We hypothesized that increased levels of blood cytokines occur in brain-dead patients, and that these cytokines are responsible for some of the endocrine and/or acute-phase reactant abnormalities found in these patients. We measured blood levels of cytokines, hormones, and acute-phase reactants in 18 brain-dead potential organ donors at the moment of establishing the legal diagnosis of brain death and compared them with levels found in a control group. Although interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) levels were within the normal range, interleukin-6 (IL-6) levels were clearly above the normal range in all patients (median, 1,444 pg/mL; range, 75 to 11,780). In the brain-dead group, total thyroxine (tT4), free T4 (fT4), triiodothyronine (T3), thyrotropin (TSH), dehydroepiandrosterone sulfate (DHEA-S), testosterone, albumin, Zn, and osteocalcin levels were decreased, T3 resin uptake index (T3 RUI), corticotropin (ACTH), cortisol, 11-deoxycortisol (11-DOC), 17-hydroxyprogesterone (17-OHPr), aldosterone, luteinizing hormone, and follicle-stimulating hormone levels were normal, and reverse T3 (rT3), renin, and C-reactive protein (CRP) levels were increased. Multiple regression analysis demonstrated significant interrelations between IL-6 and T4, T3, testosterone, and CRP. We also studied the evolution of some of these parameters in four patients with severe head injury who finally developed brain death. IL-6 levels on admission to the intensive care unit (ICU) were above the normal limits, as in other patients with cranial trauma, but when the patients developed brain death, there was a pronounced increase in IL-6 levels.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND

Polybrominated diphenyl ethers (PBDEs) reduce blood concentrations of thyroid hormones in laboratory animals, but it is unclear whether PBDEs disrupt thyroid hormones in pregnant women or newborn infants.

OBJECTIVE

We investigated the relationship between maternal PBDE levels and thyroid hormone concentrations in maternal and cord sera.

METHODS

We used data from the Health Outcomes and Measures of the Environment (HOME)Study, a prospective birth cohort of 389 pregnant women in Cincinnati, Ohio, who were enrolled from 2003 through 2006 and delivered singleton infants. Maternal serum PBDE concentrations were measured at enrollment (16 ± 3 weeks of gestation). Thyroid hormone concentrations were measured in maternal serum at enrollment (n = 187) and in cord serum samples (n = 256).

RESULTS

Median maternal serum concentrations of BDEs 28 and 47 were 1.0 and 19.1 ng/g lipid, respectively. A 10-fold increase in BDEs 28 and 47 concentrations was associated with a 0.85-μg/dL [95% confidence interval (CI): 0.05, 1.64] and 0.82-μg/dL (95% CI: 0.12, 1.51) increase in maternal total thyroxine concentrations (TT4), respectively. Both congeners were also positively associated with maternal free thyroxine (FT4). We also observed positive associations between BDE-47 and maternal total and free triiodothyronine (TT3 and FT3). A 10-fold increase in BDE-28 was associated with elevated FT3 concentrations (β = 0.14 pg/mL; 95% CI: 0.02, 0.26). In contrast, maternal PBDE levels were not associated with thyroid hormone concentrations in cord serum.

CONCLUSIONS

These findings suggest that maternal PBDE exposure, particularly BDEs 28 and 47, are associated with maternal concentrations of T4 and T3 during pregnancy.

BACKGROUND

Resistance to thyroid hormone is characterised by a lack of response of peripheral tissues to the active form of thyroid hormone (triiodothyronine, T3). In about 85% of cases, a mutation in THRB, the gene coding for thyroid receptor β (TRβ), is the cause of this disorder. Recently, individual reports described the first patients with thyroid hormone receptor α gene (THRA) defects.

METHODS

We used longitudinal clinical assessments over a period of 18 years at one hospital setting combined with biochemical and molecular studies to characterise a novel thyroid hormone resistance syndrome in a cohort of six patients from five families.

RESULTS

Using whole exome sequencing and subsequent Sanger sequencing, we identified truncating and missense mutations in the THRA gene in five of six individuals and describe a distinct and consistent phenotype of mild hypothyroidism (growth retardation, relatively high birth length and weight, mild-to-moderate mental retardation, mild skeletal dysplasia and constipation), specific facial features (round, somewhat coarse and flat face) and macrocephaly. Laboratory investigations revealed anaemia and slightly elevated cholesterol, while the thyroid profile showed low free thyroxine (fT4) levels coupled with high free T3 (fT3), leading to an altered T4 : T3 ratio, along with normal thyroid-stimulating hormone levels. We observed a genotype-phenotype correlation, with milder outcomes for missense mutations and more severe phenotypical effects for truncating mutations.

CONCLUSIONS

THRA mutations may be more common than expected. In patients with clinical symptoms of mild hypothyreosis without confirmation in endocrine studies, a molecular study of THRA defects is strongly recommended.

This review presents hormonal responses to various cold exposures and their calorigenic effects in man and some animals. Previous studies in rats have shown that cold exposures activate the hypothalamic-pituitary-thyroid axis. Increased thyroid hormone concentrations lead to heat production via general stimulation of metabolism (obligatory thermogenesis) and possibly via activation of thyroid hormone receptors and uncoupling protein 1 (UCP 1) and deiodinase enzyme genes in the brown adipose tissue (BAT). In human subjects long-term cold exposures do not seem to activate the pituitary-thyroid axis, but rather accelerate the elimination of triiodothyronine (T3), leading to low serum concentrations of free T3 hormone. In corollary to this a hypothyreotic condition with increased serum thyroid-stimulating hormone and impaired mood and cognitive performance can be observed after long-term cold exposures such as wintering. During cold exposures the sympathetic nerve system is activated and noradrenaline is released to blood circulation and to BAT, where it leads to production of cAMP, lipolysis and free fatty acids. Free fatty acids open the mitochondrial proton channel protein in BAT. Protons enter the mitochondria and inhibit ATP synthesis (uncoupling). By this way energy is transformed into heat (facultatory or adaptive thermogenesis). In adult human subjects the amount of BAT is small and adaptive thermogenesis (non-shivering thermogenesis) has a smaller role. UCP 1 with other uncoupling proteins may have other functions in the control of body weight, sugar balance and formation of reactive oxygen species.

BACKGROUND

Abnormalities in thyroid function are frequent in patients with heart failure and are associated with increased mortality. However, the relation between thyroid hormone levels and echocardiographic parameters has not been investigated sufficiently.

OBJECTIVE

The aims of this study were to investigate the correlations of thyroid hormone levels with echocardiographic parameters and to evaluate their associations with subsequent mortality in a group of patients with dilated cardiomyopathy (DCMP).

METHODS

Serum levels of thyroid hormones were measured in 111 consecutive patients with DCMP (35 female, 76 male, mean age: 62+/-12 years). All patients underwent echocardiographic examination and were followed-up for a period of 12+/-8 months.

RESULTS

Twenty-three patients (21%) had abnormalities in thyroid function tests. <em>Free</em> <em>triiodothyronine</em> (fT3)/<em>free</em> thyroxine (fT4) ratio was significantly correlated with most of echocardiographic parameters, such as chamber diameters and ejection fraction. Sixteen patients (14%) died during the follow-up period; their fT3/fT4 ratio was significantly lower than the patients who survived (1.31+/-0.37 vs. 2.01+/-0.72, p<0.001). A fT3/fT4 ratio of <or=1.7 was associated with an increased risk of mortality (p<0.001), independent of other prognostic markers. Sensitivity, specificity, positive and negative predictivity of fT3/fT4 ratio <or=1.7 for cardiac mortality were 100%, 71%, 36% and 100%, respectively.

CONCLUSIONS

Determination of FT3/FT4 ratio may be a valuable and simple predictor for identification of patients with DCMP who are at high risk of subsequent mortality.

Excessive concentrations of free radicals in the developing brain may lead to neurons maldevelopment and neurons damage and death. Thyroid hormones (THs) states play an important role in affecting the modulation of oxidative stress and antioxidant defense system. Thus, the objective of this study was to clarify the effect of hypothyroidism and hyperthyroidism in rat dams on the neurons development of different brain regions of their offspring at several postnatal weeks in relation to changes in the oxidative stress and antioxidant defense system. The adult female rats were administered methimazole (MMI) in drinking water (0.02% w/v) from gestation day 1 to lactation day 21 to induce hypothyroidism and exogenous thyroxine (T4) in drinking water (0.002% w/v) beside intragastric incubation of 50--200 T4 μg/kg body weight (b. wt.) to induce hyperthyroidism. In normal female rats, the sera total thyroxine (TT4) and total triiodothyronine (TT3) levels were detectably increased at day 10 post-partum than those at day 10 of pregnancy. Free thyroxine (FT4), free triiodothyronine (FT3), thyrotropin (TSH) and growth hormone (GH) concentrations in normal offspring were elevated at first, second and third postnatal weeks in an age-dependent manner. In hypothyroid group, a marked depression was observed in sera of dam TT3 and TT4 as well as offspring FT3, FT4 and GH, while there was a significant increase in TSH level with the age progress. The reverse pattern to latter state was recorded in hyperthyroid group. Concomitantly, in control offspring, the rate of neuron development in both cerebellar and cerebral cortex was increased in its density and complexity with age progress. This development may depend, largely, on THs state. Both maternal hypothyroidism and hyperthyroidism caused severe growth retardation in neurons of these regions of their offspring from the first to third weeks. Additionally, in normal offspring, seven antioxidant enzymes, four non-enzymatic antioxidants and one oxidative stress marker (lipid peroxidation, LPO) followed a synchronized course of alterations in cerebrum, cerebellum and medulla oblongata. In both thyroid states, the oxidative damage has been demonstrated by the increased LPO and inhibition of enzymatic and non-enzymatic antioxidants in most examined ages and brain regions. These disturbances in the antioxidant defense system led to deterioration in the neuronal maturation and development. In conclusion, it can be suggested that the maldevelopment of neurons and dendrites in different brain regions of offspring of hypothyroid and hyperthyroid mother rat dams may be attributed, at least in part, to the excess oxidative stress and deteriorated antioxidant defense system in such conditions.

OBJECTIVE

Paediatric reference values, although essential for interpreting patients' results, are scarce. Moreover, they are often population- and instrument-dependent. We have measured free thyroxine (Free T(4)), total triiodothyronine (Total T(3)), thyroglobulin (Tg) and thyrotropin (TSH) in samples obtained from groups of newborns, children and adolescents.

METHODS

Blood samples collected from healthy children and teenagers (100 girls and 100 boys) of age groups ranging between 9-10, 11-14 and 15-17 years and selected randomly from a cohort representative of the Quebec population, were used. Samples from infants of age ranging between 1 day and 2 years (n = 99) were obtained from a hospital-based population with benign conditions unlikely to affect thyroid function. Variables were measured on the Access 2 immunosystem.

RESULTS

Free T(4), Tg and TSH levels declined significantly with age. However, Total T(3) level presented a nonlinear variation with age, being lower in the first month of life.

The clinical implications of thyroid hormones in depression have been studied extensively and still remains disputable. Supplementation of thyroid hormones is considered to augment and accelerate antidepressant treatment. Studies on the role of thyroid hormones in depression deliver contradictory results. Here we assess theirs impact on depression severity and final clinical outcome in patients with major depression. Thyrotropin, free thyroxine (FT4), and free triiodothyronine (FT3) concentrations were measured with automated quantitative enzyme immunoassay. Depression severity and final clinical outcome were rated with 17-itemic Hamilton Rating Scale for Depression [HDRS(17)] and Clinical Global Impression Scales for severity and for improvement (CGIs, CGIi). FT3 and FT4 concentrations were significantly positively correlated with clinical improvement evaluated with CGIi (R = 0.38, P = 0.012; R = 0.33, P = 0.034, respectively). There was a significant correlation between FT4 concentrations and depression severity assessed in HDRS(17) (R = 0.31, P = 0.047). Male patients presented significantly higher FT3 serum levels (Z = 2.34, P = 0.018) and significantly greater clinical improvement (Z = 2.36, P = 0.018) when compared to female patients. We conclude that free thyroid hormones concentrations are associated with depression severity and have an impact on final clinical outcome. It can be more efficient to augment and accelerate the treatment of major depressive disorder with triiodothyronine instead of levothyroxine because of individual differences in thyroid hormones metabolism.

BACKGROUND

Cushing's disease is characterized by abnormalities of immune function.

OBJECTIVE

To evaluate the prevalence of autoimmune thyroid diseases in patients with Cushing's disease (CD), after successful treatment and the possible association between previous nodular goitre or positive thyroid autoantibodies during the active phase of CD and the subsequent development of autoimmune thyroid diseases after cure.

METHODS

Twenty patients with CD and 40 sex- and age-matched healthy controls were considered for the study. In CD patients, thyroid ultrasonography and measurement of circulating free thyroxine (fT4), free triiodothyronine (fT3), thyroid stimulating hormone (TSH), antithyroglobulin (anti-Tg) and antithyroperoxidase (anti-TPO) antibodies were performed at diagnosis and 6 months after disease cure while in controls they were performed only at study entry.

RESULTS

Serum fT3, and fT4 levels were similar in patients, either during the active phase or after cure of the disease, and controls. Conversely, in the patients, serum TSH levels were significantly lower during active disease (0. 4 +/- 0.05 mU/l, P = 0.001) and significantly higher after disease cure (4.7 +/- 0.1 mU/l, P < 0.001) than in controls (2.3 +/- 0.4 mU/l). Four patients (20%) and 11 controls (27.5%) had positive anti-Tg and/or anti-TPO titre at study entry, while eight patients (40%) developed positive anti-Tg and/or anti-TPO titre after disease cure. The prevalence of positive antithyroid antibodies titre in cured CD patients was significantly higher than that observed in the same patients during the active disease (P = 0.008) and in controls (P = 0.031). A significantly higher prevalence of autoimmune thyroiditis was found in patients cured from CD (35%) than in patients with active CD (0%) (P = 0.016) and in controls (10%) (P = 0.031). A significant association was found between the presence of autoimmune thyroiditis after CD cure and the presence of a previous nodular goitre (P = 0.017) or positive thyroid autoantibodies titre (P = 0.007) during the active phase of the disease.

CONCLUSIONS

Patients successfully treated for Cushing's disease have an increased prevalence of thyroid autoimmunity and autoimmune thyroiditis as compared to a control population. Therefore, patients with hypercortisolism need an accurate evaluation of thyroid function after remission of the disease in order to prevent the eventual onset of subclinical or overt post-thyroiditis hypothyroidism.

Low energy availability, defined as low caloric intake relative to exercise energy expenditure, has been linked to endocrine alterations frequently observed in chronically energy-deficient exercising women. Our goal was to determine the endocrine effects of low energy availability in exercising men. Six exercising men (VO2peak: 49.3 ± 2.4 ml · kg(-1) · min(-1)) underwent two conditions of low energy availability (15 kcal · kg(-1) fat-free mass [FFM] · day(-1)) and two energy-balanced conditions (40 kcal · kg(-1) FFM · day(-1)) in randomised order. During one low energy availability and one balanced condition, participants exercised to expend 15 kcal · kg(-1) FFM · day(-1); no exercise was conducted during the other two conditions. Metabolic hormones were assessed before and after each 4-day period. Following both low energy availability conditions, leptin (-53% to -56%) and insulin (-34% to -38%) were reduced (P < 0.05). Reductions in leptin and insulin were independent of whether low energy availability was attained with or without exercise (P>> 0.80). Low energy availability did not significantly impact ghrelin, triiodothyronine, testosterone and IGF-1 (all P>> 0.05). The observed reductions in leptin and insulin were in the same magnitude as changes previously reported in sedentary women. Further research is needed to understand why other metabolic hormones are more robust against low energy availability in exercising men than those in sedentary and exercising women.

The effect of ingesting seaweed "Kombu" (Laminaria japonica) on thyroid function was studied in normal Japanese adults. Ingesting 15 and 30 g of Kombu (iodine contents: 35 and 70 mg) daily for a short term (7-10 days) significantly increased serum thyrotropin (TSH) concentrations, exceeding the normal limits in some subjects. The serum free thyroxine (FT(4)) and/or free 3,5,3'-triiodothyronine (FT(3)) concentrations were slightly decreased within the normal limits. During long term daily ingestion of 15 g of Kombu (55-87 days), the TSH levels were elevated and sustained while the FT(4) and FT(3) levels were almost unchanged. Urinary excretion of iodine significantly increased during ingestion of Kombu. These abnormal values returned to the initial levels 7 to 40 days after discontinuing the ingestion of Kombu. Based on these findings that thyroid function was suppressed during ingestion of Kombu, though the effect was reversible, we recommend Japanese people avoid ingesting excessive amounts of seaweed.

BACKGROUND

Traumatic brain injury (TBI) results in a hypermetabolic and hypercatabolic status in which adequate nutrition support is essential to improve clinical outcome. The endocrine system of a patient with TBI is also affected and may play a critical role in either the metabolic or the immunologic response to the trauma. In the present study, the effect of standard, delayed enteral feeding (DEF), compared with early (within 24-48 hours) enteral feeding (EEF), on the endocrine function of patients with TBI was investigated.

METHODS

This comparative, prospective, open-labeled, randomized study included TBI patients admitted to the intensive care unit (ICU). Injury severity was assessed by the Glasgow Coma Scale and predicted mortality by the Acute Physiology and Chronic Health Evaluation II. Twenty-five patients received DEF and 34 patients received EEF. The effect of the onset of nutrition on pituitary, thyroidal, gonadal, and adrenal function was investigated on days 6 and 12 after admission to the hospital.

RESULTS

Levels of thyroid-stimulating hormone, free triiodothyronine, free thyroxine, and testosterone (in males) of DEF patients declined in comparison to levels of the day of admission to the ICU. The decrease of hormonal values was less pronounced in the EEF group. Cortisol concentrations rose in the DEF group; a lesser hormonal change was found in the EEF group. Deaths during the study for the DEF group and EEF group were 2 and 3, respectively.

CONCLUSIONS

EEF may exert beneficial effects on the hormonal profile of TBI patients, possibly contributing to a better clinical outcome in this patient group.

Both gestational diabetes mellitus (GDM) and thyroid dysfunction in pregnancy compromise maternal and fetal health. The aim of the present study was to determine the prevalence of abnormal thyroid function and antithyroid antibodies during early pregnancy in a population at high risk for GDM. Serum free triiodothyronine (FT3), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) were measured in 301 pregnant women who underwent routine 'universal screening' for GDM. The antithyroid peroxidase antibody (antiTPOAb) was also quantified in 255 of these women. GDM was confirmed by a 75-g oral glucose tolerance test using World Health Organization criteria. No statistically significant difference was found between the 80 (26.6%) women with GDM and the 221 (73.4%) women without GDM for any of the thyroid function tests. In the cohort tested for antiTPOAb, the 51 (20.0%) women who were positive for antiTPOAb had higher mean TSH (1.57 +/- 2.49 mIU/l; p < 0.001) than the women negative for antiTPOAb. Seventeen (5.6%) women had low FT4 while 12 (4.0%) women had high TSH; 28 (9.3%) women had low serum TSH, among whom three (1.0%) also had high FT4. The significantly higher prevalence of hypothyroxinemia and antiTPOAb titers than generally reported warrants routine screening for thyroid abnormalities. This screening, which can be effectively and easily incorporated into screening practices already in place for GDM, would result in improved obstetric care.

OBJECTIVE

Energetic adaptations induced by bariatric surgery have not been studied in adolescents or for extended periods postsurgery. Energetic, metabolic, and neuroendocrine responses to Roux-en-Y gastric bypass (RYGB) surgery were investigated in extremely obese adolescents.

METHODS

At baseline and at 1.5, 6, and 12 months post-baseline, 24-h room calorimetry, body composition, and fasting blood biochemistries were measured in 11 obese adolescents relative to five matched controls.

RESULTS

In the RYGB group, mean weight loss was 44 ± 19 kg at 12 months. Total energy expenditure (TEE), activity EE, basal metabolic rate (BMR), sleep EE, and walking EE significantly declined by 1.5 months (P = 0.001) and remained suppressed at 6 and 12 months. Adjusted for age, sex, fat-free mass, and fat mass, EE was still lower than baseline (P = 0.001). Decreases in serum insulin, leptin, and triiodothyronine (T3), gut hormones, and urinary norepinephrine (NE) paralleled the decline in EE. Adjusted changes in TEE, BMR, and/or sleep EE were associated with decreases in insulin, homeostatic model assessment, leptin, thyroid stimulating hormone, total T3, peptide YY3-36, glucagon-like peptide-2, and urinary NE and epinephrine (P = 0.001-0.05).

CONCLUSIONS

Energetic adaptations in response to RYGB-induced weight loss are associated with changes in insulin, adipokines, thyroid hormones, gut hormones, and sympathetic nervous system activity and persists 12 months postsurgery.

The benefits of iodine supplements during pregnancy remain controversial in areas with a mild-to-moderate iodine deficiency. The aim of the present study was to determine the effect of improving iodine intakes, with iodised salt (IS) or iodine supplements, in pregnant Spanish women. A total of 131 pregnant women in their first trimester were randomly assigned to three groups: (1) IS in cooking and at the table, (2) 200 μg potassium iodide (KI)/d or (3) 300 μg KI/d. No differences were found in thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3) or thyroid volume (TV) between the three groups. Regardless of the group in which women were included, those who had been taking IS for at least 1 year before becoming pregnant had a significantly lower TV in the third trimester (P= 0.01) and a significantly higher urinary iodine in the first (173.7 (sd 81.8) v. 113.8 (sd 79.6) μg/l, P= 0.001) and third trimesters (206.3 (sd 91.2) v. 160.4 (sd 87.7) μg/l, P= 0.03). Also, no differences were seen in TSH, FT4 or FT3. Children's neurological development was not significantly associated with the consumption of IS for at least 1 year before becoming pregnant and no differences were found according to the treatment group. In conclusion, in pregnant women with insufficient iodine intake, the intake of IS before becoming pregnant was associated with a better maternal thyroid function. The form of iodide intake was not associated with maternal thyroid function or children's neurological development.

In this study, 80 male and female sickle cell patients, aged 4-50 years, with mild (severity index, SI < 6) and severe (SI>> or = 6) forms of the disease were investigated). The levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone, cortisol, growth hormone (GH), free thyroxine (T4), and free triiodothyronine (T3) were determined. The results were evaluated and the mean +/- 2 SD values were compared with those obtained in age- and sex-matched normal controls. The findings indicated gonadal hypofunction in the sickle cell patients, but with varied deviations from the mean results. Patients with the severe form of the sickle cell disease showed more frequent abnormalities of LH, FSH, cortisol and testosterone in comparison with the patients with a mild disease. The LH, FSH, cortisol and testosterone levels were lower, while T3 and T4 did not show significant differences between patients and the controls. The results suggest that the sickle cell gene abnormality has an adverse effect on endocrine functions. Follow-up and appropriate management of endocrine dysfunctions are advocated in such patients.

Antithyroid drugs (ATDs) remain the first-line therapy in patients with Graves' disease (GD), despite a high relapse rate. The purpose of this study was to identify the predictors of remission in patients with GD treated with ATDs-retrospective study at an endocrine referral service in Northern Greece. Two-hundred and eleven patients met the study's criteria. Females (p = 0.049), non-smokers (p = 0.017), patients without ophthalmopathy (p = 0.033), and those developing pharmaceutical hypothyroidism (p = 0.018) experienced longer duration of remission. Duration of remission was positively associated with therapy duration (r s = 0.151, p = 0.030), maximum TSH levels during (r s = 0.241, p = 0.001), at the end (r s = 0.280, p < 0.001) and 3 months after therapy (r s = 0.341, p = 0.003). There was a negative association with free T4 (FT4) (r s = -0.426, p < 0.001) and free triiodothyronine (FT3) (r s = -0.467, p = 0.038) levels at 6 months after ATDs discontinuation. In multiple-regression analysis, only duration of the first ATDs course for more than 24 months independently predicted duration of remission. Female gender, non-smoking, the absence of orbitopathy, treatment duration, pharmaceutical hypothyroidism, higher TSH levels during, at the end and 3 months after ATDs discontinuation, and lower FT4 and FT3 levels 6 months after therapy were associated with longer duration of remission. However, only duration of ATDs therapy for more than 24 months independently predicted predict long-term remission in GD.

The role of type 2 deiodinase (D2) in the human skeleton remains unclear. The D2 polymorphism Thr92Ala has been associated with lower enzymatic activity, which could result in lower local triiodothyronine (T(3)) availability in bone. We therefore hypothesized that the D2 Thr92Ala polymorphism may influence bone mineral density (BMD) and bone turnover. We studied 154 patients (29 men, 125 women: 79 estrogen-replete, 46 estrogen-deficient) with cured differentiated thyroid carcinoma. BMD and bone turnover markers [bone-specific alkaline phosphatase (BAP), cross-linking terminal C-telopeptide of type I collagen (CTX), procollagen type 1 amino-terminal propeptide (P1NP), and cross-linked N-telopeptide of type I collagen (NTX)] were measured. Effects of the D2 Thr92Ala polymorphism on BMD and bone turnover markers were assessed by a linear regression model, with age, gender, estrogen state, body mass index (BMI), serum calcium, 25-hydroxyvitamin D, parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), and free triiodothyroxine (T(4)) as covariables. Sixty patients were wild type (Thr/Thr), 66 were heterozygous (Thr/Ala), and 28 were homozygous (Ala/Ala) for the D2 polymorphism. There were no significant differences in any covariables between the three genotypes. Subjects carrying the D2 Thr92Ala polymorphism had consistently lower femoral neck and total hip densities than wild-type subjects (p = .028), and this was accompanied by significantly higher serum P1NP and CTX and urinary NTX/creatinine levels. We conclude that in patients with cured differentiated thyroid carcinoma, the D2 Thr92Ala polymorphism is associated with a decreased femoral neck BMD and higher bone turnover independent of serum thyroid hormone levels, which points to a potential functional role for D2 in bone.

A few studies have shown a high prevalence of thyroid autoimmunity in patients with psoriatic arthritis. However, thyroid autoimmunity has not been investigated in patients with psoriasis who do not have psoriatic arthritis. We aimed to investigate thyroid autoimmunity in patients with psoriasis. The study included 105 consecutive patients with psoriasis who did not have psoriatic arthritis and a sex and age matching control group consisting of 96 patients with tinea pedis. All of the patients with psoriasis were examined dermatologically and PASI scores were calculated for each patient. Free triiodothyronine (FT3), free thyroxine (FT4), thyroid stimulating hormone (TSH), antithyroglobulin (AbTG), and antithyroidperoxidase antibody (AbTPO) levels were measured in all of the subjects. The levels of TSH, FT3, FT4, AbTG and AbTPO and ultrasonographic findings of thyroid gland were compared statistically between psoriasis and control groups. Also, the levels of TSH, FT3, FT4, AbTG and AbTPO of psoriasis patients were compared with PASI scores. Mann-Whitney U test was used as statistical method. The mean age of patients with psoriasis was 40.54 +/- 16.91 years. 56 patients were female, 49 were male. The levels FT4 were found to be significantly increased in the patient group. But levels of AbTPO and AbTG were not statistically different between the two groups. The patients who had thyroiditis plus nodules in thyroid ultrasonography had statistically longer disease periods. This is the first study that investigated autoimmune thyroid disorders in patients with psoriasis who did not have arthritis. We believed that thyroid autoimmunity in patients with psoriasis was no different from that found in healthy individuals.

OBJECTIVE

To address the paradox that phenytoin- and carbamazepine-treated patients have decreased serum free thyroxine (T4) and triiodothyronine (T3) concentrations but appear clinically euthyroid and have normal serum thyroid-stimulating hormone (TSH) concentrations.

METHODS

In vitro studies comparing measurements of total and free T4 and T3 by ultrafiltration assay (undiluted serum) and a commercial free T4 estimate kit in control serum samples or serum samples containing added therapeutic levels of phenytoin or carbamazepine. These measurements were made in serum samples diluted 1:5 with either identical serum or phospate buffer, pH 7.4, and in serum samples from patients with seizure disorders who were treated with phenytoin or carbamazepine.

METHODS

A 650-bed teaching hospital.

METHODS

Selected patients (n=19) who were in good health except for seizure disorder, with stable anticonvulsant drug levels in the upper half of the therapeutic range, and were not taking any other drugs that could affect thyroid parameters.

METHODS

Serum concentrations of free T4 and free T3 in patients taking phenytoin or carbamazepine vs normal controls.

RESULTS

Addition of phenytoin or carbamazepine to normal human serum in vitro resulted in a significant increase in free T4 fraction and free T4 (P<.001). In patients taking phenytoin or carbamazepine, serum total T4 decreased significantly to 60% and 74%, respectively, of the control serum concentration (P<.001 for both phenytoin and carbamazepine); free T4 fraction (by ultrafiltration assay) increased 65% and 44%, respectively (P<.001 for phenytoin, P<.01 for carbamazepine); and free T4 remained unchanged. Free T4 concentration measured by a commercial kit (1:5 serum dilution) was significantly lower than the control concentration in both phenytoin- and carbamazepine-treated patients. Serum free T3 and serum TSH were also normal in phenytoin- and carbamazepine-treated patients.

CONCLUSIONS

Therapeutic levels of phenytoin and carbamazepine displace T4 and T3 from serum binding proteins. When added to serum, the drugs effect an increase in free hormone fractions and free T4 and T3. In drug-treated patients, increased free T4 and T3 fractions offset the significant decrease in serum T4 and T3, resulting in normal free T4 and free T3 concentrations. Since currently available clinical tests will continue to show decreased free T4 concentrations in patients taking phenytoin or carbamazepine, clinicians should rely on serum TSH measurements to confirm the euthyroid status of these patients.

BACKGROUND

The metabolic syndrome (MetS) is a combination of unfavourable health factors which includes abdominal obesity, dyslipidaemia, elevated blood pressure and impaired fasting glucose. Earlier studies have reported a relationship between thyroid function and some MetS components or suggested that serum free thyroxine (FT4) or free triiodothyronine (FT3) levels within the normal range were independently associated with insulin resistance. We assessed how thyroid function relates to MetS prevalence in a large population-based study.

METHODS

Data of 26,719 people of western European descent, aged 18-80 years from the Dutch LifeLines Cohort study, all with normal thyroid stimulating hormone (TSH), FT4 and FT3 levels (electrochemiluminescent immunoassay, Roche Modular E170 Analyzer), were available. MetS was defined with the revised National Cholesterol Education Programs Adults Treatment Panel III (NCEP ATP III) criteria. We calculated prevalence of all MetS components according to TSH, FT4 and FT3 quartiles.

RESULTS

At similar TSH levels and age (mean 45 yrs), men had significantly higher levels of FT4, FT3, blood pressure (BP), heart rate, total and LDL-cholesterol, triglycerides (TG), and creatinine, but lower HDL-cholesterol compared to women (all p < 0.001). In total, 11.8% of women and 20.7% of men had MetS. In men, lower FT4 levels were associated with higher prevalence of MetS and all MetS components. In women, lower FT4 quartile was only associated with a higher prevalence of elevated TG, waist circumference, and MetS. However, when corrected for confounding factors like age, BMI, current smoking and alcohol consumption, a significant relationship was found between FT3 and three MetS components in men, and all five components in women. Moreover, the highest quartiles of FT3 and the FT3FT4 ratio predicted a 49% and 67% higher prevalence of MetS in men, and a 62 and 80% higher prevalence in women.

CONCLUSIONS

When corrected for possible confounding factors, higher plasma levels of FT3 are associated with several components of the MetS. Only in men, lower FT4 is related to MetS. In the highest FT3 and FT3FT4 quartiles, there is a 50-80% increased risk of having MetS compared to the lowest quartile. Further studies are needed to assess the possible causality of this relationship.

MGL-3196 is an oral, liver-targeted selective agonist for the thyroid hormone receptor-β (THR-β) that is being developed for the treatment of dyslipidemia. The safety profile and tolerability of THR-β agonist MGL-3196 was assessed in first-in humans studies, including a single ascending dose study (NCT01367873) in which MGL-3196 appeared safe at all doses tested. A two-week multiple dose study was conducted at doses of 5, 20, 50, 80, 100, and 200 mg per day in healthy subjects with mildly elevated low density lipoprotein (LDL) cholesterol (>110 mg/dL) (NCT01519531). MGL-3196 was well-tolerated at all doses with no dose-related adverse events or liver enzyme, ECG or vital-sign changes. At the highest dose, there was a reversible reduction of ∼20% in the level of pro-hormone, free thyroxine (free T4) that was significantly different from placebo (p < 0.0001) that may be explained by increased hepatic metabolism of T4. There was no change in thyrotropin (TSH) or triiodothyronine (free T3) or other evidence of central thyroid axis dysfunction at any dose. Doses ranging from 50 to 200 mg demonstrated highly statistically significant reductions relative to placebo of up to: 30% for LDL cholesterol (range, p = 0.05-<0.0001); 28% for non- high density lipoprotein (HDL) cholesterol (range, p = 0.027-0.0001); 24% for Apolipoprotein B (range, p = 0.008-0.0004), and statistical trends of up to 60% reduction in triglycerides (TG) (range, p = 0.13-0.016). The near maximal lipid effects were observed at a dose of 80 mg daily. In summary, in a two-week study in healthy volunteers with mild LDL cholesterol elevation, MGL-3196 appeared safe, was well-tolerated and showed a beneficial effect on lipid parameters.

BACKGROUND

The presence of thyroid peroxidase antibodies (TPOab) are reported to be associated with improved outcome among breast cancer patients. We evaluated the correlation between TPOab and diagnostic parameters among newly diagnosed breast cancer patients.

METHODS

Three hundred and fourteen newly diagnosed patients with breast cancer, diagnosed and treated in Bethesda Essen between January 2002 and June 2006, were included in this study; 258 (82.2%) without TPOab (≤100 IU/mL) and 56 (17.8%) with TPOab (>100 IU/mL). Blood analysis was performed to measure serum levels of carcinoembryonic antigen (CEA), cancer antigen 15-3 (CA-15-3), free triiodothyronine (fT3), free thyroxine (fT4), thyroid-stimulating hormone (TSH) and TPOab by radioimmunoassay. Data regarding age, tumor size, grading, TNM classification, receptor status, lymph node, and distant metastases were collected and analyzed from patient reports. Statistics were performed using Pearson’s χ2-test and logistic regression analysis.

RESULTS

There were no incidences of distant metastasis among 56 patients with TPOab, whereas 17 (6.6%) of 258 cases without TPOab displayed distant metastases (p=0.04). Logistic regression showed an inverse association of TPOab with CA-15-3 and CEA levels (p<0.001, respectively). Both groups, with and without TPOab, revealed no significant differences with respect to age, tumor size, grading, TNM classification, fT3, fT4, and receptor status. TPOab positive patients had higher TSH levels (2.55±3.58), compared to TPOab negative cases (1.20±1.15) (p<0.001).

CONCLUSIONS

TPOab occurrence is associated with significantly lower frequency of distant metastases in breast cancer. TPOab level inversely correlates with the conventional tumor markers CA-15-3 and CEA.

BACKGROUND

There is strong clinical and experimental evidence that altered thyroid homeostasis negatively affects survival in cardiac patients, but a negative effect of the low triiodothyronine (T3) syndrome on the outcome of coronary artery bypass grafting (CABG) has not been demonstrated. This study was designed to evaluate the prognostic significance of low T3 syndrome in patients undergoing CABG.

METHODS

The thyroid profile was evaluated at hospital admission in 806 consecutive CABG patients. Known thyroid disease, severe systemic illness, and use of drugs interfering with thyroid metabolism were considered exclusion criteria. The effect of the baseline free T3 (fT3) concentration and of preoperative low T3 syndrome (fT3 <2.23 pmol/L) on the risk of low cardiac output (CO) and death was analyzed in a logistic regression model.

RESULTS

There were 19 (2.3%) deaths, and 64 (7.8%) patients experienced major complications. After univariate analysis, fT3, low T3, New York Heart Association class greater than II, low left ventricular ejection fraction (LVEF), and emergency were associated with low CO and hospital death. History of atrial fibrillation, cardiopulmonary bypass time, and peripheral vascular disease were associated only with low CO. At multivariate analysis, only fT3, low T3, emergency, and LVEF were associated with low CO, and fT3 (odds ratio, 0.172, 95% confidence interval, 0.078 to 0.379; p < 0.0001) and LVEF (odds ratio, 0.934, 95% confidence interval, 0.894 to 0.987; p = 0.03) were the only independent predictors of death.

CONCLUSIONS

Our study demonstrates that low T3 is a strong predictor of death and low CO in CABG patients. For this reason, the thyroid profile should be evaluated before CABG, and patients with low T3 should be considered at higher risk and treated accordingly.