The Normal Thyroidal Uptake of Iodine

The range of values for the 24-hour thyroidal accumulation of radioactive iodine in euthyroid persons varies with geographic location. In the San Bernardino Valley region of Southern California the “normal range” is 6 percent to 33 percent in euthyroid subjects. This is lower than in studies from other areas of the United States. The urinary iodide excretion and the absolute iodine uptake of the thyroid are higher than in studies from many other areas of the United States, pointing to iodine abundance as the reason for this difference. The geographic variation and the possibility of changing dietary iodine intake of normal persons point to the necessity of current and local determinations of the “normal range” of the thyroidal uptake of radioiodine if the results of this thyroid function test are to be properly interpreted.     

The nature of thyrotropin stimulation of thyroid function in Japanese quail: prolonged thyrotropin exposure is necessary to increase thyroidal 125I uptake

Single injections of thyrotropin (TSH) increase serum T4 and thyroidal 32P uptake but not thyroidal 125I uptake regardless of dosage, exposure time or age. Chronic TSH exposure, with 3 or more days of injection, does increase thyroidal 125I uptake. Studies using iodine (I) supplementation indicated that the increased thyroidal radioiodine uptakes seen with chronic TSH administration were not due to an I deficiency in the thyroid resulting from high hormone release. Labeled and unlabeled experiments comparing the effects of single vs. multiple injections of TSH were used to describe the effects of TSH on hormone release, hormone production and thyroidal I uptake.     

Diurnal rhythms of thyroid hormones in rooster chicks (Gallus domesticus). 1. Studies on the colloid epithelium portion, the radioiodine accumulation in the thyroid gland and the plasma radioiodide concentration]

Four and five week old White Leghorn cockerels were investigated concerning diurnal changes of thyroidal activity. They were kept under normal conditions, including the changes in day light (light from 5.00 am to 8.00 pm). In the thyroid maxima of the per cent amount of colloid were found at 3.00 am and at noon. The values differed significantly from the intermediate ones (2P less than 0.001) which reached only 22 per cent of the maxima. The thyroidal uptake of radioiodine had also a maximum at 3.00 am (51 percent and 78 percent resp., 90 min. or 24 hours p.i.). The 24-h uptake at 3.00 am was significant different from the corresponding uptakes between 6.00 am and 6.00 pm (53-61 percent; 2P less than 0.05). The plasma radioiodide increased at afternoon and in the evening. The 9.00 pm concentration differed significantly from the 9.00 am concentration (2P less than 0.001). Since in the afternoon most of the food is ingested the thyroid can take up a greater amount of untracered iodide and therefore the radioiodide concentration of plasma may remain high. The above observations may be explained in the following way: (1) The thyroidal iodine uptake is increased in the afternoon corresponding to the increase in colloid; however these increase is not detectable by measuring the radioiodine uptake because of dilution effects (during the night the increase in colloid coincidences with the increase in iodine uptake); (2) looking at the daily changes of colloid and radioiodine uptake the thyroid may be stimulated in the early morning and in the evening.     

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.     

Diazepam and Tests of Thyroid Function

The effect of diazepam on thyroid function tests was examined in 12 euthyroid patients requiring the drug for psychiatric reasons and in six patients with thyrotoxicosis. Assessment was made before and after four weeks'' therapy.There was no significant difference in results from tests of thyroid iodide trapping and binding (thyroid radioiodine uptake, thyroid clearance, and absolute iodine uptake) except in the one-hour thyroid uptake in the euthyroid group, which was increased after diazepam. This increase occurred without alteration in serum thyroid stimulating hormone levels. No change occurred in either group in tests of thyroid hormone release (protein-bound iodine, T-3 resin uptake, or Thyopac-3 and free thyroxine index).Patients with suspected thyroid disease who are taking diazepam do not need to stop therapy while their thyroid status is being determined.     

Diurnal rhythms of thyroid hormones in rooster chicks (Gallus domesticus). 2. Studies on the protein-bound radioiodine and the "free" hormone portion]

In four week old cockerels the plasma was investigated for cyclic changes in total radioactivity, PB131I, PI131I, and "free" thyroid hormones 24 hours after injection of Na131I. Maxima in total radioactivity were observed at 3.00 am and 9.00 pm. They were significant different from the minima at noon (2P less than 0.005). At the same points of the day maxima, resp. minima were found in the PB131I and the "free" hormones. The "free" hormones expressed in per cent of total hormones showed low values at 6.00 am, 3.00 pm, and 9.00 pm. The diurnal changes in haematocrit and albumin concentration were not responsible for the variation of PB131I. In order to eleminate effects of isotope dilution by ingested iodine the PB131I was expressed in per cent of total radioactivity of plasma (= conversion rate) or resp. in per cent of thyroidal radioiodine uptake. The obtained values showed maxima at 6.00 am and 9.00 pm. From that we conclude again on a stimulation of the thyroid at these times.     

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.     

Radioactive iodoprotein in thyroid lymph and blood

1. Samples of thyroid and non-thyroid lymph and of thyroid and peripheral venous blood were obtained from primates and cats that had previously been given radioactive iodine. The distribution of the organic radioiodine between the protein and non-protein fractions in these samples was determined. 2. The proportion of the organic radioiodine in the form of iodoprotein was assessed by paper chromatography, acid-ethanol precipitation, hot-butanol washing, column chromatography and separate estimation of iodotyrosines after enzymic hydrolysis. 3. In thyroid lymph the relative proportion of the organic radioiodine in the form of iodoprotein was 75–98%; in blood it was much lower, probably no more than 6–7%. The absolute concentration of iodoprotein radioactivity also was considerably greater in thyroid lymph than in blood. 4. Enzymic hydrolysis of the protein of the thyroid lymph yielded a pattern of iodoamino acids that corresponded closely with that obtained after hydrolysis of protein extracted from the thyroid gland itself. 5. It can be concluded that the iodoprotein in thyroid lymph consists mainly of thyroglobulin or a closely related compound.     

THE USE OF RADIOACTIVE IODINE IN THE TREATMENT OF GRAVES' DISEASE

Fifty patients with uncomplicated Graves'' disease were treated with radioactive iodine (I₁₃₁). Twenty-six patients who were followed for one year or longer are the basis of this report. Twenty-five are now euthyroid; only one is not completely well.The total dose of radioiodine administered varied from 0.5 to 10 millicuries. The average length of time necessary for return to a euthyroid state was from three to four months.Hypometabolism developed in three patients, and in one the signs and symptoms of myxedema developed. No other complications ensued. One patient who apparently relapsed had complete return to normal after further iodine administration.The determination of the uptake of radioactive iodine by the thyroid gland is a useful diagnostic procedure in differentiating conditions simulating hyperthyroidism.Following treatment with radioactive iodine, the thyroid gland becomes smaller, the uptake of iodine by the gland is reduced, and the level of organic iodine in the plasma becomes normal.In acute thyroiditis, in spite of a high basal metabolic rate, high content of organic iodine in the plasma and other evidences of “hyperthyroidism,” the uptake of I₁₃₁ has been very low.     

Effect of methyl thiouracil on radioiodine thyroidal retention in rats

Summary Some goitrogens like methyl thiouracil (MTU) because of their thynamide grouping act as antithyroid drugs inhibiting the organification of iodide, but do not alter the iodide transport. Their administration to an intact animal, therefore, might alter the thyroidal iodine kinetics. Here an attempt has been made to study the effect of MTU on thyroidal iodine kinetics in rats as well as to find out whether any difference in kinetics could be detected between different radioiodines, viz.,¹³¹I,¹²⁵I, and¹²³I. Cumulated thyroidal activity which is a time integral of the activity has been taken as the parameter to represent the sum effect of thyroidal iodine kinetics over a specific time period of interest.From the in vivo thyroidal activity measurements, carried out over extended periods of time, the cumulated activity was calculated for both MTU treated and normal rats that received¹³¹I,¹²⁵I, or¹²³I at different times before the MTU start. Within a day of the start of the MTU there is a rapid loss of thyroidal iodine. The severity of the loss depended upon the time that elapsed between the start of the MTU schedule and the particular radioiodine administered. The absence of isotopic effect on the uptake as well as on the rate of uptake for the three different radioiodine isotopes studied has been brought out.Alexander von Humboldt Fellow, on leave from Institute of Nuclear Medicine and Allied Sciences, Delhi -7, India     

Disturbance of thyroidal iodine metabolism in BB/W rat.

To investigate the thyroid function in Bio-Breeding Worcester (BB/W) rats, we have examined the iodine metabolism, serum TSH and thyroid hormone levels in 8- and 16-week-old BB/W and normal Wistar (W) rats. At 8 weeks of age, serum TSH levels were significantly higher in BB/W rats than in W rats, although there was no difference in the serum levels of free T3 and free T4. Furthermore, the thyroidal radioactive iodine incorporation at 48 h was significantly lower in BB/W rats, suggesting that they might have some defects in iodine organification. At 16 weeks of age, serum TSH levels were also significantly higher in BB/W rats than in W rats. Furthermore, serum TSH levels in 16-week-old BB/W rats were significantly higher than in 8-week-old BB/W rats. The thyroid weight was significantly greater in BB/W rats, probably due to the increased serum TSH. The thyroidal radioactive iodine uptake at 48 h and the iodine content in the thyroid homogenates were significantly lower in BB/W rats. These results suggest that BB/W rats have some defect in iodine metabolism resulting in impaired thyroid hormone synthesis.     

The use of radioactive iodine in the treatment of Graves disease

Fifty patients with uncomplicated Graves' disease were treated with radioactive iodine (I(131)). Twenty-six patients who were followed for one year or longer are the basis of this report. Twenty-five are now euthyroid; only one is not completely well. The total dose of radioiodine administered varied from 0.5 to 10 millicuries. The average length of time necessary for return to a euthyroid state was from three to four months. Hypometabolism developed in three patients, and in one the signs and symptoms of myxedema developed. No other complications ensued. One patient who apparently relapsed had complete return to normal after further iodine administration. The determination of the uptake of radioactive iodine by the thyroid gland is a useful diagnostic procedure in differentiating conditions simulating hyperthyroidism.Following treatment with radioactive iodine, the thyroid gland becomes smaller, the uptake of iodine by the gland is reduced, and the level of organic iodine in the plasma becomes normal. In acute thyroiditis, in spite of a high basal metabolic rate, high content of organic iodine in the plasma and other evidences of "hyperthyroidism," the uptake of I(131) has been very low.     

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.     

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.     

Compartmental models for human iodine metabolism

Compartmental models for the various aspects of human iodine metabolism are reviewed, emphasizing the role of Mones Berman in the development of this field. The review first presents published submodels for the peripheral distribution of inorganic iodine, for the thyroidal iodide trapping function, and for the peripheral distribution and metabolism of the thyroid hormones. Approaches to improving understanding of the physiology of the thyroid gland itself through compartmental modeling techniques are then discussed in more detail. The three submodels described above are incorporated into overall models of thyroid iodine metabolism after being simplified to various degrees. Previously published models for thyroid-gland radioiodine metabolism, as well as current work in progress, are illustrated by attempting to fit the models to data from a single (previously unpublished) detailed prolonged ¹²⁵I feeding experiment in a normal human subject. Published thyroid gland models reviewed include: (1) the usual presentation, where the thyroid is a single homogeneous iodine compartment; (2) the model of DeGroot and colleagues, where thyroidal iodine is presented as MIT, DIT, T3, and T4, each with an active and linked storage compartment; (3) the thyroid model developed by Berman and colleagues, with less chemical subcategorization but incorporating a delay compartment, in which a fraction of the iodinated material in the thyroid is partially or completely inaccessible to secretion during the delay; and the later updating of Berman's model to include a thyroidal iodide recirculation pool. The experimental data presented fits most of these models for the first 1–2 weeks, but the fit could not be extended to longer data collection times. To overcome this shortcoming, a new thyroid gland model is introduced. It is based on the latest Berman model but describes thyroglobulin metabolism as incorporating multiple delay compartments of various time periods. The overall fit of the long term data is better with this model construct than with any of the published models. It appears that a complex thyroidal substructure, such as that of the multidelay model under development, will be required to account for overall thyroid iodine metabolism as isotopic equilibrium in man is approached.     

The snake thyroid gland V. effects of hypophysectomy on iodine metabolism in the striped racer,Elaphe taeniura

Summary Thyroidal iodine metabolism in the hypophysectomized snake,Elaphe taeniura, was examined in vivo and in vitro using¹²⁵I. Hypophysectomy decreased, and TSH increased, both in vivo and in vitro thyroidal accumulation and uptake of radioiodine, and the amount of all labelled substances in the thyroid gland. The operation also altered the distribution of the relative amounts of labelled iodoamino acids in vivo, but not in vitro; nor was there any effect on release of these labelled substances in vitro. In view of the paucity of information available on poikilothermic species, the data are discussed in relation to those of hypothysectomized rats.Abbreviations DIT diiodotyrosine - KRPG Krebs-Ringer-phosphate solution, containing glucose - MIT monoiodotyrosine - PTU propylthiouracil - T ₄ thyroxine - TSH thyroid stimulating hormone     

Thyroidal radioiodine uptake and thyrotropic potency of the pituitary in a freshwater catfish,Mystus vittatus (Bloch), in response to L-thyroxin,antithyroid drugs,and heavy doses of 131I

Summary Experiments were conducted to ascertain the thyroidal ¹³¹I uptake and thyrotropic potency of the pituitary gland in a freshwater catfish, in response to L-thyroxine, antithyroid drugs and heavy doses of radioiodine. L-thyroxine treatments slightly lowered thyroidal radioiodine uptake, and there was at least a trend of lowered TSH content in the pituitaries of these animals. Administration of antithyroid drugs (propylthiouracil, thiourea, KSCN) caused a significant decrease in radioiodine uptake and a highly significant increase in TSH content of the pituitary. Heavy doses of I¹³¹ almost completely blocked thyroidal iodine uptake but they were as effective as antithyroid drugs in elevating TSH content of the pituitary.I am greatly indebted to Dr. G. E. Pickford, Yale University, U.S.A. for her helpful suggestions; to Dr. A. G. Sathyanesan, Banaras Hindu University, India, for encouragements; to Professor S. P. Ray-Chaudhuri, Banaras Hindu University, India, for providing laboratory facilities. I am also grateful to Baxtor Laboratories Inc., Morton Grove, Illinois, U.S.A. for the gift of Crystalline L-thyroxine which was made available through the courtesy of Professor Paul Starr and Dr. Thomas Garrett.     

A Comparative Toxicological Assessment of Perchlorate and Thiocyanate Based on Competitive Inhibition of Iodide Uptake as the Common Mode of Action

Thiocyanate and perchlorate are known to competitively inhibit thyroidal iodide uptake at the sodium-iodide symporter. Estimates of their relative potencies have recently been refined; thiocyanate is 15 times less potent than perchlorate on a serum concentration basis. Numerous studies have been published relating serum thiocyanate concentrations (or surrogate measures) with thyroid function in various populations including pregnant women and neonates in regions with varying degrees of iodine deficiency. Fifteen published studies were located that relate serum thiocyanate concentrations with thyroid function. In the absence of severe iodine deficiency or iodine excess, adverse thyroidal effects occur with chronic serum thiocyanate concentrations ≥ 200 μ mol/L whereas non-adverse effects are observed with concentrations in the range of 65–85 μ mol/L. No adverse or non-adverse effects are observed at serum concentrations below 50 μ mol/L, even among sensitive subpopulations. Recently, studies relating serum perchlorate concentrations with perchlorate dose have become available, thus making it possible to predict the perchlorate dose associated with a serum perchlorate concentration. Serum thiocyanate concentrations found to induce non-adverse or adverse thyroid effects can thereby be used to predict the perchlorate concentration and thus the perchlorate dose that would be expected to induce similar effects. To place a perspective on environmental perchlorate exposure, a serum thiocyanate concentration of 50 μ mol/L is equivalent to a serum perchlorate concentration of 3.3 μ mol/L in terms of iodine uptake inhibition. This serum perchlorate concentration would require a perchlorate dose of 0.27 mg/kg-day, or a drinking water equivalent level of 9 mg/L using standard default assumptions of a 70 kg adult drinking 2 liters of water daily.     

NEWS AND NOTES

In an investigation of relationships between ovarian function and thyroid function, three groups of ten women each were studied by means of radioactive iodine uptake. In the first group no significant changes were noted during normal menstrual cycles.The second group, women who had dysfunctional uterine bleeding and were under treatment with diethylstilbestrol, most of the patients had no significant change in the uptake of radioactive iodine. Three patients did show a small increase in the uptake. (A fourth patient had a very bizarre result with a very great increase in the uptake, but it is felt that some undetected error was involved.)The third group was made up of women without evident ovarian function. Under treatment with diethylstilbestrol one patient showed a small increase in iodine uptake. The other nine had no significant change.No convincing evidence was found of any change in thyroid function as measured by the uptake of radioactive iodine—either during normal menstrual cycles or following the administration of diethylstilbestrol in dosages of 3 mg. daily for two to three weeks.     

Transfer of iodine through the milk in protein-restricted lactating rats

Iodine supply is important to avoid neonatal hypothyroidism. This study evaluated whether protein restriction during lactation affects iodine transfer to the pups through the milk. We studied lactating rats fed an 8% protein-restricted diet (PR), a control 23% protein diet (C), and an energy-restricted diet group (ER). On days 4, 12 and 21, mothers were separated from their pups for 4 h, injected with (131)I IP, and put together with their pups. The animals were killed 2 h later. PR pups had a significant decrease in iodine uptake in the gastric content and duodenal mucosa on the 4th day. On the contrary, at 12 and 21 days radioiodine was increased in the gastric content and in the duodenal mucosa. ER pups had an increase in iodine uptake in the gastric content and in the duodenal mucosa only at the end of lactation. The thyroid iodine uptake in PR pups was significantly decreased on the 4th day and significantly increased on the 21st day compared to control. When injected IP with an equivalent amount of (131)I, the PR pups had a decrease in thyroid iodine uptake on the 4th and 12th day, while ER pups had no significant changes. So, these data suggest that protein restriction during lactation was associated with lower iodine secretion into the milk in the beginning of lactation. However, at the end of lactation, an adaptation process seems to occur leading to a higher transfer of iodine through the milk that compensates the impairment of thyroid iodine uptake in these pups.