Thyrostatic Drugs Research Articles

Amiodarone-induced thyrotoxicosis type 2: the role of differential diagnosis in patient management

The antiarrhythmic drug amiodarone can affect the function of the thyroid gland, contributing to the development of thyrotoxicosis or hypothyroidism. The development of thyrotoxicosis exacerbates the cardiovascular pathology present in patients: it leads to the progression of left ventricular dysfunction, recurrence of rhythm disturbances, increasing the risk of adverse outcomes. Timely diagnosis of thyrotoxicosis in the treatment of amiodarone is of fundamental importance in choosing the right therapeutic tactics, which is determined by the type of amiodarone-induced thyrotoxicosis (AmIT), the state of the cardiovascular system, and the risk of recurrent arrhythmias. In type 1 AMIT, the main method of controlling the relief of thyrotoxicosis is thyroostatic therapy with the possibility of subsequent radical treatment (radioiodine therapy, thyroidectomy). Type 2 AmIT is a self-limiting process, however, for the treatment of patients with moderate to severe amiodarone-induced thyrotoxicosis type 2, glucocorticoids are the first-line drugs. With a mixed version of AmIT, a combination of antithyroid drugs and glucocorticoids is recommended. This review presents a clinical case of a patient with type 2 AmIT who was treated with thyrostatic drugs for a long time without achieving an effect.

Thyrotoxic hepatitis during pregnancy (clinical case)

A rare clinical case of thyrotoxic hepatitis detected in a pregnant woman is presented. A diagnostic search was carried out to clarify the cause of hepatitis, during which the pathology of the thyroid gland was revealed. The patient was prescribed adequate therapy with a thyrostatic drug, which in a short time allowed to achieve a significant decrease in the activity of the hepatic pathological process, which made it possible to prolong pregnancy.

Лімфоцитарний профіль периферичної крові жінок, хворих на дифузний токсичний зоб, залежно від ступеня його компенсації

Актуальність. В Україні на сьогодні основним методом лікування дифузного токсичного зоба (ДТЗ) є призначення антитиреоїдних препаратів з метою досягнення еутиреозу. При цьому в ініціації розвитку ДТЗ і його рецидивів основну роль відводять порушенню різних ланок імунної системи, тому конкретизація таких порушень залишається актуальним завданням у розробці системи профілактики розвитку рецидивів ДТЗ. Мета роботи — встановити вплив тиреостатиків на лімфоцитарний профіль периферичної крові у хворих на ДТЗ для призначення адекватної імунотропної терапії. Матеріали та методи. Проведено порівняльний аналіз лімфоцитарного спектра периферичної крові жінок, хворих на ДТЗ, на тлі гіпертиреозу і в стані медикаментозної компенсації. Встановлено відхилення окремих показників, які могли б стати тригерами рецидивування захворювання. Результати. У групі жінок із ДТЗ в стані гіпертиреозу на тлі курсу терапії препаратами тіосечовини відбулася нормалізація тиреоїдного гомеостазу. Це супроводжувалося позитивною динамікою (зниженням) активності Т-хелперів і В-лімфоцитів, що необхідно для зменшення утворення антитіл. У той же час спостерігалося зниження Т-супресорної активності з підвищенням імунорегуляторного індексу супресії, а також формуванням дефіциту натуральних кілерів. Відзначалося підвищення індексів CD4/CD16 і CD8/CD16, що свідчить про переважання антитілозалежного імунного процесу над неспецифічною клітинною цитотоксичністю. Висновки. Проведення терапії ДТЗ за допомогою препаратів тіосечовини не тільки сприяє медикаментозній компенсації, але й має імуномодулюючий вплив. Лімфограма периферичної крові у пролікованих хворих на ДТЗ характеризується зниженням Т-хелперної активності та рівня В-лімфоцитів (р < 0,05), що дозволяє зменшити антитілоутворення, та зниженням рівнів Т-супресорів, а також натуральних кілерів (р < 0,001), що створює умови для рецидиву захворювання. Хворі на ДТЗ, які отримують курс тиреостатиків, потребують додаткового призначення імуномодуляторів (у тому числі селеновмісних), здатних підвищити Т-супресорну активність.

Subclinical hyperthyroidism in the course of autonomous nodules - clinical evaluation.

Subclinical hyperthyroidism (SCH), also known as mildly symptomatic hyperthyroidism, has recently been diagnosed more frequently. One of the main endogenous causes of this disorder is autonomously functioning thyroid nodule (AFTN). Despite the fact that it is usually asymptomatic, SCH entails repercussions on the cardiovascular system and bone, and it carries a risk of progression to overt hyperthyroidism with a typical clinical picture. Treatment is still controversial, and its benefits are widely debated in literature. From 459 patients authors selected a group of 49 patients (10.6% of all subjects with hyperthyroidism), 41 women (83.7%) with AFTN at the stage SCH treated in the Outpatient Endocrinological Clinic and the Department of Endocrinology of the Medical University of Lublin over a three-year period. The method applied in the study was a retrospective analysis of medical records with a particular account of medical history, physical examination, and additional tests obtained during the process of diagnostic and therapeutic procedures. Forty-one patients (83.7%) suffered from typical symptoms of hyperthyroidism; only eight patients (16.3%) were asymptomatic. The most frequently reported symptoms were tachycardia in women (51.2%) and anxiety in men (50%). The type of thyrostatic drugs and the length of therapy did not affect the outcome of iodine-131 therapy. In the vast majority of the patients (87.8%) radioidodine therapy was effective; 30 patients (61.2%) reached euthyreosis and 13 patients (22.5%) developed hypothyroidism. Most patients with SCH in the course of AFTN suffered from typical symptoms of overt hyperthyroidism; only every sixth patient was asymptomatic. The volume of autonomous adenomas did not affect the result of 131I therapy; however, the impact of AFTN volume as well as the thyroid volume on RIT efficacy requires futher investigation. In the vast majority of patients 131I therapy was an effective method of treatment, and an earlier therapeutic effect was observed more often in the patients with focal lesions located in the right lobe.

Genetic predictors of the development and recurrence of Graves' disease.

Graves' disease affects approximately 3 % of women and 0.5 % of men. The first-choice therapy is based on the administration of thyrostatic drugs. However, approximately half of patients relapse within two years of discontinuation. These patients must then decide whether to re-initiate thyrostatics, which may have serious side effects, or to undergo surgery or radioiodine treatment. Familial forms of Graves' disease indicate a significant genetic component, with twin studies demonstrating a contribution of genetic factors up to 70-80 %. The autoimmune nature of the disease involves the human leukocyte antigen (HLA) complex, which has a decisive impact on each individual's immune response. Within HLA, some variants of the DRB1, DQA1 and DQB1 genes appear to be possible predictors of the development and recurrence of Graves' disease. Outside the HLA region, many variants of immunocompetent genes have also been identified as potential Graves' disease predictors. Apart from the immune system, some thyroid-specific genes have been described in relation to the disease. Here, we present current knowledge regarding the genetic components involved in the development and recurrence of Graves' disease. Further, we present original pilot results from a cohort of Czech Graves' disease patients regarding the HLA variants.

Höhepunkte der Thyreologie: eine historische Vignette

This review gives a historical overview about the development of today's understanding of benign thyroid diseases and the possibilities of their treatment.Little was known about the thyroid gland until the nineteenth century: the state of knowledge was (1) that something in food, especially in seaweed, avoided the development of goiters, (2) that goiters seemed to have something to do with cretinism, and (3) that the thyroid gland is an organ consisting of two lobes connected by an isthmus. Shortly after the detection of iodine in 1811, its impact on its ability to avoid the development and the growing of goiters has been realized. The existence of iodine within the thyroid and in human plasma was detected approximately a decade later. The clinical picture of hyperthyroidism including endocrine orbitopathy was described in detail in the middle of the nineteenth century, the etiology of the disease remaining, however, unclear until a century later. In early nineteenth century, surgical goiter exstirpation was the only available form of treatment. Vienna and Berne were the centers leading worldwide in their expertise. Subcutaneous injections of sheep thyroid extracts were developed for treatment of postoperative hypothyroidism as well as congenital myxedema. Another approach suggested by Swiss surgeons was thyroid transplantation. Radioiodine therapy of hyperthyroidism was introduced in the middle of the twentieth century. Thyrostatic drugs are available since about the same time. The different forms of thyroiditis were described at the turn of the twentieth century. The etiology of chronic autoimmune thyroiditis was, however, clarified only some 50 years later independently by two groups of scientists, one in London, UK, and the other in Buffalo, USA. Thyroxine was isolated from bovine thyroid extracts in the beginning of the twentieth century. Its synthesis and correct chemical structure were described some 10 years later. The existence of 3,5,3'-triiodothyronine (T3), the biologically most active thyroid hormone, was detected in the 1950s of the past century by a group in Paris and another in London. The extrathyroidal conversion of thyroxine to T3, as the main source of circulating T3, was suggested shortly thereafter and substantiated in 1970. Finally, the development of the radioimmunoassay method for determination of hormone serum concentrations in 1959 enabled today's exact laboratory diagnosis of thyroid diseases.

Thyrotoxic Hypokalemic Periodic Paralysis (THPP): a challenge for the Emergency Medicine physician in Western countries. A case report

Thyrotoxic hypokalemic periodic paralysis (THPP) is an endocrine emergency with sudden onset of acute muscle hypo-asthenia associated with severe hypokalemia and normal acid-base balance, due to thyrotoxicosis. It may develop in patients of Asian and Native American descent, but it is very rare and undiagnosed in Western countries. Standard treatment includes β-blockers and thyrostatic drugs, but hypokalemia should not be treated with high potassium doses due to the risk of hyperkalemic rebound. Since early diagnosis and correct treatment can prevent life-threatening cardio-pulmonary complications, the emergency physician should keep in mind this rare possibility. We report a case of a 43 year old Caucasian man presenting at ED with tetraparesis as the first symptom of thyrotoxicosis with no other remarkable symptoms or signs.

Primary hyperthyroidism — diagnosis and treatment. Indications and contraindications for radioiodine therapy

Isotope therapy is one of the methods used in primary hyperthyroidism. The therapy is based on short-range beta radiation emitted from radioactive iodine. Radioiodine administration must always be preceded by pharmacological normalization of thyroid function. Otherwise, post-radiation thyrocyte destruction and thyroid hormones release may lead to hyperthyroidism exacerbation. Indications for radioiodine therapy in Graves-Basedow disease include recurrent hyperthyroidism after thyrostatic treatment or thyroidectomy and side-effects observed during thyrostatic treatment. In toxic nodule, isotope therapy is the first choice therapy. Radioiodine is absorbed only in autonomous nodule. Therefore, it destroys only this area and does not damage the remaining thyroid tissue. In toxic goitre, radioiodine is used mostly in recurrent nodules. Absolute contraindications for radioiodine treatment are pregnancy and lactation. Relative contraindications are thyroid nodules suspected of malignancy and age under 15 years. In patients with thyroid nodules suspected of malignancy, radioiodine treatment may be applied as a preparation for surgery, if thyrostatic drugs are ineffective or contraindicated. In children, radioiodine therapy should be considered in recurrent toxic goitre and when thyrostatic drugs are ineffective. In patients with Graves-Basedow disease and thyroid-associated orbitopathy, radioiodine treatment may increase the inflammatory process and exacerbate the ophthalmological symptoms. However, thyroid-associated orbitopathy cannot be considered as a contraindication for isotope therapy. The potential carcinogenic properties of radioiodine, especially associated with tissues with high iodine uptake (thyroid, salivary glands, stomach, intestine, urinary tract, breast), have not been confirmed.

Energy Homeostasis and Body Weight before and after Cessation of Block and Replacement Therapy in Euthyroid Patients with Graves' Disease

Patients with Graves' hyperthyroidism (GH) treated with a combination of thyrostatic drugs and T4, that is, block and replacement therapy (BRT), often report body weight (BW) gain. We aimed to determine changes in BW and energy metabolism upon cessation of BRT in these patients, and to identify possible endocrine determinants. We analysed 22 patients with GH (i) during BRT, and (ii) 12 weeks after BRT cessation. Patients were euthyroid at both visits. There were no differences in BW or resting energy expenditure (REE) between visits. At visit 1, after 13.5 (9.5–48.0) months of BRT, serum free (F)T4 correlated positively with REE (r = 0.433, P = 0.044) and negatively with body fat % (r = -0.450, P = 0.035). Plasma FT3 and FT3/FT4 ratio showed an increase 12 w after cessation of BRT (20%, P < 0.0001 and 16%, P = 0.007, resp.). Moreover, the relative change in FT3/FT4 ratio showed a significant, positive correlation with the relative change in REE between the 2 visits (r = 0.465, P = 0.029). In conclusion, serum FT4 determines REE in euthyroid patients with GH treated with BRT. Twelve weeks after BRT cessation, BW and energy homeostasis are unaltered. However, as serum FT3/FT4 ratio increases after cessation of BRT, which is a positive determinant of changes in REE, a longer term BW decrease is likely to occur.

Action of Thyroid Inhibitor Propyl Thiouracil on Thyroid and Interrenal Axes in the Freshwater Tilapia Oreochromis mossambicus Peters

The actions of propyl thiouracil (PTU), a thyrostatic drug, on thyroid hormones (THs) and cortisol production were examined in freshwater tilapia (Oreochromis mossambicus) to examine whether the hypothyroid state affects the function of interrenal axes in this fish. The plasma levels of triiodothyronine (T 3 ), thyroxine (T 4 ), and cortisol along with branchial and renal Na + , K + -ATPase activities were measured after feeding varied doses (5-20 μg g -1 ) of PTU for over 10 or 15 days. Feeding low dose (5 μg g -1 ) of PTU produced significant rise in plasma T 4 level but both T 3 and T 4 levels were decreased significantly after feeding a high dose (20 μg g -1 ) of PTU for 15 days. All doses of PTU failed to alter the plasma cortisol. No significant correlation was found between the plasma levels of T 3 , T 4 and cortisol after varied doses of PTU. Treatment of T 3 or T 4 (40 ng g -1 ) to the high dose PTU-fed tilapia produced a significant rise in plasma cortisol, suggesting a link to the thyroid and interrenal axes in this fish. The rise in T 3 or T 4 level in the PTU-treated tilapia after TH injections correlated with the branchial and renal Na + , K + -ATPase activities, which imply an effective Na handling, though a tight regulation of Na + and K + transport was maintained in the plasma of these fish. The data show that high dose of PTU inactivates the thyroid axis resulting in the decreased production of T 3 and T 4 , though a low dose of PTU activates the thyroid axis. Our results provide evidence that exogenous T 3 activates interrenal axis to produce cortisol and both exogenous T 3 and T 4 promote branchial and renal Na handling in PTU-induced hypothyroid tilapia.

Propylthiouracil: Clinical Overview of its Efficacy and its Side Effects more than 50 Years after the Introduction of its Use in Thyrostatic Treatment

This minireview gives a clinical overview of the efficacy and of the side effects of the thyrostatic drug propylthiouracil, which is in use for the treatment of Graves' disease for more than 5 decades. It is the aim of this minireview to give convincing evidence of the value of propythiouracil in the treatment of thyrotoxic patients with Graves' disease: The modalities of treatment are given. The advantages in comparison to methimazole are mentioned: Especially for thyrotoxic nursing mothers it represents the only thyrostatic drug approved by the American Academy of Pediatrics. Patients who experience side effects with methimazole usually can be switched successfully to propylthiouracil and vice versa. Its use for the treatment of thyrotoxicosis in pregnant women is recommended by many centres because of the comparatively little placental transfer of the drug, although the effect for the newborn does not seem to differ from that of methimazole. The minireview should remind the medical community of the value of propylthiouracil as a very valuable thyrostatic drug representing a good alternative to methimazole. It should attract interest in the drug, in spite of the fact that after 5 decades in the market there is probably only little financial profit left in selling it.

Modeling the relations of thyroid hormones in rats

The relations between the concentration of thyroxine, triiodothyronine, and thyrotropic hormone in the peripheral blood of white rats are studied in an experiment with the administration of a thyrostatic drug (merkazolil) in an optimally allowable daily dose. A high reliability of the mathematical model developed for reproducing the level of the content of hormones of the hypophysial-thyroid system is established.

Hyperthyroidism in TSH-producing hypophyseal adenoma

For 5 years a 59-year-old man had been treated with thyrostatic drugs for hyperthyroidism of unknown aetiology. As he had been losing weight, computed tomography had been performed in the search for a malignancy. It revealed a hypophyseal space-occupying lesion. Peripheral thyroid hormone activities were raised, while thyroid-stimulating hormone (TSH) was also raised to 12.4 mU/l and there was evidence of partial hypophyseal insufficiency. Octreotide scintigraphy demonstrated increased activity in the area of the hypophysis. The transsphenoidal surgery and immunohistochemical tests confirmed the diagnosis of TSH-producing hypophyseal adenoma. The patient became euthyroid after the operation. TSH-producing hypophyseal adenoma should be considered as a rare cause of hyperthyroidism when it is combined with non-suppressed TSH.

Thyroid gland development and defects

During the functional ontogenesis of the thyroid gland an increasing number of transcription factors play fundamental roles in thyroid-cell differentiation, maintenance of the differentiated state, and thyroid-cell proliferation. The early growth and development of the fetal thyroid appears to be generally independent of thyroid-stimulating hormone (TSH). TSH and thyroxine (T4) levels increase from the 12th week of gestation until delivery, whereas triiodothyronine (T3) levels remain relatively low. At birth, a cold-stimulated short-lived TSH surge is observed, followed by a TSH decrease until day 3 or 4 of life by T4 feedback inhibition. Disorders of thyroid gland development and/or function are relatively common, affecting approximately one newborn infant in 2000-4000. The most prevalent disease, congenital hypothyroidism, is frequently caused by genetic defects of transcription factors involved in the development of the thyroid or pituitary gland. A major cause of congenital hyperthyroidism is the transplacental passage of stimulating thyrotropin antibodies from the mother to the fetus. Hypothyroxinaemia or hypotriiodthyroninaemia is frequently observed in preterm infants with or without severe non-thyroidal illness. Whereas congenital hypo- and hyperthyroidism may be treated successfully with T4 or thyrostatic drugs, there is still insufficient evidence on whether the use of T4 for treatment of the latter condition results in changes in neonatal morbidity or reductions in neurodevelopmental impairment.

Graves' disease and radioiodine therapy

This study was performed to analyse the impact of the choice of antithyroid drugs (ATD) on the outcome of ablative radioiodine therapy (RIT) in patients with Graves' disease. A total of 571 consecutive patients were observed for 12 months after RIT between July 2001 and June 2004. Inclusion criteria were the confirmed diagnosis of Graves' disease, compensation of hyperthyroidism and withdrawal of ATD two days before preliminary radioiodine-testing and RIT. The intended dose of 250 Gy was calculated from the results of the radioiodine test and the therapeutically achieved dose was measured by serial uptake measurements. The end-point measure was thyroid function 12 months after RIT; success was defined as elimination of hyperthyroidism. The pretreatment ATD was retrospectively correlated with the results achieved. Relief from hyperthyroidism was achieved in 96% of patients. 472 patients were treated with carbimazole or methimazole (CMI) and 61 with propylthiouracil (PTU). 38 patients had no thyrostatic drugs (ND) prior to RIT. The success rate was equal in all groups (CMI 451/472; PTU 61/61; ND 37/38; p = 0.22). Thyrostatic treatment with PTU achieves excellent results in ablative RIT, using an accurate dosimetric approach with an achieved post-therapeutic dose of more than 200 Gy.

Unambiguous identification of thiouracil residue in urine collected in non‐treated bovine by tandem and high‐resolution mass spectrometry

Thyrostats are banned compounds in Europe since 1981 (directive 81/602/EC) because of their carcinogenic and teratogenic properties. However, the occurrence of thiouracil (TU) in bovine urines from national monitoring plans with quantifications in the range 1-10 microg . L(-1) occasionally raises the question of its origin which might either be the consequence of an illegal administration or the result of 'endogenous' production. In order to definitively and unambiguously identify the so-called thiouracil signal in non-treated bovine urines, independent mass spectrometry (MS) approaches have been used. Different reagents (3-IBBr, 3-BrBBr and PFBBr) were used to derivatise and to extract TU from urine samples and characterisation of the residues was performed by means of different MS approaches [LC/(ESI-)MS/MS, GC/(EI+)MS/MS and HRMS (EI and NCI)]. These combined strategies allowed for an independent and confident identification of TU in bovine urine samples collected from animals never treated with any thyrostatic drugs. This result is of prime importance for laboratories and risk managers involved in the field of forbidden growth promoters control: detection of TU residue in bovine urine will have to be carefully considered as a non-systematic proof of illegal administration.

Therapiebedingte Veränderungen der Schilddrüse

Therapy related alterations to the thyroid gland are associated with more or less specific morphological changes. The therapy (thyrostatic drugs, radio-iodine) may be administered for the treatment of thyroid dysfunction (hyperthyroidism), or the thyroid gland is involved during or after the treatment (irradiation, various drugs) of primarily non-thyroid related diseases. The present review summarizes the most important morphological changes related to therapy.

High pre-therapy [99mTc]pertechnetate thyroid uptake, thyroid size and thyrostatic drugs: predictive factors of failure in [131I]iodide therapy in Graves' disease

Several factors may interfere with the success rate of radioiodine therapy (RIT) in Graves' disease. Our aim was to evaluate, retrospectively, some of these factors in the outcome of RIT. Patient gender, age at diagnosis, ophthalmopathy, disease duration, thyroid size, drug used as clinical treatment, thionamide withdrawal period during RIT preparation, FT4, TSH and [99mTc]pertechnetate thyroid uptake prior to RIT were studied as potential interference factors for RIT success. Eighty-two Graves' disease patients were submitted to RIT after thionamide treatment failure. Prior to RIT, 67 patients were receiving methimazole and 15 propylthiouracil. Thirty-three patients received thionamides during RIT; in 49 patients the medication was withdrawn for 2-30 days. [99mTc]pertechnetate thyroid uptake was determined before RIT. Fixed doses of 370 MBq of [131I]iodide were administered to all patients. Eleven patients became euthyroid; 40 became hypothyroid and 31 remained hyperthyroid. There was no association between outcome and age at diagnosis, gender, ophthalmopathy, pre-RIT FT4, TSH, antithyroid antibodies or thyrostatic drug. Multiple logistic regression showed higher probability of treatment success in patients with thyroid mass <53 g (odds ratio (OR)=8.9), with pre-RIT thyroid uptake <12.5% (OR=4.1) and in patients who withdrew thionamide before RIT (OR=4.9). Fixed doses of 370 MBq of radioiodine seem to be practical and effective for treating Graves' disease patients with [99mTc]pertechnetate uptake <12.5% and thyroid mass <53 g. This treatment is clearly not recommended for patients with large goitre. In contrast to what could be expected, patients with a high pre-RIT thyroid uptake presented a higher rate of RIT failure.

Biochemical Mechanisms of Thyroid Hormone Deiodination

Deiodination is the foremost pathway of thyroid hormone metabolism not only in quantitative terms but also because thyroxine (T(4)) is activated by outer ring deiodination (ORD) to 3,3',5-triiodothyronine (T(3)), whereas both T(4) and T(3) are inactivated by inner ring deiodination (IRD) to 3,3',5-triiodothyronine and 3,3'-diiodothyronine, respectively. These reactions are catalyzed by three iodothyronine deiodinases, D1-3. Although they are homologous selenoproteins, they differ in important respects such as catalysis of ORD and/or IRD, deiodination of sulfated iodothyronines, inhibition by the thyrostatic drug propylthiouracil, and regulation during fetal and neonatal development, by thyroid state, and during illness. In this review we will briefly discuss recent developments in these different areas. These have resulted in the emerging view that the biological activity of thyroid hormone is regulated locally by tissue-specific regulation of the different deiodinases.

Withdrawal of the Parenterally Applicable Form of Thyrostatic Drugs in Austria; Comparative Modeling of the Thyrotropin Receptor

Withdrawal of the Parenterally Applicable Form of Thyrostatic Drugs in Austria; Comparative Modeling of the Thyrotropin Receptor