Shifting gears: Study of immune system parameters of male habitual marathon runners.

Aim: Marathon is a running event in which athletes must cover a distance of 42.195 km. In addition to participating in marathons, marathoners have incorporated extensive running into their lifestyle. In the present study, we investigated the effect of long-term strenuous exercise in the form of marathon running on the immune system. Methods & Results: We collected peripheral blood samples from 37 male marathoners before/after a race and 37 age/sex/body mass index (BMI)-matched healthy sedentary controls. Hematological and biochemical tests revealed race-induced leukocytosis attributable to neutrophilia and significant increases in plasma lactate dehydrogenase (LDH), creatine phosphokinase (CPK), and cortisol concentrations. Phenotypic analysis of lymphocytes revealed race-induced significant decrease in the number of lymphocytes, memory helper T (Th) cells, naive, memory and activated cytotoxic T (Tc) cells, natural killer (NK), NKT, and B1 cells, and a significant increase in the number of activated Th and regulatory Th cells (Tregs). Compared with controls, marathoners maintained significantly lower levels of memory and activated Th cells and higher levels of activated Tc and B1 cells. Measurement of plasma cytokine levels revealed a pro-inflammatory cytokine polarization that increased after the race. Examination of gene expression of cytokines and Th-cell signature transcription factors in peripheral blood mononuclear cells revealed a significant decrease in tumor necrosis factor α (TNF-α) and interleukin (IL)-17, and a significant increase in IL-6, IL-10 and forkhead box P3 (FoxP3) after the race. Compared with controls, marathoners maintained significantly higher levels of TNF-α. Assessment of the suppressive capacity of Tregs in co-cultures of isolated effector Th cells and Tregs showed significantly increased suppressive capacity of marathoners' Tregs after the race. Conclusions: Compared with controls, marathoners live with permanent changes in certain immune parameters. Marathoners exhibit a stable pro-inflammatory cytokine polarization that increases after the race and is counterbalanced by increased numbers of Tregs overexpressing FoxP3 and having increased suppressive capacity.

Benign thyroid nodules respond to a single administration of 0.3mg recombinant human thyrotropin with highly variable volume increase.

Introduction: The nature of thyroid nodules is heterogenous. Most of them are benign and, in the absence of pressure symptoms of adjunct structures, no treatment is needed. Our objective was to investigate the acute effects of a low dose of recombinant human TSH (rhTSH) on the volume of benign thyroid nodules. Methods: we studied 27 nodules (14 isoechoic and 13 hypoechoic) in 15 (11 women and 4 men; mean age: 51.0 ± 15.9 years) consecutive patients with one to three well-separated asymptomatic benign thyroid nodules. All subjects were euthyroid, with negative thyroid antibodies, and none received levothyroxine. The total thyroid volume and thyroid nodule volume were sonographically determined by two independent examiners (P.B. and M.M.) before, 48 hours and 6 months post intramuscular (IM) administration of 0.3mg rhTSH, and the mean values of the two examiners' measurements were used; thyroid function tests were obtained at the same time points. Results: The mean volume of isoechoic nodules increased by 57.3%, of hypoechoic nodules by 46.6% and of the surrounding thyroid parenchyma by 70.4% 48 hours post-rhTSH; mean volumes had returned to baseline levels 6 months later. A large variance in the volume change responses was observed. The relative change in nodule volume (defined as the percent change in nodule volume divided by the percent change in the surrounding parenchyma) from baseline to 48 hours was significantly higher in isoechoic versus hypoechoic nodules (p<0.05). Conclusions: A single dose of 0.3 mg rhTSH transiently increased the volume of benign thyroid nodules. The increase was more pronounced in isoechoic nodules and had a great variability. Our findings could be useful in the management of benign thyroid nodules, by helping in understanding which nodules would be more responsive to TSH suppression therapy.

Improving the prediction of persistent and recurrent differentiated thyroid cancer using the American Thyroid Association 2015 risk stratification system.

PURPOSE: The 2015 American Thyroid Association risk stratification system (ATA RSS) is used in patients with differentiated thyroid carcinoma (DTC) to assess their risk of persistent/recurrent disease. Our aims were to validate the 2015 ATA RSS in a registry of DTC patients and to examine whether the addition of factors not included in it, such as pre-radioactive iodine therapy stimulated thyroglobulin (pre-RAI sTg), gender, and age could increase its predictive ability. METHODS: We studied 403 patients with DTC, treated at a tertiary center from 1990 to 2018 and subjected to total thyroidectomy. All patients had received RAI therapy, except those with low-risk papillary microcarcinoma. RESULTS: Of our patients, 81.9% were women and 91.1% had papillary thyroid carcinoma. After a median follow-up of 5.0 years, 53 cases of persistent and 21 cases of recurrent disease were recorded. The proportion of variance explained (PVE) regarding the outcome (presence or absence of recurrent/persistent disease) using the 2015 ATA RSS alone was 18.3% (persistence) and 16.9% (recurrence), increasing to 74.4% and 52.0%, respectively, when pre-RAI sTg was added to the logistic regression model. Gender and age were not associated with the disease outcome. In ROC analysis, pre-RAI sTg had a high predictive value for persistent (AUC 0.983, 95% CI 0.962-1.000) and recurrent disease (AUC 0.856, 95% CI 0.715-0.997). The optimal cut-offs and sensitivity, specificity, and positive and negative predictive value for pre-RAI sTg were the following: for persistence 12.75 ng/ml, 100%, 90.5%, 64%, and 100%, and for recurrence 8.05 ng/ml, 77.8%, 85.5%, 36.8%, and 97%. CONCLUSIONS: The 2015 ATA RSS displayed moderate performance in predicting recurrent/persistent disease in patients with DTC, which improved with the inclusion of pre-RAI sTg values; pre-RAI sTg was an independent predictor of the disease outcome, with high negative prognostic value.

Therapeutic Equivalence of a New Preparation of Liquid Levothyroxine with Tablets in Patients with Overt Primary Hypothyroidism.

BACKGROUND: A new liquid levothyroxine (LT4) dissolved in glycerol and water has recently been developed by a Greek pharmaceutical company (Uni-Pharma, Athens, Greece). OBJECTIVES: To evaluate the therapeutic equivalence of this new liquid LT4 preparation versus the already existing tablet formulation of the same manufacturer, in order to obtain approval by the Greek National Organization for Medicines. METHODS: This was a prospective, randomized, cross-over phase III study. The study included 50 patients (9 men and 41 non-pregnant women, with a mean age of 42.5 ± 12.5 years), with documented overt primary hypothyroidism. All subjects were well controlled on substitution therapy with various LT4 formulations. None of the patients had known LT4 malabsorption. The patients were randomized into 2 groups (A and B). The individuals of group A initially received T4® tablets for 10 ± 2 weeks and subsequently switched to T4® drops (100 µg/mL solution) at the same dose for another 10 ± 2 weeks. In group B, the reverse procedure was followed. Total T3 (T3), free T4 (fT4), and TSH were measured in all participants at enrollment and at the end of each 10 ± 2-week trial period. RESULTS: Out of the 50 recruited patients, 6 were lost to follow-up and 5 were excluded due to non-compliance with the study protocol. In the 39 patients who completed the study, the serum TSH levels after 10 ± 2 weeks of treatment either with T4® tablets or with T4® drops did not differ (1.759 ± 1.104 vs. 2.076 ± 1.334 mIU/L, mean ± SD). CONCLUSIONS: In hypothyroid patients, the new liquid LT4 preparation (T4® drops) is therapeutically equivalent to the tablet form (T4® tablets).

A shift to more targeted thyroidectomies increased the detection of thyroid cancer and in particular low-risk papillary tumors in Southwestern Greece the decade 2007 to 2016.

OBJECTIVES: Data regarding thyroid cancer (TC) epidemiology in Greece in the last decade are scarce, so we investigated the trends in TC detection during 2007 to 2016. METHODS: We retrospectively studied 2040 pathology reports of total thyroidectomies performed at our institution from 2007 to 2016. RESULTS: A number of 478 cases of TC were identified in the studied decade. The overall incidence of TC among thyroidectomies rose over the years. The proportion of papillary T1 tumors among thyroidectomies increased in the second period of our study (2012-2016), while that of papillary T2 to T4 tumors and other TC subtypes remained unchanged. Papillary T1 tumors represented 63.6% of all TC cases and 75.3% of them were low-risk microcarcinomas (papillary thyroid microcarcinoma). The strategy of fine needle aspiration (FNA) prior to surgery in the management of thyroid nodules was adopted by more clinical endocrinologists in the area of Southwestern (SW) Greece in the second period of our study (2012-2016:29.7% vs 2007-2011:18.4%, P < .001). Consequently, the indication for thyroidectomy was set by FNA more frequently in 2012 to 2016 than in 2007 to 2011 (42.5% vs 26.4% of cases, P < .001). CONCLUSIONS: The wider use of FNA in the triage of thyroid nodules led to increased rates of TC in thyroidectomies performed in SW Greece during the decade 2007 to 2016; low-risk, small papillary tumors represented the majority of TC cases.

Standardized Map of Iodine Status in Europe.

Background: Knowledge about the population's iodine status is important, because it allows adjustment of iodine supply and prevention of iodine deficiency. The validity and comparability of iodine-related population studies can be improved by standardization, which was one of the goals of the EUthyroid project. The aim of this study was to establish the first standardized map of iodine status in Europe by using standardized urinary iodine concentration (UIC) data. Materials and Methods: We established a gold-standard laboratory in Helsinki measuring UIC by inductively coupled plasma mass spectrometry. A total of 40 studies from 23 European countries provided 75 urine samples covering the whole range of concentrations. Conversion formulas for UIC derived from the gold-standard values were established by linear regression models and were used to postharmonize the studies by standardizing the UIC data of the individual studies. Results: In comparison with the EUthyroid gold-standard, mean UIC measurements were higher in 11 laboratories and lower in 10 laboratories. The mean differences ranged from -36.6% to 49.5%. Of the 40 postharmonized studies providing data for the standardization, 16 were conducted in schoolchildren, 13 in adults, and 11 in pregnant women. Median standardized UIC was <100 µg/L in 1 out of 16 (6.3%) studies in schoolchildren, while in adults 7 out of 13 (53.8%) studies had a median standardized UIC <100 µg/L. Seven out of 11 (63.6%) studies in pregnant women revealed a median UIC <150 µg/L. Conclusions: We demonstrate that iodine deficiency is still present in Europe, using standardized data from a large number of studies. Adults and pregnant women, particularly, are at risk for iodine deficiency, which calls for action. For instance, a more uniform European legislation on iodine fortification is warranted to ensure that noniodized salt is replaced by iodized salt more often. In addition, further efforts should be put on harmonizing iodine-related studies and iodine measurements to improve the validity and comparability of results.

The impact of thyroid diseases starting from birth on reproductive function.

The aim of this review is to provide relevant information regarding the impact of thyroid disease, starting from birth and mainly concerning hyperthyroidism and hypothyroidism, on reproduction. Hyperthyroidism occurs much less commonly in children than hypothyroidism, with Graves' disease (GD) being the most common cause of thyrotoxicosis in children. Children born with neonatal GD have no defects in the reproductive system that could be related to hyperthyroidism. Current treatment options include antithyroid drugs (ATD), surgery, and radioactive iodine (RAI). In males, normal thyroid function seems important, at least in some parameters, for maintenance of semen quality via genomic or non-genomic mechanisms, either by locally acting on Sertoli cells, Leydig cells, or germ cells, or by affecting crosstalk between the HPT axis and the HPG axis. Sexual behavior may also be affected in thyroxic men, although many of these patients may have normal free testosterone levels. In women, menstrual irregularities are the most common reproduction-related symptoms in thyrotoxicosis, while this disorder is also associated with reduced fertility, although most women remain ovulatory. An increase in sex hormone-binding globulin (SHBG) and androgens, thyroid autoimmunity, and an impact on uterine oxidative stress are the main pathophysiological mechanisms which may influence female fertility. Thyroid hormones are responsible for normal growth and development during pre- and postnatal life, congenital hypothyroidism (CH) being the most common cause of neonatal thyroid disorders, affecting about one newborn infant in 3500. The reproductive tract appears to develop normally in cretins. Today, CH-screening programs allow for early identification and treatment, and, as a result, affected children now achieve normal or near-normal development. Hypothyroidism in males is associated with decreased libido or impotence. Although little is currently known about the effects of hypothyroidism on spermatogenesis and fertility, it has been established that sperm morphology and motility are mainly affected. In women of reproductive age, hypothyroidism results in changes in cycle length and amount of bleeding. Moreover, a negative effect on fertility and higher miscarriage rates has also been described.

Plasma Beta-Glucuronidase Activity: A Novel Tool to Distinguish Type 1 from Type 2 Amiodarone-Induced Thyrotoxicosis?

BACKGROUND: Amiodarone-induced thyrotoxicosis (AIT) is a common and deleterious side effect of amiodarone use. There are two types of AIT, characterized by distinct pathogenic mechanisms and, hence, different treatments. Discriminating between type 1 (AIT1) and type 2 (AIT2) AIT is often very challenging. Beta-glucuronidase (ß-G) is a lysosomal enzyme released into the extracellular fluid during inflammation. OBJECTIVES: To examine whether the determination of the plasma activity of ß-G is useful in distinguishing AIT1 from AIT2. METHODS: The study included 67 subjects: 9 with AIT1, 9 with AIT2, 14 with hyperthyroidism due to Grave's disease or toxic multinodular goiter, 14 with subacute thyroiditis, and 21 euthyroid controls. Thyroid function tests and plasma ß-G activity were determined in all participants, while thyrotoxic patients also underwent thyroid ultrasound/scintigraphy and urine iodine excretion assessment. RESULTS: Plasma ß-G activity (expressed as mean ± SD in nmol 4-methylumbelliferone [4-MU]/mL plasma/h) in AIT2 was higher compared to AIT1 (2,263.6 ± 771 vs. 1,101.8 ± 201.9, p < 0.05) and similar to subacute thyroiditis (2,263.6 ± 771 vs. 2,083.2 ± 987.5, p = ns). ß-G activity did not differ significantly between AIT1 and controls (1,101.8 ± 201.9 vs. 954.6 ± 248.6, p = ns). ROC curve analysis revealed that ß-G activity had a high predictive value for destructive processes, namely AIT2 and subacute thyroiditis (AUC 0.846, 95% CI 0.748-0.943) and a cut-off value of 1,480.5 nmol 4-MU/mL plasma/h was able to discriminate between destructive and non-destructive thyroid conditions with 74% sensitivity and 82% specificity. CONCLUSION: In our study, plasma ß-G activity performed well in distinguishing AIT1 from AIT2. Further studies are warranted to establish its usefulness as a discriminator between the two AIT types.

Thyroid-stimulating hormone is not the primary regulator of thyroid development in euthyroid children and adolescents living in an iodine-replete area.

OBJECTIVES: It is known that there are multiple factors which can affect thyroid gland development during childhood and adolescence. Our aim was to investigate this issue by examining the relationships between age, sex, several anthropometric parameters, pubertal status, thyroid function tests, and iodine intake status with thyroid volume (TV) in children and adolescents. STUDY DESIGN: This was a cross-sectional field study conducted in 11 representative cities and villages of Uzbekistan. Six hundred and ten children and adolescents participated. Anthropometric indices and TV were estimated. In addition, thyroid function tests (TFTs) and urinary iodine excretion (UIE) measures were obtained. RESULTS: Median UIE was 151 µg/L, thus the studied areas were iodine-sufficient. TFTs fluctuated in both genders during childhood and adolescence and the thyroid growth spurt was observed, in both sexes, at the ages of 12 and 13 years, which coincided with the age of menarche in girls. Thyroid volume was positively correlated with body surface area (BSA) (r = 0.800, p < 0.001), age (r = 0.780, p < 0.001), fat-free mass (FFM) (r = 0.797, p < 0.001) and negatively correlated with serum TSH (r = -0.154, p = 0.05). No association between thyroid volume and UIE was observed. CONCLUSIONS: In euthyroid children and adolescents living in iodine-replete areas, thyroid gland development appears to follow the pattern of linear growth and displays a growth spurt at the onset of puberty, probably due to the abrupt increase of circulating sex steroids. At this age, TSH does not appear to be the main regulator of thyroid gland development.

Pregnant Greek Women May Have a Higher Prevalence of Iodine Deficiency than the General Greek Population.

BACKGROUND: Adequate dietary iodine consumption, predicted via the urinary iodine concentration (UIC), is necessary for normal thyroid function and for the neurodevelopment of fetuses and neonates. The general population of Greece is considered to be iodine sufficient, but our preliminary findings suggest that Greek pregnant women are at risk of iodine deficiency. OBJECTIVE: Our aim was to estimate the thyroid function and UIC in a representative population of pregnant Greek women. METHODS: UIC and thyroid function were assessed in 1,118 women from 19 representative areas of the country. RESULTS: The median UIC was found to be 127.1 µg/l (range 7.8-2,296), which is indicative of insufficient iodine intake according to the standard of the World Health Organization (WHO) for pregnant women. The median UIC was below the minimal recommended value of 150 µg/l in 61% of the women, and below 100 or 50 µg/l in 32 and 7%, respectively. An optimal iodine intake (150-250 µg/l) was observed in 26%, and was over the cut-off of 500 µg/l in 2% of the subjects. Serum thyrotropin significantly increased between trimesters, from 1.57 ± 1.2, to 1.68 ± 1.0 and to 2.02 ± 1.2 mU/l (p < 0.001). Serum-free thyroxine decreased significantly between trimesters, from 1.22 ± 0.34, to 1.01 ± 0.21 and 0.96 ± 0.2 ng/ml (p < 0.05). Serum thyroglobulin levels remained unchanged over the trimesters and were not correlated with UIC. CONCLUSIONS: While the general population of Greece is iodine sufficient, these findings suggest that, according to the WHO, the majority of pregnant Greek women are iodine deficient. These data strongly suggest that a proactive policy should be developed to lower iodine deficiency risk in this population of women.

Effect of excess iodine intake on thyroid on human health.

The recommended daily intake of iodide, is 150 µg for adolescents and adults, 250 µg for pregnancy and lactation. Thyroid gland is an effective collector of iodine. The active iodine uptake along the basolateral membrane of thyroid cell is followed by its transport to the apical edge of the cell and then to the follicle lumen. TSH acts through cAMP and stimulates NIS gene expression and protein synthesis. The major proportion of iodine in the thyroid gland is bound to Thyroglobulin. The non-organic intrathyroidal iodine is usually low, but significantly greater compared to plasma. Large doses of iodine reduce both the uptake and the organification (Wolff-Chaikoff effect) and cause partial inhibition of Tg proteolysis. The thyroid gland has several protective mechanisms resulting on the maintenance of normal thyroid function despite wide fluctuations of the daily iodine intake. Ingestion of several commonly used drugs and food conservatives results in acute or chronic excessive iodine intake. Failure to escape from the iodine induced organification inhibition can cause hypothyroidism, which is temporary and subsides after iodine exposure ceases. Iodine excess may also establish a status of excessive thyroid hormone synthesis and release, thus inducing autonomic thyroid function in iodopenic areas or can contribute to the development of iodine-induced hyperthyroidism in iodine abundant areas. The anti-arrhythmic Amiodarone, is a benzofuranic product with a very high iodine content, is associated with either hypo- or hyperthyroidism development. In the presence of defective auto-protective mechanisms, excessive iodine ingestion can divert the normal thyroid function.

Serum Thyroglobulin Concentration Is a Weak Marker of Iodine Status in a Pregnant Population with Iodine Deficiency.

OBJECTIVE: To assess the reliability of thyroglobulin (Tg) as a marker of iodine status during pregnancy. DESIGN: 299 women aged 30.5 ± 4.8 years (mean ± SD) were studied. METHODS: In every subject, we measured urinary iodine concentration (UIC), serum thyrotropin (TSH), Tg, free thyroxine (fT4), Tg autoantibodies (TgAbs) and human chorionic gonadotropin (hCG) levels. We excluded samples with increased TgAbs from the analysis. RESULTS: According to WHO criteria, the study population was iodine deficient in every trimester. Serum Tg levels did not differ during the three trimesters of pregnancy. Serum hCG levels fell significantly as pregnancies advanced. A weak, significantly negative correlation (limited to the 3rd trimester) was found between Tg and UIC (ρ = -0.187, p = 0.039). Serum fT4 decreased as pregnancies advanced and TSH increased. Serum fT4 was negatively correlated with TSH (ρ = -0.161, p = 0.006) and positively with hCG (ρ = +0.165, p = 0.005). The multiple regression equation of Tg based on hCG, TSH, UIC and trimester of pregnancy was significant but weak (F = 4.057, p = 0.003; R(2) = 0.055), with hCG as a significant predictor Tg (p for log hCG = 0.041). CONCLUSIONS: Tg cannot be considered as a valid marker of iodine deficiency in pregnancy, at least in a mildly iodine-deficient environment. Further studies in a larger patient cohort with differences in iodine status, as well as studies on Tg changes after improving iodine status in pregnant women, are needed in order to corroborate these results.

Ensuring Effective Prevention of Iodine Deficiency Disorders.

BACKGROUND: Programs initiated to prevent iodine deficiency disorders (IDD) may not remain effective due to changes in government policies, commercial factors, and human behavior that may affect the efficacy of IDD prevention programs in unpredictable directions. Monitoring and outcome studies are needed to optimize the effectiveness of IDD prevention. SUMMARY: Although the need for monitoring is compelling, the current reality in Europe is less than optimal. Regular and systematic monitoring surveys have only been established in a few countries, and comparability across the studies is hampered by the lack of centralized standardization procedures. In addition, data on outcomes and the cost of achieving them are needed in order to provide evidence of the beneficial effects of IDD prevention in countries with mild iodine deficiency. CONCLUSION: Monitoring studies can be optimized by including centralized standardization procedures that improve the comparison between studies. No study of iodine consumption can replace the direct measurement of health outcomes and the evaluation of the costs and benefits of the program. It is particularly important that health economic evaluation should be conducted in mildly iodine-deficient areas and that it should include populations from regions with different environmental, ethnic, and cultural backgrounds.

No increase in renal iodine excretion during pregnancy: a telling comparison between pregnant women and their spouses.

OBJECTIVE: Adequate dietary iodine intake is necessary for normal thyroid gland function at all times, and most particularly during pregnancy. Increased iodine loss is cited, among other factors, as responsible for the increased iodine demand in this period. Our aim was to compare renal iodine excretion between women during all three pregnancy trimesters with that of their spouses and thereby to estimate the iodine intake in an a large sample of pregnant women in urban areas in Greece. DESIGN: Four hundred twenty-four healthy pregnant women were included prospectively (residents of Athens n=218, residents of Patras n=206). The spouses of 177 of these women following the same diet were also studied. Determinations included serum FT4, TSH and aTPO and urinary iodine excretion (UIE). RESULTS: No difference was found either in median UIE throughout pregnancy or between the UIE of the pregnant women and their spouses during the trimesters. Throughout pregnancy, mild iodine deficiency was noted and was classified as mild in 60%, moderate in 30% and severe in 10% of the women studied. Users of iodized salt had significantly higher median UIE compared with non-users. Serum FT4 levels decreased and TSH increased as pregnancy progressed. CONCLUSIONS: Our study indicates that renal iodine excretion is not increased during pregnancy. This finding needs to be confirmed by further investigation in other populations with different iodine intakes. Thus, increased iodine requirements in pregnancy are possibly due to extra-renal causes. The population of pregnant women in Greek urban areas is mildly-and often moderately and severely-iodopenic and needs to be treated accordingly.

The effect of prolonged aerobic exercise on serum adipokine levels during an ultra-marathon endurance race.

OBJECTIVE: To evaluate the effect of prolonged intensive aerobic exercise and acute energy deficit (180 km ultra-marathon race) on serum leptin, adiponectin, resistin and visfatin levels and their association and interaction with serum cortisol and insulin levels in highly trained ultra-endurance runners. DESIGN: The study included 17 highly trained ultra-endurance male athletes (mean age 51.29±6.84 years and body mass index (ΒΜΙ) 23.51±1.90) participating in the 5th Olympian Race held in Greece on May 2010. Anthropometric values were assessed; Serum cortisol, insulin, leptin, adiponectin, resistin and visfatin levels were measured at baseline, post-exercise and ~20 hours after the end of the race. RESULTS: All hormonal values of the post-exercise and recovery status were corrected for plasma volume changes. The estimated energy deficit during the ultra-endurance event was about 5000 Kcal. At the end of the race serum resistin levels were elevated (p<0.001) and serum leptin levels were reduced (p<0.001) and failed to reach pre-exercise levels, although showing a tendency towards restoration. No significant changes were noted in serum adiponectin and visfatin levels. CONCLUSIONS: Ultra-endurance aerobic exercise and acute negative energy balance lead to an up-regulation of serum resistin levels and a down-regulation of serum leptin levels.