Thyroid Radioiodine Uptake Research Articles

6537 Recurrent Graves Thyrotoxicosis After Prolonged Radioiodine-Induced Hypothyroidism

Abstract Disclosure: H.K. Deveaux: None. A. Gundeti: None. K. Mitrollari: None. A.P. Calimag: None. T. Yasmeen: None. Radioactive iodine (I-131) ablation (RAI) is one of the effective therapies for Graves’ disease (GD). Successful treatment is indicated by sustained, irreversible hypothyroidism requiring lifelong replacement for which recurrence of disease rarely develops. Recurrent hyperthyroidism is a rare development without apparent predisposition. Here, we describe a case of recurrent thyrotoxicosis after 36 years of RAI.70-year-old female PMH atrial fibrillation (AFib) on apixaban s/p cardioversion, HTN, HFpEF, Pulmonary HTN, and Graves’ Disease s/p RAI ablation 36 years ago with RAI-induced hypothyroidism. The patient was initially on levothyroxine for post-ablative hypothyroidism and stopped taking levothyroxine around 2019. NM scintigraphy done in 2019 showed an abnormal I-123 thyroid uptake and scan with the five-hour radioiodine thyroid uptake showed mildly hyperthyroid. On the thyroid scan, there is a note of a prominent pyramidal lobe with some thyroid gland asymmetry. In 2022, the patient was admitted for new-onset AFib and was noted to have subclinical hyperthyroidism with TSH 0.157, fT4 1.4, TrAb>40, and TSI 34.8. The patient was started on methimazole, which she stopped one month later. During this admission, the patient presented secondary to a mechanical fall and was found to be in AFib with a rapid ventricular rate. Her labs were significant for TSH<0.008 fT4 4.2, TrAb >40. Methimazole was restarted with maximal doses of diltiazem and metoprolol for rate control. Thyroid ultrasound demonstrated an enlarged, heterogeneous thyroid gland with increased vascularity and multiple bilateral TR3 thyroid nodules.Hyperthyroidism affects approximately 1.2% of the population. GD involves autoantibodies activating the thyrotropin receptor, increasing synthesis and release of thyroid hormone and is for 50-60% of cases with a 5-to-10-fold preference for females. RAI ablation is preferred, being inexpensive, with a cure rate approaching 100%. The incidence of transient hypothyroidism post-RAI varies from 9-17%. Retrospective studies have observed hyperthyroidism within the first 12 months post-RAI; however, some cases have seen a resurgence as late as 22 years later. Recurrent hyperthyroidism is an uncommon occurrence with various postulated aetiologies, such as inadequate dosing/incomplete ablation with residual cells remaining viable and regenerating in the setting of increased TSIiv, Marine-Lenhart syndrome (MLS), or an unclear mechanism associated with autoimmunity in the presence of TSI. Hyperthyroidism rarely recurs in GD after successful post-ablative treatment with RAI. Our case, while an uncommon presentation and underlying aetiology yet to be determined, illustrates the importance of continued surveillance, even after successful treatment.‌ Presentation: 6/3/2024

Comparison of Thyroid Uptake Values Measured from 131I Scintigraphy and Uptake Probe in Hyperthyroid Patients

Objective: Thyroid uptake test plays an important role in diagnosis, treatment planning and radioiodine dose determination in patients with hyperthyroidism. The aim of this study was to compare the % uptake values calculated with gamma camera and uptake probe after diagnostic 131I application in hyperthyroid patients. Materials and Methods: In this study, % uptake values were measured using a thyroid uptake probe and gamma camera in 32 patients who underwent thyroid radioiodine uptake measurement in our Nuclear Medicine center. Thyroid uptake measurements were prepared in the neck phantom with 0.74–0.925 MBq activity of 131I radionuclide. After counting the phantom with 131I separately in the uptake probe and gamma camera, 131I sample was orally administered to the patient. % uptake values were calculated by the uptake probe measurements and drawing regions of interest (ROI) from scintigraphic images at 2 and 24 h. Results: The 2-h mean % uptake values in the probe and gamma camera were calculated as 30.5 ± 20.4 and 27.1 ± 18.6, respectively. The 24-h mean % uptake values in the thyroid probe and gamma camera were calculated as 57.6 ± 21.9 and 55.3 ± 21.5, respectively. Linear regression analyses for the 2- and 24-h % uptake values calculated with the probe and gamma camera were found as R2 = 0.8412 and R2 = 0.7313, respectively. Conclusion: The 2- and 24-h % uptake values with the probe and gamma camera were found to be consistent with each other, indicating that they can be safely used interchangeably in patients with hyperthyroidism.

Concomitant lithium increases radioiodine uptake and absorbed doses per administered activity in graves' disease: comparison of conventional versus lithium-augmented radioiodine therapy.

BackgroundLithium inhibits iodine and thyroid hormone release from thyroid cells, possibly increasing radioiodine retention and anti-hyperthyroid efficacy when given adjunctively to radioiodine therapy (RAI) of Graves’ disease (GD). However, the literature contains limited dosimetric data regarding the influence of concomitant lithium in this setting.MethodsWe retrospectively compared dosimetric variables in patients undergoing RAI with/without adjunctive lithium (n = 52 each). We assessed two low-dose, short-duration oral lithium carbonate regimens, 450 mg/d (n = 22) or 900 mg/d (n = 30), for a mean of 4.7 ± 1.4 d starting upon RAI administration. Patients underwent diagnostic testing to measure thyroidal radioiodine uptake (RAIU) 24 h ± 2 h after ingesting up to 5 MBq radioiodine, receiving individualized RAI activities 24 h later. Using ≥3 RAIU daily measurements starting 24 h post-RAI, researchers were able to determine the effective radioiodine half-life and absorbed dose to the thyroid; we also calculated the absorbed dose per administered activity concentration within that organ. Rates of GD cure, defined as reaching euthyroidism or hypothyroidism post-RAI, were evaluated in patients with ~6 months or longer post-RAI follow-up.ResultsThe lithium dosage subgroups had similar dosimetric values and thus are considered together. Lithium patients and controls had similar average “diagnostic” RAIU (51.1% ± 15.7% vs. 50.6% ± 13.8%, p = 0.820), but the former had significantly higher RAIU post-RAI (56.3% ± 13.5% vs. 49.1% ± 13.5%, p = 0.002), reflecting significantly greater change in the former (+16.2% ± 30.4% vs. -1.8% ± 16.1%, p = 0.001). Radioiodine effective half-life was non-significantly longer in lithium patients (5.43 ± 1.50 d vs. 5.08 ± 1.16 d, p = 0.192). The mean RAI administered activity was 27% less in lithium patients (677 ± 294 MBq vs. 930 ± 433 MBq, p = 0.001), but GD cure rates were similar (83% [39/47] vs. 82% [33/40], p = 0.954), possibly due to the significantly higher thyroid dose in the lithium patients, especially in thyroid gland with a volume ≤ 20 mL (1.04 ± 0.44 Gy/MBq vs. 0.76 ± 0.30 Gy/MBq, p = 0.020). Day 3 serum lithium concentrations were low (450 mg/d: 0.26 ± 0.12 mmol/L, 900 mg/d: 0.50 ± 0.18 mmol/L); no lithium toxicity was noted.ConclusionLithium augmentation may increase the RAIU and thyroid absorbed dose, permitting potentially decreased RAI activities without sacrificing efficacy. Our observations should be confirmed in a prospective, randomized trial.

Utility of 99m Technetium Pertechnetate Thyroid Scan and Uptake in Thyrotoxic Patients: Jordanian Experience.

Objective The objective of this study was to assess our local experience with 99m Technitium thyroid uptake (TcTU) in thyrotoxicosis by examining mean and range of TcTU in both euthyroid patients and thyrotoxic patients. We also wanted to see how well TcTU performed as a substitute for radioiodine thyroid uptake in thyrotoxicosis. Methods The medical records of thyrotoxic patients were reviewed retrospectively. Inclusion criteria were: (1) thyrotoxicosis was proven biochemically, (2) the patient underwent TcTU at the time of thyrotoxicosis diagnosis, (3) at least 6 months of follow-up, and (4) the final diagnosis was documented. All TcTU of euthyroid patients were also reviewed to determine local normal TcTU mean and range. Patients were divided into three groups: Graves' disease, toxic nodular goiter, and subacute thyroiditis. Each patient group's TcTU mean and range were assessed separately. Results There were 209 patients in total (54 euthyroid, 112 Graves' disease, 26 toxic nodules, and 17 patients with subacute thyroiditis). TcTU mean±standard deviation and range for euthyroid patients were 1.5±1.1% and 0.17 to 4.8%, 10.6±10% and 0.43 to 40% for Graves' disease, 4.5±4% and 0.6 to 15% for toxic nodules, and 0.5±0.4% and 0.18 to 1% for subacute thyroiditis. Although one-third of thyrotoxic patients' TcTU values overlapped with the normal TcTU range, the diagnosis was made using qualitative image analysis. Subacute thyroiditis was characterized by poor thyroid visualization, whereas Graves'/toxic nodular goiter was well visualized. Conclusion The mean and range of our local normal TcTU were similar to those previously published. TcTU was a useful alternative to radioiodine in the evaluation of thyrotoxicosis. About two-thirds of the patients had accurate test results. The diagnosis was reached in the remaining one-third of patients by combining quantitative and qualitative image features. This method allowed us to stop giving radioiodine to our patients, resulting in a significant reduction in patient radiation exposure.

Real-time quantitation of thyroidal radioiodine uptake in thyroid disease with monitoring by a collar detection device

Radioactive iodine (RAI) is safe and effective in most patients with hyperthyroidism but not all individuals are cured by the first dose, and most develop post-RAI hypothyroidism. Postoperative RAI therapy for remnant ablation is successful in 80–90% of thyroid cancer patients and sometimes induces remission of nonresectable cervical and/or distant metastatic disease but the effective tumor dose is usually not precisely known and must be moderated to avoid short- and long-term adverse effects on other tissues. The Collar Therapy Indicator (COTI) is a radiation detection device embedded in a cloth collar secured around the patient’s neck and connected to a recording and data transmission box. In previously published experience, the data can be collected at multiple time points, reflecting local cervical RAI exposure and correlating well with conventional methods. We evaluated the real-time uptake of RAI in patients with hyperthyroid Graves’ disease and thyroid cancer. We performed a pilot feasibility prospective study. Data were analyzed using R© (version 4.0.3, The R Foundation for Statistical Computing, 2020), and Python (version 3.6, Matplotlib version 3.0.3). The COTI was able to provide a quantitative temporal pattern of uptake within the thyroid in persons with Graves’ disease and lateralized the remnant tissue in persons with thyroid cancer. The study has demonstrated that the portable collar radiation detection device outside of a healthcare facility is accurate and feasible for use after administration of RAI for diagnostic studies and therapy to provide a complete collection of fractional target radioactivity data compared to that traditionally acquired with clinic-based measurements at one or two time-points.Clinical Trials Registration NCT03517579, DOR 5/7/2018.

Rare Case of Thyroid Storm Masked by Diabetic Ketoacidosis

Abstract Introduction: Diabetic ketoacidosis can be triggered many other clinical conditions. In this case we describe uncommon presentation of diabetic ketoacidosis in the setting of thyroid storm. Clinical Case: An 82-year-old woman with history of type 2 diabetes treated with Insulin and Metformin presented with multiple falls preceded by fatigued and decreased oral intake for two weeks. On initial presentation, she was noted to have hyperglycemia and labs consistent high anion gap metabolic acidosis and positive serum and urine ketones suggesting diabetic ketoacidosis. Investigations were negative for any triggering infections. Diabetic ketoacidosis resolved with intravenous fluids and Insulin. However, patient remained consistently tachycardic. Repeated thyroid workup showed declining TSH (from 0.66 to 0.12 mIU/mL) (n: 0.270 - 4.200 mIU/mL), free T4 of 4.3 ng/dL (n: 0.9 - 1.7 ng/dL) and free T3 of 9.7 ng/dL (n: 79 - 165 ng/dL), thyroid peroxidase antibodies and thyroid stimulating immunoglobulin were both elevated of 293 IU/mL (n: <5.6 IU/mL) and 7.2 IU/L (n: <0.55 IU/L) respectively. Thyroid ultrasound showed several nodules in the isthmus and left lobe with multiple nodules with largest one measuring 1 X 2.3 cm. Treatment with Methimazole and Prednisone was initiated with good response. On follow up with endocrinology, repeated TSH was 28 mIU/mL and her Methimazole dose was reduced. Due to patient wishes of being conservative in management, no thyroid radioiodine uptake scan to evaluate the nodules. Conclusion: Literature review shows several similar case reports of newly diagnosed thyrotoxicosis manifested by DKA in known type 1 and type 2 diabetic and obscured by other confounding conditions including pericarditis, flu syndrome, psychosis and cellulitis ultimately delaying diagnosis and treatment of thyroid storm. Fortunately, none of these cases were associated with adverse outcome. By presenting this case we emphasis on including thyroid function test as part of initial work up of diabetic ketoacidosis to avoid any potential adverse outcomes.

A Case for Lithium Pretreatment Prior to Radioactive Iodine Ablation in Grave’s Disease

Radioactive iodine ablation (RAIA) therapy with Iodine-131 (I-131) is an established treatment for grave’s thyrotoxicosis. However, there is 10 to 20% chance of treatment failure. Lithium, a drug used to treat bipolar disorder, has significant effects on thyroid function. The most clinically relevant is the inhibition of thyroid hormone release. It is also known to inhibit colloid formation, and is involved in blocking organic iodine as well as thyroid hormone release from the thyroid gland without an effect on radioiodine uptake. This leads to increased radioiodine retention in the thyroid gland. Here, we present a case which exemplifies this action of lithium. A 46 year old male with a history of atrial fibrillation and grave’s disease presented to the endocrine clinic. TSH was <0.01 and FT4 was 36. RAI uptake (RAIU) scan showed diffusely increased uptakes with 4 and 24 hour values of 61.2 and 54.6 %. He subsequently underwent RAI ablation with 18 mCi of I 131. He then presented three years later with persistent hyperthyroid symptoms. TSH <0.01 and FT4 4.3. RAIU showed 24-h thyroid uptake of 41%. Patient opted for a second treatment with RAIA and was treated with 30 millicuries of I 131. He however continued to have clinical and biochemical evidence of thyrotoxicosis and was started on methimazole (MMI). Although he was biochemically euthyroid on MMI, he continued to complain of hyperthyroid symptoms such as palpitations, tremors and weight loss. When methimazole was briefly held six months after initiation, TSH was undetectable and FT4 had increased from 0.83 to 1.42. He subsequently underwent a third RAIU off MMI which showed normal 4 and 24 hour uptake, measuring 15.7% and 28% respectively. Patient subsequently opted for third trial of RAI ablation with lithium pretreatment. He declined surgery. He was started on lithium 900mg/day for 6 days, starting on the day of RAI ablation. He underwent RAI ablation with 45 mCi I-131. Patient tolerated the procedure well with subsequent tests indicating hypothyroidism requiring levothyroxine supplementation. Patient’s hyperthyroid symptoms resolved. Several factors affect the efficacy of radioiodide therapy for hyperthyroidism including the short persistence of radioiodide in the thyroid gland. In hyperthyroid Graves’ patients, radioactive iodide uptake is enhanced due to presence of TSH receptor antibody, however, radioiodide is also rapidly discharged because of its increased turnover. Lithium can significantly reduce the release of iodine from the thyroid gland and thus increase iodine retention. There is evidence to suggest that adjuvant lithium can increase thyroidal radioiodine uptake in patients with a low baseline RAIU (< 30%). This case demonstrate that lithium can be used safely prior to RAI therapy in cases of RAI ablation failure even with low baseline RAIU.

Platelet-Lymphocyte Ratio as a Novel Surrogate Marker to Differentiate Thyrotoxic Patients with Graves Disease from Subacute Thyroiditis: a Cross-Sectional Study from South India

Graves disease (GD) and the toxic phase of subacute thyroiditis (SAT) have similar clinical and biochemical presentations, and differentiating them requires sophisticated investigations. Since thyroid hormones have been noted to affect all hematologic cell lines, we have used the platelet lymphocyte ratio (PLR)-an index usually utilized in inflammatory or malignant disorders-to compare patients with and without thyrotoxicosis and to analyze its use in distinguishing between patients with GD and SAT prior to therapy. This was a cross-sectional study conducted in the Department of Endocrinology, Christian Medical College, Vellore, India. During the study period, 800 patients with features of thyrotoxicosis visited the outpatient clinic. Those who had thyroid radioiodine (131I) uptake (RAIU) study and complete blood count (CBC) at diagnosis were included (N = 500). Based on the RAIU values, these were divided as GD (n = 354) and SAT (n = 146). Baseline characteristics, thyroid function tests, and components of the CBC and PLR were obtained. The data were compared with a group of 250 matched euthyroid controls. Analyses were performed using SPSS version 21.0 software. PLR showed significant reductions in both GD and SAT patients when compared to euthyroid controls (P = .01), with greater reductions seen in GD than SAT (74.5 ± 19 vs. 84.4 ± 26; P = .01). Using receiver operating characteristic analysis of PLR, an optimal PLR cut-off of 70.4 was found to differentiate GD from SAT with a sensitivity of 86% and specificity of 74%. PLR can be used as a novel surrogate marker to differentiate between patients with GD and SAT prior to therapy, especially in resource-limited settings.

Painless thyroiditis in a dupilumab-treated patient.

SummaryDupilumab an inhibitor of the interleukin (IL)-4R-alpha subunit is used for the treatment of allergic diseases. The patient was a 49-year-old man who received dupilumab for the treatment of severe atopic dermatitis. He presented hyperthyroidism with elevated thyroglobulin and anti-thyroid antibody negativity at 4 months after the initiation of therapy. On scintigraphy, the thyroid radioiodine uptake was low. Ultrasonography showed a diffuse hypoechoic area in the thyroid gland. A pathological study revealed lymphocytic infiltration. The administration of dupilumab was continued because of his atopic dermatitis that showed an excellent response. The patient`s hyperthyroidism changed to hypothyroidism 3 weeks later. Six months later his thyroid function normalized without any treatment. We herein describe the case of a patient with atopic dermatitis who developed painless thyroiditis under treatment with dupilumab. To the best of our knowledge, this is the first report of this event in the literature.Learning points:Dupilumab, a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13, has been shown to be effective in the treatment atopic dermatitis and asthma with eosinophilia.Painless thyroiditis is characterized by transient hyperthyroidism and hypothyroidism and recovery without anti-thyroid treatment.This is the first report of painless thyroiditis as an adverse effect of dupilumab, although conjunctivitis and nasopharyngitis are the main adverse effects of dupilumab.

SAT-LB89 Choriocarcinoma Induced Hyperthyroidism: Molecular Mimicry Between HCG and TSH

Introduction: Human chorionic gonadotropin(HCG) induced hyperthyroidism is a rare cause of hyperthyroidism. It is usually seen in conditions with extremely high beta HCG levels like hyperemesis gravidarum, hydatiform moles and germ cell tumors. We present a young male patient who had primary mediastinal choriocarcinoma with widespread lung metastasis and hyperthyroidism. Case: 18-year-old male presented to the emergency department for a fever of 105 F, cough, shortness of breath and night sweats for 9 days. He also reported unintentional weight loss for the past few weeks. Upon presentation, he was tachycardic at 104 beats/min, tachypneic and febrile. Physical examination revealed bibasilar crackles. Thyroid and scrotal examination were unremarkable. Laboratory work was significant for leukocytosis of 18.7 k/cmm, AST: 69 Unit/L, ALT: 60 Unit/L, ALP: 123 unit/L and LDH: 438Unit/L. Chest radiology showed bilateral multiple cannonball lesions with mediastinal and periaortic lymphadenopathy. CT chest, abdomen, and pelvis revealed innumerable diffuse bilateral lung masses, large anterior mediastinal mass, enlarged periaortic and paratracheal lymph nodes. Infectious workup was unremarkable. MRI brain revealed leptomeningeal involvement and vasogenic edema. Ultrasound of testicles revealed bilateral severe microlithiasis. CT guided biopsy of lung mass showed poorly differentiated choriocarcinoma. Treatment was initiated with systemic steroids, bleomycin, and cisplatin. Additional blood work revealed, B-HCG:736,598 mIU/mL, TSH:0.009UIU/ml, free T4:2.95ng/dL and total T3: 292.3ng/Dl. Thyroid radioiodine uptake scan was normal and planar imaging was also normal. Treatment with methimazole was deferred due to the up-trending transaminases and the resolution of tachycardia. Repeat labs after chemotherapy were TSH: 0.005UIU/mL, free T4: 2.04ng/dL, free T3:1.70pg/mL and BHCG: 202,471UIU/mL. Unfortunately, the patient had chemotherapy-resistant choriocarcinoma and succumbed to death after 4 cycles. Discussion: Beta HCG has an intrinsic thyroid-stimulating activity. The HCG -alpha subunit is common to all glycoprotein hormones like follicle-stimulating hormone, luteinizing hormone or thyroid-stimulating hormone. Frankly elevated levels should be treated symptomatically with beta-blockers and/or anti-thyroid drugs. Subclinical hyperthyroidism should be monitored closely. Some patients do not develop hyperthyroidism or a toxic goiter, as it is dependent on the timing of onset of cancer or due to the secondary modifications of HCG that can affect the bioactivity of HCG on the TSH receptor. This case draws our attention to the importance of focusing on the molecular mimicry of the HCG and TSH and management of HCG mediated hyperthyroidism.

Thyroid-disrupting effects and mechanism of thiazole-Zn-induced thyroid cell hypertrophy and hyperplasia in male Sprague-Dawley rats.

Thiazole-Zn is a systemic fungicide synthesized and developed in China that has been used for the prevention and treatment of bacterial and fungal diseases on fruits and vegetables. Thiazole-Zn is a new thyroid disruptor chemical. The purpose of this study was to clarify the thyroid-disrupting property of thiazole-Zn and the mechanism responsible for thyroid hormone (TH) biosynthesis inhibition in male rats induced by thiazole-Zn. First, the effects of different thiazole-Zn doses and exposure times on the thyroid weights, thyroid morphology and serum hormone levels of rats were investigated. The results showed that thiazole-Zn increased thyroid weights and serum thyroid-stimulating hormone (TSH) levels and induced thyroid cell hypertrophy and hyperplasia in a dose-related and time-related manner. Furthermore, measurement of thyroid radioiodine uptake in vivo in rats confirmed that thiazole-Zn inhibited active iodide uptake into the thyroid, which reduced circulating levels of serum T3 and T4. Decreases in circulating THs resulted in a compensatory increase in serum TSH levels through a negative feedback system. Subsequently, sustained excessive stimulation of the thyroid gland by TSH led to thyroid follicular cell hypertrophy and hyperplasia. In addition, thiazole-Zn increased sodium/iodide symporter (NIS) expression in the rat thyroid, and the increased NIS expression promoted and restored iodide uptake into the thyroids of rats. The risk of iodine intake inhibition by thiazole-Zn to humans, especially susceptible individuals, such as children and pregnant women, warrants additional attention.

Tissue quantification of radioiodine thyroid uptake in humans by an isotopic imaging technique on slides.

Thyroid metabolism involves iodine, which allows us to use radioactive iodine for diagnostic and therapy purposes. The efficiency of radioiodine therapy depends on several parameters; the ability of thyroid tissue to uptake radioactive iodine is one of them. The objective of this work is to quantify the radioactive iodine uptake on thyroid tissue. In this work, we developed a method to quantify the in vivo uptake of iodine-131 on sections of thyroid glands removed by thyroidectomies. We performed an analysis of histological sections of the thyroid tissue by beta imaging. We had the opportunity to quantify the fixed radioactivity and to analyze its distribution in the thyroid gland, thanks to the good spatial resolution available with the type of detector used. The results gave a high image resolution showing the heterogeneity of iodine-131 fixation by the thyroid tissue. We were able to quantify the tissue radioactivity in mega Becquerel (MBq) per volume unit. This work has shown that the direct quantification of the thyroid tissue uptake is possible using the beta imaging system.

Abstract 920: p97/VCP: A novel interactor of the sodium iodide symporter, which can be pharmacologically targeted to increase radioiodine uptake in thyroid and breast cancer cells

Abstract By exploiting the canonical function of the sodium iodide symporter (NIS), ablative radioiodine therapy is an effective treatment for papillary thyroid cancer (PTC). Unfortunately, ~25% of PTC patients are unable to accumulate therapeutically sufficient radioiodine due to diminished expression and/or altered plasma membrane localization of NIS. Patients with radioiodine-refractory PTC have reduced mean survival times. Radioiodine therapy has been proposed as a viable treatment for breast cancer but is hampered by low levels of membranous NIS localization. Currently, however, the regulation of NIS membrane localization remains ill-defined. Mass spectrometry identified the protein p97/VCP as a novel NIS interactor, which was validated through co-immunoprecipitation and proximity ligation assays. p97 siRNA depletion increased NIS-mediated radioiodine uptake by 97% and 141% in the lentivirally-expressing NIS MDA-MB-231 breast and TPC1 thyroid cancer cell lines respectively (p&amp;lt;0.05), and significantly boosted endogenous NIS function in human primary thyrocytes (p&amp;lt;0.05). Conversely, p97 overexpression significantly repressed NIS function in all cell systems, accompanied by lowered membranous NIS localization (p&amp;lt;0.05), as quantified via cell surface biotinylation assays. We next identified five different allosteric p97 inhibitors - Eeyarestatin-1, NMS-873, Astemizole, Clotrimazole and Ebastine - which were all able to overcome p97 inhibition of NIS function in TPC1 and MDA-MB-231 cell lines lentivirally-expressing NIS, significantly increasing NIS function by at least 100%. TCGA analyses of matched PTCs revealed p97 mRNA expression is highly upregulated in PTC compared to matched normal thyroid (n=58, p&amp;lt;0.05), providing a putative explanation for repressed NIS function. In a wider cohort of 413 PTC patients, high tumoral p97 expression was associated with a worse disease-free survival when compared to low p97 expression (p&amp;lt;0.01, hazard ratio (HR): 2.924 (95% CI, 1.280-6.683)). Strikingly, in patients that did not receive radioiodine, high tumoral p97 expression had no significant effect on disease-free survival (n=136, p=NS, HR: 0.020 (95% CI, 0.000013-31.192)), whereas in patients who received radioiodine, high tumoral p97 expression resulted in a markedly worse disease-free survival (n=194, p&amp;lt;0.01, HR: 6.043 (95% CI, 1.749-20.879)). This is indicative that high p97 expression correlates with a worse response to radioiodine therapy. Our data therefore highlight a new pathway of NIS regulation. Critically, two of these p97 inhibitors are already FDA-approved, highlighting a novel potential therapeutic strategy for enhancing radioiodine uptake in patients with radioiodine-refractory PTC and increasing the feasibility of radioiodine therapy in breast cancer via the transient inhibition of p97 activity. Citation Format: Alice Fletcher, Martin L. Read, Vikki L. Poole, Vicki E. Smith, Christopher J. McCabe. p97/VCP: A novel interactor of the sodium iodide symporter, which can be pharmacologically targeted to increase radioiodine uptake in thyroid and breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 920.

Improving individualised dosimetry in radioiodine therapy for hyperthyroidism using population biokinetic modelling

The application of an individualised dosimetric procedure for radioiodine therapy requires the intensive use of resources in nuclear medicine facilities. In practice, the amount of data taken per patient is too limited to obtain an accurate estimate of the absorbed dose in the thyroid. The individualised absorbed dose estimates can be enhanced using statistical tools for population-based approaches. The aim of this work was to build a population biokinetic model of thyroid uptake and elimination of radioiodine using a nonlinear mixed-effects approach in patients with Graves’ disease. Input data for the model development were taken from a dosimetric method based on 123I imaging data. 123I decay-corrected uptake values were estimated at 4, 24, and 96 h post-administration and for 58 patients. The root mean squared error (RMSE) for predicted 123I uptake values by the fitted model was 4%. The root mean squared error of prediction (RMSEP) for out-of-sample 123I uptake values, computed by a leave-one-out cross-validation, was 12%. We calculated 131I activity to administer from out-of-sample predicted 123I uptake values and compared the result with that calculated from observed 123I uptake values. RMSEP values for therapeutic activity revealed that there were measuring points with higher weight than others in the model. The mixed-effects approach can be used to enhance the accuracy of dosimetric calculations in therapies using 131I. Assessing the accuracy of the predictive model enables choosing among different time-sampling schedules of the radioiodine thyroid uptake curve. This methodology can also be applied in other areas of radiation dosimetry.

SAT-550 High Fat Diet-Induced ER Stress Affects Hypothyroidism

Recent studies revealed the emerging role of excess uptake of lipids in the development of hypothyroidism. Both dietary high-fat lard intake in rats and diet-induced obese mice displayed thyroid hypofunction (1,2). However, the underlying mechanism is largely unknown. We investigated the effect of high fat diet (HFD) on thyroid function and the role of endoplasmic reticulum (ER) in HFD induced hypothyroidism. Male Sprague Dawley rats were fed with HFD or control diet (CD) for 18 weeks. HFD rats showed increased serum TSH (n=15-16) and decreased T4 (n=15-16) compared to CD rats. Thyroid function was also evaluated by thyroid radioiodine uptake for 24 hours in vivo. Consistently, HFD decreased thyroid iodine uptake (-60%, n=5). To understand the molecular mechanism, we assessed the expression of proteins critical to thyroid production via Western blotting. Compared to CD, HFD rats showed significantly decreased thyroglobulin (Tg) (-40%, n=4), whereas TPO and NIS showed no difference. Meanwhile, luminal swelling of ER in thyroid epithelial cell of HFD rats was observed via transmission electron microscopy. Furthermore, We found PERK/eIF2a/ATF4 -- one of three traditional UPR pathways triggered under ER stress -- was activated in HFD rat thyroid glands compared to CD (n=4). In vitro, ER stress was induced in primary human thyrocytes by palmitate. Under the treatment of palmitate, Tg was degraded more rapidly than the control, indicating the activating of the ER-associated protein degradation pathway under ER stress. In addition, alleviation of ER stress by applying 4-phenyl butyric acid (4-PBA) in HFD rats or by the withdrawal of HFD improved the decrease of Tg (n=4-6) and thyroid function (n=3-6). In conclusion, we demonstrate that ER stress mediates the HFD induced hypothyroidism, probably by impairing the production of Tg, and attenuation of ER stress improves thyroid function. Reference: (1) Shao et al., Acta Pharmacol Sin 2014, 35: 1411-1420. (2) Lee et al., Endocrinology 2015, 156: 1181-1193. Conflict of interest: The authors declare they have no conflicts of interest. Sources of Research Support: National Natural Science Foundation of China (81430020, 81230018, 81600604, 81300644, and 81670720) and the Natural Science Foundation of Shandong Province (ZR2016HB07).

Vemurafenib Restores Radioiodine Uptake in Some Metastatic Thyroid Cancers

Clinical ThyroidologyVol. 30, No. 11 SummariesVemurafenib Restores Radioiodine Uptake in Some Metastatic Thyroid CancersJerome M. HershmanJerome M. HershmanSearch for more papers by this authorPublished Online:14 Nov 2018https://doi.org/10.1089/ct.2018;30.516-518AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetailsCited byKinase Inhibitors May Enhance I-131 Uptake in Thyroid Cancer Brian W. Kim18 December 2018 | Clinical Thyroidology, Vol. 30, No. 12 Volume 30Issue 11Nov 2018 InformationCopyright 2018 American Thyroid Association, Inc.To cite this article:Jerome M. Hershman.Vemurafenib Restores Radioiodine Uptake in Some Metastatic Thyroid Cancers.Clinical Thyroidology.Nov 2018.516-518.http://doi.org/10.1089/ct.2018;30.516-518Published in Volume: 30 Issue 11: November 14, 2018PDF download

Thyroid Uptake and Effective Half-Life of Radioiodine in Thyroid Cancer Patients at Radioiodine Therapy and Follow-Up Whole-Body Scintigraphy Either in Hypothyroidism or Under rhTSH.

Adjuvant radioiodine therapy (RITh) for differentiated thyroid carcinoma is performed either with thyroid hormone withdrawal or with administration of recombinant human thyroid-stimulating hormone (rhTSH). Heterogeneous results have been obtained on the impact of the method of patient preparation on thyroid uptake and whole-body effective half-life. A higher radiation exposure using thyroid hormone withdrawal for several weeks compared with rhTSH was reported in prior studies. It was the aim to examine whether these findings are reproducible in a modern protocol with a short interval between surgery and RITh. Methods: A retrospective study was performed on patients admitted for adjuvant RITh for differentiated thyroid carcinoma at the University Hospital of Cologne over a 5-y period from 2010. Dose rate measurements were analyzed for 366 patients, and subgroup analyses were performed for papillary thyroid cancer (n = 341) and follicular thyroid cancer (n = 25) patients, sex, length of hypothyroidism, and normal versus decreased glomerular filtration rate (GFR). Results: The median interval between surgery and RITh was 18 d for thyroid hormone withdrawal and 25 d for rhTSH (P < 0.01). The mean thyroid uptake was 4.2% ± 1.8% for the 300 hypothyroid patients versus 3.8% ± 1.6% (P = 0.12) for the 66 rhTSH patients. Whole-body half-life in the hypothyroid group was significantly longer at 19.3 ± 7.7 h versus 16.4 ± 4.6 h in the rhTSH group (P < 0.01). Results were predominantly influenced by data from the largest subgroup, that is, female papillary thyroid cancer patients. Within this group, whole-body half-life was significantly shorter in the rhTSH treatment arm. Duration of hypothyroidism and a decrease in GFR less than 60 mL/min/1.73 m2 significantly influenced results, with an increased whole-body half-life occurring in the hypothyroid group. When patients returned for whole-body scintigraphy, thyroid, half-life, and whole-body half-life were significantly shorter in the rhTSH groups, resulting in a low thyroid and remaining-body dose. Conclusion: With a shortening of the time between surgery and adjuvant RITh, thyroid uptake is not significantly changed but whole-body half-life becomes longer in the hypothyroid group. Radiation exposure for most patients is not significantly different. However, patients with a hypothyroid phase of more than 4 wk, and in particular those with a decreased GFR, experience higher radiation exposure.

Radioiodine Thyroid Uptake and Scintigraphy in the Evaluation of Hyperthyroidism with Multinodular Goiter

The role of radioactive iodine uptake and scintigraphy were studied over 111 subjects with a mean age of 42±13 years, 65% females and 35% males, in the evaluation of hyperthyroidism with multinodular goiter. The uptake study was performed by oral administration of 4.5 – 10.0 μCi of 131I as sodium-iodide thyroid scintigraphy was performed 20 minutes after an intravenous injection of 2.0 – 4.0 mCi of 99mTc as pertechnetate. The Mean ± SD uptake values for the study subjects were found to be 36.1±15.4% ranging from 14% to 75% at 2 h and 59.9±15.9% ranging from 32% to 90% at 24 h measurements. The present results of uptake values clearly exceed the normal range (3% – 12% for 2 h; 8% – 25% for 24 h), which indicate the hyper-functioning of thyroid, and therefore, demonstrated successfully the efficient role of radioactive iodine uptake and scintigraphy to diagnose the hyperthyroidism.

P081] A population-based and mixed model approach for enhancing iodine biokinetics in radioiodine therapy for hyperthyroidism

Purpose Individualized calculation of radioiodine 131 I activity for the treatment of benign thyroid disease is imperative according to Euratom Directive 59/13. In general, measurements taken per patient are very limited to obtain an accurate estimate of the absorbed dose in the thyroid. The application of statistical tools can improve the accuracy of the biokinetic parameters used to calculate personalized activity. The aim of this work was to model the population biokinetics of thyroid for hyperthyroid patients using a nonlinear mixed-effects approach. Methods The model data were obtained from planar scintigraphic images obtained 4, 24 and 96 hours after the pretherapeutic administration of 111 MBq of 123 I-NaI . A total of 174 uptake measurements corrected for physical decay in patients who received 131 I - NaI for Graves’ disease were included in the study. The root mean squared error (RMSE), coefficient of determination (R2) and leave-one-out cross-validation (LOOCV) method were used to evaluate the goodness of the fit and performance of the model. The predicted and calculated uptake values were used to calculate the activity of 131 I for giving 120 Gy in thyroid from the MIRD (Medical Internal Radiation Dose) formula and the differences were evaluated using RMSE. Results The model fit to the data was very good (R2=0.9977 and RMSE=4%) and the standard deviation of the residual error was of 3%. The fitted model predicts with high accuracy the left-out observations and the calculated activities of I-131(RMSE=12%) and especially, when the 24-h observation was left out (RMSE=7% and 8.5%,respectively). The highest RMSE corresponded to the 96-hours measurement. Conclusions A population-based and mixed model approach can enhance the accuracy of biokinetic parameters included in the MIRD formula for the calculation of the optimum therapeutic activity of 131I. A high ability for predicting new observations and observed uptake values was found. The quantification of the accuracy of prediction of the model enables choose among different time sampling schedules of the radioiodine thyroid uptake curve. In our case, we could use a 2-point schedule with a low loss of accuracy against a 3-points schedule. This methodology could be extended to other areas where repeated measurements are made.

Outcome of Fixed Dose of Radioiodine Therapy in Hyperthyroid Patients at NINMAS

&lt;p&gt;&lt;strong&gt;Objective:&lt;/strong&gt; The modified fixed doses of radioactive iodine (RAI) in different types of hyperthyroidism had been practiced at National Institute of Nuclear Medicine &amp;amp; Allied Science (NINMAS) according to Society of Nuclear Medicine Bangladesh (SNMB) protocol since 2002 which was upgraded in 2015. The objective of the study was to observe the treatment outcome in modified fixed dose on previous protocol. Patients and Methods: In the present study the outcome of radioiodine therapy of hyperthyroid patients was retrospectively evaluated in 1349 consecutive primary hyperthyroid patients treated from January 2010 to December 2014 at NINMAS. Diagnosis of hyperthyroidism was done by thyroid function test; thyroid stimulating hormone (TSH), free triiodothyronine (FT3) &amp;amp; free thyroxine (FT4), 99m Technetium scan, thyroid radioiodine uptake and ultrasound imaging of thyroid gland. All patients received a fixed dose (8-29 m Ci) of radioactive iodine (RAI) depending on types of hyperthyroidism, visual assessment of gland size and severity of disease at diagnosis. They were followed up at 2 months of therapy, then every three months intervals for first year and thereafter 6 monthly up to 5 years or as needed during fluctuation of thyroid function.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results:&lt;/strong&gt; Among the study population, 832 patients had diffuse toxic goiter (Graves’ disease), 369 patients were diagnosed as toxic multinodular goiter and 148 patients with single toxic nodule. At one year follow-up, permanent hypothyroidism occurred in 61.62% of patients and the cumulative incidence of hypothyroidism progressively increased up to 79.25% after 5 years. Cure or success of RAI therapy was considered as attainment of euthyroid state or hypothyroid state. About 11.26 % patients received more than single dose.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion:&lt;/strong&gt; Fixed dose RAI therapy is very much cost effective mode of treatment for primary hyperthyroidism with ~89% success by giving single dose.&lt;/p&gt;&lt;p&gt;Bangladesh J. Nuclear Med. 20(1): 37-40, January 2017&lt;/p&gt;