Preoperative platelet distribution width-to-platelet ratio combined with serum thyroglobulin may be objective and popularizable indicators in predicting papillary thyroid carcinoma.

OBJECTIVES: The incidence of papillary thyroid carcinoma (PTC) has increased more rapidly than that of any other cancer type in China. Early indicators with high sensitivity and specificity during diagnosis are required. To date, there has been a paucity of studies investigating the relationship between preoperative platelet distribution width-to-platelet count ratio (PPR) and PTC. This study thus aimed to assess the diagnostic value of PPR combined with serum thyroglobulin (Tg) in patients with PTC. METHODS: A total of 1001 participants were included in our study. 876 patients who underwent surgery for nodular goiter were divided into the PTC group or benign thyroid nodule (BTN) group according to pathology reports, and 125 healthy controls (HCs) were included. Preoperative hemogram parameters and serum Tg levels were compared among three groups. Receiver operating characteristic (ROC) curve was used to evaluate the value of PPR combined with serum Tg for diagnosing PTC. RESULTS: Platelet distribution width (PDW) and PPR levels were higher in the PTC group than in the BTN and HC groups (both p < 0.05) but did not significantly differ between the BTN and HC groups. PDW and PPR levels significantly differed in the presence/absence of lymph node metastasis, the presence/absence of capsule invasion (p = 0.005), and TNM stages (p < 0.001). Multivariable analyses indicated that high serum Tg levels [adjusted odds ratio (OR), 1.007; 95% confidence interval (CI), 1.004-1.009; p < 0.001], high neutrophil-to-lymphocyte ratio (NLR,adjusted OR, 1.928; 95% CI, 1.619-2.295; p < 0.001), and high PPR (adjusted OR, 1.378; 95% CI, 1.268-1.497; p < 0.001) were independent risk factors for PTC. In ROC analysis, the areas under the curves (AUCs) of serum Tg, PDW, PPR, and NLR for predicting PTC were 0.603, 0.610, 0.706, and 0.685, respectively. PPR combined with serum Tg (PPR + Tg) had a higher diagnostic value (AUC, 0.738; sensitivity, 60%; specificity, 74.7%) compared with PDW + Tg (AUC, 0.656; sensitivity, 64.4%; specificity, 59.9%) and NLR + Tg (AUC, 0.714; sensitivity, 61.6%; specificity, 71.1%). CONCLUSIONS: Preoperative PPR combined with serum Tg may be objective and popularizable indicators for effective predicting PTC.

Use of Thyroid Hormones in Hypothyroid and Euthyroid Patients: A 2020 THESIS Questionnaire Survey of Members of the Swedish Endocrine Society.

Background: The standard treatment of hypothyroidism is levothyroxine (LT-4). However, there are several controversies regarding treatment of hypothyroid patients. Aim: To investigate the Swedish endocrinologists' use of thyroid hormones in hypothyroid and euthyroid individuals. Methods: Physician members of the Swedish Endocrine Society (SEF) were invited by e-mail to participate in an online survey investigating this topic. Results: Out of the eligible 411 members, 116 (28.2%) responded. The majority (98.9%) stated that L-T4 is the treatment of choice. However, around 50% also prescribed liothyronine (L-T3) or a combination of L-T4+L-T3 in their practice. Combination therapy was mostly (78.5%) used in patients with persistent hypothyroid symptoms despite biochemical euthyroidism on L-T4 treatment. Most respondents prescribed L-T4 tablets and did not expect any major changes with alternative formulations such as soft-gel capsules or liquid formulations in situations influencing the bioavailability of L-T4. In euthyroid patients, 49.5% replied that treatment with thyroid hormones was never indicated, while 47.3% would consider L-T4 for euthyroid infertile women with high thyroid peroxidase (TPO) antibody levels. Conclusion: The treatment of choice for hypothyroidism in Sweden is L-T4 tablets. Combination therapy with L-T4+L-T3 tablets was considered for patients with persistent symptoms despite biochemical euthyroidism. Soft-gel capsules and liquid solutions of L-T4 were infrequently prescribed. Swedish endocrinologists' deviation from endocrine society guidelines merits further study.

T cell exhaustion is associated with the risk of papillary thyroid carcinoma and can be a predictive and sensitive biomarker for diagnosis.

BACKGROUND: The incidence of papillary thyroid carcinoma (PTC) has been steadily increasing over the past decades. Hashimoto's thyroiditis (HT) is the most common autoimmune disease, and is related to the pathogenesis of PTC. Programmed death-1 (PD-1) is currently used for the treatment of PTC, but there are very few studies on the clinical value of PD-1 in the diagnosis and targeted therapy of PTC. METHODS: The expression of T, B, NK cells and PD-1 in the peripheral blood of 132 patients with PTC (PTC group), 48 patients with nodular goiter (NG group) and 63 healthy subjects (HP group) were detected by flow cytometry. The expression of plasma T3, T4, FT3, FT4, TSH, TGAb and TPO was detected by chemiluminescence immunoassay. Among 132 PTC, 49 PTC&HT and 83 PTC&noHT were included. Among 48 NG, 10 NG&HT and 38 NG&noHT were included. The expressions of programmed death- ligand1(PD-L1) in tumor tissues of PTC group and thyroid tissues of NG group, PD-1 and CD3 in tumor infiltration lymphocyte (TIL) were detected by immunohistochemistry. RESULTS: The expression of FT3, TGAb, CD3+PD-1+, CD3+CD4+PD-1+ and CD3+CD8+PD-1+ in PTC and NG was significantly higher than that in the HP group. Moreover, CD3+PD-1+, CD3+CD4+PD-1+ and CD3+CD8+PD-1+ expression had significant differences between the PTC group and the NG group. In addition, the expression of TGAb, TPO, CD3+PD-1+, CD3+CD4+PD-1+ and CD3+CD8+PD-1+ in PTC&HT group was significantly higher than that in the PTC&noHT group. While, the expression of B cells, CD3+PD-1+, CD3+CD4+PD-1+ and CD3+CD8+PD-1+ in PTC&HT group was higher than that in NG&HT group. PD-1 showed a significant correlation with PTC lymph node metastasis. CD3+PD-1+ and CD3+CD4+PD-1+ was higher in N1 stage than in N0 stage. Immunohistochemical results showed that the expression of PD-1, CD3 and PD-L1 in PTC was significantly higher than that in NG. CONCLUSIONS: T cell exhaustion might act as a biomarker for the differential diagnosis of PTC and NG. Patients with PTC&HT have obvious T cell exhaustion and increased expression of PD-1, PD-L1.Targeting the PD-1/PD-L1 pathway could be a new approach to prevent malignant transformation from HT to PTC&HT in the future.

Altered methylarginine levels after surgery in subjects with multinodular goiter.

OBJECTIVES: Thyroid disorders are important risk factor for cardiovascular diseases. Levels of methylarginines such as asymmetric dimethyl arginine (ADMA), L-monomethyl arginine (L-NMMA), symmetric dimethyl arginine (SDMA) are increase in cardiovascular diseases. Multinodular goiter (MNG) is the most common type of goiter in adults. To date, no study has been conducted to determine the levels of methylarginine in euthyroid MNG patients. Our aim in this study is to compare levels of methylarginines and related metabolites in the preoperative, postoperative MNG patients and controls. METHODS: Serum ADMA, SDMA, L-NMMA, homoarginine (hArg), arginine and citrulline concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: ADMA (p<0.001), L-NMMA (p=0.002), l-arginine (p=0.006) and citrulline (p<0.001) levels were statistically significantly higher in preop group than postop group. ADMA (p=0.003), L-NMMA (p=0.003) levels were statistically significantly higher and SDMA/ADMA (p<0.001), hArg/ADMA (p<0.001) levels were statistically significantly lower in preop group than control group. CONCLUSIONS: The levels of methylarginines and related metabolites altered in the euthyroid MNG patients compared to the control group, and more importantly, there were significant differences between the preop and postop groups. Therefore, these metabolites can be useful in the diagnosis and prognosis of thyroid disorders, even if thyroid hormone levels are normal.

Mice Hypomorphic for Keap1, a Negative Regulator of the Nrf2 Antioxidant Response, Show Age-Dependent Diffuse Goiter with Elevated Thyrotropin Levels.

Background: Familial nontoxic multinodular goiter (MNG) is a rare disease. One of the associated genes is Kelch-like ECH-associated protein 1 (KEAP1), which encodes the main inhibitor of nuclear factor erythroid 2-related transcription factor 2 (Nrf2), a central mediator of antioxidant responses. The association of KEAP1 with familial MNG is based on only two loss-of-function mutations identified in two families, only one of which included proper phenotyping and adequate demonstration of co-segregation of the phenotype and the mutation. There is no experimental evidence from model organisms to support that decreased Keap1 levels can, indeed, cause goiter. This study used mice hypomorphic for Keap1 to test whether decreased Keap1 expression can cause goiter, and to characterize the activation status of Nrf2 in their thyroid. Methods: C57BL/6J Keap1flox/flox (Keap1 knock-down [Keap1KD]) mice were studied at 3 and 12 months of age. Plasma and thyroid glands were harvested for evaluation of thyroid function tests and for gene and protein expression by real-time polymerase chain reaction and immunoblotting, respectively. Results: Keap1KD mice showed diffuse goiter that began to develop in early adult life and became highly prominent and penetrant with age. The goiter was characterized by a markedly increased size of thyroid follicles, most notably of the colloid compartment, and by absence of thyroid nodules or hyperplasia. Keap1KD mice also showed decreased T4 levels in early adult life that were eventually well compensated over time by increased thyrotropin (TSH) levels. Nrf2 was activated in the thyroid of Keap1KD mice. Despite a known stimulatory effect of Nrf2 on thyroglobulin (Tg) gene transcription and Tg protein abundance, the expression levels were decreased in the thyroid of Keap1KD mice. No clear patterns were observed in the expression profiles of other thyroid hormone synthesis-specific factors, with the exception of Tg-processing and Tg-degrading cathepsins, including an increase in mature forms of cathepsins D, L, and S. Conclusions: Keap1KD mice develop age-dependent diffuse goiter with elevated TSH levels. The precise mechanism accounting for the thyroidal phenotype remains to be elucidated, but it may involve enhanced Tg solubilization and excessive lysosomal Tg degradation.

Effect of thyroidectomy on circulating angiogenic cytokines in papillary thyroid carcinoma and benign goiter: Potential for new biomarkers?

BACKGROUND: Circulating angiogenic factors have been associated with clinical outcomes of papillary thyroid carcinoma, although they may also be released in the context of benign multinodular goiter. We sought to investigate the effect of thyroidectomy on the activity and importance of multiple circulating angiogenic factors in papillary thyroid carcinoma and benign multinodular goiter. METHODS: Between May 2015 and December 2016, patients scheduled for total thyroidectomy for papillary thyroid carcinoma or benign multinodular goiter were offered to enroll in this study. Serum levels of angiopoietin-2, fibroblast growth factor-2, hepatocyte growth factor, platelet-derived growth factor-BB, placenta growth factor, heparin-binding epidermal growth factor, and vascular endothelial growth factor-A and -C were collected preoperatively and 2 weeks postsurgery. These levels were measured by enzyme-linked immunosorbent assay and compared with those of 35 healthy control subjects. RESULTS: Sixty patients with a median age of 52 years, 37 of whom were females, were included: 36 had papillary thyroid carcinoma, and 24 had benign multinodular goiter. In both benign multinodular goiter and papillary thyroid carcinoma, preoperative, circulating angiogenic factors levels were increased with respect to controls (P < .0001), and a decrease after total thyroidectomy was observed in the levels of angiopoietin-2 (P < .0001), fibroblast growth factor-2 (P < .0001), hepatocyte growth factor (P < .001), and heparin-binding epidermal growth factor (P < .01 each). Only patients with papillary thyroid carcinomas, however, showed decrease in the postoperative levels of platelet-derived growth factor-BB and vascular endothelial growth factor-A (P = .001 each). CONCLUSION: Results from this study raise the potential for vascular endothelial growth factor-A and platelet-derived growth factor-BB to be used as biomarkers of the effectiveness of treatment of papillary thyroid carcinoma. These results warrant further investigation and may have potential prognostic implications.

Delta Neutrophil Index and Neutrophil-to-Lymphocyte Ratio in the Differentiation of Thyroid Malignancy and Nodular Goiter.

BACKGROUND: It was aimed to evaluate the relationship between delta neutrophil index (DNI) and neutrophil-to-lymphocyte ratio (NLR) in the preoperative differentiation of nodular goiter and thyroid malignancy. METHODS: Patients over the age of 18 who underwent thyroid surgery between November 2014 and November 2019 were evaluated in this retrospective cohort study. Patients were divided into two groups according to their pathology results: malignant (Group M) and benign (Group B) thyroid disorders. White blood cell (WBC) count, neutrophil count, lymphocyte count, IG count and DNI were measured using an automated hematological analyzer from blood samples obtained at the preoperative period and postoperative 6th month of the follow-up. Neutrophil-to-lymphocyte ratio (NLR) values were manually calculated. Numerical data are expressed as means ± standard deviations (minimum-maximum values) or medians (minimum-maximum values) according to the normal distribution. Categorical values are expressed as percentages (%). RESULTS: A total of 243 patients (190 patients in Group B and 53 patients in Group M) who met the inclusion criteria were evaluated. The male/female ratio was 49/194. A statistically significant difference between Group M and Group B in terms of preoperative NLR, DNI and IG count was observed (p = 0.001, < 0.001 and < 0.001, respectively). No statistically significant difference was observed between the groups in terms of the control values performed in the postoperative period in terms of the NLR, DNI and IG count (p = 0.711, 0.333 and 0.714, respectively). A significant decrease was observed in the preoperative and postoperative DNIs, IG counts and NLRs in Group M (p = 0.009, < 0.001 and < 0.001, respectively). For the diagnosis of malignant thyroid diseases, the cut-off value of DNIs was ≥0.35%, and DNI sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 79.2%, 78.9%, 79.2% and 77.9%, respectively (area under the curve [AUC]: 0.847; confidence interval [CI]: 0.784-0.911). The cut-off value of the IG count was ≥25/mm3, and its sensitivity, specificity, PPV and NPV were 83%, 72.1%, 83%, and 72.1%, respectively (AUC: 0.847; CI: 0.784-0.911). CONCLUSION: DNI and IG counts are cheap and easily accessible tests that can be automatically calculated from automated systems without additional cost in differentiation of thyroid malignancies from benign disorders in the preoperative period.

Low level of plasma fibulin-1 in patients with thyroid lesions: a case-control study and literature review.

Investigating novel biomarkers discriminating thyroid nodules is a matter of great importance for differential diagnosis. The current study was planned to investigate the diagnostic value of fibulin-1 in plasma specimens of patients with thyroid nodules. A literature review was also performed to gain an understanding of the existing research relevant to the main role of fibulin-1 in carcinogenesis. In this case-control study, the levels of plasma fibulin-1 were compared in 82 subjects including papillary thyroid cancer (PTC; n = 30), multinodular goiter (MNG; n = 30), and healthy subjects (n = 22) using enzyme-linked immunosorbent assay (ELISA). Fibulin-1 levels of patients with PTC and MNG were documented to be significantly lower than those of healthy subjects (PTC vs. Healthy; P = 0.000, MNG vs. Healthy; P = 0.000). No statistically significant differences were found between PTC and MNG groups when fibulin-1 levels were compared (P > 0.05). Low level of plasma fibulin-1 was associated with an increased risk of PTC tumorigenesis (odds ratio = 0.810; 95% CI: 0.704-0.933; P = 0.003). Further, fibulin-1 had an appropriate diagnostic value for detecting PTC patients with a sensitivity of 73.33%, and specificity of 100% at the cutoff value > 4.9 (ng/ml). According to the results of the present research which are tied well with previous studies, the abnormal downregulation of fibulin-1 may play a role in the PTC and MNG tumorigenesis. In addition, fibulin-1 probably promotes the development and progression of other human cancer; however, further studies are needed to improve current understandings.

Predictors of euthyreosis in hyperthyroid patients treated with radioiodine 131I-: a retrospective study.

BACKGROUND: Radioiodine (RAI) treatment for hyperthyroidism is a very common modality, chosen by physicians worldwide. The outcome of the therapy, however, is not always predictable. While rendering a patient hypo- or euthyroid is meant as a therapeutic success, the latter does not require lifelong hormonal supplementation. The aim of our study is to determine predictors of euthyreosis in patients who underwent RAI treatment. METHODS: Medical records of 144 patients who had undergone RAI therapy were examined. Laboratory and clinical data were analyzed statistically. Ultrasonography findings, such as thyroid volume, nodules' size and characteristics had been collected at the beginning of treatment and 6 months after the administration of radioiodine 131I-. Moreover, scintigraphy results were taken into account. Multivariate logistic regression analysis model has been used to find predictors of euthyroidism after 12 months of follow-up. The predictors of normal thyroid function have also been analyzed separately for patients with GD (Graves' disease) and TMNG (toxic multinodular goiter). RESULTS: The analysis showed that age (OR 1,06; 95%CI 1.025-1.096, p = 0,001), thyroid gland volume (OR 1,04; 95%CI 1,02-1,06; p < 0.001) and iodine uptake level (OR 0,952; 95%CI 0,91-0,98; p = 0,004) were significant factors of achieving normal thyroid function after RAI therapy. According to multivariate logistic regression analysis, in GD patients only age has been shown to be a significant factor (OR 1,06; 95%CI 1,001-1,13; p = 0.047), while in TMNG patients' age (OR 1,04; 95%CI 1-1,09; p = 0.048), thyroid gland volume (OR 1.038; 95%CI 1.009-1.068; p = 0.009) and iodine uptake level (OR 0.95; 95%CI 0.9-0.99; p = 0.02) all have been proven to be significant predictors of achieving euthyroidism. CONCLUSIONS: The more advanced age, larger volume of thyroid gland and lower iodine uptake level are predictors of euthyreosis after RAI treatment.

The significance of serum thyroglobulin measurement before and after the treatment of toxic nodular goiter with 131I.

OBJECTIVES: Thyroglobulin is routinely used as a tumor marker in follow up of patients with thyroid carcinoma, but is also elevated in patients with toxic nodular goiter. The aim of this study was to evaluate the role of thyroglobulin measurement prior to and after the radioiodine therapy (RIT) in patients with toxic nodular goiter and to compare the results with the therapy outcome. PATIENTS AND METHODS: In 109 patients with toxic nodular goiter (102 females, 7 males, aged 45-85 years), 61 with multinodular toxic goiter and 48 with toxic adenoma, thyroglobulin level was measured before RIT and during the first 12 months after the treatment and compared to therapy outcome, defined as euthyroid, hypothyroid and persistent hyperthyroidism. RESULTS: In patients with euthyroid and hypothyroid outcome, a significant fall of thyroglobulin level was noted during the first 12 months after RIT, more prominent in the latter group. In patients with persistent hyperthyroidism, the initial thyroglobulin level was higher than in other two groups and no significant decrease was noted by the end of the first year after therapy, especially in patients with multinodular toxic goiter. CONCLUSIONS: The significant fall of thyroglobulin after RIT observed in patients in whom euthyroidism and hypothyroidism was achieved indicates that thyroglobulin values can be related to the treatment outcome. In patients with high initial thyroglobulin levels (above 400 ng/l), and possible unfavorable RIT outcome, higher radioiodine activities or other treatment options might be considered.Video abstract: http:/links.lww.com/NMC/A163.

Association Between Thyroid Hormone Status and Trace Elements in Serum of Patients with Nodular Goiter.

The present study investigated the status of calcium and magnesium as well as essential trace elements including iodine, selenium, copper, iron, and zinc in adults residing in the Zhytomyr region of Ukraine. In addition, the relative risk of goiter occurrence was evaluated. In this comparative study, 40 adults without goiter (control group) and 16 adults with diagnosed nodular goiter (NG) were examined. Inductively coupled plasma optical emission spectrometry (ICP-OES) was used for the measurements of Mg, Ca, Se, Zn, Cu, and Fe in serum of patients with NG and control group. Patients with nodular goiter had lower serum values of Ca, Mg, Se, Cu, Fe, and Zn than those in the control group. The presence of mild iodine deficiency was evident in both groups with the median urinary iodine excretion (UIE) 80.5 µg/L in the control group and 64.5 µg/L in goiter group. There was a positive association between goiter presence and low concentration of Ca in serum (odds ratio (OR) = 2.29 (1.26-3.55), p < 0.05) in the NG group. High relative risk of goiter was observed at low concentrations of magnesium (OR = 3.33 (1.39-7.62), p < 0.05) and selenium (OR = 1.63, (1.16-1.78), p < 0.05) in comparison with OR values in the control group. Low concentrations of Ca, Mg, Zn, and Se in serum combined with reduced UIE resulted in the highest risk of goiter (OR = 12.5, (2.15-79.42), p < 0.01). This study proved that Thyroglobulin concentration in serum is the reliable indicator of nodular goiter. We also suggest that a combination of low concentrations of Ca, Mg, Zn, Cu, and Se in blood serum, and reduced iodine concentration in urine resulted in the highest risk of nodular goiter development.

Elevated serum concentrations of IGF-1 and IGF-1R in patients with thyroid cancers.

BACKGROUND: The rising incidence of thyroid cancer observed in the last few decades requires an improvement in diagnostic tools and management techniques for patients with thyroid nodules. AIMS: The aim of this study was to assess serum concentrations of IGF-1 and IGF-1R in patients diagnosed with thyroid cancers. METHODS: 36 patients diagnosed with papillary thyroid cancer (PTC), 11 subjects with follicular thyroid cancer (FTC), 9 patients with anaplastic thyroid cancer (ATC) and 19 subjects with multinodular nontoxic goiter (MNG) were enrolled to the study. The control group (CG) consisted of 20 healthy volunteers. Blood samples were collected one day before surgery. Serum IGF-1 and IGF-1R concentrations were measured using specific ELISA methods. RESULTS: Significantly higher concentrations of IGF-1 were found in patients with PTC as compared with controls but not that obtained from subjects diagnosed with MNG. The concentration of IGF-1R was significantly elevated in subjects with PTC and ATC as compared with healthy volunteers. Similarly, patients diagnosed with PTC or ATC presented significantly higher serum concentration of IGF-1R in comparison to the MNG group. CONCLUSIONS: Our results show that the IGF-1 - IGF-1R axis plays a significant role in the development of PTC and ATC and imply that serum concentrations of both cytokines may be considered as additional markers for the differentiation of malignancies during the preoperative diagnosis of patients with thyroid gland tumors. These results indicate that IGF-1R serum concentrations allow us to differentiate between MNG and PTC or ATC. Moreover IGF-1R serum values appear to be better predictor of PTC and ATC than IGF-1 concentrations.

A comparison of haemogram parameters of patients with thyroid papillary cancer and nodular goiter in Van, Turkey.

OBJECTIVE: To compare the haemogram parameters of patients with thyroid papillary cancer and nodular goiter. METHODS: The retrospective comparative study was conducted at Van Training and Research Regional Hospital, Van, Turkey, and comprised data of patients who underwent thyroidectomy from 2011 to 2015. The data was compared between patients with papillary thyroid cancer (group 1) and those with nodular hyperplasia (group 2) in terms of age, gender and thyroid stimulating hormone level as well as haemogram parameters, neutrophil-lymphocyte ratio and platelet-lymphocyte ratio. SPSS 20 was used for statistical analysis. RESULTS: Of the 90 patients, 53(59%) were in group 1 with papillary thyroid cancer and 37(%) in group 2 with nodular hyperplasia. Platelet-lymphocyte ratio was significantly higher in group 1 (p=0.015). Mean platelet volume was significantly higher in group 1 patients with a diameter of 1cm or more (p<0.05). Within group 1, lymphocyte count was significantly high in patients with invasion (p<0.05). In correlation analysis, group 1 patients with a tumour diameter of 1cm or more showed a significant correlation in mean platelet volume, tumour multicentricity, lymphocyte count, vascular invasion, thyroglobulin, platelet distribution width, platelet number and tumour multicentricity (p<0.05). CONCLUSION: Only platelet-lymphocyte ratio could assist in distinguishing benign goiter from thyroid cancer. Also, mean platelet volume, lymphocyte count, and platelet distribution width appeared to be effective prognostic markers for papillary thyroid cancer.

Association between TSH Level and Pregnancy Outcomes in Euthyroid Women Undergoing IVF/ICSI: A Retrospective Study and Meta-analysis.

The aim of this study was to determine the association between thyroid-stimulating hormone (TSH) level and pregnancy outcomes in euthyroid women undergoing in vitro fertilization (IVF)/intra-cytoplasmic sperm injection (ICSI). A total of 1185 women were enrolled in the retrospective study, and 12 studies with a total of 6624 women were included in the meta-analysis (including the data of the present retrospective study). Participants in the retrospective study were divided into two groups in terms of their serum TSH levels: TSH ≤2.5 mIU/L group (n=830) and TSH >2.5 mIU/L group (n=355). They were monitored for the status of clinical pregnancy or miscarriage. In the TSH ≤2.5 mIU/L group, 441 (53.1%) women achieved clinical pregnancy, while 48 (5.8%) had early pregnancy loss and 12 (1.4%) had ectopic pregnancy. In the TSH >2.5 mIU/L group, 175 (49.3%) women achieved clinical pregnancy, while 21 (5.9%) had early pregnancy loss and 3 (0.8%) had ectopic pregnancy. No significant differences were observed between the two groups in pregnancy outcomes (P=0.126, P=0.512, P=0.297). The meta-analysis also revealed no significant difference in the clinical pregnancy rate and the miscarriage rate between women with serum TSH ≤2.5 mIU/L and those with serum TSH >2.5 mIU/L. In conclusion, high TSH levels (TSH level >2.5 mIU/L) did not affect clinical pregnancy rate or increase miscarriage rate in euthyroid women undergoing IVF/ICSI.

Comparison of a Bridge Immunoassay with Two Bioassays for Thyrotropin Receptor Antibody Detection and Differentiation.

A rapid and fully automated chemiluminescent immunoassay for the detection of thyrotropin receptor autoantibodies (TSHR-Ab) based on a bridge technology was compared with two bioassays that measure either stimulating (TSAb) or blocking (TBAb) antibodies for the detection and differentiation of TSHR-Ab. A total of 229 patients with various thyroid disorders [151 with Graves' disease (GD), 35 with Hashimoto's thyroiditis (HT), 32 with nodular goiter, and 11 with thyroid cancer] were included. The bridge immunoassay was performed according to the manufacturer's instructions (cut-off>0.55 IU/l). TSAb and TBAb were measured with reporter bioassays. Blocking activity was defined as percent inhibition of luciferase expression relative to induction with bovine TSH alone (cut-off>34% inhibition). TSAb was reported as percentage of specimen-to-reference ratio (> 140 SRR%). The 3 TSHR-Ab assays were negative in all patients with benign euthyroid nodular goiter and differentiated thyroid cancer. In contrast, in all patients with GD, irrespective of the disease duration, TSHR-Ab positivity was present in 127 of 151 (84%) and 140 (93%) for the bridge assay and TSAb bioassay, respectively (p<0.001). Fifteen of 151 (10%) GD samples were positive in the TSAb bioassay but negative in the bridge assay. The bridge assay and the TSAb bioassay correlated positively (r=0.39, p<0.0001) in patients with GD. Both assays detected TSHR-Ab in all ten untreated hyperthyroid patients with GD. In GD patients with a duration of less than six months, 27/29 (93%) and 28 (97%) were TSHR-Ab positive with the bridge and TSAb bioassay, respectively. In comparison, TSHR-Ab were present in two of 35 (6%) and five (14%) HT patients with the bridge and TSAb bio-assay, respectively. TSHR blocking antibodies were present in one (3%) patient with HT and in two (1%) patients with GD; these two GD patients were also bridge assay positive but TSAb bioassay negative. In conclusion, the bridge immunoassay and both bioassays are highly sensitive for the detection of TSHR-Ab. The bridge assay is, however, also positive in the presence of TSHR blocking antibodies detected in a TBAb bioassay.

Neutrophil to Lymphocyte Ratio is Useful in Differentiation of Malign and Benign Thyroid Nodules.

OBJECTIVE: Significant amount of thyroid nodules are malignant. Inflammation plays crucial role in the pathogenesis of many disorders, including cancer. Neutrophil to lymphocyte ratio (NLR), has been suggested as an index of inflammatory response and association between increased NLR and cancer has also been reported. In this retrospective analysis, we aimed to study NLR levels in patients with malign and benign thyroid nodules and healthy control subjects. METHODS: The patients who underwent surgery for nodular goiter in general surgery clinics of our university hospital between June 2012 and June 2015 and 68 healthy volunteers were included. Patients with thyroid nodules divided into malign or benign nodule groups according to the pathology report. Thyroid carcinomas other than micropapillary tumor were excluded. Preoperative hemogram parameters of these groups were compared. RESULTS: Mean NLR of malign nodule group (2.1±0.9%) was significantly higher than both those in benign nodule (1.7±0.9%) and control groups (1.7±0.6%). CONCLUSION: We suggest that elevated NLR in patients with thyroid nodules in preoperative period may be an indicator of underlying malign nodular disease. Increased NLR in such patients should encourage physician to perform cancer screening in thyroid gland.

Long-term sequelae of the less than total thyroidectomy procedures for benign thyroid nodular disease.

INTRODUCTION: Nodular goiter is the most common disorder of the thyroid gland. Less than total thyroidectomy procedures are considered the gold standard in the surgical management of nodular thyroid disease despite its propensity for recurrence. The aim of the study was to assess long-term sequelae of the less than total thyroidectomy procedures. MATERIAL AND METHODS: In this single-center retrospective study, records of 154 patients that underwent less than total thyroidectomy, for nodular disease and/or hyperthyroidism between 1998 and 2013, were reviewed. Patients with malignant findings in the histology report and a follow-up of less than 5 years were excluded. RESULTS: The mean age of the recorded patients was 65.1 ± 12.91 years of which 132 were females. Subtotal thyroidectomy was performed in 45.5% of the study population, 22.1% underwent partial thyroidectomy, while the remaining 32.5% underwent lobectomy. Long-term thyroxine supplementation was administered in 138 patients (89.6%). Recurrence of clinically important nodules (>1 cm) was observed in 68.2% of patients but only 11% of the population underwent completion thyroidectomy. In the univariate analysis, the duration of follow-up (p = 0.00005, C.I.: 0.903-0.965) as well as the type of operation (p = 0.035, C.I.: 1.031-2.348) appeared to have a significant correlation with nodular recurrence. The multivariate analysis identified the duration of follow-up (p = 0.0005, C.I.: 0.908-0.973) as the only significant predictive factor of nodular recurrence. CONCLUSION: This is the first study with such a long duration of post-operative follow-up. The high rate of nodular recurrence in less than total thyroidectomy procedures along with the lifelong need for thyroxine supplementation suggest that a more conservative surgical approach is needed. When surgery is recommended, we suggest total thyroidectomy as the treatment of choice to avoid the recurrence of disease, the high cost associated with frequent follow-ups by means of sonography as well as thyroxine replacement therapy.

Determinants of Visfatin/NAMPT Serum Concentration and its Leukocyte Expression in Hyperthyroidism.

We aimed to analyze the potential influence of thyroid autoimmunity on visfatin/NAMPT serum concentration and its leukocyte expression in hyperthyroid patients. This is a single-center, cross-sectional study with consecutive enrollment. All patients with newly diagnosed overt hyperthyroidism in a course of Graves' disease or toxic nodular goiter were included in the study. They underwent physical examination, laboratory investigation, body composition analysis, and thyroid ultrasound. NAMPT mRNA leukocyte expressions were measured using RT-qPCR. Of the 173 patients, 95 were enrolled in further analysis [67 patients with Graves' disease (GD) and 28 with toxic nodular goiter (TNG)]. Control group consisted of 43 healthy volunteers adjusted for age, sex, and BMI. Higher NAMPT/visfatin serum concentration was found in patients with GD comparing with patients with TNG (p=0.03855). We found significant NAMPT leukocyte overexpression in GD patients (n=32) as compared to TNG patients (n=18) and euthyroid controls (n=24) (p=0.005965). Simple linear regression analysis revealed that NAMPT/visfatin serum concentration was significantly associated with NAMPT leukocyte expression, thyroid autoimmunity, age, HOMA-IR, and fat mass percentage (FM%). NAMPT leukocyte expression was related to thyroid autoimmunity, age, and TRAb levels. The stepwise multiple regression analysis revealed FM% and HOMA-IR as independent predictors of visfatin/NAMPT serum levels. In a separate stepwise multiple regression analysis, we confirmed the association between NAMPT leukocyte expression and TRAb levels. We found that fat mass percentage together with HOMA-IR are the most significant predictors of visfatin/NAMPT serum elevation in hyperthyroid patients.

[Recommendation for Calcitonin Screening in Nodular Goiter]. / Empfehlung zum Calcitonin-Screening bei Struma nodosa.

Medullary thyroid cancer (MTC) arises from parafollicular C cells of the thyroid gland and is characterized by a calcitonin secretion. Basal calcitonin correlates with the tumor mass and is used as highly sensitive and specific tumor marker for MTC. Based on former assays, unspecific calcitonin increase has frequently been seen in Hashimoto's thyroiditis, kidney insufficiency, proton pump inhibitors etc. This phenomenon is now less often seen with modern assays. The consequent use of calcitonin measurement in nodular goiter helps to identify the rare MTC at an early stage. The best cut-off values to differentiate micro-MTC from C-cell hyperplasia and other unspecific calcitonin elevations were achieved by the use of a 30 pg/ml and a 60 pg/ml threshold in women and men, respectively. This approach is not less sensitive than formerly used pentagastrin stimulation. A calcitonin value > 100 pg/ml is nearly 100 % predictive for MTC. Therefore, the Thyroid Section of the German Society of Endocrinology recommends a thyroidectomy in woman with serum calcitonin values > 30 pg/ml (grey zone 20 - 30 pg/ml) and in man with serum calcitonin values > 60 pg/ml (grey zone 30 -60 pg/ml). Lower calcitonin values should be re-evaluated in intervals of 3 - 6 months; rising calcitonin levels may indicate an MTC. In this case, thyroid operation should be performed. The cure rate of MTC with calcitonin values < 100 pg/ml is nearly 100 % done by high volume surgeons.

Potential Use of 1-25-dihydroxyvitamin D in the Diagnosis and Treatment of Papillary Thyroid Cancer.

BACKGROUND Low levels of 1-25-dihydroxyvitamin D3 [1,25(OH)2D3] in serum may be a risk factor for several tumor types. Also, high cathelicidin antimicrobial peptide (CAMP) expression is regarded to be important against tumor progression. We evaluated the potential importance of 1,25(OH)2D3 in the diagnosis and treatment of papillary thyroid cancer (PTC). MATERIAL AND METHODS The preoperative serum level of 1,25(OH)2D3 was measured using a double-antibody sandwich enzyme-linked immunosorbent assay. Vitamin D3 receptor (VDR) expression was detected by streptavidin-peroxidase immunohistochemical staining in PTC specimens. Receiver operating characteristic (ROC) curves were created to assess the diagnostic value of 1,25(OH)2D3. The effect of 1,25(OH)2D3 on the proliferation and apoptosis of PTC cell lines were studied by Cell Counting Kit (CCK)-8 assay and Annexin V/propidium iodide staining, respectively. CAMP expression was measured by qRT-PCR and western blotting. Short interfering RNAs were used to reduce CAMP expression in PTC cell lines. RESULTS The preoperative serum level of 1,25(OH)2D3 in PTC was obviously lower than that in nodular goiter (NG) (P<0.05). The ROC curve suggested that 1,25(OH)2D3 might serve as a potential diagnostic value at a cutoff of 20.13 pg/mL, The VDR showed higher expression in PTC than in paired adjacent non-cancerous tissue. 1,25(OH)2D3 inhibited the proliferation and induced the apoptosis of PTC cells, and increased CAMP expression significantly, whereas CAMP knockdown demonstrated opposite effects. CONCLUSIONS 1,25(OH)2D3 may be a new, potential biomarker for the identification of PTC and NG. It may also become 1,25(OH)2D3 may a potential target for drug action to treat PTC through CAMP.