Thyrocyte-specific deletion of insulin and IGF-1 receptors induces papillary thyroid carcinoma-like lesions through EGFR pathway activation.

Insulin and insulin-like growth factor (IGF)-1 signaling in the thyroid are thought to be permissive for the coordinated regulation by thyroid-stimulating hormone (TSH) of thyrocyte proliferation and hormone production. However, the integrated role of insulin receptor (IR) and IGF-1 receptor (IGF-1R) in thyroid development and function has not been explored. Here, we generated thyrocyte-specific IR and IGF-1R double knockout (DTIRKO) mice to precisely evaluate the coordinated functions of these receptors in the thyroid of neonates and adults. Neonatal DTIRKO mice displayed smaller thyroids, paralleling defective folliculogenesis associated with repression of the thyroid-specific transcription factor Foxe1. By contrast, at postnatal day 14, absence of IR and IGF-1R paradoxically induced thyrocyte proliferation, which was mediated by mTOR-dependent signaling pathways. Furthermore, we found elevated production of TSH during the development of follicular hyperplasia at 8 weeks of age. By 50 weeks, all DTIRKO mice developed papillary thyroid carcinoma (PTC)-like lesions that correlated with induction of the ErbB pathway. Taken together, these data define a critical role for IR and IGF-1R in neonatal thyroid folliculogenesis. They also reveal an important reciprocal relationship between IR/IGF-1R and TSH/ErbB signaling in the pathogenesis of thyroid follicular hyperplasia and, possibly, of papillary carcinoma.

Radiofrequency ablation of low-risk small papillary thyroidcarcinoma: preliminary results for patients ineligible for surgery.

PURPOSE: The purpose of this study is to retrospectively evaluate the outcomes of radiofrequency ablation (RFA) of low-risk small papillary thyroid carcinomas (PTCs) in patients who were ineligible for surgery. MATERIALS AND METHODS: Between 2005 and 2009, six PTCs (mean diameter, 0.92 cm; range, 0.6-1.3 cm) in six patients were treated with RFA by three radiologists in two hospitals. The inclusion criteria for this study were (1) pathologically confirmed PTC without cytological aggressiveness, (2) single PTC without extrathyroidal extension, (3) no metastatic tumours and (4) ineligibility for surgery. RFA was performed using a radiofrequency generator and an 18-gauge internally cooled electrode. The medical records were reviewed and analysed, focussing on the procedural profiles of RFA, symptoms and complications during and after RFA, and changes in tumours on follow-up ultrasonography. RESULTS: Before and after RFA, the results of thyroid function tests were normal in all patients. During 48.5 ± 12.3 months (range, 36-65 months) of follow-up, along with a significant reduction in the mean volume (98.5 ± 3.3%), four ablation zones (4/6, 66.7%) completely disappeared. Two ablation zones exhibited only small calcified residues with nearly complete disappearance of the corresponding non-calcified solid portions, and in one of them, malignant cells were absent as assessed by fine-needle aspiration and core-needle biopsy. Transient hypertension with mild headache (n = 1) and mild neck pain (n = 1) developed during the procedure and subsided without any treatment. CONCLUSION: Besides surgery and active surveillance, which are conflicting currently used management plans, RFA might represent an effective and a safe alternative for managing low-risk small PTCs, especially in patients ineligible for surgery.

Postoperative biochemical remission of serum calcitonin is the best predictive factor for recurrence-free survival of medullary thyroid cancer: a large-scale retrospective analysis over 30 years.

CONTEXT: The increase in thyroid screening in the general population may lead to earlier detection of medullary thyroid carcinoma (MTC). OBJECTIVE: We aimed to evaluate secular trends in clinicopathological characteristics and long-term prognosis of MTC and its prognostic factors. DESIGN: This was a retrospective analysis from 1982 to 2012. PATIENTS: Three hundred and thirty-one patients with MTC were included and grouped based on the year of diagnosis (1982-2000, 2001-2005, 2006-2010 and 2011-2012). MEASUREMENTS: These included recurrence and mortality as well as biochemical remission (BCR) of serum calcitonin. RESULTS: Mean tumour size (from 2·5 cm to 1·7 cm, P < 0·001) and percentage of extrathyroidal extension (from 52·0% to 26·0%, P = 0·026) decreased. The percentage of patients achieving BCR within six postoperative months (po-BCR) increased with time (from 39·6% to 76·1%, P < 0·001). The 5-year overall recurrence rate significantly decreased in 2006-2012 compared to 1982-2005 (10% vs 18%, respectively, P = 0·031), although the 5-year survival rate did not improve (92% vs 92%, P = 0·929). Failure to achieve po-BCR was the strongest predictive factor associated with recurrence (hazard ratio [HR] = 58·04, 95% CI 7·14-472·11; P < 0·001). Male gender (HR = 3·18, 95% CI 1·18-8·56; P = 0·022), tumour size >2 cm (HR = 18·33, 95% CI 2·35-143·06; P = 0·006) and distant metastasis (HR = 4·00, 95% CI 1·31-12·21; P = 0·015) were significant prognostic factors for mortality. CONCLUSIONS: Clinicopathological characteristics and recurrence of MTC improved with time. Po-BCR was the best predictive factor for recurrence-free survival.

Efficacy and Safety of Radiofrequency Ablation for Treatment of Locally Recurrent Thyroid Cancers Smaller than 2 cm.

PURPOSE: To evaluate the efficacy and safety of radiofrequency ablation (RFA) for localized small recurrent thyroid cancers less than 2 cm by comparing them with those at repeat surgery. MATERIALS AND METHODS: This retrospective study was institutional review board-approved, and informed consent was waived. From December 2008 to December 2011, this study evaluated 73 patients (17 men and 56 women; age, 50.3 years ± 13.6) with recurrent thyroid cancer who had been treated with RFA (n = 27) or repeat surgery (n = 46) who met the following criteria: (a) three or fewer recurrences or lesions with high probability of recurrence at ultrasonography; (b) no tumor other than the target tumors; and (c) at least 1 year of follow-up. RFA was recommended and performed in cases of surgical ineligibility, such as patient refusal and poor medical condition. Recurrence-free survival rates and posttreatment complication rates (eg, hoarseness and hypocalcemia) were compared between RFA and reoperation groups after adjustment with weighted analysis by using inverse probability of treatment weights. RESULTS: After this adjustment, the 1- and 3-year recurrence-free survival rates were comparable (P = .681) for RFA (96.0% and 92.6%, respectively) and reoperation (92.2% and 92.2%, respectively) groups. The posttreatment hoarseness rate did not differ between the RFA (7.3% [1.8 of 24]) and reoperation (9.0% [3.6 of 39.5]) groups (P = .812), and posttreatment hypocalcemia occurred exclusively in the reoperation group (11.6% [4.6 of 39.5]) but not in the RFA group (0% [0 of 24]) (P = .083). CONCLUSION: RFA may be an effective and safe alternative to repeat surgery in patients with locally recurrent small thyroid cancers.

The risk of second primary malignancy is increased in differentiated thyroid cancer patients with a cumulative (131)I dose over 37 GBq.

BACKGROUND: The aim of this study was to investigate the risk factors for second primary malignancy (SPM) diagnosed after differentiated thyroid cancer (DTC). METHODS: A total of 2468 DTC patients who underwent thyroidectomy were reviewed. SPM was defined as a non-thyroidal malignancy, diagnosed at least 1 year after the diagnosis of thyroid cancer. Patients were divided into five groups according to cumulative (131)I dose: very high-activity (≥ 37.0 GBq), high-activity (22.3-36.9 GBq), intermediate-activity (5.56-22.2 GBq), low-activity (1.1-5.55 GBq) and no RAI. RESULTS: Among the 2468 patients, 61 (2.5%) had SPMs during 7.0 (1.0-33.0) years of median follow-up. Age above 40 years, male sex and very high-activity RAI were independent risk factors for the development of SPM. SPM-related mortality was highest in the very high-activity group, while DTC-related mortality was highest in the high-activity group. The overall mortality both from SPM and DTC was highest in the high-activity group. CONCLUSION: A cumulative (131)I dose <37.0 GBq did not increase the risk of SPM. A cumulative (131) I dose ≥ 37.0 GBq increased the risk of SPM and SPM-related mortality and decreased the DTC-specific mortality, resulting in a similar all-cause mortality compared with the low-activity RAI group. Using repeated high-dose RAI for treating RAI-responsive but persistent DTC patients needs careful consideration of the individual benefits from RAI vs the risk of developing SPM.

IGF-1 receptor deficiency in thyrocytes impairs thyroid hormone secretion and completely inhibits TSH-stimulated goiter.

Although thyroid-stimulating hormone (TSH) is known to be a major regulator of thyroid hormone biosynthesis and thyroid growth, insulin-like growth factor 1 (IGF-1) is required for mediating thyrocyte growth in concert with TSH in vitro. We generated mice with thyrocyte-selective ablation of IGF-1 receptor (TIGF1RKO) to explore the role of IGF-1 receptor signaling on thyroid function and growth. In 5-wk-old TIGF1RKO mice, serum thyroxine (T4) concentrations were decreased by 30% in concert with a 43% down-regulation of the monocarboxylate transporter 8 (MCT8), which is involved in T4 secretion. Despite a 3.5-fold increase in circulating concentrations of TSH, thyroid architecture and size were normal. Furthermore, thyrocyte area was increased by 40% in WT thyroids after 10 d TSH injection, but this effect was absent in TSH-injected TIGF1RKO mice. WT mice treated with methimazole and sodium perchlorate for 2 or 6 wk exhibited pronounced goiter development (2.0 and 5.4-fold, respectively), but in TIGF1RKO mice, goiter development was completely abrogated. These data reveal an essential role for IGF-1 receptor signaling in the regulation of thyroid function and TSH-stimulated goitrogenesis.

The association of the BRAF(V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: a meta-analysis.

BACKGROUND: The effects of the BRAF(V600E) mutation on prognostic factors and poor clinical outcomes in papillary thyroid cancer (PTC) have not been fully quantified. The authors performed comprehensive meta-analysis to assess the strength of associations between these conditions and the BRAF(V600E) mutation. METHODS: The authors identified the clinical studies that examined the association of the BRAF(V600E) mutation in surgical specimens with clinicopathologic outcomes between January 2003 and October 2010 using the Medline database. One hundred thirty-one relevant studies were hand-searched. The authors selected 27 studies that included 5655 PTC patients. They calculated the pooled odds ratios (ORs) or risk ratios with 95% confidence intervals (CIs) for each study using a random effect model. RESULTS: The average prevalence rate of the BRAF(V600E) mutation was 49.4%. In 26 studies, compared with the patients who had the wild-type BRAF genes, the PTC patients with the BRAF(V600E) mutation had increased ORs of an extrathyroidal invasion (OR, 2.14; 95% CI, 1.68-2.73), a lymph node metastasis (OR, 1.54; 95% CI, 1.21-1.97), and an advanced TNM stage (OR, 2.00; 95% CI, 1.61-2.49). In 8 studies, patients with the mutation had 2.14-fold increased risk of recurrent and persistent disease (95% CI, 1.67-2.74). The associations were generally consistent across the different study populations. CONCLUSIONS: This meta-analysis demonstrates that the BRAF(V600E) mutation is closely related to the high-risk clinicopathological factors and poorer outcome of PTC. The results obtained here suggest that the BRAF(V600E) mutation should be considered as a poor prognostic marker in PTC and may lead to better management for individual patients.

Serum thyroglobulin level measured after thyroxine withdrawal is useful to predict further recurrence in whole body scan-negative papillary thyroid cancer patients after reoperation.

The best treatment option for recurrent papillary thyroid carcinoma (PTC) is reoperation when the recurrent lesion is locoregional. The prognostic significance of serum thyroglobulin (Tg) levels before reoperation and the association between the outcome of reoperation and Tg level remain unclear. Our study aimed to determine the outcomes of patients who underwent reoperation and their association with serum Tg levels. We retrospectively studied 79 patients with PTC with locoregional recurrence whose whole-body scan results were negative for any recurrence but whose serum Tg levels were detectable after first-line treatment. All the patients underwent reoperation and follow-up examinations, which involved serial serum Tg measurements after thyroxine withdrawal (T4-off Tg), neck ultrasonography, chest computed tomography, and/or fluorodeoxyglucose-positron emission tomography, to detect further recurrence. During the median follow-up duration of 89 months (range, 38-332 months), 30 patients (38.0%) experienced a second recurrence even after the reoperation. Among all patients, only 12 whose Tg levels decreased postoperatively to undetectable levels showed no recurrence. Most recurrences were detected in the patients with high T4-off Tg levels after the reoperation (T4-off Tg level (ng/mL), number of patients with recurrence, %: <1, 0/12, 0%; 1-10, 9/31, 33.3%; >10, 16/22, 72.7%; P < 0.001). In conclusion, recurrence occurred in 38.0% of the patients even after the reoperation. The postoperative T4-off Tg level was a good indicator of recurrence after the reoperation. Therefore, patients who experience recurrence should undergo follow-up examinations that involve routine measurements of T4-off Tg levels, especially when postreoperative values exceed 10 ng/mL.

Clinical Outcomes of Repeated Radioactive Iodine Therapy for Graves' Disease.

BACKGRUOUND: Radioactive iodine (RAI) therapy is a successful therapeutic modality for Graves' disease. However, RAI therapy can fail, and RAI therapy after antithyroid drugs (ATDs) has a lower remission rate. Therefore, many patients require repeated RAI therapy. This study investigated the clinical outcomes of repeated RAI therapy for Graves' disease. METHODS: Patients who underwent RAI therapy as second-line therapy after failure of ATD treatment between 2001 and 2015 were reviewed. Remission was defined as hypothyroid or euthyroid status without ATD, and with or without levothyroxine at 12 months after RAI therapy. RESULTS: The 1-year remission rate after 2nd RAI therapy (66%, 152/230) is significantly higher than that after 1st RAI therapy (48%, 393/815) or long-term ATD treatment after 1st RAI therapy failure (42%). The clinical response to 2nd RAI therapy was more rapid. The median time intervals from the 2nd RAI therapy to ATD discontinuation (1.3 months) and to the start of levothyroxine replacement (2.5 months) were significantly shorter than those for the 1st RAI therapy. A smaller goiter size, a longer time interval between the 1st and 2nd RAI therapies, and a longer ATD discontinuation period predicted remission after the 2nd RAI therapy. Finally, in 78 patients who failed the 2nd RAI therapy, the mean ATD dosage significantly reduced 5.1 mg over 12 months. CONCLUSION: Repeated RAI therapy can be a good therapeutic option, especially in patients with smaller goiters and those who are more responsive to the 1st RAI therapy.

Combined therapy with 131I and retinoic acid in Korean patients with radioiodine-refractory papillary thyroid cancer.

PURPOSE: The aim of this study was to assess the clinical outcome of redifferentiation therapy using retinoic acid (RA) in combination with 131I therapy, and to identify biological parameters that predict therapeutic response in Korean patients with radioiodine-refractory papillary thyroid carcinoma (PTC). MATERIALS AND METHODS: A total of 47 patients (13 men, 34 women; age 54.2±13.6 years) with radioiodine-refractory PTC underwent therapy consisting of consecutive treatment with 131I and RA. Each 131I/RA treatment cycle involved the administration of oral isotretinoin for 6 weeks at 1-1.5 mg/kg daily followed by a single oral dose of 131I (range 5.5-16.7 GBq). Therapeutic responses were determined using serum thyroglobulin (Tg) levels and the change in tumour size 6 months after completing the 131I/RA therapy. Biological parameters and pathological parameters before and after combined therapy were compared. RESULTS: After completing 131I/RA therapy, 1 patient showed a complete response, 9 partial response, 9 stable disease, and 28 progressive disease, representing an overall response rate of 21.3%. Univariate analysis revealed that an age of <45 years and a persistently high serum Tg level were related to a good response. No clinical response was achieved when metastases showing no iodine uptake were present. Multivariate regression analysis showed that an age of <45 years was significantly associated with a good response. Of the 24 patients with well-differentiated carcinoma, 5 (20.8%) responded to 131I/RA therapy, whereas all 6 patients with poorly differentiated carcinoma failed to respond. CONCLUSION: 131I/RA therapy was found to elicit a response rate of 21.3% among patients with radioiodine-refractory PTC, and an age of <45 years was found to be significantly associated with a good response.

Malignancy rate in sonographically suspicious thyroid nodules of less than a centimeter in size does not decrease with decreasing size.

We evaluated the malignancy and nondiagnostic rates using fine needle aspiration cytology (FNAC) results in thyroid nodules smaller than 1 cm according to the subdivided size. We retrospectively reviewed the medical records of all subjects underwent FNAC from 2003 to 2009 in our hospital, and 2,756 patients of subcentimeter thyroid nodules with one or more suspicious sonographic features and 7,105 with nodule sized 1 cm or more were included. The malignancy rate was higher in those subcentimeter nodules with suspicious sonographic findings than the nodule sized 1cm or more (19.7% vs 7.8%, P < 0.001). We grouped the nodules based on size with mm interval and observed that the malignancy rate did not decrease but the nondiagnostic results increased its size decrement. When we divided the subjects arbitrarily into a 5 mm or smaller and a 6-9 mm sized group, nondiagnostic cytology findings were reported more frequently in the smaller group (24.3% vs 18.1%, P = 0.001), while the rate of "malignant" was similar (18.3% vs 15.5%, P = 0.123) and the rate of "suspicious for malignancy" was higher (6.8% vs 2.9%, P < 0.001). Therefore when we decide to perform FNAC or not in subcentimeter-sized nodules, we should consider sonographic findings and other clinical risk factors but not the nodular size itself.

Secular Trends in Ablation Therapy for Graves' Disease: An Analysis of a 15-Year Experience at a Tertiary Hospital in South Korea.

Ablation therapy, such as radioactive iodine (RAI) therapy or thyroidectomy, is generally used as the second-line treatment for Graves' disease (GD) in Asia. This study investigated changes in the clinical characteristics and outcomes of ablation therapies for GD over 15 years. Patients who underwent ablation therapy between 2001 and 2015 at a single tertiary hospital were included. Among the 10,991 GD patients treated over this 15-year period, 1357 (12.3%) underwent ablation therapy, and the most common reason was intractable GD. The proportion of patients who underwent any type of ablation therapy significantly decreased from 9.0% (2001-2005) to 7.7% (2011-2015). However, the proportion of patients who underwent surgery significantly increased from 1.1% (2001-2005) to 2.4% (2011-2015), and the proportion of patients who received ablation therapy due to suspected thyroid cancer increased from 5% to 13% over time. With a median follow-up duration of 6.2 years, remission was achieved in 86% and 98% of patients in the RAI and surgery groups, respectively, and these rates remained stable over time. In conclusion, although the proportion of patients who underwent ablation therapy for GD decreased during 15 years, the proportion of those who underwent surgery increased in association with the increased rate of suspected thyroid cancers.

Interaction between cigarette smoking and iodine intake and their impact on thyroid function.

OBJECTIVE: Several population-based studies in iodine-deficient areas have shown an association between smoking and thyroid function. There are no population-based studies about the effects of smoking in iodine-sufficient areas. We examined the effect of smoking on thyroid function and the association with iodine intake in Korea, an area with sufficient iodine intake, much more than recommended by the World Health Organization (WHO). DESIGN: Of 5018 subjects in a population-based cohort, we included 3399 who had no history of thyroid disease were not taking thyroid medication and whose blood samples were available for measurement of thyroid function. MEASUREMENTS: Thyroid function test, questionnaire about smoking status and dietary intake. RESULTS: Of 3399 subjects, 397(11.7%) had subclinical hypothyroidism (SCH). Female sex was an independent risk factor for SCH. Multivariate analysis in female subjects showed the following were independent risk factors for SCH: older age, positive antithyroid peroxidase (anti-TPO) antibody status and iodine intake, whereas current smoking was inversely related with SCH. However, in male subjects, only age showed a weak association with SCH. When the interaction between smoking and other risk factors was analysed, smoking showed no association with anti-TPO antibody status, whereas it showed a significant negative interaction with iodine intake (odds ratio, 0.930; 95% CI, 0.869-0.996; P = 0.037). Furthermore, the risk for SCH was observed only in the never-smoker group; however, it was abolished in current- and ex-smoker groups. CONCLUSION: Cigarette smoking was associated with a lower prevalence of SCH in a negative interaction with iodine intake.

Subclinical hypothyroidism has little influences on muscle mass or strength in elderly people.

Sarcopenia, the age-related decline in muscle mass, affects the muscle strength and muscle quality, and these changes decrease functional capacity. The prevalence of thyroid dysfunction increases with age, and changes in thyroid hormone level lead to neuromuscular deficits. We investigated the effects of subclinical hypothyroidism on the muscle mass, strength or quality in elderly people. One thousand one hundred eighteen subjects aged > or = 65 yr were randomly selected from a local population and classified into a euthyroid (280 men and 358 women), subclinically hypothyroid (61 men and 75 women), or overtly hypothyroid (7 men and 16 women) group. Although women with subclinical hypothyroidism had a higher prevalence of sarcopenia, defined according to the ratio of appendicular skeletal muscle mass to the square of height, muscle mass, strength or quality did not differ in relation to thyroid status in men or in women. Multivariate analysis including age, diabetes, hypertension, acute coronary event, alcohol, smoking, presence of pain, physical activity score, and lipid profile, showed that thyroid-stimulating hormone level was not associated with muscle mass, strength or quality. In conclusion, subclinical hypothyroidism has little influences on muscle mass, strength or quality, and may not be associated with sarcopenia.

Malignancy rate of Bethesda category III thyroid nodules according to ultrasound risk stratification system and cytological subtype.

The risk of malignancy is considered to be 10% to 30% for cases of thyroid nodules with atypia or follicular lesion of undetermined significance (AUS/FLUS). However, only a minority of patients with AUS/FLUS undergo surgery; therefore, the risk of malignancy might be overestimated due to selection bias. To overcome this problem, we categorized cases of thyroid nodules with AUS/FLUS using the ultrasound risk stratification system (US-RSS) to calculate the malignancy rate and identify the patients most suitable for surgical treatment.In this retrospective observational study, we subcategorized 382 pathologically confirmed thyroid nodules with AUS/FLUS using current US-RSSs (American Thyroid Association, Korean-Thyroid Imaging Report and Data System, American College of Radiology-Thyroid Imaging, Reporting and Data System, European Thyroid Imaging Report and Data System) and calculated the malignancy rate. Additionally, cases of nodules with AUS/FLUS were categorized according to their cytological subtypes, and the malignancy rate was calculated.Current US-RSSs showed good or moderate agreement among them. The overall malignancy rate for thyroid nodules with AUS/FLUS was 38.7%. On categorization of the nodules with AUS/FLUS, the malignancy rates were found to be 60% to 67.5% for the high suspicion category, 32.2-36.6% for the intermediate suspicion category, and 12.4% to 16.3% for the low suspicion category. The malignancy rate for nodules with cytologic atypia was significantly higher than that for nodules with architectural atypia, especially in the intermediate suspicion category.Categorization of thyroid nodules with AUS/FLUS using current US-RSSs helps to determine the optimal course of management of patients, especially when combined with cytological subtype characterization.

Recurrent/metastatic thyroid carcinomas false negative for serum thyroglobulin but positive by posttherapy I-131 whole body scans.

PURPOSE: Serum Tg and I-131 WBS have been used to detect recurrent and metastatic thyroid cancers postoperatively. Tg is known to be more sensitive than I-131 WBS, and therefore, false-negative WBS cases with elevated Tg levels are frequently found. However, the clinical characteristics of false-negative Tg cases with positive WBS have not been clarified. MATERIALS AND METHODS: The authors evaluated 824 postoperative patients with differentiated thyroid carcinoma who underwent post-ablation/therapy I-131 WBS. Tg negativity was defined as a Tg level of < or = 2 ng/mL without TgAb under thyroid-stimulating hormone stimulation. Remission, recurrence, and metastasis were confirmed using pathologic or clinically findings. RESULTS: Fifty-two patients (6.3%) with functioning metastasis and negativity for TgAb were Tg-negative and posttherapy I-131 WBS-positive (TgN group), and 128 patients with functioning metastases were Tg positive and WBS positive (TgP group). The TgN group consisted of 45 cases of cervical/mediastinal lymph node metastases (86.5%) and seven cases of distant metastasis to lung or bone by follow-up WBS. The TgN group demonstrated significantly higher profiles of regional involvement than the TgP group (P < 0.029). In 47 patients in the TgN group, metastatic uptake disappeared in 33, ameliorated in four, and persisted in ten during follow-up. CONCLUSIONS: A significant number of differentiated thyroid cancer patients were Tg-/TgAb-negative despite a positive WBS finding. Cervical and mediastinal lymph nodes were predominant sites of metastasis in the TgN group. WBS should be undertaken routinely as a complementary modality to detect functioning recurrence and metastasis regardless of serum Tg results.

Retinol binding protein-4 elevation is associated with serum thyroid-stimulating hormone level independently of obesity in elderly subjects with normal glucose tolerance.

CONTEXT: Elevated levels of retinol binding protein-4 (RBP4) are positively correlated with insulin resistance, obesity, diabetes mellitus, and cardiovascular disease (CVD). Subclinical hypothyroidism (SCH) has also been associated with CVD; however, the factors linking SCH to CVD are not clear. OBJECTIVE: The objective of the study was to evaluate risk factors for CVD in elderly patients grouped according to thyroid function. DESIGN: 217 subjects (> or =65 yr old) were randomly selected from a population and allocated to a euthyroid group (n = 177) and an SCH group (n = 40) on the basis of plasma concentrations of TSH and free T(4). We included subjects with normal glucose tolerance by a 75-g oral glucose tolerance test and subjects with impaired fasting glucose. We measured anthropometric parameters, levels of fasting glucose and insulin, hemoglobin A(1c), adiponectin, RBP4, lipid profiles, total body fat content, and the area of sc and visceral fat. RESULTS: The SCH group had higher RBP4 levels than the euthyroid group, irrespective of body mass index and fat content. Subcutaneous and visceral fat areas and total body fat percentage did not differ between groups and were not correlated with RBP4 level. Other CVD risk factors did not differ between groups. RBP4 level was positively correlated with TSH level (r = 0.241, P = 0.001) after adjustment for age, sex, and body mass index. CONCLUSIONS: Plasma RBP4 levels were associated with SCH independent of obesity in elderly subjects with normal glucose tolerance, indicating that RBP4 level could be used as an index of CVD risk in SCH.

Ghrelin enhances the proliferating effect of thyroid stimulating hormone in FRTL-5 thyroid cells.

Ghrelin regulates cell proliferation through the growth hormone secretagogue receptor (GHS-R). We confirmed the expression of GHS-R in FRTL-5 thyroid cells and investigated the effects of ghrelin in thyrocytes using FRTL-5 cells. Ghrelin increased intracellular calcium levels but not intracellular cyclic AMP levels. Ghrelin activated Erk within 2min, then activated Akt and STAT3. Erk phosphorylation was inhibited by the calcium inhibitor cyclopiazonic acid (CPA). Ghrelin alone did not stimulate FRTL-5 cell proliferation but enhanced the effects of thyroid stimulating hormone (TSH). Pretreatment with TSH potentiates the growth effects of ghrelin in thyroid cells, and p66Shc, a growth factor receptor adaptor protein, might mediate these synergistic effects. Ghrelin phosphorylated TSH-induced p66Shc, which was inhibited by CPA. Ghrelin did not affect the proliferation of ARO cells, which showed no increased expression of p66Shc after TSH treatment. Thus, ghrelin-induced intracellular calcium signaling enhanced the TSH-induced proliferation of thyrocytes, possibly mediated by the p66Shc pathway.

Maximal safe dose of I-131 after failure of standard fixed dose therapy in patients with differentiated thyroid carcinoma.

OBJECTIVE: The maximal safe dose (MSD) on the basis of bone marrow irradiation levels allows the delivery of a large amount of I-131 to thyroid cancer tissue. The efficacy of MSD therapy in differentiated metastatic thyroid cancers that persisted after conventional fixed dose therapy is investigated. METHODS: Forty-seven differentiated thyroid carcinoma patients with non-responsive residual disease despite repetitive fixed dose I-131 therapy were enrolled in this study. Their postoperative pathologies were 43 papillary carcinomas and 4 follicular carcinomas. The MSD was calculated with the Memorial Sloan-Kettering Cancer Center protocol using serial blood samples. The MSDs were administered at intervals of 6 months. Treatment responses were evaluated using I-131 whole-body scans and serum thyroglobulin measurements. RESULTS: The mean calculated MSD was 12.5 +/- 2.1 GBq (339.6 +/- 57.5 mCi). Of the 46 patients, 7 (14.9%) showed complete remission, 15 (31.9%) partial remission, 19 (40.4%) stable disease, and 6 (12.8%) disease progression. Of the patients who showed complete or partial remission, 15 (65%) showed response after the first MSD session and 6 (26%) showed response after the second session. Twenty-nine patients (62%) experienced transient cytopenia after therapy, but three did not recover to the baseline level. CONCLUSIONS: The maximal safe dose provides an effective means of treatment in patients who failed to respond adequately to conventional fixed dose therapy. I-131 MSD therapy can be considered in patients who fail fixed dose therapy.

Effects of Pioglitazone on Nonalcoholic Fatty Liver Disease in the Absence of Constitutive Androstane Receptor Expression.

Nonalcoholic fatty liver disease or steatohepatitis (NAFLD/NASH) is a fatty liver disease that is closely related to obesity, diabetes, and dyslipidemia. Pioglitazone, which was developed as an antidiabetic drug, is known to improve NALFD. Pioglitazone is metabolized by multiple cytochrome P450 (CYP) enzymes, which are regulated by the xenobiotic receptor constitutive androstane receptor (CAR). In this study, we investigated the effects of pioglitazone on NAFLD by absence of CAR activity under high-fat (HF)-fed conditions. CAR-/- mice showed significant improvement in NALFD after 12 weeks of pioglitazone treatment compared to wild-type mice. This improvement in NAFLD persisted in CAR-/- mice regardless of blood pioglitazone concentration. The expression of lipogenesis genes in the liver, sterol-regulatory element binding protein-1c (SREBP-1c), and stearoyl-CoA desaturase (SCD)-1 was decreased after pioglitazone treatment in HF-fed CAR-/- mice. In addition, the expression of peroxisome proliferator-activated receptor gamma 2 (PPARγ2) was decreased by pioglitazone in HF-fed CAR-/- mice. Changes in SREBP-1c and PPAR γ2 remained constant over short-term (6 h) pioglitazone and lipid injection. Our results showed that NAFLD was improved significantly by pioglitazone in a CAR deletion state. These results might be valuable because they suggest that interaction with CAR and pioglitazone/PPARγ2 may be important in regulating gene expression associated with NAFLD.