Epidemiologic foundation for population studies of program MZ-XVII]

Epidemiological foundation included: aim of studies, knowledge about epidemiology of thyroid disorders in Poland, evaluation of radioiodine dose accumulated in thyroids of inhabitants of different age living in different par of Poland, information about relative diet iodine deficiency in different parts of Poland and identification of research teams (manpower) capable to carry on population studies. The final identification of epidemiological foundation was proceeded by pilot studies performed in 4 different regions of Poland. Finally it was decided that population studies would be performed in so called Regions of 6 different University Medical Schools (Bia?ystok, Kraków, Lód?, Poznań, Szczecin, Wroc?aw). The sample will be selected randomly on the base of information from the voting lists (random selection of vovoidoship, then towns and villages, then streets and number of houses, then number of flats. All living in selected flat or house during Czernobyl accident and born between January 1974 and December 1985 (children) and between January 1926 and December 1973 (adults) will be considered "the sample". In all cases the sample will be examined by means of unified questionnaire and protocol of medical and laboratory examination. The same kits (of the same producers) will be used to evaluate serum TSH, T4, T3 and thyroid autoantibodies. The data obtained will be evaluated by unified computerized system. Separate studies involved the sample of newborns exposed to radioiodine during last trimester of pregnancy, found to be euthyroid and given potassium iodide in first days of life. Separate system was also used to investigate effect of radioiodine and of prophylactic dose of potassium iodide in those with past history of thyroid disorders.     

Results of studies performed with the MZ-XVII program on a national scale; summary and conclusions]

MOST IMPORTANT OBSERVATIONS: (FROM COUNTRY-WIDE POPULATION STUDIES) 1. In some voivodships localized in south-east and north-east parts of Poland thyroids of young children would, without protective measures, accumulate more then 60 MsV of radioiodine, thus exceeding intervention level settled for the country. 2. Thyroid function of newborns exposed to radioiodine during neonatal life was normal and frequency of neonatal hypothyroidism similar to that seen in years before Czernobyl accident. 3. Potassium iodide administrated to newborns in some of them profuced transient rise of TSH (Wolff-Chaikoff phenomenon), thus suggesting, that ki dose settled for newborns could be to high. 4. Thyroid radioiodine dose accumulated in thyroids of older children, teenagers and adults was in majority of regions well below the dose of 50 MsV. 5. The frequency of non-toxic diffuse goiter, especially in traditional endemic goiter area was found to be high, but is also relatively high in others regions of Poland and seems to depend on iodine deficiency or relative iodine deficiency. 6. The frequency of other thyroid disorders is within the limit reported in countries with relative iodine deficiency. 7. More than 95% of children and teenagers took protective, single dose of potassium iodide (about 10 millions). 8. Approximately 27% of adults took protective dose of potassium iodide (about 7 millions). 9. Organization of protective action in 11 north-east and south-east voivodoships was good about 75% of all obtain ki solution within 24 hours. In the rest of the country where protective action was ordered april 30, in afternoon hrs only about 25% obtained ki the same day and the rest during next 48-72 hrs. 10. The fact that prior to the protective action limited number of children was given iodine alcohol solution permitted for external use speaks about the fear and panic observed in Poland in first days after Czernobyl accident. 11. Extrathyroidal side-effects after ki administration appeared in about 5% were usually light or moderate and in majority of cases disappearing without medical assistance. Vomiting was most commonly seen side-effect in young children, thus suggesting that either dose, or the chemical form of the drug for this group of age was unproper. 12. Intrathyroidal side-effects of single dose of ki was rare phenomenon seen mostly in newborns, very young children and some adults with history of thyroid disease in the past. 13. Its possible that even small dose of radioiodine accumulated in thyroid produce immunological response leading to the appearance of thyroid antibodies in blood serum.     

From the molecular characterization of iodide transporters to the prevention of radioactive iodide exposure

In the event of a nuclear reactor accident, the major public health risk will likely result from the release and dispersion of volatile radio-iodines. Upon body exposure and food ingestion, these radio-iodines are concentrated in the thyroid, resulting in substantial thyroidal irradiation and accordingly causing thyroid cancers. Stable potassium iodide (KI) effectively blocks thyroid iodine uptake and is thus used in iodide prophylaxis for reactor accidents. The efficiency of KI is directly related to the physiological inhibition of the thyroid function in the presence of high plasma iodide concentrations. This regulation is called the Wolff-Chaikoff effect. However, to be fully effective, KI should be administered shortly before or immediately after radioiodine exposure. If KI is provided only several hours after exposure, it will elicit the opposite effect e.g. lead to an increase in the thyroid irradiation dose. To date, clear evaluation of the benefit and the potential toxicity of KI administration remain difficult, and additional data are needed. We outline in this review the molecular characterization of KI-induced regulation of the thyroid function. Significant advances in the knowledge of the iodide transport mechanisms and thyroid physiology have been made. Recently developed molecular tools should help clarify iodide metabolism and the Wolff-Chaikoff effect. The major goals are clarifying the factors which increase thyroid cancer risk after a reactor accident and improving the KI administration protocol. These will ultimately lead to the development of novel strategies to decrease thyroid irradiation after radio-iodine exposure.     

Potassium iodide (KI) to block the thyroid from exposure to I-131: current questions and answers to be discussed

Thyroid cancer in children and adolescents has to be considered as the most severe health consequence of a nuclear reactor emergency with release of radioiodine into the atmosphere. High doses of potassium iodide are effective to block radioiodine thyroid uptake and to prevent development of thyroid cancer years later. However, there are controversies concerning thyroid cancer risk induced by radioiodine exposure in adults. Further, the interaction of nutritional supply of potassium iodide and radioiodine uptake as well as the interaction of radioiodine with certain drugs has not been addressed properly in existing guidelines and recommendations. How to proceed in case of repeated release of radioiodine is an open, very important question which came up again recently during the Fukushima accident. Lastly, the side effects of iodine thyroid blocking and alternatives of this procedure have not been addressed systematically up to now in guidelines and recommendations. These questions can be answered as follows: in adults, the risk to develop thyroid cancer is negligible. In countries, where nutritional iodine deficiency is still an issue, the risk to develop thyroid cancer after a nuclear reactor emergency has to be considered higher because the thyroid takes up more radioiodine as in the replete condition. Similarly, in patients suffering from thyrotoxicosis, hypothyroidism or endemic goitre not being adequately treated radioiodine uptake is higher than in healthy people. In case of repeated or continued radioiodine release, more than one dose of potassium iodide may be necessary and be taken up to 1 week. Repeated iodine thyroid blocking obviously is not harmful. Side effects of iodine thyroid blocking should not be overestimated; there is little evidence for adverse effects in adults. Newborns and babies, however, may be more sensitive to side effects. In the rare case of iodine hypersensitivity, potassium perchlorate may be applied as an alternative to iodine for thyroid blocking.     

Influence of initial large dose on subsequent uptake of therapeutic radioiodine in thyroid cancer patients

Fifty-two patients with differentiated thyroid cancer, following thyroidectomy were studied by administering a quantity of up to 5 mCi of [¹³¹I]sodium iodide. In most of these patients, radioiodine uptake values obtained with the subsequent therapeutic dose were markedly lower than those observed with the initial doses. This observation was verified in seven of the patients with differentiated thyroid cancer, by measuring the radioiodine uptake with a second dose of 4.5 mCi of [¹³¹I]sodium iodide. Calculations showed that the major etiology was probably therapeutic irradiation of the thyroid by the first dose.     

The effect of long-term external ionizing radiation on the functional activity of rat thyroid under enhanced potassium iodide consumption

The study was devoted to the effect of long-term (20 days) external ionizing radiation at a dose of 0.5 Gy on the iodide metabolism in the rat thyroid under supplementation of high iodine doses (10 daily KI doses). It was found that the potassium iodide administration partially prevented the effects of a post radiation decrease of serum thyroid hormone levels (the level of T4 was normal and that of T3 was 77.4% of the controls). After the supplementation of 10 daily iodide doses, the rat thyroid tissue showed the most pronounced increase in the levels of total, free and protein-bound iodide compared to the groups of animals consuming normal and elevated KI doses. Pronounced inhibition of thyroid peroxidase activity (3.1-fold) was noted in the same group. The data obtained indicate a radiation-induced activation of iodide uptake during its enhanced supplementation and disturbed iodide enzymatic oxidation and organification.     

Effects of prophylactic doses of potassium iodide on the course of thyroid diseases (1986-1990) diagnosed due to the atomic accident at Czernobyl in adult patients at the outpatient endocrinologic hospital clinic in Lodz]

2521 patients of the Lód? Outpatient Endocrinological Clinic (2290 females, 231 males; inhabitants of the central region of Poland Lód? City, Lód? Metropolitan Area, Piotrków, P?ock, Sieradz, Skierniewice and W?oc?awek Provinces in which committed dose equivalent to the thyroid was between 2.7-7.0 mSv [min.-max.] in Skierniewice Province and 4.6-11.7 mSv in P?ock Province) were included in the study. The patients were divided into 5 groups: I--persons who did not take the protective dose of potassium iodide (KI) after Chernobyl Nuclear Power Plant accident and did not received any treatment with thyroid preparations or hormones at that time (n = 1282), II--patients who receive KI, once or several times (n = 774), III--patients who took orally iodine tincture or other iodine-containing preparations for the above purposes (n-37), IV--patients who took tablets of Thyroideum (Polfa) Thyroideum siccum (dry thyroid extract), once or several times, as a prophylactic action (n = 79), V--patients who were in the course of continuous treatment with Thyreoideum or thyroid hormones at the time of Chernobyl accident (n = 349). The analysis was performed for all the patients jointly, as well as separately for: either sex, three age groups (18-30, 31-55, 56-70 yrs) and 7 administrative areas specified above. All the patients were subjected into complex clinical examination, serum TSH, T3, T4 concentrations, anti-thyroid membrane antibodies (ATMA) and antithyroglobulin antibodies (ATg) titres, as well as ultrasound, scintigraphy, and fine needle aspiration biopsy of the thyroid (the last two according to indications) included. The patients were also examined by means of a special questionnaire (Patient's Inquiry Sheet), which was subsequently submitted to computer analysis. All the doctors' diagnoses from 1986 (17 different diagnoses) and 1990 (27 different diagnoses), as well as the course of diseases, were verified with use of a specially prepared IBM PC/AT computer program ChernStat.(ABSTRACT TRUNCATED AT 400 WORDS)     

Epidermal growth factor (EGF) inhibits stimulated thyroid hormone secretion in the mouse

It is known that epidermal growth factor (EGF) inhibits iodide uptake in the thyroid follicular cells and lowers plasma levels of thyroid hormones upon infusion into sheep and ewes. In this study, the effects of EGF on basal and stimulated thyroid hormone secretion were investigated in the mouse. Mice were pretreated with 125I and thyroxine; the subsequent release of 125I is an estimation of thyroid hormone secretion. It was found that basal radioiodine secretion was not altered by intravenous injection of EGF (5 micrograms/animal). However, the radioiodine secretion stimulated by both TSH (120 microU/animal) and vasoactive intestinal peptide (VIP; 5 micrograms/animal) were inhibited by EGF (5 micrograms/animal). At a lower dose level (0.5 microgram/animal), EGF had no influence on stimulated radioiodine secretion. In conclusion, EGF inhibits stimulated thyroid hormone secretion in the mouse.     

Effect of long-term injection of high doses of potassium iodide on iodine metabolism in rat thyroid gland

Concentration of thyroid hormones in the serum of the rats after 14-day injections of potassium iodide (1, 3, 10, 100, and 500 physiological daily doses) did not differ from the control values. Excessive administration of potassium iodide increased the total iodide content in the rat thyroid tissue by 60–121% (35–108% and 94–128% for the protein-bound and free iodide, respectively), indicating the activation of the uptake and organification of iodide. The long-term injection of both low and high doses of potassium iodide increased the activity of catalase by 8–18% and SOD by 33–50% and enhanced the level of toxic LPO products reacting with thiobarbituric acid by 15–38%. It is suggested that reactive oxygen species and the excessive iodination of proteins (particularly thyroglobulin) induced by the long-term administration of high doses of potassium iodide can play an important role in the development of thyroid dysfunctions and autoimmune diseases.     

A new method to evaluate the residual activity in patients undergoing 131I thyroid therapy

The radioiodine administration is a standard therapeutic approach to both benign thyroid diseases, such as hyperthyroidism, and carcinomas. The high administered ¹³¹I activities are of radiation protection concern, due to relevant patient residual contamination. The aim of this work was to develop a new procedure based on external radiometric surveys and on a mathematical model in order to estimate the ¹³¹I activity in patients undergoing hyperthyroidism radioiodine therapy.In the first stage of this study, a suitable detector was chosen and its response vs. activity was characterized. The experimental verification was performed measuring the ambient dose equivalent rate from patients receiving radioiodine administration. The results confirm the reliability of the proposed method, as shown by the slight differences between the administered activities and the ones calculated from external measurements. Furthermore, the same procedure was applied to detect the percentage residual activity in patients at two preset time intervals: 4 hours and 4 days after the radioiodine administration. The obtained results clearly highlight that the method can ensure a level of reliability compatible with the radiation protection purposes.     

The perinatal thyroid in iodine deficient regions: risks of radioiodines--hazards of stable iodine overload. A study in the newborn rat.

Administration of large quantities of stable iodine is an effective means of reducing the radiation burden on the thyroid in the event of a nuclear power-plant accident. Such administration may involve countries with low baseline dietary iodine intake. It is questioned whether stable iodine overload is safe, and in particular, what are its effects in newborn infants? Iodine-deficient newborn rats were submitted to a single acute administration of stable iodine (100 microg) on the second day of life. The effects on thyroid structure were studied, after 24 hr and after 7 days, using light microscopy. Compared to controls, the thyroids of animals submitted to stable iodine overload showed, 7 days after treatment, signs of acute toxicity including marked desquamation of epithelial cells and rupture of a large number of thyroid follicles. Our findings in iodine deficient newborn rats suggest that stable iodine overload may have side effects during perinatal life. This prophylactic measure should, therefore, be accompanied by follow-up of thyroid function. Thyroid hormones are critical for brain development, during the first period of life.     

Mammary radioiodine accumulation due to functional sodium iodide symporter expression in a benign fibroadenoma

The sodium iodide symporter (NIS) has been characterized to mediate the active transport of iodide not only in the thyroid gland but also in various non-thyroidal tissues, including lactating mammary gland and the majority of breast cancers, thereby offering the possibility of diagnostic and therapeutic radioiodine application in breast cancer. In this report, we present a 57-year-old patient with multifocal papillary thyroid carcinoma, who showed focal radioiodine accumulation in a lesion in the right breast on a posttherapy (131)I scan following radioiodine therapy. CT and MR-mammography showed a focal solid lesion in the right breast suggestive of a fibroadenoma, which was confirmed by histological examination. Immunostaining of paraffin-embedded tumor tissue sections using a human NIS antibody demonstrated NIS-specific immunoreactivity confined to epithelial cells of mammary ducts. In conclusion, in a thyroid cancer patient we identified a benign fibroadenoma of the breast expressing high levels of functionally active NIS protein as underlying cause of focal mammary radioiodine accumulation on a posttherapy (131)I scan. These data show for the first time that functional NIS expression is not restricted to lactating mammary gland and malignant breast tissue, but can also be detected in benign breast lesions, such as fibroadenomata of the breast.     

Optimization of 131I ablation in patients with differentiated thyroid carcinoma: comparison of early outcomes of treatment with 100 mCi versus 60 mCi

INTRODUCTION: The aim of this study was to compare the early outcomes between two groups of patients with differentiated thyroid carcinoma (DTC) who received 60 or 100 mCi of (131)I for remnant ablation. MATERIAL AND METHODS: 224 DTC patients with primary tumor > 1 cm of diameter or multifocal were randomised into prospective clinical trial. Patients with extrathyroideal extension of primary tumor and nodal metastases or M1 were not enrolled. 99 patients received 60 mCi, and 125--100 mCi of radioiodine as the first ablative dose. RESULTS: The effectiveness of thyroid ablation was evaluated after one year, during endogenous TSH (thyroid stimulating hormone) stimulation, and after two years during Lthyroxine therapy. Whole body scintigraphy (WBS) was performed under thyroxine withdrawal and thyroglobulin serum level was assessed. Distant micrometastases were detected in 9.8% of patients by post-therapy WBS, 11 patients in group A treated with 60 mCi and 11 in group B treated with 100 mCi. In other patients no symptoms of persistent disease were detected. At one year follow up full remission was diagnosed in 176 patients: 76 in group A and 100 in group B. The remaining ones, 13.3% and 11.2% respectively, received the second course of (131)I for remnant ablation. There were no statistically significant differences in Tg (thyroglobulin) serum level either 12 or 24 months after 131I treatment. CONCLUSIONS: Our evaluation of early efficacy of adjuvant radioiodine treatment in low risk DTC patients shows no differences between two radioiodine activities - 60 and 100 mCi in relation to thyroid ablation. Thus, the activity of 60 mCi is recommended.     

Effect of potassium iodide and perchlorate on the process of thyroid hormone secretion]

The influence of potassium iodide and perchlorate on the parameters characterizing the thypoid hormones secretion, such as the cAMP level in the gland tissue and the number of intracellular colloid droplets under condition of stimulation by thyrotropic hormone was studied. It was shown that the abovementioned parameters were depressed by an excess of iodide, but perchlorate administration prevented the inhibitory effect of iodide. The results obtained favour the conception on the sensitivity of the thyroid adenylate cyclase system to the organic iodine concentration. Apparently and excess of iodide depressed the capacity of perchlorate to influence its concentration in the gland, and thereby the process of iodine organification and of the thyroid hormone secretion maintained at the optimal leve.     

The experimental optimization of iodine prophylaxis for decreasing the radiation load from the accidental uptake of radioiodine]

As is proved by nuclear disaster in Chernobyl Nuclear Power Plant (NPP), iodine prophylaxis may be respected as one of the most urgent and effective methods of prevention of radiation injury of the thyroid gland in the population affected. Author has studied factors and methods of its efficacy and reliability. On the basis of experiments in rats, analytical ways of determination of the dietary iodine intake (iodine supply) of people living around NPP Paks (Hungary) as well as compartment modelling, experiments it is shown, that for optimisation of iodine prophylaxis in masses it is very important to increase the iodine supply up to the recommended values. Combined use of decreased doses of potassium iodide and perchlorate was found to be the optimal way for removal of radioiodine from pregnant organisms and their offsprings following accidental intake of radioiodine.     

Long-Term Outcomes of Radioiodine Therapy for Juvenile Graves Disease with Emphasis on Subsequently Detected Thyroid Nodules: A Single Institution Experience from Japan

Objective: To investigate the long-term outcomes of radioiodine therapy (RIT) for juvenile Graves disease (GD) and the ultrasonographic changes of the thyroid gland.Methods: All of 117 juvenile patients (25 males and 92 females, aged 10 to 18 [median 16] years) who had undergone RIT for GD at our clinic between 1999 and 2018 were retrospectively reviewed. Each RIT session was delivered on an outpatient basis. The maximum ¹³¹I dose per treatment was 13.0 mCi, and the total ¹³¹I dose per patient was 3.6 to 29.8 mCi (median, 13.0 mCi). ¹³¹I administration was performed once in 89 patients, twice in 26, and three times in 2 patients. Ultrasonography of the thyroid gland was regularly performed after RIT. The duration of follow-up after the initial RIT ranged from 4 to 226 (median 95) months.Results: At the latest follow-up more than 12 months after RIT (n = 111), the patients' thyroid functions were overt hypothyroidism (91%), subclinical hypothyroidism (2%), normal (5%), or subclinical hyperthyroidism (2%). New thyroid nodules were detected in 9 patients, 4 to 17 years after initial RIT. Patients with newly detected thyroid nodules underwent RIT with lower doses of ¹³¹I and had larger residual thyroid volumes than those without nodules. None of the patients were diagnosed with thyroid cancer or other malignancies during the follow-up period.Conclusion: Over a median follow-up period of 95 months (range, 4 to 226 months), RIT was found to be effective and safe in juvenile GD. However, cumulative evidence from further studies is required to confirm the long-term safety of RIT for juvenile GD.Abbreviations: ATD = antithyroid drug; GD = Graves disease; KI = potassium iodide; LT4 = levothyroxine; MMI = methimazole; PTU = propylthiouracil; RAIU = radio-active iodine uptake; RIT = radioiodine therapy; ^99mTc = technetium-99m; TSH = thyrotropin     

Sodium iodide symporter in physiology and diseases -- the current state of knowledge

The sodium iodide symporter, called also the NIS protein is responsible for iodine trapping to the cell what is significant for the thyroid function. Identified and described for the first time in 1996 NIS protein is the matter of interest of investigators concerning the thyroid physiology and pathology as well as others organs which concentrate the iodine. Existing studies on the sodium iodide symporter include among others: indicating NIS protein expression in the thyroid diseases and extrathyroidal tissues, studying of the NIS antygenicity in the autoimmune diseases of thyroid, finding the molecular aspects of the difference in the NIS protein activity. The sodium iodide symporter is a base of radioiodine therapy of, as for now, thyroid diseases only. Showing NIS protein expression in other cancerous tissues provide a new therapeutic strategy for a variety of human cancers. Additionally, latest explorations indicate at an innovative destination of the studies concerning the sodium iodide symporter that is the gene therapy with the use of gene NIS transfer.     

Estimation of 131I thyroid doses for the evacuees from Pripjat

  The thyroid doses of 49 360 inhabitants of Pripjat evacuated after the accident at Chernobyl were reconstructed. During their evacuation most of the evacuees passed through highly contaminated territories. The evaluation of a large-scale public survey showed that only about 50% of the evacuees had left the contaminated areas within 5 days and that 30% of them stayed there for more than 30 days. As a first step, the model of dose estimations was improved, and thyroid doses were assessed for the group of evacuees for whom the ¹³¹I activity in the thyroids was measured. The ¹³¹I incorporation during the first 5 days after the accident was described by a single-intake model (inhalation); later incorporations were assumed to be proportional to the radioiodine activity in milk. As a second step, the correlation between the calculated doses and individual parameters (place of residence in Pripjat, intake of stable iodine, and age at the time of the accident) was described by an empirical equation. This equation was applied to all evacuees who completed the questionnaires of the public survey. Previous dose assessments were found to overestimate the thyroid doses especially for the younger evacuees. On the basis of these estimations, collective doses and the resulting radiation risks for thyroid cancer were assessed for different age groups. Received: 28 November 1995 / Accepted in revised form: 6 March 1996     

Biological effects of phytoecdysteroids and chronic low-dose irradiation

The influence of serpistene in dose of 5 and 50 mg/kg on chronic low-dose gamma-irradiation (22.6 cGy) effects on cytogenetic (abnormal sperm cell, marrow bone micronucleus) and function and morphology (thyroid and adrenal glands) parameters of mice was estimated. The serpistene modifies effects of gamma-irradiation depends on the administration regime and a dose of the substance. The most expressive radioprotective effect on endocrine organs after serpistene prophylactic administration was found. The prophylactic dose was 5 mg/kg for adrenal gland and both doses--for thyroid gland. The most expressive radioprotective effect on marrow bone cells after serpistene therapeutic administration in a dose of 5 mg/kg was found. The most expressive antimutagenic effect on somatic and germinal cells of prophylactic and therapeutic administration in a dose of 50 mg/kg was found.     

Inhibitory effect of large doses of propylthiouracil and methimazole on an increase of thyroid radioiodine release in response to thyrotropin.

Thyroidal radioiodine release increased shortly after a single injection of small doses of PTU, while moderate doses of MMI produced a similar increase of thyroidal radioiodine release with a latency of 7-9 hr. Large doses of PTU and MMI failed to augment thyroidal radioiodine release for at least 29 to 34 hr after the initial administration of goitrogens, although plasma TSH increased significantly because of goitrogen administration. An increase of thyroid hormone release in response to exogenous TSH was depressed by PTU and MMI in rats and mice treated with T4. Since this depression of TSH action only continued for a short period in spite of continuous administration of goitrogens, and since final thyroidal radioiodine release rate was similar to that produced by small doses of PTU, the effects mentioned were not simply due to general toxic action of goitrogens. It is suggested that large doses of PTU and MMI not only block thyroid hormone synthesis but also interfere with the action of TSH on thyroid hormone secretion.