Quemeiteng granule relieves goiter by suppressing thyroid microvascular endothelial cell proliferation and angiogenesis via miR-217-5p-mediated targeting of FGF2-induced regulation of the ERK pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Goiters are enlargements of the thyroid gland and are a global public issue. Quemeiteng granule (QMTG) is a traditional Chinese medicine (TCM) formula used to treat goiter in Yunnan Province. However, the effectiveness and underlying mechanism of these treatments have not been fully elucidated. AIM OF THE STUDY: This study aimed to investigate the therapeutic effects of QMTG on goiter and the downstream regulatory mechanisms. MATERIALS AND METHODS: In this study, we first evaluated the antigoiter efficacy of QMTG through biochemical indices [body weight, thyroid coefficient, triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH)] and hematoxylin-eosin (HE) staining in a Propylthiouracil (PTU)-induced model. Based on microRNA sequencing (miRNA-seq) and bioinformatics analysis, key miRNA was screened out. A dual-luciferase reporter assay was performed to confirm the transcriptional regulation of the target gene by the miRNA. The viability of rat thyroid microvascular endothelial cells (RTMECs) and human thyroid microvascular endothelial cells (HTMECs) was assessed using the CCK-8 assays. The migration and angiogenesis of RTMECs and HTMECs were visualized through tube formation and wound scratch assays. Proteins involved in angiogenesis and the ERK pathway were assessed via Western blotting. RESULTS: QMTG significantly increased body weight, decreased the thyroid coefficient, increased the levels of T3, T4, FT3 and FT4 and reduced TSH levels in rats with goiter. QMTG also promoted the morphological recovery of thyroid follicles. MiR-217-5p was identified as a key miRNA. Our studies revealed that miR-217-5p directly targets FGF2 and that QMTG promotes the recovery of thyroid hormone (TH) levels and morphological changes in the thyroid, suppresses thyroid microvascular endothelial cell vitality, tube formation and migration, and reduces the expression of VEGF, Ang-1 and VCAM-1 triggered by miR-217-5p, thereby inhibiting the Ras/MEK/ERK cascade through FGF2. CONCLUSIONS: Our experiments demonstrated that the QMTG had therapeutic effects on goiter. These effects were attributed to the inhibition of ERK pathway-induced proliferation and angiogenesis through the targeting of FGF2 by miR-217-5p.

Exploring the effect and mechanism of Haizao Yuhu decoction containing three variants of glycyrrhiza on goiter using an integrated strategy of network pharmacology and RNA sequencing.

ETHNOPHARMACOLOGICAL RELEVANCE: Haizao Yuhu decoction (HYD) is a classic Chinese herbal formula described in the surgical monographs of the Ming Dynasty "Waikezhengzong." It has been widely used to treat goiter for approximately 500 years and found to be particularly effective. HYD contains glycyrrhiza and sargassum. This pair of herbs belongs to "18 incompatible medicaments" of traditional Chinese medicine theory. Although these two herbs are opposite, our preliminary study proved that they have superior effect when added into HYD at 2 times the dose of Chinese Pharmacopoeia. However, the species of glycyrrhiza in HYD that are the most effective have not been recorded in ancient Chinese medical texts. According to the Chinese Pharmacopoeia, glycyrrhiza is divided into the following three species: Glycyrrhiza uralensis Fish., G. glabra L., and G. inflata Bat. The effect of HYD containing different species of glycyrrhiza and their mechanisms remain to be further explored. AIM OF THE STUDY: To investigate the effect of HYD containing three species of glycyrrhiza on goiter, and to elucidate the molecular mechanism using network pharmacology combined with RNA sequencing (RNA-seq). MATERIALS AND METHODS: A rat model of goiter was established by 14 days of intragastric gavage of propylthiouracil (PTU), and the rats were treated for 4 weeks with HYD containing three different species of glycyrrhiza. The body weight and rectal temperature of rats were tested weekly. At the end of the experiment, the serum and thyroid tissues of rats were collected. The effect of the three HYDs was assessed based on general observations (including body weight, rectal temperature, and living status of rats), absolute/relative thyroid weight, thyroid function (including triiodothyronine, thyroxine, free triiodothyronine, free thyroxine, and thyroid-stimulating hormone levels), and thyroid tissue pathology. Next, we explored their pharmacological mechanisms using network pharmacology combined with RNA-seq and validated key targets using real-time quantitative reverse-transcription polymerase chain reaction (RT-qPCR), western blotting (WB), and immunofluorescence (IF) assays. RESULTS: The three HYDs reduced the absolute/relative weights of thyroid tissues and improved the pathological structure, thyroid function, and general findings of rats with goiter. Overall, the effect of HYD-G. uralensis Fish. (HYD-U) was better. Results from network pharmacology and RNA-seq jointly suggested that both the pathogenesis of goiter and the mechanism of action of HYD for goiter were related to the phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) pathway. We validated the key targets in the pathway, namely, vascular endothelial growth factor (VEGF) A, VEGF receptor 2, phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) and its encoded protein PI3K (p85), AKT serine/threonine kinase 1 (AKT1), phospho-AKT and cyclin D1 using RT-qPCR, WB, and IF assays. The PI3K-Akt pathway was hyperactivated in rats with PTU-induced goiter, whereas the three HYDs could inhibit the pathway. CONCLUSION: This study confirmed the definite effect of the three HYDs in the treatment of goiter, and HYD-U was found to be more effective. The three HYDs inhibited angiogenesis and cell proliferation in goiter tissue by inhibiting the PI3K-Akt signaling pathway.

Use of thyroid hormones in hypothyroid and euthyroid patients: A THESIS questionnaire survey of UK endocrinologists.

OBJECTIVE: Management of hypothyroidism is controversial because of medication cost pressures and scientific uncertainty on how to address treatment dissatisfaction experienced by some patients. The objective was to investigate the experience and preferences of UK endocrinologists in use of thyroid hormones. DESIGN: Web-based survey. PATIENTS: UK endocrinologists were invited to participate. MEASUREMENTS: Responses to questionnaire. RESULTS: The response rate was 21% (272/1295). While levothyroxine monotherapy is regarded as the treatment of choice for hypothyroidism, 51% of respondents stated that combined treatment with levothyroxine and liothyronine could be considered for levothyroxine-treated patients whose symptoms persist despite normalisation of serum thyroid stimulating hormone (TSH) concentration. However, only 40% are currently prescribing such treatment, and just 23% would consider taking it themselves. A small minority prescribe desiccated thyroid extract, and those most likely to do so are aged over 60 years. Most respondents stated that they have no influence over brand or formulation of levothyroxine dispensed to their patients and expect no major differences in efficacy between different formulations. A total of 9% would prescribe levothyroxine for euthyroid enlarging goitre, and 29% for euthyroid female infertility with high titre thyroid peroxidase antibodies, despite recent trials finding no benefit. CONCLUSIONS: UK endocrine practice in management of hypothyroidism is broadly in line with international guidance. However, a minority of respondents would consider thyroid hormone supplementation in euthyroid individuals for female infertility, enlarging goitre, and other indications in which evidence of efficacy is lacking. Willingness to consider prescribing combined levothyroxine and liothyronine, for hypothyroid symptoms which persist despite normalised TSH, has increased in comparison to previous international surveys, despite inconsistent evidence of benefit.

Use of levothyroxine in the management of hypothyroidism: A historical perspective.

The thyroid operates within a complex system of homeostatic regulation, where the level of thyrotropin (TSH) influences the rate of secretion of the principal thyroid hormones, thyroxine (T4) and triiodothyronine (T3). The devastating consequences of untreated thyroid dysfunction have been evident for centuries. Indeed, sources from antiquity described goitre and cretinism, two of the clinical sequelae of untreated overt thyroid disease. It was not until the first part of the 19th century that goitre and cretinism were first associated with iodine status; however, the endocrine function of the thyroid was not clearly identified until the early part of the 20th century. Three principal innovations in the 20th century supported the use of levothyroxine (LT4) replacement therapy for the management of hypothyroidism: a practical technique for the synthesis of LT4 suitable to support pharmaceutical use (late 1940s), the discovery that LT4 is converted to the active thyroid hormone, T3, in the peripheral tissues (1970), and the development of robust and sensitive assay methodology for measuring thyroid hormones in the blood (1960 onwards). Synthetic LT4, titrated to bring the level of TSH within a predefined "normal" reference range, is now established as the mainstay of treatment for hypothyroidism, and provides adequate restoration of thyroid hormone function for most people with this condition. Future research will explore further the nuances of the hypothalamic-pituitary-thyroid axis, and the place, if any, for T3 within the management of thyroid dysfunction.

Use of GLP-1 Receptor Agonists and Occurrence of Thyroid Disorders: a Meta-Analysis of Randomized Controlled Trials.

The association between glucagon-like peptide-1 (GLP-1) receptor agonists and the risk of various kinds of thyroid disorders remains uncertain. We aimed to evaluate the relationship between the use of GLP-1 receptor agonists and the occurrence of 6 kinds of thyroid disorders. We searched PubMed (MEDLINE), EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) and Web of Science from database inception to 31 October 2021 to identify eligible randomized controlled trials (RCTs). We performed meta-analysis using a random-effects model to calculate risk ratios (RRs) and 95% confidence intervals (CIs). A total of 45 trials were included in the meta-analysis. Compared with placebo or other interventions, GLP-1 receptor agonists' use showed an association with an increased risk of overall thyroid disorders (RR 1.28, 95% CI 1.03-1.60). However, GLP-1 receptor agonists had no significant effects on the occurrence of thyroid cancer (RR 1.30, 95% CI 0.86-1.97), hyperthyroidism (RR 1.19, 95% CI 0.61-2.35), hypothyroidism (RR 1.22, 95% CI 0.80-1.87), thyroiditis (RR 1.83, 95% CI 0.51-6.57), thyroid mass (RR 1.17, 95% CI 0.43-3.20), and goiter (RR 1.17, 95% CI 0.74-1.86). Subgroup analyses and meta-regression analyses showed that underlying diseases, type of control, and trial durations were not related to the effect of GLP-1 receptor agonists on overall thyroid disorders (all P subgroup > 0.05). In conclusion, GLP-1 receptor agonists did not increase or decrease the risk of thyroid cancer, hyperthyroidism, hypothyroidism, thyroiditis, thyroid mass and goiter. However, due to the low incidence of these diseases, these findings need to be examined further. Systematic Review Registration: PROSPERO https://www.crd.york.ac.uk/prospero/, identifier: CRD42021289121.

[SHENG Can-ruo's experience in treatment of goiter with integrated acupuncture and herbal medication].

The paper introduces professor SHENG Can-ruo's experience in treatment of goiter with the combination of acupuncture and herbal medication. Professor SHENG believes that this disease is mostly related with emotional injury, improper diet and geographical and climatic factors, as well as body constitution. Qi stagnation, phlegm retention, blood stagnation and interaction of phlegm and stasis are the essential pathogenesis of goiter. Either acupuncture or herbal medication should focus on "phlegm and stasis" in treatment. Besides, the theory of western medicine should also be considered. In western medicine, thyroid enlargement is classified into Ⅰ, Ⅱ and Ⅲ degrees of struma, thus, the pathogenesis and treatment with Chinese medicine should be adjusted accordingly. The created "four throat points", combined with acupuncture at distal points, relieve the local masses. The basic herbal formula is prepared and the couplet medicines are modified based on syndrome differentiation. The integrated acupuncture and herbal medication regulates emotions and provides a comprehensive treatment for goiter.

Xiao-Luo-Wan treats propylthiouracil-induced goiter with hypothyroidism in rats through the PI3K-AKT/RAS pathways based on UPLC/MS and network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Goiter with hypothyroidism occurs in several thyroid diseases. Xiao-Luo-Wan (XLW), which contains Scrophularia ningpoensis Hemsl., Fritillaria thunbergii Miq. and Ostrea gigas Thunberg, has been used as an effective Chinese medicine for the treatment of goiters in China for hundreds of years. Based on clinical observations and experimental studies, XLW also exerts a certain effect on hypothyroidism. However, the therapeutic mechanism of XLW remains unclear. AIM OF THE STUDY: The present study aimed to investigate the therapeutic effect of XLW on propylthiouracil (PTU)-induced goiter with hypothyroidism in rats and to uncover the underlying molecular mechanism using ultra high-performance liquid chromatography-mass spectrometry (UPLC/MS), network pharmacology, and molecular docking simulations. MATERIALS AND METHODS: After successful modeling, the remaining rats were randomly divided into a model group, an Euthyrox group, an XLW group, and a control group. The corresponding drugs were given by gavage for four consecutive weeks. The growth status was monitored, the relative thyroid weight was calculated, and the total serum T3, T4, and TSH content were detected. Hematoxylin-eosin (H&E) staining was used to observe the pathological changes in the thyroid glands. The chemical components of the XLW were identified by UPLC/MS and the putative targets of XLW were predicted using multiple databases. We performed network pharmacology based on the intersection of goiter/hypothyroidism-related targets and XLW targets. Then, we performed KEGG pathway enrichment analysis, and key targets were further screened using protein-protein interaction (PPI) networks. Finally, molecular docking was used to predict the binding ability of XLW identified components and the key targets. RESULTS: XLW significantly increased the levels of T3 and T4, and reduced TSH, increased body weight, and decreased swollen thyroid glands in PTU-induced rats. XLW promoted the morphological recovery of thyroid follicles and epithelial cells. Twenty-one main chemical components of XLW were identified using UPLC/MS. 270 potential gene targets of XLW and 717 known targets of goiter/hypothyroidism disease were obtained by searching the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP), Swiss Target Prediction, and UniProt databases. A total of 83 KEGG pathways were enriched with phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) and RAS signaling pathways. PPI analysis revealed nine key targets of kinase-protein kinase B (AKT) 1, interleukin (IL) 6, vascular endothelial growth factor A (VEGFA), tumor necrosis factor (TNF), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), epidermal growth factor receptor (EGFR), GTPase HRas (HRAS), matrix metalloproteinase (MMP) 9, and heat shock protein 90 alpha family class A member 1 (HSP90AA1). Molecular docking verified which drug components had good binding ability to key targets (all ≤5 kcal/mol). CONCLUSION: For PTU-induced goiter with hypothyroidism in rats, XLW improves thyroid function, reduces goiter, increases body weight, and promotes the recovery of thyroid follicles and epithelial cells. The underlying molecular mechanism suggests that XLW may regulate thyroid hormone signaling by regulating the PI3K-AKT, RAS, and other signaling pathways. This study provides a pharmacological and biological basis for using XLW to treat goiter with hypothyroidism.

[Analysis of experience in diagnosis and treatment of fetal goiter in patients with Graves' disease complicated with pregnancy].

This article reported the clinical diagnosis and treatment experience of two cases of fetal goiter in Graves' disease (GD) complicated with pregnancy. Two GD patients took antithyroid drugs regularly during pregnancy and their thyroid functions were well controlled, but the levels of thyrotropin receptor antibody (TRAb) of the two cases were still above the upper limit in the second and third trimester. Two fetuses had fetal goiter in the middle and late stages of pregnancy. After continuously controlling maternal thyroid function and closely monitoring fetal ultrasound, there was no aggravation of the fetal goiter, and the delivery went smoothly. One case had neonatal hyperthyroidism. It is suggested that although the thyroid function was well controlled during pregnancy in patients with GD, the high level of serum TRAb still needs to be alert to the occurrence of fetal goiter, and fetal ultrasound is the most direct non-invasive monitoring method.

What an endocrinologist should know for patients receiving lithium therapy.

Lithium is an efficient treatment of bipolar disorder. Besides renal insufficiency, many endocrine side effects are described such as the occurrence of thyroid disorders, hypercalcaemia and nephrogenic diabetes insipidus. Lithium inhibits the secretion of thyroid hormones. The prevalence of goiter is 4 times more common in Lithium-treated patients compared as to the general population. Hypothyroidism (8-20%) is more frequent in women and in case of pre-existing thyroid autoimmunity. Grave's disease and other hyperthyroidisms are sometimes reported. Lithium stimulates the proliferation of parathyroid cells by activating the Wnt pathway. An increase in serum calcium and PTH is described in patients treated with Lithium with a 4 to 6-fold higher risk of primary hyperparathyroidism than in the general population. Nevertheless, 24-hour urine calcium is not often increased, and the phenotype can mimic a hypercalcemia-hypocalciuria syndrome that may regress with Lithium discontinuation. Surgery should be cautious since parathyroid hyperplasia is more common than parathyroid adenoma. Nephrogenic diabetes insipidus is frequently reported and may be debilitating, sometimes intricated with severe dehydration, hypernatremia, and acute renal insufficiency. Nephrogenic diabetes insipidus is not generally reversible after Lithium discontinuation, especially in patients who have chronic kidney disease due to interstitial tubule nephritis. In conclusion, clinical assessment (goiter, diuresis) and biological monitoring of serum calcium, sodium creatinine, TSH and lithium are recommended in patients receiving Lithium therapy. The risk of Lithium discontinuation in case of side effects should be weighed against the psychological risk, and must be discussed with the psychiatrist.

Incidence of iodine deficiency and congenital goitre in goats and kids of Darreh Garm region, Khorramabad, Iran.

One of the thyroid disorders of ruminants is goitre, which is triggered by iodine deficiency. This study evaluates goitre in the goats of the Darreh Garm region in the vicinity of the Khorramabad city. Three goats with congenital enlarged thyroid glands were referred to the Veterinary Teaching Hospital of the Lorestan University with signs of arrhythmia, dyspnea and anorexia. Clinical examination, radiographic and sonographic evaluations were performed. Afterward, a comprehensive visual observation was accomplished in the outbreak region and blood samples were taken for thyroid hormones measurement in does and kids. Moreover, soil and forage samples were collected to assess the iodine concentration and soil parameters. Results indicated that the thyroid hormone concentration in the serum of the affected does and kids were significantly lower than healthy and treated animals. Treatment with sodium thyroxine significantly increased the concentration of T3 and T4 hormones. Pasture (5.28 ± 1.57 mg/kg) and soil (11.0 ± 1.49 mg/kg) iodine levels were lower than normal levels in this region. Histopathological slides of the thyroid glands from the dead kids indicated thyroid follicles with different sizes and hyperplasia of the glands. Overall, a 0.5 mg/kg iodine in the diet meal of the goats needs to be considered for prevention of the iodine deficiency.

Prescription of Sageretia hamosa Brongn Relieved Goiter through Promoted Apoptosis of Thyroid Cells via miR-511-3p and PTEN/PI3K/Akt Pathway.

Goiter is thyroid enlargement, in China, Sageretia hamosa Brongn (SHB) can be used to treat goiter, but it has not been reported. Therefore, data analytics of SHB prescription on thyroid were explored in this study to provide a theoretical support for SHB in the treatment of goiter. In this study, rat in goiter model was constructed by using propylthiouracil (PTU) and treated with SHB prescription. Thyroid function about the triiodothyronine (T3), free thyroxine (T4), free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) were measured by ELISA; thyroid coefficient was calculated after weighed thyroid; and HE staining was applied to assess the morphology of thyroid tissue. miRNA microarrays were employed to detect miRNA expression in thyroid tissue of rats. Expression of miR-511-3p was measured by RT-qPCR; expression of proteins (PTEN and apoptosis-related proteins) was tested by western blotting; relationship between miR-511-3p and PTEN was investigated by dual luciferase reporter gene assay; cell viability rate was determined by CCK-8; and cell cycle distribution and apoptosis rate were detected by flow cytometry. The results showed that SHB prescription ameliorated goiter and downregulated miR-511-3p. miR-511-3p targeted PTEN in thyroid cells and PTEN negatively regulated the activation of PI3K/Akt pathway. Furthermore, the inhibition of apoptosis in thyroid cells caused by the overexpression of miR-511-3p or the activation of PI3K/Akt pathway was reversed by treatment of SHB prescription, inhibition of miR-511-3p, or overexpression of PTEN. In conclusion, SHB prescription promoted apoptosis of thyroid through decreased miR-511-3p and regulated PTEN/PI3K/Akt pathway, it might suggest possible medical applications.

Long-Term Antithyroid Drug Treatment of Graves' Disease in Children and Adolescents: A 20-Year Single-Center Experience.

Background/purpose: Graves' disease (GD) is the most common cause of thyrotoxicosis in children and adolescents. There is some debate regarding the optimal treatment and predicting factors of remission or relapse in children and adolescents with GD. In this study, we report a retrospective study of 195 children and adolescents with GD treated at a single tertiary institution in Korea. Methods: This study included children and adolescents with GD diagnosed before 19 years of age from January of 2000 to October of 2020. The diagnosis of GD was based on clinical features, high thyroxine (FT4), suppressed thyroid-stimulating hormone, and a positive titer of thyrotropin receptor antibodies. Remission was defined as maintenance of euthyroid status for more than six months after discontinuing antithyroid drug (ATD). Results: A total of 195 patients with GD were included in this study. The mean age at diagnosis was 12.9 ± 3.2 years, and 162 patients (83.1%) were female. Among all 195 patients, five underwent thyroidectomy and three underwent radioactive iodine therapy. The mean duration of follow-up and ATD treatment were 5.9 ± 3.8 years and 4.7 ± 3.4 years, respectively. The cumulative remission rates were 3.3%, 19.6%, 34.1%, 43.5%, and 50.6% within 1, 3, 5, 7, and 10 years of starting ATD, respectively. FT4 level at diagnosis (P = 0.001) was predicting factors for remission [HR, 0.717 (95% CI, 0.591 - 0.870), P = 0.001]. Methimazole (MMI)-related adverse events (AEs) occurred in 11.3% of patients, the most common of which were rash and hematologic abnormalities. Of a total of 26 AEs, 19 (73.1%) occurred within the first month of taking MMI. Conclusions: In this study, the cumulative remission rate increased according to the ATD treatment duration. Long-term MMI treatment is a useful treatment option before definite treatment in children and adolescents with GD.

Goiter disease in traditional Chinese medicine: Modern insight into ancient wisdom.

Goiter is a disease with history perhaps as long as human has been around. Almost all the available references are in Western language works of literature while information concerning the occurrence of goiter disease in ancient China and the comparison between the treatment in traditional Chinese medicine (TCM) with current Western medicine remains lacking. In this article, the description of goiter, the history of surgical intervention for goiter disease, and the general concept of goiter disease treatment in ancient China literature such as seaweed decoction and acupuncture analgesia for surgery were reviewed.

Fetal Goitrous Hyperthyroidism in a Pregnant Woman with Triiodothyronine-Predominant Graves' Disease.

Triiodothyronine (T3)-predominant Graves' disease is characterized by increased serum free T3 (FT3) levels after free thyroxine (FT4) levels become normal or even low during antithyroid drug treatment. We encountered a 34-year-old pregnant woman, gravida 5 para 4, who was complicated by T3-predominant Graves' disease. She was diagnosed with Graves' disease at 20 years old, and had received methimazole. Methimazole was changed to potassium iodide to reduce the risk of congenital anomalies during the first trimester. The dose of antithyroid drugs was adjusted based on maternal FT4 levels, so that maternal Graves' disease deteriorated and fetal goitrous hyperthyroidism appeared during the second trimester. Since the fetus presented goiter and tachycardia at 27-28 gestational weeks, doses of methimazole and potassium iodide were increased. A male newborn weighing 2604 g was delivered by a cesarean section at 35 gestational weeks. The newborn was diagnosed with neonatal hyperthyroidism, and received methimazole for six months. He developed normally with normal thyroid function at 1 year old. In pregnancies complicated by T3-predominant Graves' disease, the kinds and doses of antithyroid drugs have to be carefully selected to maintain maternal levels of FT4 as well as FT3 within the normal range, considering trimesters of pregnancy, teratogenicity of medication, and maternal levels of thyroid-stimulating hormone receptor antibody.

First case of fetal goitrous hypothyroidism due to SLC5A5/NIS mutations.

BACKGROUND: Among patients with congenital hypothyroidism, 35% have dyshormonogenesis (DH) with thyroid gland in situ with or without goiter. The majority of DH cases are due to mutations in genes involved in thyroid hormone production as TG, TPO, SLC5A5/NIS, SLC26A4/PDS, IYD/DEHAL1, DUOX2, and DUOXA2, and are usually inherited on an autosomal recessive basis. Most previously reported cases of fetal hypothyroidism and goiter were related to TG or TPO mutations and recently DUOXA2. PATIENT: In a male patient with antenatal goiter treated with intraamniotic levothyroxine injections, whose long-term follow-up is described in detail, two novel NIS mutations were detected. Mutations of NIS were located in exon 1 (c.52G>A, p.G18R) and exon 13 (c.1546C>T, p.R516X), each mutation was inherited from parents, who are healthy carriers. The p.G18R mutation affecting the first transmembrane domain of the protein can be responsible for deficient iodide uptake. However, the second is a nonsense mutation leading probably to mRNA degradation. In addition, the patient has undergone a thyroidectomy and we have studied the thyroid tissue. The thyroid histology showed heterogeneity with large follicles, epithelial hyperplasia and many areas of fibrosis. Immunohistochemistry with NIS specific antibody showed NIS staining at the basolateral plasma membrane of the thyrocytes. CONCLUSIONS: We report the first case of fetal goitrous hypothyroidism due to two novel NIS mutations with access to thyroid tissue of the patient, specific histology studies and long-term follow-up. This case expands our knowledge and provides further insights on molecular causes of fetal goiter in humans.

Monitoring and Evaluation of Thyroid Function Tests, Serum Electrolytes and Creatinine Levels Before and After 131I Therapy.

BACKGROUND: Serum electrolytes, Creatinine, and thyroid profile play an important role in 131I treated patients of thyroid disorders. OBJECTIVES: To determine the effect of radioactive iodine (131I) on renal parameters, serum electrolytes and the correlation among TFT'S, creatinine, and chloride levels before and after I131 treatment in thyroid disorders. METHODS: The study was performed on 55 patients of thyrotoxicosis with age ranging from 16-65 years (mean age= 41±14years and BMI=24.8±4.46). The significance of the differences between the results of 1st, 2nd, and 3rd-time serum analysis was assessed by paired Student's t-test. Association between parameters was assessed by Spearman correlation analysis. RESULTS: 40 patients were taking Carbimazole, and 15 were directly recommended for I131 therapy. Strongly significant variations were observed for TFT'S (T3=0.012, T4 =0.017, and TSH=0. 001) during the follow-up treatment. Before taking I131 (Serum analyzed at 1st time), there observed negative correlation of T3(r=-.46, p=0. 002) and TSH (r=-0.31, p=0.02) with creatinine, and positive correlation of TSH(r=0.29,p=0.02) with chloride. BMI was negatively correlated with potassium(r=-0.30, p=0.02). At the 2nd time (after stopping the Carbimazole), no correlation results were observed. Two months after oral administration of 131I, creatinine, and chloride level was significantly increased (p=0.000), (P=0. 03) respectively, but had no correlation with TFT'S. CONCLUSION: Our findings suggest that patients with goiter (diffused or toxic) have association of TFT'S and BMI with serum electrolytes and creatinine, 131I therapy is also associated with the increase in creatinine and chloride levels of patients leading to kidney problems.

Graves' disease complicated by fetal goitrous hypothyroidism treated with intra-amniotic administration of levothyroxine.

Fetal goitrous hypothyroidism is a rare entity and is caused mainly by maternal treatment of Graves' disease (GD). We report a case of a 22-year-old woman referred at 12 weeks of gestation due to hyperthyroidism subsequent to recently diagnosed GD. She started treatment with propylthiouracil and, at 21 weeks of gestation, fetal goitre was detected. A cordocentesis confirmed the diagnosis of fetal goitrous hypothyroidism, and intra-amniotic administration of levothyroxine (LT4) was performed and repeated through the pregnancy due to maintenance of fetal goitre. The pregnancy proceeded without further complications and a healthy female infant was born at 37 weeks of gestation, with visible goitre and thyroid function within the normal range at birth. Although there is no consensus on the optimal dose, the number of injections and the interval between them, intra-amniotic LT4 administration is recommended once fetal goitrous hypothyroidism is suspected, in order to prevent long-term complications of fetal hypothyroidism.

Pycnogenol® prevents oxidative stress and side effects in patients with hypothyroidism during levothyroxine treatment.

BACKGROUND: In this study we aimed to evaluate the efficacy of Pycnogenol® supplementation in controlling oxidative stress levels and in reducing the frequency and severity of side effects of levothyroxine (LT4) treatment in patients who had recently started this therapy. METHODS: The registry included 60 females affected by primary hypothyroidism with multi-nodular goiter. LT4 was administered at the dosage of 100 µg/day.The registry study included only subjects under initial treatment, and followed up for a period of at least 30 days. A group took 150 mg Pycnogenol® daily and another served as control. RESULTS: The global occurrence of symptoms during the 30-day period was significantly lower with the supplement (P<0.05). CONCLUSIONS: Pycnogenol® may represent a useful tool to reduce LT4- related side effects in patients treated with hormone replacement therapy for hypothyroidism.

Wide Spectrum of DUOX2 Deficiency: From Life-Threatening Compressive Goiter in Infancy to Lifelong Euthyroidism.

Six patients are described with bi-allelic DUOX2 variants and widely variable phenotypes. Patient 1 is an infant with a compressive hypothyroid goiter causing respiratory distress, which was promptly alleviated by levothyroxine (LT4). He was a compound heterozygote for DUOX2 variants, including a novel deletion of 540 base pairs. Patients 2 and 3 are siblings with the same compound heterozygous mutations of DUOX2, yet one had overt hypothyroidism at 14 months and the other lifelong euthyroidism. Patient 4 is a compound heterozygote individual and has mild persistent congenital hypothyroidism; his sister (patient 5) only had a borderline thyrotropin elevation at newborn screening, consistent with homozygous DUOX2 variants with a mild impact on enzyme activity. Their euthyroid mother (patient 6) is a compound heterozygote for the same DUOX2 mutations as her son. Targeted exome sequencing did not reveal any relevant modifiers. It is concluded that (i) prompt LT4 replacement in infants with respiratory distress due to a hypothyroid goiter makes surgery unnecessary; and (ii) the clinical expression of DUOX2 deficiency varies widely between individuals and over time, justifying periodic reevaluation of the need for LT4 replacement.

ANNIVERSARY REVIEW: Antithyroid drug therapy: 70 years later

The thionamide antithyroid drugs were discovered in large part following serendipitous observations by a number of investigators in the 1940s who found that sulfhydryl-containing compounds were goitrogenic in animals. This prompted Prof. Edwin B Astwood to pioneer the use of these compounds to treat hyperthyroidism in the early 1940s and to develop the more potent and less toxic drugs that are used today. Despite their simple molecular structure and ease of use, many uncertainties remain, including their mechanism(s) of action, clinical role, optimal use in pregnancy and the prediction and prevention of rare but potentially life-threatening adverse reactions. In this review, we summarize the history of the development of these drugs and outline their current role in the clinical management of patients with hyperthyroidism.