Early Structural, Biochemical, and Metabolic Responses to Anlotinib in Patients With Progressive Radioactive Iodine Refractory Differentiated Thyroid Cancer.

OBJECTIVE: We aimed to assess the early efficacy of anlotinib in patients with progressive radioactive iodine refractory differentiated thyroid cancer at the structural, biochemical, and metabolic levels. METHODS: Ten eligible patients were prospectively enrolled to receive anlotinib. Their responses were assessed at 6 weeks. Apart from the structural response according to Response Evaluation Criteria in Solid Tumors version 1.1, the biochemical response was assessed by serum thyroglobulin (Tg), and the metabolic response was assessed by 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) according to the European Organization for Research and Treatment of Cancer criteria. A safety profile was recorded. RESULTS: Structurally controlled disease (20% partial response + 80% stable disease) was observed in all patients. The median longest diameter of target lesions shrank from 20.8 mm (IQR, 14.9-27.5) to 17.0 mm (IQR, 14.1-23.7) (P < .001), and the average shrinkage rate was -15.1 ± 14.1%. Sharp serum Tg reduction by 72.8 ± 16.4% was observed in 8 measurable patients. The 18F-FDG PET/CT-mapped glucose metabolic response was not quite comparable to the structural response, with 90% of the patients having controlled disease (30% partial metabolic response + 60% stable metabolic disease), whereas 10% presented progressive metabolic disease. The most common treatment-emergent adverse events (AEs) were hypertension (100%) and proteinuria (70%). Most AEs were grade 1 or 2, whereas grade 3 AEs occurred only in hypertension. CONCLUSION: Anlotinib is generally well tolerated and can bring early disease control within the initial 6 weeks of treatment. The sharp biochemical response suggests Tg to be an early sensitive biomarker to anlotinib, whereas the heterogeneous metabolic response might play a complementary role.

Clinical efficacy of selenium supplementation in patients with Hashimoto thyroiditis: A systematic review and meta-analysis.

BACKGROUND: Evidence suggests that selenium supplementation could be useful in the treatment of Hashimoto thyroiditis (HT), but the available trials are heterogeneous. This study investigates clinically relevant effects of selenium supplementation in patients with HT. METHODS: A systematic search was performed in PubMed, Web of Science, EMBASE, Scopus, and the Cochrane Library. The latest update was performed on December 3, 2022. We investigated the changes in thyroid peroxidase antibodies (TPOAb) and thyroglobulin antibodies (TgAb) after selenium supplementation. The effect sizes were expressed as weighted mean difference (WMD) with 95% confidence intervals (CIs). RESULTS: After screening and full-text assessment, 7 controlled trials comprising 342 patients were included in the systematic review. The results showed that there was no significant change in TPOAb levels (WMD = -124.28 [95% CI: -631.08 to 382.52], P = .631, I2 = 94.5%) after 3 months of treatment. But there was a significant decrease in TPOAb levels (WMD = -284.00 [95% CI: -553.41 to -14.60], P < .05, I2 = 93.9%) and TgAb levels (WMD = -159.86 [95% CI: -293.48 to -26.24], P < .05, I2 = 85.3%) after 6 months of treatment. CONCLUSIONS: Selenium supplementation reduces serum TPOAb and TgAb levels after 6 months of treatment in patients with HT, but future studies are warranted to evaluate health-related quality or disease progression.

Iodine deficiency in pregnancy along a concentration gradient is associated with increased severity of preeclampsia in rural Eastern Cape, South Africa.

BACKGROUND: Preeclampsia is a leading cause of maternal mortality and morbidity in South Africa. Iodine deficiency in pregnancy, which is amenable to correction through iodine supplementation, has been reported to increase the risk of preeclampsia. However, the association of iodine nutrition status with preeclampsia in South Africa has not been studied. METHODS: We enrolled 51 randomly selected normotensive pregnant controls at term together with 51 consecutively selected cases of preeclampsia and 51 cases of severe preeclampsia/eclampsia, all in the third trimester, from Mthatha Regional and Nelson Mandela Academic Hospital in the Eastern Cape Province. Urinary iodine concentration (UIC), serum thyroid-stimulating hormone (TSH), triiodothyronine (FT3), thyroxine (FT4) and thyroglobulin (Tg) levels were compared between cases and controls. RESULTS: The respective chronological and gestational ages at enrolment for normotensive, preeclampsia and severe preeclampsia/eclampsia participants were: age 23, 24 and 19 years (p = 0.001), and gestational age 38, 34, and 35 weeks (p < 0.001). The median gravidity was 1 for all three groups. The median UIC, FT4, FT3 revealed a decreasing and Tg a rising trend with the severity of preeclampsia (p < 0.05). TSH had a non-significant rising trend (p > 0.05). The respective median values for normotensive, preeclampsia and severe preeclampsia/eclampsia participants were UIC 217.1, 127.7, and 98.8 µg/L; FT4 14.2, 13.7, and 12. pmol/L; FT3 4.8, 4.4, and 4.0 pmol//L; Tg 19.4, 21.4, and 32. Nine microgram per liter; TSH 2.3, 2.3, and 2.5 mIU/L. UIC < 100 µg/L, Tg > 16 µg/L and FT4 < 11.3 pmol/L were independent predictors of preeclampsia/eclampsia syndrome. CONCLUSION: Women with severe preeclampsia/eclampsia had significantly low UIC and high Tg, suggesting protracted inadequate iodine intake. Inadequate iodine intake during pregnancy severe enough to cause elevated Tg and FT4 deficiency was associated with an increased risk of severe preeclampsia/eclampsia.

The effects of selenium supplementation on antibody titres in patients with Hashimoto's thyroiditis.

INTRODUCTION: The objective of this study was to evaluate the effect of selenium supplementation on autoantibody titres, thyroid ultrasonography, and thyroid function in patients with Hashimoto's thyroiditis (autoimmune thyroiditis) and normal thyroid reference range. MATERIAL AND METHODS: A total of 100 patients were given 200 ug/d selenium yeast orally, their thyroid function, levels of serum selenium, thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TGAb), and urine iodine were measured, and thyroid ultrasonography was performed before administration and three and six months afterwards, and the data were statistically analysed. RESULTS: The subjects exhibited a selenium deficiency before the administration of selenium, and the serum levels increased to moderate levels three and six months after the selenium supplementation (p < 0.05). The titres of TGAb decreased significantly in patients after six months of selenium supplementation (p < 0.05). In the high antibody group, TgAb decreased after 6 months compared with baseline (p = p < 0.05), and TPOAb decreased after 3 and 6 months of selenium supplementation compared with baseline (p < 0.05). CONCLUSION: In patients with autoimmune thyroiditis and normal thyroid reference range, there was a general selenium deficiency, but after six months of treatment it was shown that selenium supplementation may be effective in reducing the titres of TGAb and TPOAb.

Iodine supplementation for pregnant women: a cross-sectional national interventional study.

BACKGROUND: Although Iran has been considered iodine replete since 2000, the first national survey of iodine intake among Iranian pregnant women in 2014 indicated that despite the adequate intake of iodine by the general population, this vulnerable group has moderate iodine deficiency. Therefore, in this national cross-sectional interventional study, we aimed to assess the iodine intake and thyroid function of Iranian pregnant women 2 years after implementing national iodine supplementation for this vulnerable group. MATERIALS AND METHODS: In this cross-sectional study, we conducted a national interventional survey of pregnant women. A total of 1200 pregnant women (400 women from each trimester) from 12 provinces of Iran were recruited from the antenatal care clinics from October 2018 to March 2019. The median urinary iodine concentration (MUIC), as an indicator of iodine status in three spot urine samples, was measured, along with the serum total T4 (TT4), thyrotropin (TSH), thyroglobulin (Tg), thyroid peroxidase antibody (TPO-Ab), and iodine content of household salt. RESULTS: The mean age of the cohort was 28 ± 6.2 years, with the mean gestational age of 22.7 ± 13.0 weeks. The overall MUIC (IQR) of pregnant women was 188 µg/L (124.2-263 µg/L). Also, the MUICs in the three trimesters of pregnancy were 174 µg/L (110-254), 175 µg/L (116-251), and 165 µg/L (114-235), respectively. The MUICs ≥ 150, 100-149, and < 100 µg/L were found in 63, 19.8, and 16.2% of the subjects, respectively. The mean TT4 level was 12 ± 4.5 µg/dL, and the median (IQR) level of TSH was 2.37 mIU/L (1.66-3.18 mIU/L). According to our local reference range, 118 (10.5%) pregnant women had subclinical hypothyroidism, 6 (0.53%) women had isolated hypothyroxinemia, and 65 (5.7%) women were TPO-Ab positive. Also, the median (IQR) level of Tg was 10.08 µg/dL (5.7-20.4 µg/dL), and the median iodine content of household salt was 29.6 µg/g; the iodine content was ≥ 30 µg/g in 85% of household salt. The results showed that more than 95% of households were under iodized salt coverage. CONCLUSION: The results of this study indicated that iodine supplementation with at least 150 µg of iodine per day improved the iodine intake of pregnant women. Except for subclinical hypothyroidism, the prevalence of clinical hypothyroidism, clinical/subclinical thyrotoxicosis, TPO-Ab positivity, and isolated hypothyroxinemia decreased significantly, which emphasizes the importance of iodine supplementation during pregnancy.

Development of a pregnancy-specific reference material for thyroid biomarkers, vitamin D, and nutritional trace elements in serum.

OBJECTIVES: Matrix differences among serum samples from non-pregnant and pregnant patients could bias measurements. Standard Reference Material 1949, Frozen Human Prenatal Serum, was developed to provide a quality assurance material for the measurement of hormones and nutritional elements throughout pregnancy. METHODS: Serum from non-pregnant women and women in each trimester were bottled into four levels based on pregnancy status and trimester. Liquid chromatography tandem mass spectrometry (LC-MS/MS) methods were developed and applied to the measurement of thyroid hormones, vitamin D metabolites, and vitamin D-binding protein (VDBP). Copper, selenium, and zinc measurements were conducted by inductively coupled plasma dynamic reaction cell MS. Thyroid stimulating hormone (TSH), thyroglobulin (Tg), and thyroglobulin antibody concentrations were analyzed using immunoassays and LC-MS/MS (Tg only). RESULTS: Certified values for thyroxine and triiodothyronine, reference values for vitamin D metabolites, VDBP, selenium, copper, and zinc, and information values for reverse triiodothyronine, TSH, Tg, and Tg antibodies were assigned. Significant differences in serum concentrations were evident for all analytes across the four levels (p≤0.003). TSH measurements were significantly different (p<0.0001) among research-only immunoassays. Tg concentrations were elevated in research-only immunoassays vs. Federal Drug Administration-approved automated immunoassay and LC-MS/MS. Presence of Tg antibodies increased differences between automated immunoassay and LC-MS/MS. CONCLUSIONS: The analyte concentrations' changes consistent with the literature and the demonstration of matrix interferences in immunoassay Tg measurements indicate the functionality of this material by providing a relevant matrix-matched reference material for the different stages of pregnancy.

Moderate Iodine Deficiency Is Common in Pregnancy but Does Not Alter Maternal and Neonatal Thyroid Function Tests.

Introduction: An Israeli national survey found that 85% of pregnant women had urinary iodine content (UIC) levels below the adequacy range (<150 µg/L). Widespread desalinated water usage and no national fortification plan are possible causes. Studies assessing relationships between iodine status and maternal and neonatal thyroid function provided varying results. Our aims were to determine whether iodine deficiency was associated with altered maternal or neonatal thyroid function and the factors leading to iodine deficiency. Methods: A cross-sectional study including 100 healthy women without prior thyroid disease, in their first trimester of a singleton pregnancy were recruited from an HMO clinic in central Israel. The women were followed from their first trimester. All women completed a 24-h dietary recall and life habits questionnaires. We tested for UIC, maternal and neonatal thyroid function, maternal autoantibodies, and neonatal outcomes. Results: Median UIC in our cohort was 49 µg/L [25%-75% interquartile range (IQR) 16-91.5 µg/L], with 84% below adequacy range. No correlation was found between iodine deficiency and maternal or neonatal thyroid function which remained within normal ranges. Antibody status did not differ, but thyroglobulin levels were significantly higher in iodine insufficient subjects. UIC was higher in women consuming an iodine containing supplement. There was no association between UIC and dietary iodine content or water source. Conclusions: Moderate iodine deficiency is common in our healthy pregnant women population. Our data imply that moderate iodine deficiency in pregnancy seem sufficient to maintain normal maternal and neonatal thyroid function.

Association between clinical and tumor features with postoperative thyroglobulin in pediatric papillary thyroid cancer.

BACKGROUND: Why certain patients after total thyroidectomy for thyroid cancer who do not have distant metastasis have increased serum stimulated thyroglobulin (s-Tg) is unknown. The aim of our study was to systematically investigate the associations of preablation s-Tg with clinical and tumor characteristics in children and young adults less than 20 years old after total thyroidectomy for papillary thyroid cancer. METHODS: We performed a retrospective analysis of 93 children and young adults younger than 20 years old who had undergone total thyroidectomy and were without known distant metastases who underwent remnant ablation. Before any remnant preablation, we assessed the association of s-Tg after thyroid hormone withdrawal with the clinical and histopathologic characteristics according to the American Thyroid Association pediatric initial risk classification system. RESULTS: The median age was 18 years, and the majority of patients were female (80%). The preablation s-Tg ranged from 0.02 to 902.00 ng/mL, with a median of 9.2 ng/mL. Forty-five (48%) patients had an increased preablation s-Tg >10 ng/mL. In multivariate analyses of clinical and tumor characteristics, high-risk stratification and high neck uptake (>2%) were the independent predictive factors for the presence of an increased preablation s-Tg. CONCLUSION: Children and young adults younger than 20 years old with high-risk stratification and high neck uptake are likely to present a high level of preablation s-Tg after total thyroidectomy for papillary thyroid cancer. Continued long-term surveillance is necessary in this cohort of patients to confirm the role of preablation s-Tg as a biomarker for monitoring postoperative residual disease.

Comparison of thyroid hormone withdrawal and recombinant human thyroid-stimulating hormone administration for adjuvant therapy in patients with intermediate- to high-risk differentiated thyroid cancer.

OBJECTIVE: To compare the clinical outcome in patients who received adjuvant therapy with radioactive iodine (RAI) using different preparation methods, namely, thyroid hormone withdrawal (THW) and recombinant human thyroid-stimulating hormone (rhTSH), after undergoing thyroidectomy for intermediate- to high-risk differentiated thyroid carcinoma (DTC) according to the American Thyroid Association criteria. METHODS: Between May 2012 and October 2018, 136 patients who underwent adjuvant therapy with high-dose (3700 MBq) RAI for DTC without any metastatic lesions or macroscopic residual lesions after surgical resection were retrospectively selected. Patients were excluded if distant metastasis was confirmed during adjuvant therapy or if the outcome could not be confirmed; thus, 112 patients were finally evaluated. Patients underwent either a 3-week I restriction with thyroxine withdrawal or a 2-week I restriction with rhTSH administration. The serum thyroglobulin (Tg) concentration was measured, and 131I scintigraphy (370 MBq) was performed 6-12 months after adjuvant therapy. The definition of the initial achievement of adjuvant therapy was the disappearance of the uptake of 131I at the thyroid bed and serum Tg concentration < 2.0 ng/mL. The results of the adjuvant therapy between the groups were compared using the Fisher's exact test, and the TSH levels and estimated glomerular filtration rate (eGFR) were compared using the Welch's t test. RESULTS: The THW and rhTSH groups included 47 and 65 patients, respectively, and the intermediate- and high-risk groups included 63 and 49 patients, respectively. No patient was assigned to the low-risk group. In the THW and rhTSH groups, the initial RAI adjuvant therapy goal was achieved in 30/47 (63.8%) and 46/65 patients (70.8%), respectively (p = 0.54); mean ± standard deviation of the TSH levels was 123.8 ± 46.4 µIU/mL and 274.5 ± 97.7 µIU/mL, respectively (p < 0.01), and eGFR (treatment/pre-treatment) was 0.81 and 0.99, respectively (p < 0.01). In the intermediate- and high-risk groups, the initial RAI adjuvant therapy goal was achieved in 43/63 patients (68.3%) and 33/49 (67.3%), respectively (p = 1.0). CONCLUSION: No significant differences were observed between the preparation methods in the initial achievement of RAI adjuvant therapy. However, patients in the rhTSH group demonstrated higher TSH levels and retained eGFR.

Low intake of iodized salt and iodine containing supplements among pregnant women with apparently insufficient iodine status - time to change policy?

BACKGROUND: Iodine is an essential nutrient for human health throughout the life cycle, especially during early stages of intrauterine life and infancy, to ensure adequate neurocognitive development. The growing global reliance on desalinated iodine-diluted water raises the specter of increased iodine deficiency in several regions. The case of Israel may be instructive for exploring the link between iodine status and habitual iodine intake in the setting of extensive national reliance on desalinated water. The aim of this study was to explore the relationship between iodine intake, including iodized salt and iodine-containing supplements intake, and iodine status among pregnant women residing in a sub-district of Israel that is highly reliant on desalinated iodine-diluted water. METHODS: A total of 134 consecutive pregnant women were recruited on a voluntary basis from the obstetrics department of the Barzilai University Medical Center during 2018. Blood was drawn from participants to determine levels of serum thyrotropin (TSH), thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb) and thyroglobulin (Tg). An iodine food frequency questionnaire (sIFFQ) was used to assess iodine intake from food, IS and ICS. A questionnaire was used to collect data on demographic and health characteristics. RESULTS: A total of 105 pregnant women without known or reported thyroid disease were included in the study. Elevated Tg values (≥ 13 µg/L), were found among 67% of participants, indicating insufficient iodine status. The estimated iodine intake (median, mean ± SD 189, 187 ± 106 µg/d by sIFFQ) was lower than the levels recommended by the World Health Organization and the Institute of Medicine (250 vs. 220 µg/day respectively). The prevalence of iodized salt intake and iodine containing supplement intake were 4 and 52% (respectively). Values of Tg > 13 µg/L were inversely associated with compliance with World Health Organization and Institute of Medicine recommendations. CONCLUSIONS: While the Israeli Ministry of Health has recommended the intake of iodized salt and iodine containing supplements, this is apparently insufficient for achieving optimal iodine status among Israeli pregnant women. The evidence of highly prevalent probable iodine deficiency in a sample of pregnant women suggests an urgent need for a national policy of iodized salt regulation, as well as guidelines to promote iodine containing supplements and adherence to them by caregivers. In addition, studies similar to this one should be undertaken in additional countries reliant on desalinated iodine-diluted water to further assess the impact of desalinization on maternal iodine status.

Effects of an Iodine-Containing Prenatal Multiple Micronutrient on Maternal and Infant Iodine Status and Thyroid Function: A Randomized Trial in The Gambia.

Background: Iodine supplementation is recommended to pregnant women in iodine-deficient populations, but the impact in moderate iodine deficiency is uncertain. We assessed the effect of an iodine-containing prenatal multiple micronutrient (MMN) supplement in a rural Gambian population at risk of moderate iodine deficiency. Materials and Methods: This study uses data and samples collected as a part of the randomized controlled trial Early Nutrition and Immune Development (ENID; ISRCTN49285450) conducted in Keneba, The Gambia. Pregnant women (<20 weeks gestation) were randomized to either a daily supplement of MMNs containing 300 µg of iodine or an iron and folic acid (FeFol) supplement. Randomization was double blinded (participants and investigators). The coprimary outcomes were maternal urinary iodine concentration (UIC) and serum thyroglobulin (Tg), assessed at baseline and at 30 weeks' gestation. Secondary outcomes were maternal serum thyrotropin (TSH), total triiodothyronine (TT3), total thyroxine (TT4) (assessed at baseline and at 30 weeks' gestation), breast milk iodine concentration (BMIC) (assessed at 8, 12, and 24 weeks postpartum), infant serum Tg (assessed at birth [cord], 12, and 24 weeks postpartum), and serum TSH (assessed at birth [cord]). The effect of supplementation was evaluated using mixed effects models. Results: A total of 875 pregnant women were enrolled between April 2010 and February 2015. In this secondary analysis, we included women from the MMN (n = 219) and FeFol (n = 219) arm of the ENID trial. At baseline, median (interquartile range or IQR) maternal UIC and Tg was 51 µg/L (33-82) and 22 µg/L (12-39), respectively, indicating moderate iodine deficiency. Maternal MMN supplement increased maternal UIC (p < 0.001), decreased maternal Tg (p < 0.001), and cord blood Tg (p < 0.001) compared with FeFol. Maternal thyroid function tests (TSH, TT3, TT4, and TT3/TT4 ratio) and BMIC did not differ according to maternal supplement group over the course of the study. Median (IQR) BMIC, maternal UIC, and infant Tg in the MMN group were 51 µg/L (35-72), 39 µg/L (25-64), and 87 µg/L (59-127), respectively, at 12 weeks postpartum, and did not differ between supplement groups. Conclusions: Supplementing moderately iodine-deficient women during pregnancy improved maternal iodine status and reduced Tg concentration. However, the effects were not attained postpartum and maternal and infant iodine nutrition remained inadequate during the first six months after birth. Consideration should be given to ensuring adequate maternal status through pregnancy and lactation in populations with moderate deficiency.

Associations of telomerase reverse transcriptase rs10069690 and rs2736100 polymorphisms with papillary thyroid carcinoma.

Papillary thyroid carcinoma is one of the most common endocrine malignancies. Telomerase reverse transcriptase rs10069690 and rs2736100 polymorphisms have been studied in thyroid carcinomas with different ethnicity, but the results were inconsistent. Therefore, we evaluated the relationship between rs10069690 and rs2736100 polymorphisms and papillary thyroid carcinoma risk and furtherly investigated the associations of these polymorphisms with stimulated thyroglobulin (sTg) positivity and adverse reactions of I treatment in papillary thyroid carcinoma. Four hundred thirty-six papillary thyroid carcinoma patients and 345 controls of Chinese Han population were included in our study. Rs10069690 and rs2736100 were genotyped using improved multiple ligase detection reactions. Analysis of inheritance model was performed using the unconditional logistic regression. In our study, rs10069690 and rs2736100 were associated with papillary thyroid carcinoma risk, especially in females over 45 years of age (P = 0.002 and P = 0.032, respectively). Rs10069690 was associated with sTg positivity and with an rs10069690-related occurrence risk order of thyroglobulin antibody (Tg-Ab)(+) + Tg(+) > Tg-Ab(+) + sTg(-) > Tg-Ab(-) + sTg(+). Patients with the homozygous TT genotype of rs10069690 had an increased risk of neck discomfort (P = 0.033), while the homozygous CC genotype of rs2736100 had a decreased risk of gastrointestinal toxicity (P = 0.048). Our data demonstrated that rs10069690 and rs2736100 might be bio-indicators related to papillary thyroid carcinoma risk in females over 45 years of age and I treatment-related toxicity. In addition, rs10069690 may be a predictor of bad clinicopathological features and poor prognosis from a serological point of view.

Iodine deficiency in pregnant women in Sweden: a national cross-sectional study.

PURPOSE: Voluntary salt iodization at 50 mg/kg salt ensures adequate iodine nutrition in Swedish school-aged children, but iodine status in pregnant women is uncertain. METHODS: We conducted a cross-sectional national study of 743 pregnant women, at median gestational age of 23 weeks (IQR 9, 38), recruited from maternal health care centers. We measured: urinary iodine concentration (UIC) and urinary creatinine concentration in spot urine samples; thyroglobulin (Tg), thyroid-stimulating hormone (TSH), and total thyroxine (tT4) on dried blood spots (DBS); and thyreoperoxidase antibodies in serum samples. Data on dietary supplement use were obtained, and women were classified as supplement users (consuming multivitamins containing ≥ 150 µg iodine/day) and non-supplement users (no supplements or < 150 µg iodine/day from supplements). RESULTS: Overall median UIC [bootstrapped 95% confidence interval (CI)] was 101 µg/L (95, 108; n = 737): 149 µg/L (132, 164) in supplement users (n = 253) and 85 µg/L (79, 92) in non-supplement users (n = 440) (p < 0.001). Overall geometric mean DBS-Tg (95% CI) was 22.1 µg/L (20.8, 23.5; n = 675) and the prevalence of elevated DBS-Tg was 19%. DBS-Tg was lower in supplement users (n = 229) than in non-supplement users (n = 405) (19.1 vs 24.4 µg/L, p < 0.001). DBS-TSH, DBS-tT4, and S-TPOab positivity did not differ between the two groups. CONCLUSIONS: Pregnant women in Sweden have inadequate iodine nutrition. Women not taking iodine supplements containing ≥ 150 µg iodine/day are affected by mild iodine deficiency and are at higher risk for increased thyroid activity, while maintaining euthyroidism. Iodine intake should be improved in women both before and after conception by promotion of iodized salt instead of non-iodized salt. We urge regular monitoring of iodine status in the general Swedish population, as well as in risk groups.

Estimating the Growth Rate of Lung Metastases in Differentiated Thyroid Carcinoma: Response Evaluation Criteria in Solid Tumors or Doubling Time?

Background: Estimating the growth rate of lung metastases for the treatment of patients with metastases of differentiated thyroid carcinoma (DTC) is important. This study aimed to evaluate survival outcomes according to different criteria for estimating the growth rate of lung metastases. Methods: Patients with macronodular (≥1 cm) lung metastases of DTC who underwent total thyroidectomy and high-dose radioactive iodine therapy between 1995 and 2013 were enrolled. The time to progressive disease (PD) by the Response Evaluation Criteria in Solid Tumors (RECIST), average tumor volume doubling time of the two dominant target lung lesions (midDT), and thyroglobulin doubling time (TgDT) were measured in each patient, and their association with disease-specific survival (DSS) was evaluated. Results: Forty-four patients with target lung metastatic nodules with an initial maximal diameter of 1.3 cm (median) were followed-up for a median of 6.8 years after the diagnosis of lung metastases. Based on RECIST, 12 patients (27.3%) showed fast tumor progression, with time to PD <1 year. When assessed by midDT, nine patients (20.5%) had midDT ≤1 year, showing rapid tumor progression. Seven of 33 patients (21.2%) who were negative for thyroglobulin antibody had midDT <1 year. Growth rates assessed by all three criteria were significantly associated with DSS. However, midDT had the highest predictive value for DSS, with a proportion of variation explained of 33.6%. Five-year DSS was 29.6% in patients with midDT ≤1 year, 50.0% in patients with time to PD <1 year, and 42.9% in patients with TgDT <1 year. Conclusions: Among the different criteria for estimating the growth rate of metastases in patients with lung metastases of DTC, midDT was the most powerful for predicting DSS, in comparison with RECIST and TgDT. Performing at least three serial chest computed tomography scans during the first year from the diagnosis of lung metastases can facilitate early detection of patients with rapid tumor progression and provide objective guidance for initiation of systemic therapy.

The Effects of Iodine Supplementation in Pregnancy on Iodine Status, Thyroglobulin Levels and Thyroid Function Parameters: Results from a Randomized Controlled Clinical Trial in a Mild-to-Moderate Iodine Deficiency Area.

BACKGROUND: Iodine supplementation during pregnancy in areas with mild-to-moderate iodine deficiency is still debated. METHODS: A single-center, randomized, single-blind and placebo-controlled (3:2) trial was conducted. We enrolled 90 women before 12 weeks of gestation. From enrollment up until 8 weeks after delivery, 52 women were given an iodine supplement (225 ug/day, potassium iodide tablets) and 38 were given placebo. At recruitment (T0), in the second (T1) and third trimesters (T2), and 8 weeks after delivery (T3), we measured participants' urinary iodine-to-creatinine ratio (UI/Creat), thyroid function parameters (thyroglobulin (Tg), TSH, FT3, and FT4), and thyroid volume (TV). The newborns' urinary iodine concentrations were evaluated in 16 cases. RESULTS: Median UI/Creat at recruitment was 53.3 ug/g. UI/Creat was significantly higher in supplemented women at T1 and T2. Tg levels were lower at T1 and T2 in women with UI/Creat ≥ 150 ug/g, and in the Iodine group at T2 (p = 0.02). There was a negative correlation between Tg and UI/Creat throughout the study (p = 0.03, r = -0.1268). A lower TSH level was found in the Iodine group at T3 (p = 0.001). TV increased by +Δ7.43% in the Iodine group, and by +Δ11.17% in the Placebo group. No differences were found between the newborns' TSH levels on screening the two groups. CONCLUSION: Tg proved a good parameter for measuring iodine intake in our placebo-controlled series. Iodine supplementation did not prove harmful to pregnancy in areas of mild-to-moderate iodine deficiency, with no appreciable harmful effect on thyroid function.

Analysis of Biomarkers and Association With Clinical Outcomes in Patients With Differentiated Thyroid Cancer: Subanalysis of the Sorafenib Phase III DECISION Trial.

PURPOSE: The phase III DECISION trial (NCT00984282; EudraCT:2009-012007-25) established sorafenib efficacy in locally recurrent or metastatic, progressive, differentiated thyroid cancer (DTC) refractory to radioactive iodine. We conducted a retrospective, exploratory biomarker analysis of patients from DECISION. EXPERIMENTAL DESIGN: Candidate biomarkers [15 baseline plasma proteins, baseline and during-treatment serum thyroglobulin, and relevant tumor mutations (BRAF, NRAS, HRAS, and KRAS)] were analyzed for correlation with clinical outcomes. RESULTS: Plasma biomarker and thyroglobulin data were available for 395 of 417 (94.7%) and 403 of 417 (96.6%) patients, respectively. Elevated baseline VEGFA was independently associated with poor prognosis for progression-free survival [PFS; HR = 1.82; 95% confidence interval (CI), 1.38-2.44; P = 0.0007], overall survival (HR = 2.13; 95% CI, 1.37-3.36; P = 0.013), and disease-control rate (DCR; OR = 0.30; P = 0.009). Elevated baseline thyroglobulin was independently associated with poor PFS (HR = 2.03; 95% CI, 1.52-2.71; P < 0.0001) and DCR (OR = 0.32; P = 0.01). Combined VEGFA/thyroglobulin signatures correlated with poor PFS (HR = 2.12; 95% CI, 1.57-2.87; P < 0.00001). Thyroglobulin decrease ≥30% from baseline was achieved by 76% and 14% of patients receiving sorafenib and placebo, respectively (P < 0.001). Patients with ≥30% thyroglobulin reduction had longer PFS than those without ≥30% reduction [HR (95% CI): sorafenib = 0.61 (0.40-0.94), P = 0.022; placebo = 0.49 (0.29-0.85), P = 0.009]. BRAF mutations were associated with better PFS; RAS mutations were associated with worse PFS, although neither was independently prognostic in multivariate models. No examined biomarker predicted sorafenib benefit. CONCLUSIONS: We identified biomarkers associated with poor prognosis in DTC, including elevated baseline VEGFA and thyroglobulin and the presence of RAS mutations. Serum thyroglobulin may be a biomarker of tumor response and progression.

Age, thyroglobulin levels and ATA risk stratification predict 10-year survival rate of differentiated thyroid cancer patients.

INTRODUCTION: Differentiated thyroid cancer (DTC) is the most common of endocrine cancers. Many studies have focused on recurrence-free survival of DTC patients, however, few studies have addressed overall survival rates. Given its very good prognosis, estimating overall or long-term survival in patients with DTC seems rational. So far, neither the impact of pre- and post-ablation thyroglobulin, nor that of initial American Thyroid Association (ATA) risk stratification on long-term disease-specific survival, have been sufficiently studied. OBJECTIVE: The aim of this study was to determine the factors that influence long-term disease-specific survival and thyroglobulin levels in patients with DTC who have been previously treated with thyroidectomy and radioactive iodine (RAI) remnant ablation. PATIENTS AND METHODS: This observational retrospective study included 1093 patients who were treated for DTC between 1995 and 2010 and are still monitored in our tertiary center. Only patients who needed RAI ablation after thyroidectomy were included in this study. Patients who were treated with RAI following rhTSH stimulation, patients who presented positive anti-thyroglobulin antibodies, and patients who had micro-cancers were excluded. Pre-ablation stimulated thyroglobulin (Pre-ablation sTg) was measured after thyroid hormone withdrawal (THW), just before RAI. RESULTS: According to ATA standards, 29 patients (2.7%) were classified as high-risk patients. Initial ATA high-recurrence risk rating (HR 21.9; 95% CI: 8.5-56.3), age>55 years (HR 23.8; 95%-CI: 7.5-75.3) and pre-ablation sTg≥30 µg/l (HR 8.4; 95% CI: 4.6-15.3) significantly impacted ten-year survival. Moreover, age over 45 years, ATA moderate-risk and follicular DTC were also significant. Ten-year survival was lower in ATA high-risk patients (51% vs 95% and 93% for the low and intermediate risk; p<10-7), patients older than 55 years (82% vs 98%; p<10-7), and in patients with pre-ablation sTg≥30 (78% vs 95%; p<10-7). Three rates of long-term survival were distinguished: excellent (survival rate of 99% in patients<55 years with pre-ablation sTg <30µg/l) representing 59% of the cohort, moderate (survival rate of 94.5% in patients <55 years with pre-ablation sTg ≥30µg/l or ≥55 years with pre-ablation sTg <30 µg/l) representing 38% of the cohort, and low (survival rate of 49% in patients ≥55 years with pre-ablation sTg ≥30µg/l) representing 3% of the cohort. CONCLUSION: Initial ATA high-risk classification, age over 55 years old and pre-ablation sTg ≥30 µg/l are the main negative factors that influence the ten-year survival in DTC. We suggest three categories of overall survival rates. Patients older than 55 years with pre-ablation sTg ≥30 µg/l have the worst survival rate.

The Association of Therapy Adherence and Thyroid Function in Adult Patients with Phenylketonuria.

BACKGROUND: The standard, lifelong therapy of phenylketonuria (PKU) is a natural protein-restricted diet complemented with phenylalanine (Phe)-free L-amino acid mixtures that provide the daily necessary micronutrients. OBJECTIVE: To assess thyroid function and structure and the iodine status of early-treated adult PKU (ETPKU) patients in Hungary. METHODS: Sixty-nine PKU patients (aged 18-41 years) and 50 healthy controls were enrolled in the study. Thyroid hormones, serum thyroglobulin, thyroid antibodies, urinary iodine, and selenium concentrations were measured, and thyroid ultrasound was performed. RESULTS: The incidence of thyroid dysfunction was infrequent (n = 2). Blood Phe was negatively correlated with thyroid-stimulating hormone (TSH), and PKU patients had higher free thyroxine and lower TSH levels than healthy controls. Although optimal iodine status was found in the entire PKU population, by dividing the patients according to their therapy compliance, we observed that lower therapy adherence was associated with mild iodine deficiency and lower urinary selenium levels. CONCLUSIONS: The results of this study suggest that iodine status is strongly influenced by the adherence to therapy in ETPKU patients. No or not enough medical food consumption combined with a low-Phe diet can lead to subclinical iodine deficiency.

Selenomethionine potentiates the impact of vitamin D on thyroid autoimmunity in euthyroid women with Hashimoto's thyroiditis and low vitamin D status.

BACKGROUND: Both exogenous vitamin D and selenium reduce thyroid antibody titers. The aim of the study was to investigate whether the impact of vitamin D on thyroid autoimmunity is affected by selenium intake. METHODS: The study included 47 euthyroid women with Hashimoto's thyroiditis and low vitamin D status, 23 of whom had been treated with selenomethionine (200 µg daily) for at least 12 months before the beginning of the study. During the study, all patients were treated with vitamin D preparations (4000 IU daily). Serum titers of thyroid peroxidase and thyroglobulin antibodies, as well as circulating levels of thyrotropin, free thyroid hormones and 25-hydroxyvitamin D were measured before vitamin D supplementation and 6 months later. Moreover, at the beginning and at the end of the study, we calculated Jostel's thyrotropin index, the SPINA-GT index and the SPINA-GD index. RESULTS: With the exception of the free triiodothyronine/free thyroxine ratio and the SPINA-GD index, there were no differences between the study groups. In both groups, vitamin D increased 25-hydroxyvitamin D levels, reduced thyroid peroxidase and thyroglobulin antibody titers, as well as increased the SPINA-GT index. The effects on antibody titers and the SPINA-GT index were more pronounced in women receiving selenomethionine. Neither in selenomethionine-treated nor in selenomethionine-naïve women vitamin D affected serum hormone levels, Jostel's index and the SPINA-GD index. CONCLUSIONS: The results of the study suggest that selenium intake enhances the effect of vitamin D on thyroid autoimmunity.

Thyroglobulin Is Markedly Elevated in 6- to 24-Month-Old Infants at Both Low and High Iodine Intakes and Suggests a Narrow Optimal Iodine Intake Range.

BACKGROUND: In areas with incomplete salt iodization coverage, infants and children aged 6-24 months weaning from breast milk and receiving complementary foods are at risk of iodine deficiency. However, few data exist on the risk of excessive iodine intake in this age group. Thyroglobulin (Tg) is a sensitive marker of iodine intake in school-age children and adults and may be used to estimate the optimal iodine intake range in infancy. The aim of this study was to assess the association of low and high iodine intakes with Tg and thyroid function in weaning infants. METHODS: This multicenter cross-sectional study recruited infants aged 6-24 months (n = 1543; Mage = 12.2 ± 4.6 months) receiving breast milk with complementary foods, from seven countries in areas with previously documented deficient, sufficient, or excessive iodine intake in schoolchildren or pregnant women. Urinary iodine concentration (UIC) and Tg, total thyroxine, and thyrotropin were measured using dried blood spot testing. RESULTS: Median UIC ranged from 48 µg/L (interquartile range 31-79 µg/L) to 552 µg/L (interquartile range 272-987 µg/L) across the study sites. Median Tg using dried blood spot testing was high (>50 µg/L) at estimated habitual iodine intakes <50 µg/day and >230 µg/day. Prevalence of overt thyroid disorders was low (<3%). Yet, subclinical hyperthyroidism was observed in the countries with the lowest iodine intake. CONCLUSIONS: Tg is a sensitive biomarker of iodine intake in 6- to 24-month-old infants and follows a U-shaped relationship with iodine intake, suggesting a relatively narrow optimal intake range. Infants with low iodine intake may be at increased risk of subclinical thyroid dysfunction. In population monitoring of iodine deficiency or excess, assessment of iodine status using UIC and Tg may be valuable in this young age group.