Changes in iodine mapping in rat thyroid during the course of iodine deficiency: imaging and relative quantitation by analytical ion microscope

The analytical ion microscope (AIM) makes possible imaging and relative quantitation of multiple stable or labeled elements on an even tissue section, according to their mass. The purpose of this work was to follow at the rat thyroid follicle level the changes in 127I mapping during low iodine diet (LID) in relation to the ability of thyroid to pick up radioiodine (129I) and to synthesize Tg from its precursor, 2H-labeled leucine. The overall picture of images and countings of 127I shows a progressive decrease of the luminal iodine concentration which on day 80 was 10-fold lower than that of control value. In control rat thyroid cell, concentration was 10-fold lower than that of follicular lumina and was unchanged until 35 days, but the size of the cytoplasmic compartment increased, suggesting a redistribution of iodine stores between thyroid cells and follicular lumina. 129I was always found in colloid as well as in cells at all stages. After 35 days of LID, cytoplasmic and luminal radioiodine concentrations decreased. In control rats, [2H]leucine was found mainly in the cells. During LID its localization was evidenced progressively in most of the lumina. The most striking fact was the presence up to 35 days of some large residual follicles with high 127I concentration and low 129I and 2H incorporation. These data demonstrate the follicular heterogeneity of thyroid response to progressive chronic TSH stimulation induced by LID.     

Microscopic distribution of iodine radioisotopes in the thyroid of the iodine deficient new-born rat: insight concerning the Chernobyl accident.

Thyroid cancer markedly increased in children exposed to iodine radioisotopes following the Chernobyl accident. This increase exceeded predictions based on dose estimates to the whole organ. We sought to investigate whether iodine deficiency may have influenced the pattern of microscopic distribution of radioiodines, which may be important to interpretation of the observed effects. Iodine-deficient new-born rats were injected with iodine-129 (129I) and the microscopic distribution in the thyroid tissue was studied at 24 hr and at one week after administration, using secondary ion mass spectrometry (SIMS). Twenty-four hr after administration, SIMS images showed large differences in 129I uptake among thyroid follicles, with more than a factor ten variation in the local concentration. In addition, the distribution of 129I inside follicles varied with time. At 24 hr, the highest concentration was found at the periphery of the colloid, close to the thyroid cells. There also was enhanced concentration of 129I at one pole of follicles. Distribution inside follicles was homogeneous at 7 days. Conclusions: 1/Dosimetric models, which assume uniform iodine uptake by thyroid follicles, give an oversimplified picture of radiation dosimetry in cases involving iodine deficiency, which induces patchy tissue irradiation. 2/The dynamic pattern of iodine distribution within thyroid follicles suggests that decay events from short-lived iodines will occur closer to thyroid cells than events resulting from iodine-131.     

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.     

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.     

Iodine-129 measurements in soil samples from Dolon village near the Semipalatinsk nuclear test site

Dolon village, located about 60 km from the border of the Semipalatinsk nuclear test site, is known to be heavily contaminated by the first USSR atomic bomb test in August 1949. Soil samples around Dolon were taken in October 2005 in an attempt to evaluate internal thyroid dose arising from incorporation of radioiodine isotopes (mainly (131)I). Iodine-129 in soil was measured by using the technique of accelerator mass spectrometry. The (129)I/(127)I atom ratios measured were in the range from 3.3 x 10(-9) to 3.3 x 10(-7). These values were within the range of the current background level ( approximately 10(-9) to 10(-7)) in the environment, including contributions from the global fallout of atmospheric nuclear tests and local fallout of nuclear facilities. The (129)I atom accumulated level in soil ranged from 1.28 x 10(13) to 1.59 x 10(14) atoms m(-2), the average (8.0 x 10(13)) of which was higher than the background level of (2-5) x 10(13). From the relationship between (129)I and( 137)Cs (corrected for background and decay from 1949 to 2005) accumulated levels, the background level of (129)I and the (129)I/(137)Cs ratio around Dolon were estimated to be (6.4 +/- 0.4) x 10(13) atoms m(-2) and 0.25 +/- 0.16, respectively. This (129)I/(137)Cs ratio is almost similar to the fission yield ratio for (239)Pu fast fission (0.24).     

Kinetic study of the distribution of stable iodine and radioiodine in the thyroid vesicle and cell using analytical ionic microscopy

Images of the distribution of 127I and 129I have been obtained by means of SIMS, in Mouse thyroid gland, after tracer injection. Profiles analysis performed on 60 microns area express the relative amount of iodine in thyroid vesicles. Isotopic ratio show a large discrepancy from a follicle to an other which is in situ in agreement with the functional heterogeneity of the gland. The interest of the method to study the kinetics of iodine pools is discussed.     

Radioiodine (131I) therapy of Graves' disease: use of the new high resolutional ultrasonic scanner for the determination of the accurate weight of the thyroid gland

In this series, eighteen patients with Graves' disease were treated with 8000 rads (80 Gy) of radioiodine (131I), using the new high resolutional ultrasonic scanner for the determination of the accurate weight of the thyroid gland. The mean dose of radioiodine administered orally was 4.6 +/- 3.0 mCi (170.2 +/- 110.0 MBq) and 133.7 +/- 44.6 microCi/g (4.95 +/- 1.65 MBq). At one year after treatment, twelve of eighteen patients (66.7%) became euthyroid, five (27.8%) remained hyperthyroid and one (5.6%) became hypothyroid. Analysis of various factors which may be related to the effect of radioiodine therapy revealed that the weight of the thyroid gland in the hyperthyroid and euthyroid groups was significantly different (61.7 +/- 33.5 g vs. 25.1 +/- 9.1 g, p less than 0.05). Furthermore, all patients with larger glands (more than sixty grams) remained hyperthyroid, while the incidence of euthyroidism was as high as 80% in patients with smaller glands (less than forty grams). Although the number of patients studied was small, these results indicate that a larger thyroid gland requires a larger radioiodine dose per gram of tissue than a smaller gland, suggesting that the therapeutic radiation dose should be graded according to the gland size even when the gland size is accurately estimated by ultrasound. Further study is required to determine the appropriate radiation dose graded according to the gland size.     

Acute effects of various doses of iodide on thyroid iodine autoregulation

Analytical ion microscopy (AIM) was used to determine alterations in the thyroid follicular lumen¹²⁷I stores of Wistar rats injected with different doses of¹²⁹I (low specific activity radionuclide). Animals fed a normal iodine diet (10 μg¹²⁷I/d) were divided into four groups: control group and three treated groups injected ip 24 h before sacrifice with¹²⁹I at doses of 10 μg (group 1), 30 μg (group 2), and 8500 μg (group 3). AIM was performed on thyroid semithin sections. The mean¹²⁹I concentration increased with the dose injected from group 1 (0.44±0.03 μg/mg, mean ± SEM) to group 2 (2.05±0.14 μg/mg) and decreased in group 3 (0.57±0.08 μg/mg). When compared to control group (4.14±0.17 μg/mg), the mean¹²⁷I concentration was not changed in group 1 (4.52±0.07 μg/mg), but altered in the other groups: It was significantly increased (7.14±0.41 μg/mg) in group 2 and slightly decreased (3.11±0.26 μg/mg) in group 3. These results underline the interest of AIM in the study of the effects of various doses of iodide on the thyroid autoregulation by iodide, a trace element actively trapped by this gland.     

SIMS evidence that carbimazole enhances spatial heterogeneity of thyroid iodine storage and targeting in a woman with Graves' disease.

Antithyroid drugs (ATD) are known to reduce 131I efficacy in thyrotoxicosis, though the underlying mechanism remains misunderstood. To study the impact of long term administration of carbimazole on both iodine stores (127I, secondary ion mass spectrometry microscopy) and targeting (125I, radioautography) at the intraglandular level in a woman who underwent surgery for Graves' disease. 125I distribution was dramatically heterogenous and large areas of the sample appeared poorly or no stained at all. This may correspond to flat follicles, hypofunctioning or ATD blocked ones and to the various histological changes related to the thyroiditis. SIMS counting showed huge variations of the interfollicular iodine stores (0 to 1.18 microg/mg) and lower mean values than those observed in nodular goiters. SIMS imaging depicted iodine free areas and others with preserved thyroglobulin synthesis, as assessed via 32S- mapping, but low to undetectable 127I, suggesting focal organification defects. Since ATD reduce iodine storage and uptake capabilities and enhance the iodine heterogeneity of interfollicular targeting, a related enhancement of the spatial 131I dose distribution is unavoidable. ATD may reduce 131I efficacy by variably reducing the number of follicles which can be actually or significantly targeted, e.g. irradiated (antirecruitement effect).     

Thyroid morphological and functional heterogeneity: impact on iodine secretion

Thyroid iodine turnover heterogeneity includes morphological (cellular and colloidal distribution space for iodide) and functional heterogeneity (hormone synthesis in the colloid). In 'normal' rats, both iodide actively trapped by the epithelial cell and that coming from deiodination of iodotyrosines present the same probability for thyroglobulin (Tg) iodination (Tg iodination flux: 4.0 +/- 0.3 micrograms I/day). A portion of the thyroid iodide is sequestered in the colloid lumen and is inoperative in the Tg iodination mechanisms. The masses of cell and colloid compartments are equivalent (0.018 +/- 0.002 micrograms I) while colloid iodide concentration is twice that of the cell (0.11 and 0.06, respectively). The turnover of about 3 micrograms I of colloid iodine (Tg) is follicle diameter-dependent (inter-follicular heterogeneity) and it is mainly characterized by 2 different half lives of 8 and 16 hours, respectively. Ninety percent of the thyroid iodine (hormone) secretion (1.10 +/- 0.11 micrograms I/day) is provided by this compartment rich in iodotyrosine residues (70%). The remaining 10% of iodine secretion is provided by a Tg pool (7 micrograms I) characterized by 2 compartments (intra-follicular heterogeneity) with slow and very slow turnovers. The longer the transit time of Tg molecules in the colloid, the higher their iodothyronine content.     

The early treatment results of well differentiated thyroid cancer and its dependence on chosen factors

INTRODUCTION: The aim of the study was to estimate the influence of a thyroid remnants' volume, postsurgical concentration of thyroglobulin and radioiodine dose on the early treatment efficacy of well differentiated thyroid cancer. MATERIAL AND METHODS: We retrospectively analyzed 91 patients (76 females, 15 men) with well differentiated thyroid cancer. RESULTS: Histological classification revealed 68.1% (62/91) papillary thyroid cancers, 25.3% (23/91) follicular thyroid cancers, and 6.6% (6/91) oxyphilic thyroid cancers. Among the group, 74 (81.3%) patients reached the remission criteria and the remaining 17 patients (18.7%) showed biochemical and morphological evidence of metastatic disease. The remission was obtained in 100% of patients in stage I of the disease, 68.4% - in stage II, 78.6% - in stage III and 33.3% in stage IV. The total radioiodine dose used in patients with remission, did not differ from the dose used in patients without remission. We did not observe the influence of remnant's volume on treatment efficacy, however larger remants required higher dose of radioiodine to obtain the remission. Patients with remission had lower postsurgical thyroglobulin concentration than patients without remission. (22.2 vs. 103.3 ng/ml; p = 0.00025). CONCLUSIONS: Early treatment results of well differentiated thyroid cancer depend on the clinical stage, and postoperative serum thyroglobulin level measured after endogenous TSH stimulation. Early treatment results are not dependent on age, sex, histological type of thyroid cancer, the dose of radioiodine used in brackets of 60-150 mCi and additional diseases. Total thyroidectomy is equally efficient as near total.     

A new conjugating agent for radioiodination of proteins: low in vivo deiodination of a radiolabeled antibody in a tumor model

A new radioiodinating agent, N-(p-[125I]iodophenyl)maleimide, has been synthesized for its potential utility in the radioiodination of monoclonal antibodies and other proteins. The efficiency of incorporation of 125I in the B72.3 antibody by iodine monochloride iodination or by maleimide conjugation was 19% and 43%, respectively. The thyroid uptake following intraperitoneal administration of the two 125I-labeled antibody preparations was evaluated in nude mice implanted with LS174T colon carcinoma xenografts. The iodine monochloride preparation showed substantially greater uptake in the thyroid with values of 2.1% ID at 6 h after injection and reaching a maximum of 4.3% ID after 6 days. In contrast, the maleimide preparation showed a uniformly low uptake in thyroid of 0.1%-0.2% ID. The results of these preliminary studies demonstrate that the N-(p-[125I]iodophenyl)maleimide-labeled monoclonal antibodies showed markedly less (less than 10-fold) uptake of radioiodine in the thyroid, indicating significantly less in vivo deiodination than iodine monochloride-labeled monoclonal antibodies, while retaining some tumor localization in vivo. Studies are in progress to optimize N-(p-[125I]iodophenyl)maleimide radioiodination conditions and to improve the tumor localization.     

The treatment of multinodular large non-toxic goiter using repeated doses of radioiodine (preliminary report)

INTRODUCTION: The aim of study was to establish the effectiveness of radioiodine therapy using 131I in the group of patients with multinodular large non-toxic goiter. MATERIAL AND METHODS: Therapy was undertaken in female patients disqualified from surgery due to high risk and these patients who didn't agree to surgery. Studies were performed in 7 women (age range: 62-82 yrs) with large goiters (2nd degree according to WHO classification and goiter volume assessed by USG over 100 cm(3)). Serum TSH, fT4, fT3, antithyroid antibodies (TPOAb, TgAb, TRAb) levels, urinary iodine concentration (UIE) were estimated in all patients parallel with radioiodine uptake test (after 5 and 24 hours), 131I thyroid scintigraphy and fine needle biopsy to exclude neoplasmatic transformation. These studies and therapy with 22 mCi 131I were repeated every 3 months. RESULTS: Before therapy median thyroid volume was approximately 145 cm(3) and during therapy gradually decreased to 76 cm(3) after 6 months and to 65 cm(3) after 12 months. Increase of TRAb can be a inhibiting factor of thyroid volume reduction. Other antithyroid antibodies showed marked tendency to rise but without significant correlation with radioiodine uptake and goiter reduction. After 12 months we found 2 patients with clinical and laboratory hypothyroidism. CONCLUSIONS: In some cases of multinodular large non-toxic goiter, the radioiodine therapy can be the best alternative way for L-thyroxine treatment or surgery therapy. The fractionated radioiodine therapy of multinodular large non-toxic goiter is safe and effective method but continuation of nodules observation is necessary.     

Uptake and distribution of radioiodine, and the effect of ambient nitrate, in some fish species

125I uptake by the thyroid was most pronounced in the smelt (Osmerus eperlanus), perch (Perca fluviatilis), rainbow trout (Salmo gairdneri), roach (Rutilus rutilus) and bleak (Alburnus alburnus). Unlike other tissues, only the muscle in the species studied no relative accumulation of 125I as compared to the ambient water. The Crusian carp (Cyprinus carassius) indicated the lowest levels of accumulation of 125I among the species tested. Thyroid radioiodine concentration was independent of the length of the fish in the rainbow trout and perch. In the rainbow trout, however, the liver and muscle radioiodine concentrations decreased significantly with increasing length of the fish. Exposure of rainbow trout to water containing supranormal concentration of nitrate (1500 micrograms/l) resulted in lowered 125I uptake. The same phenomenon was observed for the perch and Crusian carp, with low nitrate concentrations, while with higher nitrate concentrations, the uptake levels were again increased. Thyroid function, as judged from the conversion ratio and T/S ratio, was not affected by nitrate.     

Localization of radiolabeled monoclonal antibodies in thyroid tumor xenografts

Monoclonal antibodies to human thyroglobulin were produced using the hybridoma technique. Two monoclonal antibodies D5I and F9I were radiolabeled with 125I and used for radioimmunolocalization studies in an immunosuppressed animal model bearing xenografts of human thyroid tumor tissue. Biodistribution studies were carried out at various time intervals post-injection. Maximum tumor uptake was obtained at 72 hr after administration of the antibodies. The absolute tumor uptake (ATU) expressed as percentage of injected dose per gram of tissue (% ID/g) was 15.49 +/- 2.47, 4.51 +/- 0.69 and 2.50 +/- 0.41 for D5I, F9I and control Igs respectively. The tumor to blood ratios (T/B) obtained were 3.01 +/- 0.43 for D5I, 0.98+/-0.2 for F9I and 0.47 +/- 0.12 for control Igs. ATU as well as T/B ratio obtained with D5I was significantly higher as compared to F9I and control Igs. The results indicated the potential application of radiolabeled monoclonal antibodies to human thyroglobulin for tumor targetting in patients of differentiated thyroid carcinoma, particularly those metastases which did not concentrate radioiodine.     

Basal and induced micronucleus frequencies in human lymphocytes with different GST and NAT2 genetic backgrounds

Basal and induced frequencies of genetic damage can be modulated by different host factors, including genes involved in phase II metabolism. Since polymorphic variants in the glutathione S-transferase (GST) and N-acetyl transferase (NAT) genes have been associated with cancer risk, we explored the possible links between GSTM1, GSTP1, GSTT1 and NAT2 variants and the frequency of micronuclei (MN) in human lymphocytes. This exploratory study was carried out in 30 thyroid cancer patients, before and after receiving an average dose of 109.9+/-1.3 mCi radioactive iodine as a co-adjuvant therapy. The results indicate that none of the polymorphisms studied show any kind of association with the basal level of micronuclei. When the same patients were followed after radioiodine exposure, a significant increase in the frequency of MN was observed in practically all of them (28/30), indicating the genotoxic activity of the ionising radiation exposure. The increase in MN frequency was not associated with any of the GST polymorphisms evaluated. Nevertheless, the presence of slow acetylator phenotypes and, in particular, the presence of the NAT2*7 allele was significantly associated with a lower increase of the MN frequency after radioiodine treatment.     

Cholinergic and VIPergic effects on thyroid hormone secretion in the mouse

The thyroid gland is known to harbor cholinergic and VIPergic nerves. In the present study, the influences of cholinergic stimulation by carbachol, cholinergic blockade by methylatropine and stimulation with various VIP sequences on basal, TSH-induced and VIP-induced thyroid hormone section were investigated in vivo in mice. The 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 inhibited by both carbachol and methylatropine. Furthermore, TSH-induced radioiodine secretion was inhibited already by a low dose of carbachol. Moreover, a high dose of carbachol could inhibit VIP-induced radioiodine secretion. Methylatropine did not influence TSH- or VIP-stimulated radioiodine secretion, but counteracted the inhibitory action of carbachol on TSH- and VIP-induced radioiodine release. In addition, contrary to VIP, six various synthesized VIP fragments had no effect on basal or stimulated radioiodine release. It is concluded that basal thyroid hormone secretion is inhibited by both cholinergic activation and blockade. Furthermore, TSH-induced thyroid hormone secretion is more sensitive to inhibition with cholinergic stimulation than is VIP-induced thyroid hormone secretion. In addition, the VIP stimulation of thyroid hormone secretion seems to require the full VIP sequence.     

Radioiodine: Biokinetics,mean dose and dose distribution

Summary For the radioiodine isotopes I-123, I-125, I-131, and I-132 the mean tissue dose and local dose distribution in the epithelial cells of a follicle have been calculated and compared to each other. Moreover, dose factors have been estimated for I-131 as a function of age considering age-dependent ingestion (milk consumption) and inhalation rates. Thereby, besides age-dependent biological half-times and thyroid masses, the thyroidal iodine uptake was assumed to be independent from age and taken to be about 1.7 the normal for an insufficient dictary iodine intake as in the Federal Republic of Germany.     

Obituaries

The outcome in 110 patients first treated with radioiodine (mean dose 6.56 mCi) for hyperthyroid Graves'' disease in 1980 was reviewed. In 23% of the patients the disease had not been controlled by the initial dose after 3 months, and 17% were given one or two more doses. Within 2 years 65% of the patients required replacement thyroxine therapy. Although about half of the patients were biochemically hypothyroid 3 months after the last dose of iodine 131, this condition was transient in a third of them; five of these patients even became hyperthyroid again. Patients with transient, as opposed to permanent, hypothyroidism at 3 months tended to be clinically euthyroid but to have residual palpable thyroid tissue and only a modest reduction in the serum thyroxine level. It is therefore recommended that patients not overtly hypothyroid 3 months after treatment with 131I be observed still longer before thyroxine replacement therapy is instituted.     

Effects of different batches of 125iodine on properties of 125I-hFSH and characteristics of radioligand-receptor assays

Radioiodination of highly purified human follicle-stimulating hormone (hFSH) (4000 IU/mg) was performed every other week for 23 weeks using 2 mCI carrier free Na125I (Amersham Corp., 15 mCi/micrograms I2) in the presence of lactoperoxidase. Incorporation of 125I into hFSH was determined by the method of R. C. Greenwood, W. M. Hunter, and J. S. Grover (1963) Biochem. J. 89, 114). Hormone binding was studied in vitro under steady-state conditions (16 h, 20 degrees C) using different calf testis membrane preparations having similar receptor characteristics. Each 125I-hFSH preparation was characterized for maximum bindability, specific activity of bindable radioligand as determined by self-displacement analysis, and by determination of Ka and Rt. Incorporation of 125I into FSH was relatively constant over the large number of experiments (62.4 +/- 6.4 microCi/micrograms; n = 23). By comparison, however, specific radioactivity of the receptor bindable fraction of 125I-hFSH was related to the lot of 125I utilized, and was significantly (P less than or equal to 0.01) lower and more variable (28.7 +/- 10.5 microCi/micrograms). Maximum bindability of 125I-hFSH was not correlated to specific activity (r = 0.06) but was negatively correlated to hFSH 125I incorporation (r = -0.47; P less than or equal to 0.05). These observations demonstrate the need to assess the quality of each batch of radioligand before undertaking radioligand-receptor assays and suggest that differences in Na125I lots affect specific radioactivity of the radioligand and its receptor binding characteristics.