Backgrond: The thyroid is a hormone-producing endocrine gland which is located in the front of the throat. The thyroid gland tissue contains several microscopic and spherical cavities called follicles. Thyroid hormones thyroxine (T4) and triiodothyronine (T3) are produced from the follicle cells and regulated by a so-called three-hormone sequence. Thyroid stimulating hormone (TSH) is the second hormone in the sequence and is produced from the pituitary gland. During pregnancy, the thyroid gland produces a greater amount of hormone to cater the needs of the mother and her offspring. When the gland produces too little hormone, it is called hypothyroidism. The disease causes symptoms such as chills, dryness, depression, and hair loss. The disease is divided into different types depending on the underlying cause of the disease. It is called primary hypothyroidism when disorders are in the thyroid gland itself and secondary when the problem is elsewhere in the body, usually in the hypothalamus. Hypothyroidism during pregnancy increases the risk of obstetric complications and can also lead to reduced IQ development in the fetus. Levothyroxine is a synthetic T4 and is used as a first-line drug in the treatment of hypothyroidism. Aim: The aim of this study was to investigate whether treatment with levothyroxine in subclinical hypothyroidism in pregnancy reduces the risk of pregnancy complications and also to analyze how thyroid autoimmunity and subclinical hypothyroidism affect the pregnant woman. Method: The work is a literature study conducted using six relevant published articles retrieved from the medical database and the search engine PubMed. Results: The studies 2,4,5 concluded that subclinical hypothyroidism and thyroid autoimmunity increase the risk of pregnancy complications. Studies 1 and 6 could not show any connection between these groups. Levothyroxine treatment in pregnancy with TSH value greater than 4 mIU/L is effective and leads to reduced risk of miscarriage, admission to neonatal wards and premature birth. In addition, the studies showed that the levothyroxine treatment in patients with TSH value less than 4mIU/L is without any significant effect.   Conclusion: The evidence at present, is unclear and there is insufficient data to determine the efficacy of treatment in patients with TSH levels below 2.5 mIU / L. More and larger clinical randomized controlled trials in pregnant women with subclinical hypothyroidism and positive for thyroperoxidase antibodies are needed to increase the validity of the treatment. In contrast, levothyroxine treatment in mothers with a TSH level in serum greater than 4 mIU / L is effective and of significant importance for both the woman and her offspring.

Objectives: We systematically investigated normally or subclinically increased thyroid stimulating hormone (TSH) values associated with unexpectedly increased thyroxine (FT4) and free triiodothyronine (FT3) in findings of patients without any thyroid disease. Moreover, we looked for alternatives to overcome such states with an improved diagnostic procedure and to investigate the pathogenetic background of the respective patients. Methods: Samples with TSH concentrations within the range of 0.4–10 mU/L combined with increased concentrations of FT4 (n=120; Cobas, Roche) were collected over a period of around six years. Cobas FT4 results were compared with measurements from Liaison (DiaSorin) and Architect (Abbott) FT4 assays. For further validation all samples were measured for total thyroxine (TT4) (Cobas, Roche). Finally, FT3 and TT3 as complementary parameters were measured in samples with leftover material. To overcome potential analytical disturbances from stimulating heterophilic antibodies, we used heterophilic blocking tubes (HBTs). Results: From the 120 samples with increased FT4 concentrations by Cobas, 51/120 were also increased by Liaison, and 26/120 by Architect. However, the measurement of TT4 indicated only n=10/120 increased values. The number of increased FT3 (n=71) measurements was higher in Architect>Cobas>Liaison (28>27>9). TT3 levels of 70/71 samples were within the reference interval. HBTs were inappropriate to reduce unspecific immunoreactivity in our samples. No clear pathogenetic background could be elucidated in the anamnesis of individual patients. Conclusions: To overcome dubious constellations of TSH, FT4, and FT3, it is helpful to measure TT4 and TT3 for control or to use an immunoassay with an alternative assay design for the respective parameters.:I. Abkürzungsverzeichnis 4 I. Einleitung 5 1.1 Hintergrund 5 1.2 Regelkreis 7 1.3. Methodik zur Diagnostik von Schilddrüsenhormonen 8 1.5. Störfaktoren 9 1.6 Fragestellungen/Ziele 11 2 Publikationsmanuskript 13 3 Zusammenfassung der Arbeit 23 4 Literaturverzeichnis 27 II Anhang 37 III Darstellung des eigenen Beitrags 40 IV Erklärung über die eigenständige Abfassung der Arbeit 41 V Curriculum vitae 42 VI Publikationen 44 VII Danksagung 45

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Introduktion. Autoimmun tyreoidit (AITD) är en kronisk autoimmun sjukdom där immunförsvarets antikroppar (ab) attackerar tyreoideaproteinerna tyreoideaperoxidas (TPO) och/eller tyreoglobulin (TG). Studier visar att selentillskott hos patienter med AITD kan minska tyreoideaantikroppar, storleken och antalet noduler hos en förstorad tyreoidea. Syftet med detta arbete var att undersöka hur selentillskott påverkar serumnivåer av TPOab, samt tyreoideahormonnivåer vid AITD.   Metod. Arbetet är en litteraturstudie och därför har metoden varit att samla relevant litteratur genom PubMed med sökningar som ”selenium autoimmune thyroiditis”, ”selenium thyroid” och ”autoimmune thyroiditis”. Bland sökresultaten valdes nio artiklar ut baserat på studiekvalitet, publikationsår och relevans. Bland artiklarna granskades och sammanställdes uppmätta nivåer av TPOab samt tyreoideahormonnivåer, vilka valdes som indikation på effekt utav selentillskott. Resultat. Resultaten var inkonsekventa. Majoriteten av studierna (7 av 9) tydde på att oral administrering av selentillskott effektivt minskade serumkoncentrationerna av TPOab hos patienter med AITD i alla åldersgrupper. De studier som resulterade i störst minskning av TPOab pågick i 3-12 månader. Utav de 9 studerade artiklarna var det endast en studie som inte rapporterade någon som helst positiv klinisk effekt hos patienterna. Två av studierna visade att selen förhindrar vidare försämring av tyreoideans ekogenitet, vilket tyder på att selen kan hejda inflammationsprocessen men ej reversera tyreoideaskadorna den orsakat. Majoriteten av studierna (7 av 9) visade att selentillskott ej ger några signifikanta förändringar i tyreoideahormonerna: TSH, fT4 och fT3. Diskussion. Varför AITD-patienter svarar olika på selenadministrering är ännu okänt, men kan misstänkas bero på selenbehandlingens varaktighet, patienternas intratyroidnivåer av selen vid studiens början, förekomst av jodbrist, samt patienternas ålder och sjukdomsprogression. Slutsats. Att ha adekvata fysiologiska nivåer av selen är av stor vikt för att bevara tyreoideans hälsa och förebygga tyreoidearelaterade sjukdomar. Majoriteten utav de granskade studierna visar att tillskott av selen kan minska antalet TPOab. Selentillskott kan även ha immunrelaterade fördelar men verkar inte påverka nivån tyreoideahormonnivåer. Inga negativa effekter påvisades vid intag av selentillskott vilket gör dess administrering säker. Fler studier behöver dock göras för att fastställa effektiviteten av selentillskott vid AITD. / Introduction. Autoimmune thyroiditis (AITD) is a chronic autoimmune disease in which the immune system's antibodies (ab) attack the thyroid proteins thyroid peroxidase (TPO) and/or thyroglobulin (TG). Studies show that selenium supplementation in patients with AITD can reduce thyroid antibodies and the size and number of nodules in an enlarged thyroid. The purpose of this study was to investigate how selenium supplementation affects the serum levels of thyroid peroxidase antibodies (TPOab) and thyroid hormone levels in autoimmune thyroiditis. Method. This is a literature study and therefore the method has been to gather relevant literature through searches on PubMed such as "selenium autoimmune thyroiditis", "selenium thyroid" and "autoimmune thyroiditis". Among the search results, nine articles were selected based on quality, publication year and relevance. Among the articles, measured levels of TPOab and thyroid hormone levels were examined and compiled, and were chosen as an indication of the effect of selenium supplementation. Results. The results were inconsistent. The majority of the studies (7 of 9) suggest that oral administration of selenium supplements effectively reduced serum concentrations of TPOab in patients with AITD in all age groups. The studies that resulted in the largest decrease in TPOab lasted for 3-12 months. Out of the 9 examined studies, only one study did not report any positive clinical effect in patients. Two of the studies showed that the selenium prevents further impairment of thyroid echogenicity, suggesting that selenium can inhibit the inflammatory process but not reverse the pre-existing thyroid damage it’s caused. The majority of studies (7 out of 9) show that selenium supplementation does not produce significant changes in the thyroid hormones: TSH, fT4 and fT3. Discussion. Why AITD-patients respond differently to selenium administration is still unknown, but it may be due to the duration of selenium treatment, the patients' intrathyroid levels of selenium at the onset of the study, the presence of iodine deficiency, as well as the age and disease progression of the patients. Conclusion. Having adequate physiological levels of selenium is of great importance in preserving thyroid health and preventing thyroid-related diseases. The majority of the studies show that selenium supplementation can reduce the number of TPOab. Selenium supplementation may also have immune related benefits but does not appear to affect the thyroid hormone levels. No adverse effects were observed during selenium supplementation, which makes its administration safe. However, more studies are needed to determine the effectiveness of selenium supplementation for AITD.

Nódulos de tireoide são achados clínicos comuns e, atualmente, o método diagnóstico de escolha para diferenciar lesões benignas de lesões malignas é a análise citopatológica dos nódulos através de punção aspirativa por agulha fina (PAAF). Estudos prévios já indicaram que os níveis séricos de TSH podem estar associados ao risco de malignidade nodular. O objetivo deste estudo foi avaliar se o TSH sérico é um preditor de malignidade em nódulos de tireoide em pacientes submetidos à PAAF. A amostra contemplou 100 indivíduos puncionados consecutivamente no Centro de Pronto Diagnóstico Ambulatorial, CPDA, HCPA e que apresentavam níveis de TSH dentro da normalidade. Todos os pacientes foram submetidos à PAAF da tireoide com controle ultrassonográfico e tiveram, posteriormente, a análise citopatológica da PAAF e a avaliação histopatológica do bloco celular. A análise estatística baseou-se em dados de frequências e testes não-paramétricos foram utilizados para correlacionar as variáveis. A população de estudo foi composta por 100 pacientes, sendo 89 mulheres e 11 homens. A média de idade foi de 54,1 ± 14,2 anos e o tamanho médio dos nódulos foi de 2.53 ± 1.36 centímetros. Vinte e seis % destes pacientes apresentavam algum tipo de doença tireoidiana prévia. A média do nível de TSH sérico entre os 100 indivíduos foi de 1.81 ± 1.08 uUI/mL. De acordo com o diagnóstico citopatológico da PAAF complementado pelos achados do bloco celular foram classificados como malignos 8% dos nódulos, 70% benignos, 11% suspeitos/ indeterminados, 8% insuficientes e 3% lesões foliculares. A média de TSH para os grupos maligno, benigno, suspeito/indeterminado, insuficiente e lesão folicular foi de, respectivamente, 2.48, 1.59, 2.21, 2.35 e 2.20 uUI/ml (p>0.05). Não houve diferença estatística significante entre os grupos diagnósticos avaliados, apesar de haver uma variação entre os níveis de TSH entre os grupos refletindo, provavelmente, o pequeno tamanho da amostra. / Thyroid nodules are common and currently the first choice of investigation in distinguishing benign from malignant disease is the cytological analysis of fine needle aspiration biopsy (FNAB). Previous studies have indicated that serum TSH levels might be associated with the likelihood of malignancy. The aim of this study was to evaluate whether serum TSH is a predictor of malignancy of thyroid nodules in patients undergoing FNAB. One hundred consecutive patients, who underwent FNAB as part of clinical investigation of thyroid nodule in a multidisciplinary setting tertiary hospital, underwent ultrasonography followed by FNAB, cytology and cell block analysis. Independent-Samples Kruskal-Wallis test was used to compare the groups. The study population comprised of 89 female and 11 male patients. The mean age was 54.1 ± 14.2 years. 26% had previous thyroid disease. Mean TSH levels was 1.81 ± 1.08 uUI/mL and the mean nodule size was 2.53 ± 1.36cm. Final cytology/cell block diagnosis classified 8% as malignant, 70% as benign, 11% suspicious/indeterminate, 8% insufficient and 3% follicular lesion. The mean TSH values for malignant, benign, suspect, insufficient and follicular lesion group were as follows: 2.48, 1.59, 2.21, 2.35 and 2.20 uUI/ml, respectively. No statistical significance was detected between TSH levels and final cytology/cell block diagnosis, possibly reflecting the small sample size (P>0.05). We observed a variation between TSH levels among the groups covered in this study, but there was no statistically significant difference among them.

Durante a vida fetal e a infância, os processos fisiológicos da tireoide são peculiares, sendo os hormônios tireoidianos (T3 e T4) essenciais para o crescimento e o desenvolvimento da criança. Os níveis séricos de tireotrofina (TSH) são determinantes no diagnóstico de disfunção tireoidiana. Os dados de normalidade e os fatores que influenciam os níveis de TSH em crianças são pouco conhecidos, sendo que os estudos que disponibilizam esses dados nem sempre são bem conduzidos. A síntese de hormônios tireoidianos é dependente de iodo, e a deficiência desse elemento associa-se a alterações morfológicas e volumétricas da glândula. Os valores de normalidade para volume tireoidiano na infância são influenciados pelas medidas antropométricas e variam entre populações. Atualmente, a deficiência grave de iodo tem dado lugar a patologias relacionadas à ingestão excessiva desse elemento. É importante conhecer as particularidades e os valores de referência para função tireoidiana na infância a fim de evitar prejuízos antropométricos e cognitivos. / Distinct physiological processes occur in the thyroid gland during intrauterine life and childhood, with thyroid hormones (T3 and T4) playing an essential role in growth and development. Serum levels of thyroid-stimulating hormone (TSH) are determining factors of the diagnosis of thyroid dysfunction. Little is known about the normal range of TSH in children and the factors that influence TSH levels in this population, and the few studies that have addressed this issue have not all been well designed and conducted. Thyroid hormone synthesis is iodine-dependent, and iodine deficiency is associated with pathological changes in the morphology and volume of the thyroid gland. The normal range of thyroid volume in children is influenced by anthropomorphic parameters, and varies among populations. Severe iodine deficiency has now been surpassed by conditions associated with excessive iodine intake. Knowledge of the peculiarities of thyroid function in childhood and of the reference ranges of thyroid function tests in this period is important for the prevention of anthropometric and cognitive impairments.

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The aim of this work was to assess the long-term effect of excessive iodine intake on thyroid activity and selected immunological, haematological and biochemical parameters in blood of ewes and their lambs. The experiment was conducted from August 2009 to February 2010 in an experimental barn of Faculty of Agriculture, University of South Bohemia in České Budějovice. Into the experiment were used Šumava sheep breed ewes and their born lambs. Group A (control) consisted of 6 ewes after lambing was extended to 7 born lambs, group B (experimental) 6 of 6 ewes and lambs. Lambs were put into the experiment from the 1st to the 60th day after birth and received iodine in the milk of their mothers. Iodine supplementation to the diet of ewes was launched during the first to second months of pregnancy and finished 60 days after birth. During the experiment, a group of ewes A received 3,1 and group B 5,1 mg iodine per kg of dietary dry matter in the form of calcium iodate. During the experiment was regularly collected blood of ewes (before lambing and 1st, 10th, 30th and 60th day after birth) and lambs (1st, 3rd, 10th, 30th and 60th day after birth) to determine the concentration of thyroid stimulating hormone and immunoglobulin G (ELISA) in blood serum, thyroid hormones (RIA), total protein, urea and alkaline phosphatase activity in the blood plasma (biochemical analyser), the content of haemoglobin, white blood cell´s and red blood cell´s counts and haematocrit values in blood (haematological analyser), percentage of albumin, -1-globulins, -2-globulins, -globulins, and -globulins in blood serum (electrophoresis) and the content of iodine in the blood plasma, urine and milk of ewes (colorimetric method Sandell-Kolthoff). During the experiment were not observed in ewes and lambs clinical symptoms associated with an excessive intake of iodine. In experimental group of ewes with iodine intake 5,1 mg/kg of dietary dry matter were found higher values of thyroid stimulating hormone, lower values of free triiodothyronine, free thyroxine, IgG, white blood cells, -1-globulins, -2-globulin and -globulin, significantly lower values of -globulins after parturition, significantly higher values of urea and alkaline phosphatase activity. The iodine content in blood plasma, milk and urine of ewes is increased in direct proportion to its concentration in diet. Lambs of mothers with iodine intake of 5,1 mg/kg of dietary dry matter were significantly higher values of thyroid stimulating hormone from the 10th day after birth, significantly lower values of free triiodothyronine and free thyroxine first day after birth, immunoglobulin G and -globulins in 30th day after birth, lower (statistically significant in middle samples) values of total protein and white blood cells, higher values of urea and alkaline phosphatase activity. The weight gains of lambs were not significantly affected by iodine supplementation. These results in ewes with iodine intake of 5,1 mg/kg dietary dry matter and especially their lambs drawn to risk of reduce the activity of the thyroid gland and the negative impact of parameters of humoral immunity, mainly IgG and -globulins.

Durante a vida fetal e a infância, os processos fisiológicos da tireoide são peculiares, sendo os hormônios tireoidianos (T3 e T4) essenciais para o crescimento e o desenvolvimento da criança. Os níveis séricos de tireotrofina (TSH) são determinantes no diagnóstico de disfunção tireoidiana. Os dados de normalidade e os fatores que influenciam os níveis de TSH em crianças são pouco conhecidos, sendo que os estudos que disponibilizam esses dados nem sempre são bem conduzidos. A síntese de hormônios tireoidianos é dependente de iodo, e a deficiência desse elemento associa-se a alterações morfológicas e volumétricas da glândula. Os valores de normalidade para volume tireoidiano na infância são influenciados pelas medidas antropométricas e variam entre populações. Atualmente, a deficiência grave de iodo tem dado lugar a patologias relacionadas à ingestão excessiva desse elemento. É importante conhecer as particularidades e os valores de referência para função tireoidiana na infância a fim de evitar prejuízos antropométricos e cognitivos. / Distinct physiological processes occur in the thyroid gland during intrauterine life and childhood, with thyroid hormones (T3 and T4) playing an essential role in growth and development. Serum levels of thyroid-stimulating hormone (TSH) are determining factors of the diagnosis of thyroid dysfunction. Little is known about the normal range of TSH in children and the factors that influence TSH levels in this population, and the few studies that have addressed this issue have not all been well designed and conducted. Thyroid hormone synthesis is iodine-dependent, and iodine deficiency is associated with pathological changes in the morphology and volume of the thyroid gland. The normal range of thyroid volume in children is influenced by anthropomorphic parameters, and varies among populations. Severe iodine deficiency has now been surpassed by conditions associated with excessive iodine intake. Knowledge of the peculiarities of thyroid function in childhood and of the reference ranges of thyroid function tests in this period is important for the prevention of anthropometric and cognitive impairments.

Nódulos de tireoide são achados clínicos comuns e, atualmente, o método diagnóstico de escolha para diferenciar lesões benignas de lesões malignas é a análise citopatológica dos nódulos através de punção aspirativa por agulha fina (PAAF). Estudos prévios já indicaram que os níveis séricos de TSH podem estar associados ao risco de malignidade nodular. O objetivo deste estudo foi avaliar se o TSH sérico é um preditor de malignidade em nódulos de tireoide em pacientes submetidos à PAAF. A amostra contemplou 100 indivíduos puncionados consecutivamente no Centro de Pronto Diagnóstico Ambulatorial, CPDA, HCPA e que apresentavam níveis de TSH dentro da normalidade. Todos os pacientes foram submetidos à PAAF da tireoide com controle ultrassonográfico e tiveram, posteriormente, a análise citopatológica da PAAF e a avaliação histopatológica do bloco celular. A análise estatística baseou-se em dados de frequências e testes não-paramétricos foram utilizados para correlacionar as variáveis. A população de estudo foi composta por 100 pacientes, sendo 89 mulheres e 11 homens. A média de idade foi de 54,1 ± 14,2 anos e o tamanho médio dos nódulos foi de 2.53 ± 1.36 centímetros. Vinte e seis % destes pacientes apresentavam algum tipo de doença tireoidiana prévia. A média do nível de TSH sérico entre os 100 indivíduos foi de 1.81 ± 1.08 uUI/mL. De acordo com o diagnóstico citopatológico da PAAF complementado pelos achados do bloco celular foram classificados como malignos 8% dos nódulos, 70% benignos, 11% suspeitos/ indeterminados, 8% insuficientes e 3% lesões foliculares. A média de TSH para os grupos maligno, benigno, suspeito/indeterminado, insuficiente e lesão folicular foi de, respectivamente, 2.48, 1.59, 2.21, 2.35 e 2.20 uUI/ml (p>0.05). Não houve diferença estatística significante entre os grupos diagnósticos avaliados, apesar de haver uma variação entre os níveis de TSH entre os grupos refletindo, provavelmente, o pequeno tamanho da amostra. / Thyroid nodules are common and currently the first choice of investigation in distinguishing benign from malignant disease is the cytological analysis of fine needle aspiration biopsy (FNAB). Previous studies have indicated that serum TSH levels might be associated with the likelihood of malignancy. The aim of this study was to evaluate whether serum TSH is a predictor of malignancy of thyroid nodules in patients undergoing FNAB. One hundred consecutive patients, who underwent FNAB as part of clinical investigation of thyroid nodule in a multidisciplinary setting tertiary hospital, underwent ultrasonography followed by FNAB, cytology and cell block analysis. Independent-Samples Kruskal-Wallis test was used to compare the groups. The study population comprised of 89 female and 11 male patients. The mean age was 54.1 ± 14.2 years. 26% had previous thyroid disease. Mean TSH levels was 1.81 ± 1.08 uUI/mL and the mean nodule size was 2.53 ± 1.36cm. Final cytology/cell block diagnosis classified 8% as malignant, 70% as benign, 11% suspicious/indeterminate, 8% insufficient and 3% follicular lesion. The mean TSH values for malignant, benign, suspect, insufficient and follicular lesion group were as follows: 2.48, 1.59, 2.21, 2.35 and 2.20 uUI/ml, respectively. No statistical significance was detected between TSH levels and final cytology/cell block diagnosis, possibly reflecting the small sample size (P>0.05). We observed a variation between TSH levels among the groups covered in this study, but there was no statistically significant difference among them.