenesis of several thyroid diseases including Graves' hyperthyroidism and ophthalmopathy, non-autoimmune hyperthyroidism and thyroid cancer. Several low-molecular weight compounds (LMWCs) and anti-TSHR monoclonal antibodies (mAbs) with receptor antagonistic and inverse agonistic activities have been reported. The former binds to the pocket formed by the receptor transmembrane bundle, and the latter to the extracellular TSH binding site. Both are effective inhibitors of TSH/thyroid stimulating antibody-stimulated cAMP and/or hyaluronic acid production in TSHR-expressing cells. Anti-insulin-like growth factor 1 inhibitors are also found to inhibit TSHR signaling. Each agent has advantages and disadvantages; for example, mAbs have a higher affinity and longer half-life but are more costly than LMWCs. At present, mAbs appear most promising, yet the development of more efficacious LMWCs is desirable. These agents are anticipated to be efficacious not only for the above-mentioned diseases but also for resistance to thyroid hormone and have utility for thyroid cancer radionuclide scintigraphy/therapy as a new theranostic.

Report of a family with three generations of undiagnosed familial nonautoimmune hyperthyroidism.

SummaryFamilial nonautoimmune hyperthyroidism (FNAH) is rare and occurs due to a constitutively activating thyroid-stimulating hormone receptor (TSHR) germline mutation. Forty-one families with FNAH have been reported so far. In the study, 17 of 41 families were not diagnosed with FNAH until three generations or more were described with hyperthyroidism. We report a case of FNAH diagnosed in the third generation. The index patient was diagnosed with hyperthyroidism at age 3. Large fluctuations in thyroid hormone levels occurred during anti-thyroid drug treatment, and he developed a goiter. The patient’s mother had similar history, requiring two surgical interventions and radioiodine treatment. The younger brother of the index patient did not experience large thyroid hormone level fluctuations, nor increased thyroid growth. A heterozygous TSHR c.1357A>G mutation, resulting in a M453V amino acid exchange, was detected in all three patients leading to FNAH diagnosis, with complete genotype–phenotype segregation. Based on Sorting intolerant from tolerant (SIFT) and PolyPhen2 scores of 0.01 and 0.99, respectively, an effect on protein function can be assumed. As illustrated by this family with FNAH, total thyr oidectomy is necessary for patients with nonautoimmune hyperthyroidism. Development of goiter is common, anti-thyroid drug treatment is often difficult, and remission of hyperthyroidism does not occur after discontinuation of anti-thyroid drug treatment. Thus, early diagnosis and appropriate treatment of FNAH is necessary to avoid predictable, unnecessary complications and further surgical interventions.Learning pointsIn the study, 19/42 cases of familial nonautoimmune hyperthyroidism (FNAH), including the reported case, were not diagnosed as FNAH until the third generation; this lead to suboptimal treatment and frequent relapses of nonautoimmune hyperthyroidism (NAH).Detection of thyroid-stimulating hormone receptor (TSHR) mutations in patients with suspected FNAH to confirm diagnosis is essential to ensure proper treatment for the patient and further affected family members.NAH will persist without proper treatment by total thyroidectomy.Symptoms and age of onset may vary between family membersAll family members with a TSHR germline mutation should be monitored with thyroid-stimulating hormone and for symptoms throughout their lives.

Gene expression profile in functioning and non-functioning nodules of autonomous multinodular goiter from an area of iodine deficiency: unexpected common characteristics between the two entities

PurposeToxic multinodular goiter is a heterogeneous disease associated with hyperthyroidism frequently detected in areas with deficient iodine intake, and functioning and non-functioning nodules, characterized by increased proliferation but opposite functional activity, may coexist in the same gland. To understand the distinct molecular pathology of each entity present in the same gland, the gene expression profile was evaluated by using the Affymetrix technology.MethodsTotal RNA was extracted from nodular and healthy tissues of two patients and double-strand cDNA was synthesized. Biotinylated cRNA was obtained and, after chemical fragmentation, was hybridized on U133A and B arrays. Each array was stained and the acquired images were analyzed to obtain the expression levels of the transcripts. Both functioning and non-functioning nodules were compared versus healthy tissue of the corresponding patient.ResultsAbout 16% of genes were modulated in functioning nodules, while in non-functioning nodules only 9% of genes were modulated with respect to the healthy tissue. In functioning nodules of both patients and up-regulation of cyclin D1 and cyclin-dependent kinase inhibitor 1 was observed, suggesting the presence of a possible feedback control of proliferation. Complement components C1s, C7 and C3 were down-regulated in both types of nodules, suggesting a silencing of the innate immune response. Cellular fibronectin precursor was up-regulated in both functioning nodules suggesting a possible increase of endothelial cells. Finally, Frizzled-1 was down-regulated only in functioning nodules, suggesting a role of Wnt signaling pathway in the proliferation and differentiation of these tumors. None of the thyroid-specific gene was deregulated in microarray analysis.ConclusionIn conclusion, the main finding from our data is a similar modulation for both kinds of nodules in genes possibly implicated in thyroid growth.

Growth rate of thyroid gland in human fetus

Objectives to determine the thyroid gland growth rate in the intermediate fetal period of human ontogenesis.
 Material and methods. The thyroid glands of 60 male and female fetuses aged from 14 to 27 weeks were the subject of this research. The material was divided according to fetus age in three groups: Group I from 14 to 18 weeks, Group II from 19 to 22 weeks and Group III from 23 to 27 weeks.
 Results. The study revealed the increase in all dimensions of thyroid gland related to the increase of fetus age. During the intermediate fetal period of ontogenesis, the growth varied from 19% (for the anteroposterior isthmus size) to 59% (for the right lobe height). The thyroid gland growth rate for different sex groups varied between 24% and 60% in female fetuses, in male fetuses from 20% to 57%. Besides, the thyroid lobes and isthmus of female fetuses grew at a higher rate than those of the male fetuses. The uneven growth of the anatomical structure was also registered when comparing different age groups within the intermediate fetal period. The highest rate of thyroid gland growth was observed starting from the 22nd week of fetal life; until the 19th week the growth rate ranged between 7% (isthmus) and 25% (right lobe). The study of the thyroid gland growth rate in female and male fetuses in different age groups revealed identical tendencies involving the active growth of thyroid gland dimensions starting from the 22nd week.

Modelling of Epithelial Growth, Fission and Lumen Formation During Embryonic Thyroid Development: A Combination of Computational and Experimental Approaches.

Organogenesis is the phase of embryonic development leading to the formation of fully functional organs. In the case of the thyroid, organogenesis starts from the endoderm and generates a multitude of closely packed independent spherical follicular units surrounded by a dense network of capillaries. Follicular organisation is unique and essential for thyroid function, i.e. thyroid hormone production. Previous in vivo studies showed that, besides their nutritive function, endothelial cells play a central role during thyroid gland morphogenesis. However, the precise mechanisms and biological parameters controlling the transformation of the multi-layered thyroid epithelial primordium into a multitude of single-layered follicles are mostly unknown. Animal studies used to improve understanding of organogenesis are costly and time-consuming, with recognised limitations. Here, we developed and used a 2-D vertex model of thyroid growth, angiogenesis and folliculogenesis, within the open-source Chaste framework. Our in silico model, based on in vivo images, correctly simulates the differential growth and proliferation of central and peripheral epithelial cells, as well as the morphogen-driven migration of endothelial cells, consistently with our experimental data. Our simulations further showed that reduced epithelial cell adhesion was critical to allow endothelial invasion and fission of the multi-layered epithelial mass. Finally, our model also allowed epithelial cell polarisation and follicular lumen formation by endothelial cell abundance and proximity. Our study illustrates how constant discussion between theoretical and experimental approaches can help us to better understand the roles of cellular movement, adhesion and polarisation during thyroid embryonic development. We anticipate that the use of in silico models like the one we describe can push forward the fields of developmental biology and regenerative medicine.

Generation of Adult Stem Cell Derived Organoid Cultures From Thyroid Follicular Cells

Abstract The thyroid is essential for maintaining systemic homeostasis by regulating thyroid hormone concentrations in the bloodstream. Due to the limited number of representative model systems, there is limited understanding of fundamental thyroid biology as well as thyroid carcinogenesis. To fill the caveats in the understanding of thyroid cell biology, we aimed to develop an adult stem cell-derived three-dimensional (3D) organoid culture system using murine and human thyroid follicular cells (TFCs). We have succeeded to grow such an organoid culture system that harbours the complete machinery of hormone production visualised by the presence of colloid in the lumen and essential transporters and enzymes in a polarised cell layer. Both the established murine as human thyroid organoids express canonical thyroid markers PAX8 and NKX2.1/TTF1. Moreover, the thyroid hormone precursor thyroglobulin is expressed in both cultures to similar levels as in tissue. Extensive characterisation furthermore identifies known and new biological insights in TFC subclassification, subcellular organisation and hormone production using state-of-the art techniques like single cell RNA sequencing, transmission electron microscopy and genome editing. These 3D in vitro cultures allow for a variety of thyroid-related studies including the progression of wild type cells towards cancer. Additionally, due to the success of generating patient-specific tumour organoids of primary differentiated thyroid carcinoma and metastasis, insights in drug resistance and metastases can be identified. In short, this newly developed organoid culture of murine and human wild type TFCs as well as tumour tissue opens up an extensive area of research that will help understand the drivers for growth and development of thyroid (cancer) cells and enable studies upon drug responsiveness.

Regrowth of Thyroid Gland: Is This Possible????

Abstract Introduction: Adult Thyroid gland which derived from primitive pharynx and neural crest is considered a non-regenerative organ. In this nature, partial or total thyroidectomy is considered a curative treatment for compressive non-malignant goiter. While there is a potential regrowth from stimulating by pituitary thyroid stimulating hormone (TSH), such growth is rarely significant and suppressive TSH therapy is currently indicated only for thyroid malignancy. We present an unusual case of rapid regrowth of normal thyroid tissue that expanded both of the lobes from a single unilateral remnant. Case: 58-year-old male with prior history of multinodular goiter status post subtotal thyroidectomy due to compressive symptoms in 2006 present to our clinic for follow up. Post-operatively, case was complicated with Iatrogenic Hypoparathyroidism thus on replacement of calcium and calcitriol. Follow up neck ultrasound (US), showed no thyroid gland with minimal residual tissue in the right fossa and pathology was benign. In 2011, patient complained of new onset globus sensation, and voice changes which initially concern for gastroenterology issue as the etiology. A neck US unexpectedly revealed normal right thyroid lobe of 5.7 cm without any tissue on the left and no nodule. FNA subsequently performed which was benign tissue. Due to high risk of complication for repeat surgery, annual US was planned for monitoring. In 2013 there was a significant new growth of left thyroid of 1.7 cm in size, no nodules. A repeat US six months later revealed an increase in size in the right from 5.7 to 6.1 cm as well as 1.7 to 2.1cm on the left. Patient denied any compressive symptoms, so we continue with neck US surveillance. By 2020, the right lobe was 6.4 cm and left lobe at 2.4 cm. Within both lobes, now multiple nodules start appearing. FNA were performed on several of those nodules with a benign cytopathology in all of them. Of note, other than regrowth of his thyroid, it is also physiologically functional as patient is euthyroid without levothyroxine replacement since 2013. Discussion: When patient underwent thyroidectomy for benign multinodular goiter, thyroid function test is the only routine test for follow up without additional further images. While it is considered a curative treatment, some regeneration or recurrence is still a possibility which is shown in our case. This is one of the few cases in the literature that we could found about normal thyroid tissue regrowth. It is still unclear how the mechanism for this phenomenon occurs. Further studies may need to be pursued with regards to suppressive TSH therapy or even radioactive iodine ablation for benign goiter that have regrowth potential. It is crucial that physicians become aware of such occurrence may happen since new thyroid nodules can also develop in the new thyroid tissue and fine needle aspiration should be performed accordingly.

Histological Studies on Foetal Thyroid Gland of Developing Human Foetuses

Introduction: Thyroid gland is the first endocrine gland to develop. It is one of the organs of interest for researchers since a long time. Though, detailed study about adult thyroid is there in the literature but histological study of thyroid gland at different stages in the foetal period is far and few. The present study aims to assess the histogenesis of thyroid gland and also to correlate the functional activity with structural changes in thyroid gland.
 Methods: The study was carried out on 30 foetal thyroid gland of known gestational age ranging from 10 to 38 weeks foetuses. The midline dissection of neck was done to expose the thyroid gland. After tissue processing, paraffin blocks were prepared. All sections were stained with Haematoxylin-Eosin stain.
 Results: In the foetuses, below 12th gestational week no colloid was detected in thyroid gland. First appearance of colloid was observed at 14th gestational week. Parafollicular cells were found after 17th gestational week. Capsule thickness and gland vascularity increased with advancement of gestational age. The size of the peripheral follicles is larger than the central follicles.
 Conclusions: The study concluded the developmental stage of foetal thyroid as Precolloidal stage, Colloid formation stage, Follicular stage and Maturation stage in different gestational weeks. The knowledge on the growth and differentiation of foetal thyroid will be helpful to the clinicians to judge the thyroid structure in preterm babies.