Highly sensitive immunoradiometric assay for TSH and thyroid radioiodine uptake as predictors of thyroid suppression test

Suppression of TSH and thyroid radioiodine uptake by doses of either T4 or T3 were compared in 33 patients in whom Graves' thyrotoxicosis had been treated with thioamide drugs and the medication was discontinued for at least 4 months. Thyroidal radiodine uptake was suppressed in 19 patients and was not suppressed in the remaining 14 patients. Basal TSH levels before suppression were 2.07 microU/ml in the former, significantly exceeding those of the latter (0.91 microU/ml). A TSH level of at least 1.2 microU/ml before suppression is a good predictor of positive thyroid radioiodine suppression with a predictive value of 76%. A level lower than 0.7 microU/ml before suppression is a good predictor of negative thyroid radioiodine uptake suppression with a predictive value of 89%. The determination of TSH levels before the thyroid suppression test was helpful in predicting the result, but there were limitations. In the thyroid suppression test positive group, circulating T4 was depressed by doses of T3. In them, the magnitude of T4 depression correlated with the levels of thyroid radioiodine uptake before suppression. The levels of TSH correlated neither to changes in T4 nor to those in thyroid radioiodine uptake. This indicates that the thyroid glands which show high radioiodine uptake are sensitive to TSH and are also sensitive to suppression. The elevated sensitivity to TSH probably warrants the disappearance of abnormal thyroid stimulation more precisely.     

Stimulation of adenyl cyclase and fixation of iodine in human cancerous thyroid cells in culture

In primary cultures of cells from human thyroid cancer, functional activity was investigated by adenylate cyclase responsiveness and radioiodine uptake. In cells from well-differentiated follicular carcinomas (2 cases), TSH stimulation of cAMP accumulation is similar to that of normal thyroid cells. In contrast, in papillary carcinomas (11 cases), the mean dose-response curve is much lower than normal. In thyroid cancers, radioiodine uptake by the cells has been detected in some cases after 3 days of 125I incorporation. As previously observed, our results suggest the existence of a relationship between adenylcyclase responsiveness and 125I uptake by the cells.     

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.     

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.     

The management of hyperthyroidism due to Graves' disease in Japan in 1988. The Japan Thyroid Association

The management of hyperthyroidism due to Graves' disease in Japan was the subject of a survey of the members of the Japan Thyroid Association (JTA), and the results were compared to those of the European Thyroid Association (ETA). In the questionnaire, in vivo and in vitro diagnostic procedures, the choice of treatment and the details of the treatment for a patient with typical, moderate and uncomplicated hyperthyroidism due to Graves' disease was at first asked, and eight variations with a single alternative were proposed to evaluate how each alternative would affect the choice of treatment. For the diagnostic procedures, thyroid uptake/scintigraphy was carried out by approximately 60% of the respondents and the isotope mainly used was 123I. The number of in vitro tests used for diagnosis averaged 8.1 +/- 1.8 tests. Measurements of basal TSH and free T4 were the most frequent tests performed to confirm the diagnosis of hyperthyroidism (94 and 80%, respectively). Determinations of microsomal, thyroglobulin and TSH-receptor autoantibodies were also employed by many respondents (96, 96 and 77%, respectively). On the other hand, the free T4 index and TRH test were less frequently employed. In the treatment of these patients, antithyroid drug treatment was the first choice, and surgery was not, in general, regarded as a primary therapy except in a patient with a large goiter. The frequency of the respondents who advocated radioiodine therapy was considerably higher for patients with recurrences and old age. No respondents proposed radioiodine therapy for young patients. Specialists tended to favor their own specialist treatment regimens. The initial dose of antithyroid drugs was reduced according to thyroid function, and withdrawal of antithyroid drug treatment was determined by some specific criteria (basal TSH in supersensitive assays, TSH-receptor autoantibodies, T3 suppression test, etc.). The aim of radioiodine therapy and surgery was to restore euthyroidism. The significant differences between the results from the JTA and those from the ETA were as follows; radionuclide used for thyroid uptake/scintigraphy was mainly 123I in Japan, but 131I in Europe, the number of diagnostic studies in Japan was more than that in Europe, and the dosage of antithyroid drugs was reduced according to thyroid function and discontinued based on certain specific criteria in Japan, but after fixed periods in Europe. These results may represent actual trends in how hyperthyroidism due to Graves' disease is managed in specialist clinics in Japan today and the differences between the JTA and the ETA.     

Activity of thyroid stimulating antibody and thyroid stimulation blocking antibody determined by radioiodine uptake into FRTL-5 cells

To investigate the pathophysiology of patients with autoimmune thyroid diseases, we measured serum thyroid stimulating antibody (TSAb) activity and thyroid stimulation blocking antibody (TSBAb) activity by determining the radioiodine (125I) uptake into FRTL-5 cells. FRTL-5 cells were pre-incubated for seven days with 5H medium and then incubated for 48 hours with patients' crude IgG prepared by polyethylene glycol precipitation. In order to measure TSBAb, 10 microU/ml TSH was also added. 125I was added one hour before the end of the 48 hour incubation period. After the incubation, the medium was aspirated, and the radioactivity in the cells was counted. In patients with untreated hyperthyroid Graves' disease, TSAb was detectable in 18 of 20 patients, the detectability being 90%, and activity showed a statistically significant positive correlation with TSAb activity determined by c-AMP accumulation. Out of 41 patients with hypothyroidism, TSBAb determined by 125I uptake was positive in six cases, the detectability being 14.6%. The inhibition of 125I uptake by one of these six IgGs was suggested to be at the TSH receptor level because it inhibited TSH induced c-AMP accumulation and showed positive thyrotropin binding inhibitor immunoglobulin (TBI I) activity, but did not inhibit the forskolin- and (Bu)2cAMP-induced 125I uptake. Inhibition of another IgG was suggested at the post-receptor level because it did not inhibit TSH induced cAMP accumulation and showed negative TBI I activity, but inhibited forskolin- and (Bu)2cAMP-induced 125I uptake.(ABSTRACT TRUNCATED AT 250 WORDS)     

The value of plasma TSH estimation and TRH stimulation test in the course of treatment of differentiated thyroid cancers.

Plasma TSH levels were measured on 114 occasions in 96 patients treated for differentiated thyroid cancer. Prior to thyroid surgery, plasma TSH levels were within the range of normal. Plasma TSH levels increased slightly following partial thyroid resection and definitely after total thyroid ablation. In patients where the removal of normal thyroid induced hormonogenesis in thyroid tumours, plasma TSH levels were dependent on the hormonal secretion of the tumour as shown by inverse relationship between TSH and both PBI and 131I uptake. The increase of radioiodide uptake following stimulation by exogenous bovine TSH was inversely related to the plasma thyrotropin levels. The suppressibility of enhanced thyrotropin levels was complete with individually adjusted doses of synthetic thyroid hormones. With the exception of patients on suppressive treatment, TRH administration induced increase in plasma TSH levels. The findings are discussed with regard to the role played by TSH in the induction of hormonogenesis in thyroid tumours. The practical values of TSH estimation and TRH stimulation seem to be low; the measurements of thyrotropin levels may be important for the estimation of the suppressive effect in the course of and following withdrawal of treatment with thyroid hormones.     

Influence of the endogene TSH stimulation of thyroid volume increase in the patients after total thyroidectomy due to differentiated thyroid cancer

INTRODUCTION: The treatment-of-choice for differentiated thyroid carcinoma (DTC) is a total thyroidectomy with subsequent radioiodine therapy. In order to increase an iodine uptake in thyroid tissue remnants, the L-thyroxine withdrawal is required. It is recommended to achieve TSH levels higher than 25 mU/ml. As TSH is a known key factor in thyroid cell proliferation regulation, prolonged stimulation of the cells during L-thyroxine withdrawal can be a causative factor for a re-growth. Our aim was to assess the degree of thyroid re-growth in the patients after total thyroidectomy due to DTC and its possible clinical implications. MATERIAL AND METHODS: 23 patients operated due to papillary and follicular thyroid cancer were included into the study. Biochemical determinations and ultrasound thyroid imaging were performed (TSH, Tg) during suppressive L-thyroxine therapy as well as 4-5 weeks after the withdrawal. RESULTS: The mean volume of thyroid tissue remnants increased after withdrawal for substantial 30.1%. The difference was extremely significant. CONCLUSIONS: L-Thyroxine withdrawal in the patients after total thyroidectomy due to DTC can cause re-growth of the tissue remnants. The phenomenon may be of a clinical significance in the selected cases influencing therapeutic decisions.     

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.     

Acromegaly and hyperthyroidism associated with McCune-Albright syndrome

A 36-year-old man is described having McCune-Albright syndrome, acromegaly likely due to somatotroph hyperplasia and hyperthyroidism due to adenomatous goiter. Sexual precocity was not noted. The sella was narrow in size and no mass was seen. The decline of elevated GH by hyperglycemia and increase by GHRH-44(NH2) may support somatotroph hyperplasia, but plasma GHRH-44(NH2) levels were not elevated. A mass in the right lobe and enlargement of the left lobe of the thyroid were noted. Thyroid hormone levels in serum and thyroidal radioiodine uptake values were elevated, while TSH measurements in serum were low. The radioiodine scan showed a cold nodule in the right lobe and a hot area in the left of the thyroid. Thyroidal radioiodine was not suppressed following T3 given orally. These findings are compatible with functioning glands autonomously as the mechanism for the endocrinopathies associated with the McCune-Albright syndrome.     

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.     

Recombinant human TSH stimulation in radioiodine treatment of disseminated differentiated thyroid cancer--update of current and our own experiences

Traditionally, for diagnostic and therapeutic application of radioiodine in patients with differentiated thyroid cancer (DTC), a 4 to 6 week withdrawal of thyroid hormone was applied. Recombinant human TSH (rhTSH) was developed to provide TSH stimulation without withdrawal of thyroid hormone and associated morbidity. The results of rhTSH administration and endogenous TSH stimulation are equivalent in detecting recurrent DTC. At the present time rhTSH is approved as an adjunct for diagnostic procedures and thyroid ablation in patients with DTC. In addition, rhTSH has potential for use in facilitating the treatment of metastases in patients with DTC. In this review we have summarized our own experiences with rhTSH aided radioiodine therapy in patients with disseminated thyroid cancer. Generally, rhTSH was very well tolerated and treatment results were comparable to those achieved with thyroid hormone withdrawal.     

Screening of geriatric patients for thyroid dysfunction with thyrotropin-releasing-hormone test, sensitive thyrotropin and free thyroxine estimation

Hospitalized geriatric patients (N = 354) from an iodine-deficient area were screened with sensitive thyrotropin (TSH), free and total thyroxine (FT4, T4) and total triiodothyronine (T3) to determine the occurrence rate of clinical and subclinical thyroid dysfunction. The diagnostic value of the tests was compared to each other and to that of the thyrotropin-releasing-hormone test (TRH-test) in order to find the optimal first line screening test in geriatric patients. Clinical hyperthyroidism was found in 13, subclinical hyperthyroidism in 10, overt hypothyroidism in 6 and subclinical hypothyroidism in 8 cases. 20.6% of the patients were euthyroid but had subnormal TSH response to TRH, as a sign of possible thyroid autonomy. The low occurrence rate of clinical thyroid disorders (4.8%) does not justify the screening of geriatric patients in general, but the high probability of thyroid autonomy makes reasonable the investigation of every geriatric patient before iodine administration. Suppressed basal TSH and high FT4 were found to be both sensitive and specific in diagnosing clinical hyperthyroidism, but the predictive value was insufficient; elevated T4 and T3 are specific, but not sensitive. Basal TSH is sensitive, specific and has a good predictive value in diagnosing euthyroidism, whereas normal T4, FT4 or T3 are not specific enough for euthyroidism. Basal TSH is better as a first line test of thyroid function than FT4. A normal basal TSH confirms euthyroidism by itself. Other tests (TRH test, T4, FT4, T3) are necessary to elucidate the clinical importance of a subnormal or suppressed basal TSH.     

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.     

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 effect of exogenous TSH and Achilles tendon reflex time in man.

The effect of exogenous thyrotropin (TSH) -- 3 X 10 IU daily -- on Achilles tendon reflex time (ART) was investigated in the group of 38 in-patients, treated for thyroid cancer. A significant shortening of ART was recorded in a subgroup of hypothyroid persons after the 2nd and 3rd dose of TSH. Moreover, a significant correlation was proved between initial values of ART and their changes after the 2nd and 3rd TSH injection in this group. No significant interrelationship was observed between changes of thyroid function and ART after TSH administration. In interpretation of this finding the possibility of direct effect of TSH on muscle metabolism in hypothyroid man should be considered.     

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.     

Application of 13-cis-retinoic acid in patients with 131I scintigraphically-negative metastases of differentiated thyroid carcinoma

INTRODUCTION: The loss of iodine uptake by differentiated thyroid carcinoma (DTC) cells is a major therapeutic problem especially in patients with nonsurgical metastatic foci or local recurrence. Using 13-cis-retinoic acid, it was attempted to retain iodine uptake as a result of redifferentiation (influence by retinoic acid receptors present in DTC cells). MATERIAL AND METHODS: Between 1999 and 2005, 13-cis-retinoic acid was used in 11 patients with disseminated PTC and high serum level of thyroglobulin (Tg) before (131)I treatment (2 patients were treated twice - 13 treatment cycles in total). Side effects in skin and mucous membranes were observed in all the patients, however, their intensity did not require termination of the therapy. RESULTS: Increase of iodine uptake was observed in 5 patients (45%). Decreased Tg concentration was observed in 9 patients. In that group, increased (131)I uptake was observed in 4 patients with distant metastases. All determinations of Tg concentrations were carried out under TSH stimulation. CONCLUSIONS: 13-cis-retinoic acid causes an increase of radioiodine uptake in around half of treated patients, however, the follow-up of these patients indicates that this increase does not result in either full remission or even stabilisation of neoplastic disease. The possibility should be considered to use cis-retinoic acid as an independent therapeutic approach in patients with radioiodine non-avid foci of thyroid carcinoma especially those showing high expression of RARb and RXRg receptors.     

An elevation of plasma ISH concentration in spontaneously hypertensive rats (SHR).

Thyroid activity was tested in two substrains of SHR. Plasma level and pituitary content of TSH increased significantly in both substrains of SHR. As a result, the thyroid weight and thyroidal radioiodine uptake increased significantly. Plasma T3 concentration was decreased in Kyoto substrain but was normal in NN substrain, while plasma T4 concentration decreased significantly in both substrains. Since the pituitary content and plasma level of TSH were significantly higher in spite of the normal concentration of plasma T3, it is concluded that the pituitary "hormostat" is set at a higher level at least in the NN substrain of SHR.     

Diagnostic scintigraphy and effectiveness of 131I radioiodine therapy in differentiated thyroid carcinoma (DTC)

INTRODUCTION: Since the effect of pre-therapeutic scintigraphy on the outcome of DTC treatment is debated, we evaluated factors affecting the effectiveness of (131)I therapy with respect to the delay between diagnostic scintigraphy and the application of radioiodine. MATERIAL AND METHODS: In the studied group of 60 patients with DTC, mean age 54.6 +/- 13.0 years, four weeks prior to the planned diagnostics, L-thyroxine was withdrawn and the following tests performed: (131)I (4 MBq) uptake above the neck, thyroid volume by USG, TSH and hTg level. Wholebody scintigraphy (37 MBq) was performed. The time between this diagnostic scintigraphy and application of (131)I (3657 MBq) was calculated. Based on whole-body 131I scintigraphy (74 MBq) performed 1 year after radioiodine treatment, the patients were divided into: group I - 42 patients with no tracer accumulation, and group II--18 patients who continued to accumulate (131)I in the neck. RESULTS: The differences between the median values of (131)I uptake and of thyroid volumes, and between the TSH and hTg median values in the two groups of patients were found not to be statistically significant. The average times between diagnostic scintigraphy and (131)I treatment in group I and II (9.4 vs. 8.3 weeks, respectively) were not significantly different either. CONCLUSION: Despite the different effectiveness of supplementary (131)I treatment, patients in group I and group II showed no statistically significant differences in the studied parameters. It appears that the diagnostic (131)I activity of 37 MBq and the time between diagnostic scintigraphy and application of (131)I did not have any effect on the results of the treatment in our group of patients.