Basedow disease is the most common cause of Hyperthyroidism. It is an autoimmune disorder involving in the thyroid gland. The immune system makes TSH receptors antibody, which bind the thyroid hormone receptor (TSHR). It makes more thyroid hormone (T3 and T4) than the body needs. I analyzed the common treatments and other possible therapeutic approaches. People with Basedow disease have tree treatment options: Antithyroid drugs (ATD), radioactive iodine therapy or thyroid surgery. Methimazole, carbimazolo and propylthiouracil are the most common ATD used. Their primary effect is to inhibit thyroid hormone synthesis by interfering with the thyroid peroxidase enzyme. They induce euthyroidism and there is evidence that they may induce apoptosis of intrathyroidal lymphocytes. Propylthiouracil can block the conversion of T4 to T3 in peripheral tissues. It inhibits the iodothyronine deiodinase ID-1. Se analogues of ATD inhibit ID-1 and they exhibit antioxidant activity. ATD show to be effective but there is a significant rate of relapse. In case of relapses, according to the characteristic of the patient, people can receive radioiodine therapy with 131I or surgery. None of these therapies is pathogenesis based. Under investigation, there are different therapeutic approaches. Small molecules antagonist inhibit the antibody activation of the TSH receptor. They have high affinity for the TSH receptor and they are allosteric antagonist. The basedow disease is characterized by lymphocytic infiltration of the thyroid, which can result in tissue destruction. The inflammatory infiltrate is compost by mononuclear cells, including B and T lymphocytes and macrophages that causes the production of TSHR antibodies. T lymphocytes and macrophages produce different kind of cytokines and chemokines. There are pharmacological strategies to attenuate inflammation interfering with the chemokine system. For example, there are under investigation Small molecules antagonist the chemokine receptor. PPAR agonists and Vitamin D analogues are under investigation as pharmacological inhibitory of pro-inflammatory cytokines. Different studies are ongoing to help ATD in case of relapses due to stressful events. For example the use of ATD with Benzodiazepines or L-carnitine. I analyze also basedow ophthalmopathy that is an inflammatory disorder of the orbit. The TSH receptors are expressed on orbital fibroblast and TSH receptor antibodies recognize them. Generally, mild disease is treated with local supportive measures. A patient having moderate or severe disease may benefit from systemic therapy with glucocorticoid or orbital radiation therapy or surgery. Under investigation, there are monoclonal autoantibody and Small molecular antagonist.
Il morbo di basedow è la causa principale di ipertiroidismo. E’ una patologia autoimmune che riguarda la tiroide. Il sistema immunitario produce anticorpi contro il recettore TSH, facendo aumentare la produzione degli ormoni tiroidei. Lo scopo della mia tesi è quello di analizzare la terapia convenzionale e i nuovi approcci terapeutici attualmente in studio. Il morbo di basedow viene generalmente trattato con farmaci antitiroidei (ATD), iodio radioattivo I131, o la tiroidectomia. Le ATD impiegate sono: metimazolo, carbimazolo e propiltiouracile. Questi farmaci vanno a bloccare la formazione di T3 e T4, inibendo l’enzima tiroide perossidasi. Inducono eutiroidismo e possono indurre apoptosi dei linfociti tiroidei. Il propiltiouracile inibisce anche a livello periferico la trasformazione di T4 in T3 inibendo l’enzima deiodinasi ID-1. Tra i derivati delle ATD, gli analoghi del Se, hanno attività ID-1 inibitoria e una importante attività antiossidante. Nonostante queste terapie abbiano mostrato la loro efficacia, si verificano molte recidive. In questi casi, a seconda della grandezza della tiroide e del tipo di paziente, il paziente viene sottoposto a terapia con radioiodio 131I o tiroidectomia. Le terapie in studio cercano invece di colpire la patogenesi della malattia. Sono in studio piccole molecole antagoniste rivolte ad inibire l’attivazione del recettore TSH da parte degli anticorpi. Si legano ad un sito allosterico di tale recettore, bloccando la propagazione del segnale. Nel morbo di basedow si assiste anche ad una esagerata produzione di mediatori dell’infiammazione come linfociti T, B e macrofagi che causano la produzione di anticorpi. Questi mediatori dell’infiammazione producono diverse citochine e chemiochine. Gli agonisti del PPAR e gli analoghi della vitamina D sono in studio per la riduzione dell’infiammazione citochine-mediata. Piccole molecole antagoniste del recettore delle chemiochine, sembrano invece le più promettenti per contrastare l’azione delle chemiochine stesse. Per prevenire le recidive date da eventi stressanti sono in studio associazioni tra farmaci antitiroidei e benzodiazepine o L-carnitina. L’oftalmopatia basedowiana è invece un disordine infiammatorio del tessuto orbitale, dato anch’esso dalla produzione di anticorpi per il recettore TSH. La terapia può essere locale, sistemica con corticosteroidi, radioterapia orbitaria o intervento chirurgico. In studio ci sono anticorpi monoclonali e small molecules antagonist
MORBO DI BASEDOW: TRATTAMENTI CONSOLIDATI E NUOVI APPROCCI TERAPEUTICI
CAVALLERI, ELENA
2014/2015
Abstract
Basedow disease is the most common cause of Hyperthyroidism. It is an autoimmune disorder involving in the thyroid gland. The immune system makes TSH receptors antibody, which bind the thyroid hormone receptor (TSHR). It makes more thyroid hormone (T3 and T4) than the body needs. I analyzed the common treatments and other possible therapeutic approaches. People with Basedow disease have tree treatment options: Antithyroid drugs (ATD), radioactive iodine therapy or thyroid surgery. Methimazole, carbimazolo and propylthiouracil are the most common ATD used. Their primary effect is to inhibit thyroid hormone synthesis by interfering with the thyroid peroxidase enzyme. They induce euthyroidism and there is evidence that they may induce apoptosis of intrathyroidal lymphocytes. Propylthiouracil can block the conversion of T4 to T3 in peripheral tissues. It inhibits the iodothyronine deiodinase ID-1. Se analogues of ATD inhibit ID-1 and they exhibit antioxidant activity. ATD show to be effective but there is a significant rate of relapse. In case of relapses, according to the characteristic of the patient, people can receive radioiodine therapy with 131I or surgery. None of these therapies is pathogenesis based. Under investigation, there are different therapeutic approaches. Small molecules antagonist inhibit the antibody activation of the TSH receptor. They have high affinity for the TSH receptor and they are allosteric antagonist. The basedow disease is characterized by lymphocytic infiltration of the thyroid, which can result in tissue destruction. The inflammatory infiltrate is compost by mononuclear cells, including B and T lymphocytes and macrophages that causes the production of TSHR antibodies. T lymphocytes and macrophages produce different kind of cytokines and chemokines. There are pharmacological strategies to attenuate inflammation interfering with the chemokine system. For example, there are under investigation Small molecules antagonist the chemokine receptor. PPAR agonists and Vitamin D analogues are under investigation as pharmacological inhibitory of pro-inflammatory cytokines. Different studies are ongoing to help ATD in case of relapses due to stressful events. For example the use of ATD with Benzodiazepines or L-carnitine. I analyze also basedow ophthalmopathy that is an inflammatory disorder of the orbit. The TSH receptors are expressed on orbital fibroblast and TSH receptor antibodies recognize them. Generally, mild disease is treated with local supportive measures. A patient having moderate or severe disease may benefit from systemic therapy with glucocorticoid or orbital radiation therapy or surgery. Under investigation, there are monoclonal autoantibody and Small molecular antagonist.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/22857