Potential Role of Selected miRNAs in the Pathogenesis of Autoimmune Thyroid Diseases in Children and Adolescents.

BACKGROUND: Many epigenetic factors, including microRNAs, are involved in the process of changing gene expressions. Small non-coding RNA molecules, called miRNAs, are responsible for regulating gene translation by silencing or degrading target mRNAs. It is acknowledged that for many diseases, they may be novel diagnostic and prognostic biomarkers. Patients with autoimmune thyroid diseases are more likely to develop nodules in the thyroid tissue, and Hashimoto's thyroiditis and Graves' disease predispose patients to thyroid cancer. We evaluated the concentrations of microRNA molecules (miR-15a-5p, miR-126-3p, miR-142-5p, miR-21-5p, miR-150-5p) in the blood of children with thyroid disorders. In addition, we wished to identify molecules whose change in concentration predisposes to the development of thyroid cancer. AIM: The aim of this study is to evaluate selected epigenetic elements by analyzing the levels of miR-15a-5p, miR-126-3p, miR-142-5p, miR-150-5p and miR-21-5p in the blood of pediatric patients with Graves' disease (n = 25), Hashimoto's thyroiditis (n = 26) and thyroid nodular disease (n = 20) compared to a control group of healthy children (n = 17). MATERIALS AND METHODS: The study consists of groups of children and adolescents aged 10-18 years with autoimmune thyroid disease, with thyroid nodular disease compared to a control group. The miR-15a-5p, miR-126-3p, miR-142-5p, miR-21-5p and miR-150-5p molecules were determined through an immunoenzymatic assay using BioVendor reagents. RESULTS: There is a statistically significant decrease in the expression of the miR-15a-5p in children with Graves' disease (21.61 vs. 50.22 amol/µL, p = 0.03) and in patients with thyroid nodular disease compared to controls (20.23 vs. 50.22 amol/µL, p = 0.04). Higher levels of the miR-142-5p molecule are found in patients with thyroid disease (with GD-3.8 vs. 3.14 amol/µL, p = 0.01; with HT-3.7 vs. 3.14 amol/µL, p = NS, with thyroid nodular disease-4.16 vs. 3.14 amol/µL, p = 0.04). Lower levels of miR-126-3p were noted in the GD group compared to the control group (7.09 vs. 7.24 amol/µL, p = 0.02). No statistically significant changes in the expressions of miR-150-5p and miR-21-5p molecules were observed in the study groups. CONCLUSIONS: 1. The overexpression of the miR-142-5p molecule occurs in children and adolescents with thyroid diseases. 2. Decreased blood levels of miR-15a-5p predispose patients to the formation of focal lesions in the thyroid gland. 3. Identifying a lower expression of the miR-126-3p molecule in the blood of children with GD requires careful follow-up for the development of focal lesions in the thyroid gland and evaluation for their potential malignancy.

Prevalence of Selected Polymorphisms of Il7R, CD226, CAPSL, and CLEC16A Genes in Children and Adolescents with Autoimmune Thyroid Diseases.

Hashimoto's thyroiditis (HT) and Graves' disease (GD) are common autoimmune endocrine disorders in children. Studies indicate that apart from environmental factors, genetic background significantly contributes to the development of these diseases. This study aimed to assess the prevalence of selected single-nucleotide polymorphisms (SNPs) of Il7R, CD226, CAPSL, and CLEC16A genes in children with autoimmune thyroid diseases. We analyzed SNPs at the locus rs3194051, rs6897932 of IL7R, rs763361 of CD226, rs1010601 of CAPSL, and rs725613 of CLEC16A gene in 56 HT patients, 124 GD patients, and 156 healthy children. We observed significant differences in alleles IL7R (rs6897932) between HT males and the control group (C > T, p = 0.028) and between all GD patients and healthy children (C > T, p = 0.035) as well as GD females and controls (C > T, p = 0.018). Moreover, the C/T genotype was less frequent in GD patients at rs6897932 locus and in HT males at rs1010601 locus. The presence of the T allele in the IL7R (rs6897932) locus appears to have a protective effect against HT in males and GD in all children. Similarly, the presence of the T allele in the CAPSL locus (rs1010601) seems to reduce the risk of HT development in all patients.

Role of miRNA in Cardiovascular Diseases in Children-Systematic Review.

The number of children suffering from cardiovascular diseases (CVDs) is rising globally. Therefore, there is an urgent need to acquire a better understanding of the genetic factors and molecular mechanisms related to the pathogenesis of CVDs in order to develop new prevention and treatment strategies for the future. MicroRNAs (miRNAs) constitute a class of small non-coding RNA fragments that range from 17 to 25 nucleotides in length and play an essential role in regulating gene expression, controlling an abundance of biological aspects of cell life, such as proliferation, differentiation, and apoptosis, thus affecting immune response, stem cell growth, ageing and haematopoiesis. In recent years, the concept of miRNAs as diagnostic markers allowing discrimination between healthy individuals and those affected by CVDs entered the purview of academic debate. In this review, we aimed to systematise available information regarding miRNAs associated with arrhythmias, cardiomyopathies, myocarditis and congenital heart diseases in children. We focused on the targeted genes and metabolic pathways influenced by those particular miRNAs, and finally, tried to determine the future of miRNAs as novel biomarkers of CVD.

Mechanisms of thyrotropin receptor-mediated phenotype variability deciphered by gene mutations and M453T-knockin model.

The clinical spectrum of thyrotropin receptor-mediated (TSHR-mediated) diseases varies from loss-of-function mutations causing congenital hypothyroidism to constitutively active mutations (CAMs) leading to nonautoimmune hyperthyroidism (NAH). Variation at the TSHR locus has also been associated with altered lipid and bone metabolism and autoimmune thyroid diseases. However, the extrathyroidal roles of TSHR and the mechanisms underlying phenotypic variability among TSHR-mediated diseases remain unclear. Here we identified and characterized TSHR variants and factors involved in phenotypic variability in different patient cohorts, the FinnGen database, and a mouse model. TSHR CAMs were found in all 16 patients with NAH, with 1 CAM in an unexpected location in the extracellular leucine-rich repeat domain (p.S237N) and another in the transmembrane domain (p.I640V) in 2 families with distinct hyperthyroid phenotypes. In addition, screening of the FinnGen database revealed rare functional variants as well as distinct common noncoding TSHR SNPs significantly associated with thyroid phenotypes, but there was no other significant association between TSHR variants and more than 2,000 nonthyroid disease endpoints. Finally, our TSHR M453T-knockin model revealed that the phenotype was dependent on the mutation's signaling properties and was ameliorated by increased iodine intake. In summary, our data show that TSHR-mediated disease risk can be modified by variants at the TSHR locus both inside and outside the coding region as well as by altered TSHR-signaling and dietary iodine, supporting the need for personalized treatment strategies.

Elastographic Evaluation of Thyroid Nodules in Children and Adolescents with Hashimoto's Thyroiditis and Nodular Goiter with Reference to Cytological and/or Histopathological Diagnosis.

There are data indicating the coexistence of papillary thyroid carcinoma and autoimmune thyroiditis (AIT) in children. The aim of the study was elastographic evaluation of thyroid nodules in children and adolescents with AIT and nodular goiter in relation to cytological and/or histopathological diagnosis. We examined 215 children (57 boys and 158 girls) with 261 thyroid nodules (143 non-AIT and 118 AIT). All study participants underwent a conventional ultrasound examination with elastography followed by fine needle aspiration biopsy (FNAB). Abnormal Strain Ratio (SR ≥ 5) was observed in 36 non-AIT nodules and 15 AIT nodules. Papillary thyroid carcinoma was diagnosed in 5 patients (2% of all investigated nodules). SR of malignant thyroid nodules was statistically higher in comparison to SR of benign nodules both in the group of non-AIT (6 ± 4 vs. 3.67 ± 2.62, p = 0.024) and AIT nodules (6.3 ± 0.01 vs. 2.92 ± 1.89, p = 0.047). Comparison of non-AIT and AIT benign nodules revealed that SR was higher in non-AIT nodules (3.67 ± 2.62 vs. 2.92 ± 1.89, p = 0.01). We observed a strong positive correlation (R = 1) between TSH concentration and SR ratio in the group of all malignant thyroid nodules. Autoimmune inflammatory process of the thyroid gland does not limit the use of elastography in the diagnosis of thyroid nodules in children.

Suspected Malignant Thyroid Nodules in Children and Adolescents According to Ultrasound Elastography and Ultrasound-Based Risk Stratification Systems-Experience from One Center.

The risk of malignancy in thyroid nodules correlates with the presence of ultrasonographic features. In adults, ultrasound risk-classification systems have been proposed to indicate the need for further invasive diagnosis. Furthermore, elastography has been shown to support differential diagnosis of thyroid nodules. The purpose of our study was to assess the application of the American Thyroid Association (ATA), British Thyroid Association (BTA) ultrasound risk-classification systems and strain elastography in the management of thyroid nodules in children and adolescents from one center. Seventeen nodules with Bethesda III, IV, V and VI were selected from 165 focal lesions in children. All patients underwent ultrasonography and elastography followed by fine needle aspiration biopsy. Ultrasonographic features according to the ATA and BTA stratification systems were assessed retrospectively. The strain ratio in the group of thyroid nodules diagnosed as malignant was significantly higher than in benign nodules (6.07 vs. 3.09, p = 0.036). According to the ATA guidelines, 100% of malignant nodules were classified as high suspicion and 73% of benign nodules were assessed as low suspicion. Using the BTA U-score classification, 80% of malignant nodules were classified as cancerous (U5) and 20% as suspicious for malignancy (U4). Among benign nodules, 82% were classified as indeterminate or equivocal (U3) and 9% as benign (U2). Our results suggest that application of the ATA or BTA stratification system and elastography may be a suitable method for assessing the level of suspected malignancy in thyroid nodules in children and help make a clinical decision about the need for further invasive diagnosis of thyroid nodules in children.

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

SUMMARY: Familial 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 POINTS: In 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 members All family members with a TSHR germline mutation should be monitored with thyroid-stimulating hormone and for symptoms throughout their lives.

Analysis of Polymorphisms rs7093069-IL-2RA, rs7138803-FAIM2, and rs1748033-PADI4 in the Group of Adolescents With Autoimmune Thyroid Diseases.

Introduction: The pathogenesis of autoimmune thyroid diseases is complicated and not completely known. Among the causes of thyroid autoimmunity, we distinguish genetic predisposition and environmental factors. Graves' disease and Hashimoto's thyroiditis are associated with a disturbance of immune tolerance of thyroid antigen molecules. The IL2RA gene is located on chromosome 10 and encodes the interleukin 2 receptor (IL2RA), which is expressed by the regulatory T-cells (Tregs) responsible for suppression. It has been shown that this gene and its polymorphism occur in people with various autoimmune diseases (e.g. type 1 diabetes mellitus, rheumatoid arthritis, Graves' disease, or multiple sclerosis). The FAIM2 gene is located on chromosome 12 and encodes the molecule involved in the apoptosis inhibition process. The PADI4 gene is located on chromosome 1, and its expression is associated with activation of T-cells, differentiation of macrophages, which leads to increased inflammation. Aim: The aim of the study was to analyze the polymorphisms of the IL-2RA (rs7093069), FAIM2 (rs7138803) and PADI4 (rs1748033) genes and their correlation to thyroid hormones and anti-thyroid antibodies in pediatric patients with Graves' disease and Hashimoto's thyroiditis compared to the control group. Material and Methods: The study was performed in 180 patients with GD (mean age 16.5 ± 2), 80 with HT (mean age, 15.2 ± 2.2), and 114 children without any autoimmune diseases (mean age 16.3 ± 3) recruited from the endocrinology outpatient clinic. Three single nucleotide polymorphisms (SNPs): rs7138803-FAIM2, rs7093069-IL-2RA, and rs1748033 PADI4 were determined by TaqMan SNP QuanStudio 12K Flex-OpenArray genotyping with PCR and correlated to thyroid hormones and anti-thyroid antibodies. Results: Rs7090369-IL-2RA allele T was more frequent in patients with AITDs (33.7% in GD vs 28.7% in HT, p = 0.077, OR = 1.52) compared with healthy children (25%). Allele T of that gene predisposes to the occurrence of autoimmune thyroid diseases, especially GD and TT genotype gives a statistically significant 5.2 times higher risk of GD (p = 0.03, OR = 5.26) and increased risk of HT (p = 0.109, OR = 4.46). Allele A rs7138803-FAIM2 is more frequent in patients with GD (p = 0.071, OR = 1.45) and HT (p = 0.028, OR = 1.8). In our data the presence of GG genotype of that gene significantly reduces the risk of autoimmune thyroid diseases (p = 0.05, OR = 0.42). Allele C rs1748033PADI4 and its CC genotype were more frequent in patients with autoimmune thyroid diseases, but it was not statistically significant. The occurrence of CT genotype significantly reduces the risk of HT (p = 0.03, OR = 0.4). Conclusions: 1). Polymorphisms rs7138803-FAIM2 and rs1748033-PADI4 are more frequent in patients with autoimmune thyroid diseases, more frequent in patients with Hashimoto' thyroiditis, but the occurrence of GG rs7138803-FAIM2 genotype could reduce the risk of thyrocyte apoptosis inhibition. 2). The TT rs7093069-IL2RA genotype may increase the risk of autoimmune thyroid diseases. 3). Analysis of polymorphisms of given genes in clinical practice will allow to determine predisposition to autoimmune thyroid disease development, to find symptoms of thyroid gland dysfunction earlier and to use appropriate treatment.

Genetic Association Study of IL2RA, IFIH1, and CTLA-4 Polymorphisms With Autoimmune Thyroid Diseases and Type 1 Diabetes.

Autoimmune thyroid diseases (AITDs) which include Graves' disease (GD) and Hashimoto's thyroiditis (HT) as well as type 1 diabetes (T1D) are common autoimmune disorders in children. Many genes are involved in the modulation of the immune system and their polymorphisms might predispose to autoimmune diseases development. According to the literature genes encoding IL2RA (alpha subunit of Interleukin 2 receptor), IFIH1 (Interferon induced with helicase C domain 1) and CTLA-4 (cytotoxic T cell antigen 4) might be associated with autoimmune diseases pathogenesis. The aim of the study was to assess the association of chosen single nucleotide polymorphisms (SNPs) of IL2RA, IFIH1, and CTLA-4 genes in the group of Polish children with AITDs and in children with T1D. We analyzed single nucleotide polymorphisms (SNPs) in the IL2RA region (rs7093069), IFIH1 region (rs1990760) and CTLA-4 region (rs231775) in group of Polish children and adolescents with type 1 diabetes (n = 194) and autoimmune thyroid diseases (GD n = 170, HT n = 81) and healthy age and sex matched controls for comparison (n = 110). There were significant differences observed between T1D patients and control group in alleles of IL2RA (rs7093069 T > C) and CTLA-4 (rs231775 G > A). In addition, the study revealed T/T genotype at the IL2RA locus (rs7093069) and G/G genotype at the CTLA-4 locus (rs231775) to be statistically significant more frequent in children with T1D. Moreover, genotypes C/T and T/T at the IFIH1 locus (rs1990760) were significantly more frequent in patients with T1D than in controls. We observed no significant differences between AITD patients and a control group in analyzed SNPs. In conclusion, we detected that each allele T of rs7093069 SNP at the IL2RA locus and G allele of rs231775 SNP at the CTLA-4 locus as well as C/T and T/T genotypes of rs1990760 SNP at the IFIH1 locus are predisposing in terms of T1D development. Thereby, we confirmed that IL2RA, IFIH1, and CTLA-4 gene locus have a role in T1D susceptibility. The analysis of selected SNPs revealed no association with AITDs in a group of Polish children and adolescents.

Case report: a 10-year-old girl with primary hypoparathyroidism and systemic lupus erythematosus.

Objectives Hypoparathyroidism is a rare disease in children that occurs as a result of autoimmune destruction of the parathyroid glands, a defect in parathyroid gland development or secondary to physical parathyroid gland disturbance. Typical symptoms of hypoparathyroidism present as hypocalcaemia and hyperphosphatemia due to decreased parathyroid hormone secretion and may lead to nerve and muscles disturbances resulting in clinical manifestation of tetany, arrhythmias and epilepsy. Currently, there is no conventional hormone replacement treatment for hypoparathyroidism and therapeutic approaches include normalising mineral levels using an oral calcium supplement and active forms of vitamin D. Case presentation We present the case of a 10-year-old girl with primary hypoparathyroidism who had no prior history of autoimmune disorders, but who subsequently developed systemic lupus erythematosus.

Does Hashimoto's Thyroiditis Increase the Risk of Cardiovascular Disease in Young Type 1 Diabetic Patients?

Background: Immunological and hormonal disorders have undoubted influence on the development of atherosclerotic process. Autoimmune diseases accompanying type 1 diabetes (T1D) may additionally accelerate atherosclerosis progression and increase the risk of cardiovascular events in the future. The influence of subclinical hypothyroidism on the cardiovascular system, in particular, has recently aroused great interest. The aim of our study was to assess intima-media thickness (cIMT) of common carotid arteries and the occurrence of classical atherosclerosis risk factors together with selected new biomarkers of cardiovascular diseases in young patients with type 1 diabetes mellitus coexisting with Hashimoto's disease (HD). Patients and Methods: The study included 50 adolescents and young adults with T1D with mean age 17.1 ± 3 years, with mean diabetes duration of 10.5 ± 3.3 years, including 20 patients with diagnosed HD: T1D and HD(+), and 30 patients with no additional diseases: T1D and HD(-). Twenty-two healthy, age-matched volunteers formed control group (C). We analyzed mean HbA1c value from all years of disease, BMI, blood pressure, lipids, new biomarkers of atherosclerosis (hsCRP, adiponectin, myeloperoxidase, NT-proBNP peptide, vitamin D), and cIMT of common carotid arteries. Results: In the group of patients with T1D and HD(+), significantly higher BMI was found: 23.3 ± 4.4 vs. 21.28 ± 2.9 in group HD(-) and 19.65 ± 2.4 kg/m2 in group C (p = 0.003), and higher waist circumference: 79 ± 10.9 vs. 75.10 ± 7.6 in group HD(-) vs. 69.0 ± 7.4 cm in group C (p < 0.001). The mean value of HbA1c was higher in group T1D and HD(+): 8.8% than in group HD(-): 8.1% (p = 0.04). Significantly higher concentration of hsCRP and lower vitamin D were observed in T1D and HD(+) in comparison to T1D and HD(-) and the control group. The IMT index in the HD(+) group was 0.46 ± 0.05 mm and was comparable to the HD(-) group but significantly higher than in healthy controls: 0.41 ± 0.03 mm (P < 0.05). Conclusions: Young patients with type 1 diabetes mellitus and with coexisting Hashimoto's thyroiditis have a higher BMI, a higher waist circumference, and a higher HbA1c value, which altogether may cause faster development of macroangiopathy in the near future. Additional risk for cardiovascular disease may result from low vitamin D and increased hsCRP concentration in this group of patients. Coexistence of Hashimoto's thyroiditis did not significantly affect the cIMT value in the studied population.

Practical Application of Elastography in the Diagnosis of Thyroid Nodules in Children and Adolescents.

BACKGROUND: Ultrasound elastography is a noninvasive method of imaging based on the estimation of the mechanical properties of tissue. Data in adults indicate that decreased flexibility in comparison to the surrounding healthy tissue is characteristic of malignancy (in most thyroid carcinomas, except for follicular thyroid carcinoma). The purpose of our study was to assess the deformation of thyroid nodules and to evaluate the usefulness of elastography in predicting malignant thyroid nodules in adolescent patients. METHODS: We examined 47 children with 62 thyroid nodules. All patients underwent elastography and fine needle aspiration cytology (FNAC). RESULTS: Thirty-seven girls (79%) and 10 boys (21%) were included in the study. A strain ratio <2 was observed in 17 nodules (27% of the study group), a strain ratio between 2 and 4.9 in 34 nodules (55%) and a strain ratio >5 in 11 nodules (18%). According to cytological examination, 3 nodules (4.8% of the study group) were malignant. Two of them were hard (strain ratio ≥5), and 1 nodule had a strain ratio of 2. CONCLUSIONS: Our results suggest that elastography can be complementary to conventional ultrasonography and useful while making a decision about FNAC. At the same time, it should not replace the cytological assessment of thyroid nodules in children and adolescents.

Correlations between cerebellar and brain volumes, cognitive impairments, ApoE levels, and APOE genotypes in patients with AD and MCI.

Due to the increasing incidence of Alzheimer's disease (AD), many studies have aimed to improve its diagnosis. Particular attention has been focused on measuring volumes of brain structures. Only few studies have investigated whether the cerebellar volume changes with the stage of dementia. It is controversial whether the serum apolipoprotein E (ApoE) level is an appropriate AD marker. This study was designed to clarify the significance of both cerebellar volume measurements and ApoE level measurements as markers of neurodegenerative changes. This study included 55 subjects with AD, 30 subjects with mild cognitive impairments (MCI), and a control group with 30 subjects. We measured the brain, cerebellum, and brain stem volumes with magnetic resonance imaging (MRI). We determined serum ApoE levels, APOE genotypes, and neuropsychological test scores. In the control group, we found that ApoE levels were significantly higher for subjects with the APOE 2/3 genotype than those with the 4/4 genotype. This finding may indicate that ApoE plays a protective role against AD development in subjects with the APOE 2/3 genotype. ApoE levels were not significantly different in patients with AD and MCI. No correlations were found between serum ApoE levels and Mini-Mental State Examination (MMSE) scores or the volumes of brain structures. This study could not confirm the appropriateness of the cerebellum volume as an early AD marker. Correlations were found between cerebellar volume, brain volume, and the MMSE scores.

[Analysis of serum levels of nesfatin-1 in children and adolescents with autoimmune thyroid diseases]. / Analiza stezenia nesfatyny-1 w surowicy krwi u dzieci i mlodziezy z chorobami autoimmunizacyjnymi tarczycy.

INTRODUCTION: Overweight and diseases connected with it are an increasing problem in children and adolescents. Thyroid disease leads to a change of weight - in hyperthyroidism body mass is reduced whereas in hypothyroidism it is increased. It is emphasized that changes in hormones such as peptide levels are in close relationship with the regulation of body mass. Nesfatin-1 is a recently described anorexigenic peptide produced by the brain. Nesfatin-1 also reduces body weight gain, suggesting a role as a new modulator of energy balance. Excess nesfatin in the brain leads to a loss of appetite, less frequent hunger, a `sense of fullness´, and a drop in body fat and weight. A lack of nesfatin-1 in the brain leads to an increase of appetite, more frequent episodes of hunger, an increase of body fat and weight, and the inability to `feel full´. Aim of the study was to evaluate nesfatin-1 levels in young patients with untreated Graves´ disease, subclinical Hashimoto´ thyroiditis, and in healthy children. MATERIAL AND METHODS: The study group formed 78 patients of the Outpatient Endocrinology Clinic of Pediatrics, Endocrinology, Diabetology with Cardiology Division. In all the patients, nesfatin level was analyzed by the ELISA´s method. RESULTS: In the group with hyperthyroidism in Graves´ disease lower levels of nesfatin-1 were found compared to the group of healthy children (19.37 vs 32.96 ng/ml; p<0.02); after appropriate treatment in that group the levels of nesfatin-1 were higher compared to the group with hyperthyroidism, but lower compared to the group of healthy children (20.35 vs 32.96 ng/ml; NS). On the other hand, nesfatin-1 levels were lower in children with untreated subclinical hypothyroidism in Hashimoto´s thyroiditis compared to the group of healthy children (17.2 vs32.96 ng/ml; p<0.002). After treatment of L-thyroxine lower levels of nesfatin-1 were found compared to the control group (14.5 vs 32.96 ng/ml; NS). No relationship between nesfatin-1 and thyroid hormones was observed. CONCLUSIONS: It might be that disturbances in thyroid hormones in thyroid diseases do not have an essential effect on changes of nesfatin-1 - an appetite-controlling hormone/peptide. Secondly, nesfatin-1 levels were lower in children with untreated autoimmune thyroid diseases, however, the mechanism is also unknown.

[Evaluation of CD4+CD161+CD196+ and CD4+IL-17+ Th17 cells in the peripheral blood of young patients with Hashimoto's thyroiditis and Graves' disease]. / Analiza komórek CD4+CD161+CD196+ i CD4+IL-17+ Th17 we krwi obwodowej u mlodocianych z zapaleniem tarczycy typu Hashimoto i choroba Gravesa-Basedowa.

INTRODUCTION: Up till now, altered balance of Th1 and Th2 immune cells has been postulated to play an important role in the pathogenesis of autoimmune thyroid diseases (AITD). However, recent studies on thyroid diseases suggest a new role for Th17 (T helper 17) cells that have been classified as a new lineage, distinct from Th1, Th2 and Treg cells. Despite wide interest, the role of Th17 cells in the pathogenesis of inflammatory and autoimmune diseases is still being debated. Th17 cells are involved in immune responses against extracellular pathogens and have the ability to secrete cytokines: IL-17, IL-17F, IL-22 and IL-21. Th17 cells can be characterized by several surface markers, i.e. CCR6 (CD196), IL-23R, IL-12Rbeta2 and CD161. AIM OF THE STUDY: Was to estimate the frequencies of circulating CD4+CD161+CD196+ and CD4+IL-17+ Th17 cells in patients with Graves' disease (GD, n=20, mean age ± SEM 14.9 ± 6 years), Hashimoto's thyroiditis (HT, n=20, mean age ± SEM 15.2±3 yrs) and in healthy controls (C, n=20, mean age ± SEM 15.4 ± 2 yrs). MATERIAL AND METHODS: Polychromatic flow cytometry and several fluorochrome-conjugated monoclonal antibodies were applied to delineate Th17 cells with either CD4+CD161+CD196+ or CD4+IL-17+ phenotype using apparatus FACSCalibur (BD Biosciences). Thyroid anti-TSH receptor immunoglobulins (TRAK), anti-thyroperoxidase (anti-TPO) and anti-thyroglobulin (anti-TG) antibodies were measured in all the samples using electrochemiluminescence "ECLIA" with Modular Analytics E170 analyzer (Roche Diagnostics, Poland). RESULTS: In untreated HT children we observed an increased percentage of CD4+CD161+CD196+ (7.1 ± 3.5 vs. 3.7 ± 1.8; p <0.04) and CD4+IL-17+ (3.7 ± 2.7 vs. 1.4±0.4; p <0.01) Th17 lymphocytes in comparison to the healthy controls. In untreated and treated GD children we did not reveal such abnormalities in the population of these cells compared to the controls. In cases with HT, a positive correlation between the percentage of CD4+IL-17+ and CD4+CD161+CD196+ T cells and serum level of anti-TPO antibodies (r=0.48; p <0.025; r=0.65; p <0.01; respectively) was detected. CONCLUSIONS: We conclude that the increased percentage of Th17 cells in children with untreated Hashimoto's thyroiditis can suggest their role in initiation and development of immune and inflammatory processes in this endocrinopathy.

Analysis of serum adiponectin, resistin and leptin levels in children and adolescents with autoimmune thyroid disorders.

Leptin, adiponectin and resistin, mainly produced by adipocytes, play a major role in body weight regulation. Disturbances in the maintenance of normal body weight are found to occur also in thyroid diseases. There is a close relationship of the changes in thyroid hormones with the contents of adipose tissue and adipocyte-secreted proteins regulating energetic metabolism in the body. The study objective was to analyze the levels of leptin, adiponectin and resistin in children with untreated Graves' disease, subclinical hypothyroidism in Hashimoto's thyroiditis and in children with simple goiter. The study involved 78 patients with Graves' disease (29 girls and 2 boys, aged 6-21 years, mean 15.2) and with Hashimoto's thyroiditis (30 girls and 2 boys, aged 9-18 years, mean 14.5). The control group consisted of adolescents with simple goiter (13 girls and 2 boys, aged 9-18 years, mean 14.8). The levels of leptin, adiponectin and resistin were determined using the ELISA method (R&D System, USA). Patients with untreated Graves' disease showed higher adiponectin level than the patients with hypothyroidism in Hashimoto's thyroiditis and in simple goiter (14.24 +/- 0.89 vs. 9.18 +/- 2.65, 10.15 +/- 2.5, p < 0.007, p < 0.01), but lower resistin level as compared to simple goiter and Hashimoto's thyroiditis (10.24 +/- 5.2 vs. 13.29 +/- 3.8, 12.2 +/- 2.8, p < 0.01, NS). The analysis of leptin levels revealed no significant differences between children with subclinical hypothyroidism and untreated Graves' disease (4.42 +/- 0.87 vs. 3.1 +/- 0.45 NS). In conclusion, we suggest that disturbances in thyroid hormones in thyroid diseases have an essential effect on the levels of adiponectin and resistin released by adipose tissue.

[Analysis of serum levels of ghrelin and obestatin in children and adolescents with autoimmune thyroid diseases]. / Analiza stezenia ghreliny i obestatyny w surowicy krwi u dzieci i mlodziezy w schorzeniach autoimmunologicznych tarczycy.

INTRODUCTION: Thyroid disease is leading to a change of weight - in hyperthyroidism body mass is reduced, but in hypothyroidism it is increased. Recently researches suggest that many new bioactive substances, like ghrelin and obestatin, play a role in regulation of body mass. These closely related hormones have different effects- ghrelin increases, but obestatin decreases the appetite. The aim of the study was to evaluate ghrelin and obestatin levels in young patients with untreated Graves' disease, subclinical Hashimoto' thyroiditis and in children with nodular goiter in the euthyroid clinical state. MATERIAL AND METHODS: The study group formed 78 patients of the Outpatient Endocrinology of the 2nd Department of Children's Disease (Medical University in Bialystok) and Outpatient Endocrinology IHC in Warsaw suffering from Graves' disease (29 girls and 2 boys; aged from 6 to 21 - mean 15,2 yrs) and Hashimoto's thyroiditis (29 girls and 3 boys; aged from 9 to 18 - mean 14,5 yrs). The control group consisted of children with nodular goiter (euthyroid) - 13 girls and 2 boys; aged from 9 to 18 - mean 14,8 yrs. In all patients, ghrelin and obestatin levels were analyzed by RIA's method (Phoenix Pharmaceuticals, USA). RESULTS: In children and adolescents with hyperthyroidism in Graves' disease we found lower levels of ghrelin compared to the group of children with nodular goiter and with subclinical hypothyroidism in Hashimoto's thyroiditis (123+/-23 vs. 151+/-45; vs. 140+/-36 pg/ml, p<0,02, ns). On the other hand obestatin levels were lower in children with untreated subclinical hypothyroidism in Hashimoto's thyroiditis compared to a group with nodular goiter or Hashimoto's thyroiditis in euthyroidism (203,28+/-59 vs. 222.49+/-49; 267.24+/-70 pg/ml, p<0.03, p<0.02). In a group of untreated hyperthyroidism in Graves' disease we found correlations between ghrelin and fT3 (r=-0.36, p<0,4) and fT4 levels (r=- 0.45, p<0.01). CONCLUSIONS: In conclusion, we suggested that disturbances in thyroid hormones in thyroid diseases have an essential effect on changes of hormones controlled appetite: ghrelin (in hyperthyroidism) and obestatin (in hypothyroidism).

[Precocious puberty due to hypothalamic hamartoma]. / Przedwczesne dojrzewanie plciowe w przebiegu guza hamartoma podwzgórza.

INTRODUCTION: Central precocious puberty is usually idiopathic. Appearance of the precocious puberty symptoms in early childhood or pre-school period indicate that also it could be caused by organic disorder of the central nervous system. The aim of this work is to present the case of the 4-year-old girl, diagnosed with precocious puberty. THE CASE REPORT: The first clinical symptoms of precocious puberty such as increased growth rate and breast enlargement were observed when the girl was 4 years old. The height (above the 97 centile) and weight (90-97 centile) were measured during the physical examination. The advancement of sexual features was determined as follows: thelarche III degrees , pubarche II degrees , axillarche II degrees . The LHRH test used in this differential diagnosis revealed the pubertal level of gonadotropins, when plasma levels of dehydroepiandrosterone, prolactin, thyroid-stimulating hormone and alpha-fetoprotein levels were correct. The advanced bone age was 8 years and 10 months, while the height age was 7 years. The final diagnosis was based on MRI scan. The patient is currently treated with an analog of gonadoliberine (Diphereline). In conclusion, we aspired to notice that the pharmacological treatment of hypothalamic hamartoma may be safe and effective. Suppression of puberty to the normal time of pubescence gives a child the chance to reduce health discomforts as well as further emotional and social problems.