Thyroid Radioiodine Research Articles

Recombinant human thyrotropin stimulation prior to 131I therapy in toxic multinodular goiter with low radioactive iodine uptake

AimStimulation with recombinant human thyrotropin (rhTSH) increases thyroid radioiodine uptake, and is an aid to 131I therapy in non-toxic multinodular goiter (MNG). However, there are not many studies using rhTSH prior to 131I in toxic multinodular goiter to improve hyperthyroidism and compressive symptoms. Materials and methodsA prospective study was conducted on patients with MNG and hyperthyroidism. Patients were recruited consecutively and divided into group I, stimulated with 0.3mg of rhTSH before radioiodine therapy, and a control group or group II, without stimulation. Thyroid function, radioiodine thyroid uptake, thyroid weight, and compressive symptoms were measured, and patients were followed-up for 9 months. ResultsGroup I consisted of 16 patients (14 women), with a mean age 69.7 years, and group II with 16 patients (12 women), with a mean age 70.7 years. After stimulation with 0.3mg rhTSH in group I, 131I uptake (RAIU) at 24h increased by 78.4%, and the estimated absorbed dose by 89.3%. In group II, the estimated absorbed dose was lower than group I after stimulation with rhTSH (29.8Gy vs. 56.4Gy; P=0.001).At 9 months of follow-up, hyperthyroidism was controlled in 87.5% of patients in group I, and 56.2% in group II (P=0.049). The mean reduction in thyroid weight was higher in group I than in group II (39.3% vs. 26.9%; P=0.017), with a tendency toward subjective improvement of compressive symptoms in group I, although non-significant. Only 2 patients described tachycardias after rhTSH administration, which were resolved with beta-blockers. ConclusionStimulation with 0.3mg of recombinant human thyrotropin prior to radioiodine therapy achieves a reduction in thyroid weight and functional improvement in patients with hyperthyroidism and multinodular goiter with low uptake, and with no need for hospital admission.

Reappraisal of the indication for radioiodine thyroid ablation in differentiated thyroid cancer patients.

Radioactive iodine therapy is administered to patients with differentiated thyroid cancer (DTC) for eradication of thyroid remnant after total thyroidectomy or, in patients with metastatic disease, for curative or palliative treatment. In past years, thyroid remnant ablation was indicated in almost every patient with a diagnosis of DTC. Nowadays, careful revision of patients' outcome has introduced the concept of risk-based selection of patients candidate to thyroid remnant ablation. The present review aims to underline the indications for thyroid remnant ablation and to address methodologies to be employed.

Correlation Between Exposure Rate and Residual Activity in Felines Undergoing 131I Thyroid Ablation Therapy.

Radioiodine thyroid ablation therapy is a common method for treatment of felines exhibiting hyperthyroidism. Due to the high gamma-ray emission rate of radioiodine (I), patients following treatment must be held in isolation for several days before release to prevent unnecessary dose to owners and members of the public. Dose rate measurement on the external surface of the patient of ≤ 20 μSv h is maintained as the patient release criterion without regard to residual activity. However, the Texas Department of State Health Services regulatory guide recommends a release limit of 3.7 MBq to households with non-pregnant women and children over the age of 18 y, and a limit of 925 kBq to households of pregnant women and children who can be supervised. In this paper, Monte Carlo computational radiation transport techniques are employed to predict and standardize the patient isolation time at the clinic by correlating the thyroid burden and surface dose rates of felines. Measurements of patient dose rate as a function of time are used to determine the patient-specific effective half-life experimentally and to validate the model results. Results show that an average holding time of 8 to 9 d is sufficient to reduce the residual activity to 3.7 MBq levels. Additionally, contact dose rate measurements of 20 μSv h or less correlate to residual activity levels of approximately 925 kBq. Based on the model and measurements, a protocol was developed for clinical use at Texas A&M University Veterinary Medical Teaching Hospital to allow estimation of residual activity following injection. This in turn confirms that the surface dose rates used as the release criteria follow the release limits recommended in the regulatory guide.

Amiodarone and the thyroid.

Amiodarone, a benzofuranic iodine-rich antiarrhythmic drug, causes thyroid dysfunction in 15-20% of cases. Amiodarone can cause both hypothyroidism (AIH, amiodarone-induced hypothyroidism) and thyrotoxicosis (AIT, amiodarone-induced thyrotoxicosis). AIH is treated by L-thyroxin replacement and does not need amiodarone discontinuation. There are two main forms of AIT: type 1, a form of true iodine-induced hyperthyroidism; and type 2, a drug-induced destructive thyroiditis. However, mixed/indefinite forms exist, contributed to by both pathogenic mechanisms. Type 1 AIT usually occurs in diseased thyroid glands, whereas type 2 AIT develops in substantially normal thyroid glands. Thioamides represent the first-line treatment for type 1 AIT, but iodine-replete glands are poorly responsive; sodium/potassium perchlorate, by inhibiting thyroidal iodine uptake, may increase the response to thioamides. Type 2 AIT is best treated by oral glucocorticoids. Response depends on thyroid volume and severity of thyrotoxicosis. Mixed/indefinite forms may require a combination of thioamides, potassium perchlorate, and steroids. Radioiodine treatment is usually not feasible because amiodarone-related iodine load decreases thyroidal radioiodine uptake. Thyroidectomy represents an important and helpful option in cases resistant to medical therapy. Surgery performed by a skilled surgeon may represent an emergent treatment in patients who have severe cardiac dysfunction.

Interpretation of results of radioiodine measurements in thyroid for residents of Ukraine (1986)

The purpose of this research is to make analysis, revision and estimation both reliability and accuracy of all measurements of radioiodine in the thyroid for residents of Ukraine, which were performed in 1986, and to justify the calibration factors to be applied for interpretation of measurements performed by non-calibrated devices. The radioiodine activity in the thyroid for residents of the most contaminated oblasts of Ukraine has been calculated on the base of 150 thousands direct measurements of the content of 131I in thyroid obtained in the frames of the thyroid monitoring in 1986. A method for the calculation of measurement errors has been developed and the accuracy of the errors has been determined assuming that the density of errors' distribution for main parameters of the measurements is close to Gaussian. Using the results of laboratory measurements, the calibration factors have been determined for integrated radiometers SRP-68-01 - devices which were often used to perform the thyroid dosimetric monitoring. The distribution of estimates on the content of radioiodine in thyroid is close to the lognormal one with geometric mean being equal to 4.8 kBq and geometric standard deviation being equal to 3.8. Most of these estimates (90 %) are in the range of 0.58-47 kBq, and the main set of their relative errors (90 %) are between 0.1 and 0.6. Thus, the model of thyroid activity observation with classical additive error has been obtained.

Thyroid Doses and Skin Contaminations of Radioiodine

Radioiodine treatment, using iodine I-131, is one of the oldest clinical radionuclide therapy methods, and it is widely spread and currently used in the treatment of both thyreotoxicosis and thyroid cancer. The use of iodine may cause skin contaminations which may be a radiobiologic hazard and diagnostic problem. Reported hazards in the radiopharmaceutical production of I-131 for therapy purposes are rare, but they might cause therapeutic approaches due to radioiodine uptake in the thyroid and destruction of thyroid tissue (mean beta range, 0.8 mm). In this work a skin contamination causing a radioiodine thyroid uptake has been reported, together with thyroid cancer patients of receiving therapeutic doses of I-131 having skin contaminations from exudates. These skin contaminations were quantificated, dose calculations were performed based on serial gamma detector and quantitative whole body gamma imaging, including SPECT/CT. For serial gamma imaging, thyroid retention and whole clearance after oral administration, rhTSH stimulation and thyroxin withdrawal give different results and therefore serial uptake estimates and time-activity curves are essential parameters for dose evaluation. Similarly, accidental subcutaneous administration for calculating thyroid uptake requires serial measurement as well. In these patients, the skin contaminations did not cause any potential hazard to the environment nor to the hospital even though potential risks have been reported in the early days. Skin doses due to contaminations varied from 0.64 to 2.7 Gy. In the radiopharmaceutical production accidental skin contamination did not cause any harmful thyroid dose (80 mGy) due to rapid cleaning actions. Quantitative gamma imaging together with activity calibrated detectors is the prerequisite for appropriate dose calculations when routes of administration differ from clinical routine.

Is malignant nodule topography an additional risk factor for metastatic disease in low-risk differentiated thyroid cancer?

Differentiated thyroid cancer (DTC) is the most common endocrine malignancy. In recent decades, the incidence has been increasing, largely due to increased detection of patients with low-risk or very low-risk DTC. According to European Thyroid Association and American Thyroid Association guidelines, radioiodine (RAI) thyroid remnant ablation is not indicated in very low-risk patients, while its role is still debated in low-risk patients. Accordingly, risk stratification of DTC patients is pivotal when deciding for or against RAI ablation. Presently, risk stratification is based on pTNM staging integrated with clinical parameters. The aim of our study was to evaluate the relationship between location of malignant thyroid nodules within the thyroid gland and the presence of loco-regional and/or distant metastases in patients with pT1a-pT1b DTCs. We reviewed the records of 246 patients (214 women, 32 men; female-to-male ratio 6.7:1) affected by unifocal DTC ≤ 2 cm, who had undergone RAI thyroid remnant ablation (activity ranged 555-4588 MBq) after levothyroxine withdrawal or after recombinant human TSH (rhTSH) stimulation. The majority of the patients (91.5%) were affected by papillary thyroid carcinoma. Metastases were discovered by posttreatment whole-body scintigraphy in 29 out of 246 (11.8%) patients. In patients with metastases, malignant thyroid nodules were located in the right lobe (14/123, 11.4%), left lobe (7/95, 7.4%), and isthmus (8/27, 29.6%). The prevalence of metastases was significantly higher in patients with DTC located in the isthmus, compared to other sites (χ(2) = 9.6, p = 0.002). Our data show for the first time that a location of a thyroid cancer in the isthmus is an additional risk factor for RAI avid metastatic disease in pT1a-pT1b DTC patients, regardless of the presence or absence of other risk factors.

Radioiodine ablation with 1,850 MBq in association with rhTSH in patients with differentiated thyroid cancer

The aim of this study was to evaluate the efficacy of post-operative radioiodine ablation with 1,850 MBq after recombinant human thyrotropin (rhTSH) administration in patients with differentiated thyroid carcinoma (DTC). We also aimed to assess the prognostic role of several patient features on the outcome of ablation. We retrospectively analyzed data from a total of 125 patients with DTC who underwent post-operative radioiodine ablation with 1,850 MBq of ¹³¹I after preparation with rhTSH. One injection of 0.9 mg rhTSH was administered on each of two consecutive days; ¹³¹I therapy was delivered 24 h after the last injection, followed by a post-therapy whole-body scan. Successful ablation was assessed 6-12 months later and defined as an rhTSH-stimulated serum thyroglobulin (Tg) level ≤1.0 ng/ml and a normal neck ultrasound. Patients were stratified according to the American Thyroid Association (ATA) Management Guidelines for Differentiated Thyroid Cancer. Successful ablation was achieved in 82.4 % of patients, with an ablation rate of 95.1 % in low-risk patients and 76.2 % in intermediate-risk patients. Analyzing the correlation between ablation outcome and patient characteristics, we found a statistically significant association between failure to ablate and class of risk based on ATA guidelines (p = 0.025) and a stimulated Tg value at ablation of above 5 ng/ml (p < 0.001). The use of 1,850 MBq post-operative radioiodine thyroid remnant ablation in association with rhTSH is effective for low- and intermediate-risk patients. Moreover, in our study, we found a statistical correlation between failure to ablate and class of risk based on ATA guidelines for DTC and a stimulated Tg value at ablation.

Apigenin in Combination with Akt Inhibition Significantly Enhances Thyrotropin-Stimulated Radioiodide Accumulation in Thyroid Cells

Selectively increased radioiodine accumulation in thyroid cells by thyrotropin (TSH) allows targeted treatment of thyroid cancer. However, the extent of TSH-stimulated radioiodine accumulation in some thyroid tumors is not sufficient to confer therapeutic efficacy. Hence, it is of clinical importance to identify novel strategies to selectively further enhance TSH-stimulated thyroidal radioiodine accumulation. PCCl3 rat thyroid cells, PCCl3 cells overexpressing BRAF(V600E), or primary cultured tumor cells from a thyroid cancer mouse model, under TSH stimulation were treated with various reagents for 24 hours. Cells were then subjected to radioactive iodide uptake, kinetics, efflux assays, and protein extraction followed by Western blotting against selected antibodies. We previously reported that Akt inhibition increased radioiodine accumulation in thyroid cells under chronic TSH stimulation. Here, we identified Apigenin, a plant-derived flavonoid, as a reagent to further enhance the iodide influx rate increased by Akt inhibition in thyroid cells under acute TSH stimulation. Akt inhibition is permissive for Apigenin's action, as Apigenin alone had little effect. This action of Apigenin requires p38 MAPK activity but not PKC-δ. The increase in radioiodide accumulation by Apigenin with Akt inhibition was also observed in thyroid cells expressing BRAF(V600E) and in primary cultured thyroid tumor cells from TRβ(PV/PV) mice. Taken together, Apigenin may serve as a dietary supplement in combination with Akt inhibitors to enhance therapeutic efficacy of radioiodine for thyroid cancer.

Nothing new under the nuclear sun: towards 80 years of theranostics in nuclear medicine

Some time in the early 2000s, the word “theranostics” (or “theragnostics”) started surfacing in the medical literature. Theranostics (from the Greek therapeuein “to treat medically” and gnosis “knowledge”) is the use of individual patient-level biological information in choosing the optimal therapy for that individual [1]. In the modern era of “personalized medicine”, theranostics is increasingly pursued in many branches of medicine in order to develop ever more effective treatment regimens. There are now many studies and reviews dedicated to theranostics, and even a journal bearing the name of this principle, detailing many different concepts on how to combine imaging and therapy using, for example, complex molecules [2] or nanotechnology [3]. However, it is rarely realized by either clinicians or scientists that nuclear medicine has been employing theranostics for nearly 80 years now. In fact, the very foundations of targeted therapy in nuclear medicine are those that are only now being adopted by other medical disciplines under the designation “theranostics”. The cornerstones of theranostics can be traced back to some of the most illustrious names among the founding fathers of nuclear medicine. Soon after Chiewitz and de Hevesy [4] described the uptake of radioactive P in the bones of rats, Erf and J.H. Lawrence (brother of the physicist Ernest O. Lawrence, who built the first cyclotron) applied this same radioisotope to patients suffering from leukaemia and polycythaemia vera [5]. Although this treatment certainly was not without success, it has since been superseded by more effective nonradioactive chemotherapy. Shortly afterwards Pecher [6] discovered that Sr accumulated in secondary bone tumours in animals, and subsequently successfully used this radioisotope to treat patients with painful bone metastases (unfortunately this work was immediately classified as secret and it took more than five decades for Sr to be registered as a therapeutic drug). These two studies are perhaps the earliest examples of diagnostic studies leading to targeted therapy of cancer using radionuclides. Around the same time the most prominent example of pure nuclear theranostic medicine emerged: the diagnosis and treatment of thyroid disorders using various isotopes of iodine. Hertz et al. in 1938 described the first study of thyroidal radioiodine uptake [7], and in 1942 Hertz and Roberts reported on the treatment of the first patients with Graves’ disease with radioiodine [8]. A short time later Seidlin et al. treated the first patient with metastatic thyroid cancer with radioiodine [9] – at the time this compoundwas so rare that radioiodinewas purified from the patient’s urine and readministered. During this therapy, additional metastases were identified using a Geiger counter and the first rudimentary dosimetry was performed. It is of course only with the benefit of hindsight that we can now say that this was the first application of theranostics in targeted molecular medicine through a specific molecular target, the sodium iodine symporter, long before any of these concepts were first described as “theranostics”. Indeed, even today it is hard to think of a single combination of targeted diagnostics and therapy that is more specific than radioiodine. F. A. Verburg (*) :A. Heinzel : F. M. Mottaghy Department of Nuclear Medicine, RWTH University Hospital Aachen, Pauwelsstrase 30, 52074 Aachen, Germany e-mail: fverburg@ukaachen.de

Preoperative long-acting octreotide treatment for invasive thyrotropin-secreting pituitary macroadenoma after previous radioiodine thyroid ablation

We report a 33-year-old woman with invasive thyrotropin-secreting pituitary adenoma after previous thyroid ablation with radioiodine who was successfully treated with transsphenoidal surgery after pre-treatment with octreotide-LAR for 10months. Since invasive and aggressive thyrotropin-secreting macroadenomas are more frequently observed in patients who have undergone thyroid ablation, we suggest preoperative treatment with somatostatin analogs should be considered in these patients to reduce serum thyrotropin and stabilize or reduce tumor size.

Patients With Differentiated Thyroid Cancer Who Underwent Radioiodine Thyroid Remnant Ablation With Low-Activity 131I After Either Recombinant Human TSH or Thyroid Hormone Therapy Withdrawal Showed the Same Outcome After a 10-Year Follow-up

No long-term follow-up data are available for differentiated thyroid carcinoma (DTC) patients prepared with either exogenous or endogenous TSH and treated with low-activity (1.1 GBq [30 mCi]) radioiodine (¹³¹I). The aim of this study was to evaluate the 10-year follow-up of DTC patients who underwent remnant ablation with 1.1 GBq ¹³¹I after l-T4 withdrawal, recombinant human TSH (rhTSH) administration, or both. A total of 159 DTC patients treated with total thyroidectomy and 1.1 GBq (30 mCi) of ¹³¹I for remnant ablation and stimulated with rhTSH and/or endogenous TSH were separated into ablated (n = 115) and not ablated (n = 44) patients and prospectively followed-up for at least 10 years. In addition, we evaluated several features that could correlate with the final status of patients. During the follow-up, 4 of 115 (3.5%) ablated patients showed a recurrence and 1 was successfully cured. Among not ablated patients, 16 of 44 (36.4%) had a persistent disease. At the end of the 10-year follow-up, 140 of 159 (88.1%) patients were disease-free, whereas 19 of 159 (11.9%) remained affected. No correlation was found with the type of TSH stimulation, and no other clinical and pathological features showed any correlation with the final status. However, low levels of stimulated serum thyroglobulin (<5.4 ng/mL) at first control after remnant ablation identified a subgroup of not ablated patients who became spontaneously cured. Long-term outcomes are similar in DTC patients treated with 1.1 GBq (30 mCi) ¹³¹I and prepared either with rhTSH or endogenous TSH. It is of interest that serum thyroglobulin at first control after ablation can have a prognostic role.

Long-term thyroid hormone replacement therapy

In recent years the number of patients with hypothyroidism has significantly increased. It is the result of increased prevalence of autoimmune thyroid disease, increased frequency of total thyroid resections and also common radioiodine thyroid ablation in patients with hyperthyroidism or differentiated thyroid cancers. The treatment of hypothyroidism is considered by many physicians as effortless, simply based on L-thyroxine substitution. Universal access to therapy and to laboratory tests supports their approach. Is it true? Nowadays, both the development of diagnostic methods and current knowledge concerning pathomechanism of thyroid disorders enable to establish a diagnosis much earlier, in subclinical phase, before typical symptoms appear. The question is, whether a patient should be treated at this early stage. If a doctor decides to start a hormonal therapy, next questions concerning a dose of medication and treatment monitoring must be answered. The dose of L-thyroxine should be individually adjusted, based on both clinical and laboratory findings. Moreover, the age of patient, weight, physical activity, profession and general health state should be borne in mind. It is widely established, that the monitoring of TSH level is sufficient. However, in many cases even if TSH level is within the reference range, the patient's complaints, symptoms and quality of life are not satisfying. Therefore, assessment of other parameters of hormonal balance might be helpful. Observations of patients treated for hypothyroidism bring new clinical dilemmas, unresolved despite of long-term experience. There are still questions, whether the laboratory test should be performed before or after taking medication? Should L-thyroxine be taken on the empty stomach every morning, or there are other options? How should results of hormonal tests be interpreted? What factors modify the therapeutic approach (age, pregnancy, coexisting disorders, elective surgery and other)? To conclude, the treatment of hypothyroidism requires multifaceted approach. Therefore, medical care for patients cannot be limited only to monitoring of TSH level, what unfortunately is common in medical practice.

Radioiodine Therapy for Graves Disease

Based on the committed thyroid absorbed dose, the aim was to compare the efficiency of I therapy against Graves disease (GD) within 1 year after treatment and, by exploring the dose-response relationship, indicate an absorbed dose to be targeted into patient therapeutic planning. Thyroid-absorbed doses were calculated to 196 patients with GD by applying Medical Internal Radiation Dose formalism and taking into account administered I activity, thyroid radioiodine uptake, effective half-life, and gland tissue mass. Statistical analysis was applied to assess the relationship between absorbed doses and the patient's clinical response. Overall, successful therapy was achieved in 167 patients, whereas in 29 the disease persisted, even though 64.8% and 89.3% of all the treated patients had received, respectively, thyroid absorbed dose and activity superior to 300 Gy and 11.1 MBq/g (300 μCi/g) of thyroid tissue. Among those in whom the disease persisted, 24 (83%) had a 6- to 24-hour I uptake ratio equal or superior to 0.9, whereas only 5 (17%) presented a lower ratio. According to statistical analysis, there was no difference in cure rate between the groups that received 300 Gy or less and that which received more (84.1% vs 85.8%, P = 0.8336). A thyroid absorbed dose of 300 Gy is plausible as a targeted therapeutic dose in GD therapy planning, because statistical analysis has proven there to be no advantage in treating patients with doses above this level. On the other hand, numerous efforts should be made to develop an optimized and easily applicable protocol of patient-specific dosimetry and to provide data that show its clinical impact on patient management.

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.

Carbohydrate-Mediated Polyethylene Glycol Conjugation of TSH Improves Its Pharmacological Properties

Thyrogen (thyrotropin alfa for injection), recombinant human TSH (rhTSH), has been successfully used to enhance diagnostic radioiodine scanning and thyroglobulin testing in the follow-up of patients with thyroid cancer and as an adjunctive treatment for radioiodine thyroid remnant ablation. However, the short half-life of rhTSH in the circulation requires a multidose regimen. We developed novel sialic acid-mediated and galactose-mediated conjugation chemistries for targeting polyethylene glycol (PEG) to the three N-linked glycosylation sites on the protein, to prolong plasma half-life by eliminating kidney filtration and potential carbohydrate-mediated clearance. Conjugates of different PEG sizes and copy numbers were screened for reaction yield, TSH receptor binding, and murine phamacokinetics/pharmacodynamics studies. The best performing of these products, a 40-kDa mono-PEGylated sialic acid-mediated conjugate, exhibited a 3.5-fold longer duration of action than rhTSH in rats, as a 5-fold lower affinity was more than compensated by a 23-fold extension of circulation half-life. Biochemical characterization confirmed conjugation through the sialic acids. Correlation of PEG distribution on the three N-linked glycosylation sites and the PEG effect on receptor binding supported the previously reported structure-function relationship of rhTSH glycosylation. This long-acting rhTSH has the potential to significantly improve patient convenience and provider flexibility while reducing potential side effects associated with a sudden elevation of serum TSH.

Childhood Thyroid Radioiodine Exposure and Subsequent Infertility in the Intermountain Fallout Cohort

Background: Above-ground and underground nuclear weapon detonation at the Nevada Test Site (1951–1992) has resulted in radioiodine exposure for nearby populations. Although the long-term effect of environmental radioiodine exposure on thyroid disease has been well studied, little is known regarding the effect of childhood radioiodine exposure on subsequent fertility.Objectives: We investigated early childhood thyroid radiation exposure from nuclear testing fallout (supplied predominantly by radioactive isotopes of iodine) and self-reported lifetime incidence of male or female infertility or sterility.Methods: Participants were members of the 1965 Intermountain Fallout Cohort, schoolchildren at the time of exposure who were reexamined during two subsequent study phases to collect dietary and reproductive histories. Thyroid radiation exposure was calculated via an updated dosimetry model. We used multivariable logistic regression with robust sandwich estimators to estimate odds ratios for infertility, adjusted for potential confounders and (in separate models) for a medically confirmed history of thyroid disease.Results: Of 1,389 participants with dosimetry and known fertility history, 274 were classified as infertile, including 30 classified as sterile. Childhood thyroid radiation dose was possibly associated with infertility [adjusted odds ratio (AOR) = 1.17; 95% CI: 0.82, 1.67 and AOR = 1.35; 95% CI: 0.96, 1.90 for the middle and upper tertiles vs. the first tertile of exposure, respectively]. The odds ratios were attenuated (AOR = 1.08; 95% CI: 0.75, 1.55 and AOR = 1.29; 95% CI: 0.91, 1.83 for the middle and upper tertiles, respectively) after adjusting for thyroid disease. There was no association of childhood radiation dose and sterility.Conclusion: Our findings suggest that childhood radioiodine exposure from nuclear testing may be related to subsequent adult infertility. Further research is required to confirm this.

An Uncommon Cause of Asymptomatic Primary Hyperparathyroidism

Asymptomatic hyperparathyroidism developed in a 65-yr-old man with a history of metastatic papillary thyroid carcinoma. Pertinent laboratory values were: calcium, 10.8 mg/dl (2.70 mmol/liter) [reference range, 8.9– 10.1 mg/dl (2.22–2.52 mmol/liter)]; intact PTH, 135.1 pg/ml (14.3 pmol/liter) [15–50 pg/ml (1.6–5.3 pmol/liter)]; and albumin, 4.5 g/dl (45 g/liter) [3.5–5.0 g/dl (35–50 g/liter)]. Phosphorus, creatinine, and 25-hydroxyvitamin D levels were within normal limits. Thyroid ultrasound for follow-up of his thyroid cancer revealed a 3.0 1.3 0.7-cm cystic mass in the left thyroid bed (Fig. 1A). Twenty-five milliliters of clear fluid were removed from the cyst, revealing an intact PTH of 821 pg/ml (87.1 pmol/liter). Serum calcium was 9.0 mg/dl (2.25 mmol/liter) at 6 months and 9.1 mg/dl (2.27 mmol/liter) at 24 months, with intact PTH 56.5 pg/ml (6 ng/liter) and reduction of the cyst to 0.7 0.6 0.7 cm (Fig. 1B). Parathyroid cysts are rare. An uncommon cause of primary hyperparathyroidism is a functional parathyroid cyst (1). Few parathyroid cysts (10–15%) are functional (presenting with hyperparathyroidism) (2). Functional cysts are treated with surgical excision (3, 4), although successful treatment with aspiration has been described in one case report (3). They mimic thyroid and thymic cysts, thus presenting a diagnostic challenge (4). The presence of elevated intact PTH in aspirated fluid is diagnostic. Parathyroid cysts have absent uptake on radioiodine thyroid scans and rarely are positive on sestamibi parathyroid scans (5). Ultrasound, computed tomography, and magnetic resonance imaging show a cystic cervical or mediastinal mass (5). Aspiration of a functioning parathyroid cyst can be both diagnostic and therapeutic. Acknowledgments

Hyperthyroidism and thyroid autoimmunity induced by sorafenib in metastatic renal cell cancer

Dear Editor, Tyrosine kinase inhibitors (TKIs) are novel moleculartargeted agents used in the treatment of various cancers. Treatment with TKIs has been associated with changes in thyroid hormone status. While hypothyroidism had frequently been reported with the use of TKIs, thyroid-stimulating hormone (TSH) suppressing effect of TKIs is rare [1]. Here, we describe a case with metastatic renal cell cancer (RCC), who initially became hyperthyroid under sorafenib treatment and later long-term hypothyroid under sunitinib treatment. A 58-year-old male with metastatic RCC presented with the complaints of weakness, palpitations, restlessness, and trembling in his hands for 4 weeks after starting his new cancer treatment using sorafenib. He did not have any other medication or recent iodinated-contrast exposure. On examination, he had tachycardia, fine tremor, hyperactive deep tendon reflexes, and a smooth, non-tender, slightly enlarged thyroid gland. His test results were compatible with overt hyperthyroidism [TSH: 0.011 lIU/ml (0.55–4.78); free thyroxine (fT4): 8.14 ng/dl (0.89–1.76); and free triiodothyronine (fT3): 17.3 pg/dl (2.3–4.2)], and he had high titers of thyroglobulin (anti-TG) (2,500 U/ml; normal \60), thyroid peroxidase (anti-TPO) (2,723 U/ml; normal \60), and TSH-receptor (TRAb) [24.6 U/L (0–14) antibodies; however, thyroglobulin levels were not elevated [4.76 (1.6–59.9 ng/mL)]. Thyroid function tests, anti-TG and anti-TPO, were normal before sorafenib treatment. His family history was negative for Graves disease. The ultrasonography revealed heterogeneous enlargement of the thyroid gland and the Tc-99 scintigraphy showed a homogeneously increased absorption; 4 and 24 h I uptakes were 49.5 % (15–25 %) and 70.1 % (25–35 %), respectively. Graves disease, induced by sorafenib, was diagnosed based on positivity of anti-TSH receptor antibodies and high radio-iodine thyroid uptake and methimazole (20 mg/dl) and propranolol were prescribed. Completing his first cycle of sorafenib, the patient was switched to sunitinib. He had substantial improvement 1 month after the onset of antithyroid medication. Three months after starting methimazole, he developed features of hypothyroidism with low levels of fT4 (0.59 ng/dl) and fT3 (2.36 pg/dl) despite a sustained suppression of TSH (0.026 lIU/ml). Methimazole was stopped. Four weeks after, TSH increased to 11 lIU/ml and fT4 decreased to 0.47 ng/dl. Levothyroxine treatment was initiated and the patient achieved euthyroidism in 2 months. Currently, he is on follow-up with 150 mcg/day levothyroxine for the last 7 months without significant symptoms. Few cases of thyroid hormone excess have been reported with sunitinib; however, they were whether mild and self-limiting or if overt, was associated with low uptake in thyroid scan and elevated thyroglobulins suggesting destructive thyroiditis [1]. There is even fewer data on the TSH-suppressing effect of sorafenib. Miyake et al. [2] reported that 23.9 % of patients with metastatic RCC receiving sorafenib had TSH suppression before the development of hypothyroidism. One case with overt hyperthyroidism was reported after sorafenib treatment in a C. Konca Degertekin (&) F. Balos Toruner M. Akturk Department of Endocrinology and Metabolism, Faculty of Medicine, Gazi University, Gazi Universitesi Hastanesi, Endokrinoloji ve Metabolizma BD, 06100 Besevler, Ankara, Turkey e-mail: ceylakonca@hotmail.com

Recurrence of Hyperthyroidism in a Female Patient With Thyroidectomized Grave's Disease Diagnosed 15 Years Earlier

A computer-assisted Bayesian individual estimation of radioiodine thyroid uptake kinetics for patients suffering from Grave's disease is proposed. The program provides a fast computation of the activity to be administered to a given patient to achieve a target thyroid absorbed dose. This determination relies upon the patient biological covariates and upon a small number of measurements performed during a preliminar kinetic study of radioiodine thyroid uptake. Our results indicate that a two-sample Bayesian approach is reliable when external thyroid counts are performed at 2 h and 168 h after a test dose and has advantages over conventional kinetic experiments in terms of patients acceptability. This method is implemented on widespread computers and interfaced with a patient database. An interactive user interface with in-line data checking is provided. The program could be also a tool to better study the relationship between the absorbed dose and the clinical effect.