Thyroxine-binding Globulin Research Articles

Association of antiepileptic drug usage, trace elements and thyroid hormone status.

Levels of thyroid hormone (TH) and trace elements (copper (Cu) and selenium (Se)) are important for development and function of the brain. Anti-epileptic drugs (AEDs) can influence serum TH and trace element levels. As the relationship between AEDs, THs, and trace elements has not yet been studied directly, we explored these interactions. In total 898 participants, from the Thyroid Origin of Psychomotor Retardation study designed to investigate thyroid parameters in subjects with intellectual disability (ID), had data available on serum Se, Cu, thyroid stimulating hormone (TSH), free thyroxine (FT4), tri-iodothyronine (T3), reverse T3, T4, and thyroxine-binding globulin (TBG); 401 subjects were on AED treatment. Differences in trace elements according to medication usage was investigated using ANOVA, and associations between trace elements and thyroid parameters were analysed using (non-) linear regression models. Study participants were not deficient in any of the trace elements analyzed. AED (carbamazepine, valproate and phenytoin) usage was negatively associated with serum Se and showed compound-specific associations with Cu levels. After correction for drug usage, Se was positively associated with TSH levels, negatively associated with FT4 levels, and positively with T3 levels. Cu was positively associated with T4, T3, and rT3, which was largely dependent on TBG levels. The subjects with ID did not display profound deficiencies in trace element levels. AEDs were associated with serum Se and Cu levels, while serum Se and Cu were also associated with thyroid parameters. Further studies on the underlying mechanisms and potential clinical importance are warranted.

Late pregnancy thyroid-binding globulin predicts perinatal depression

Previously we found that late pregnancy total and free thyroxine (TT4, FT4) concentrations were negatively related to greater pre and/or postpartum depressive symptoms. In a much larger cohort, the current study examined whether these thyroid indices measured earlier in the third trimester (31–33 weeks) predict subsequent perinatal depression and anxiety ratings as well as syndromal depression. Thyroid-binding globulin (TBG) concentrations increase markedly during pregnancy and may be an index of sensitivity to elevated estrogen levels. TBG was examined in this study because prior findings suggest that postpartum depression is related to sensitivity to mood destabilization by elevated sex hormone concentrations during pregnancy. Our cohort was 199 euthyroid women recruited from a public health obstetrics clinic (63.8% Hispanic, 21.6% Black). After screening and blood draws for hormone measures at pregnancy weeks 31–33, subjects were evaluated during home visits at pregnancy weeks 35–36 as well as postpartum weeks 6 and 12. Evaluations included psychiatric interviews for current and life-time DSM-IV psychiatric history (M.I.N.I.-Plus), subject self-ratings and interviewer ratings for depression and anxiety (Edinburgh Postnatal Depression Scale, Montgomery-Ǻsberg Depression Rating Scale; Spielberger State-Trait Anxiety Inventory, Hamilton Anxiety Inventory), as well as a standardized interview to obtain life-time trauma history. Numerous covariates were included in all regression analyses. Trauma and major depression history were robustly significant predictors of depression and anxiety ratings over the study period when these variables were analyzed individually or in a combined model including FT4 or TBG (p<.001). When analyzed alone, FT4 levels were a less strong but still significant predictor of all depression and anxiety ratings (p<.05) while TBG levels was a significant or nearly significant predictor of most ratings. FT4, TBG and trauma history, but not major depression history, were significant individual predictors of syndromal depression during the study period (p<.05) in single predictor models. In models combining each with trauma and major depression history, FT4 and TBG generally were not significantly predictive of depression or anxiety ratings, and FT4 was also not a significant predictor of syndromal depression: however, in the combined model TBG was a particularly strong predictor of perinatal syndromal depression (p=.005) and trauma history was also significant (p=.016). Further study of the interactions among TBG, FT4, sex hormones, trauma history and perinatal depression may provide insights into the pathophysiological basis of individual variance in vulnerability to mood destabilization by the hormone conditions of pregnancy.

A Novel Small Animal Model to Test on-Target Off-Tumor Cytoxicity of Adoptive Immune Therapies

Chimeric antigen receptor (CAR) engineered T cells have been used clinically to improve outcomes in patients with hematopoietic malignancies owing to the ability of CAR T cells to recognize tumor antigens and kill malignant cells. CAR T cells possess the antigen recognizing capability of an antibody through the single chain variable fragment (scFv) and their cytotoxicity is enhanced through signaling via the intracellular domains of T cell receptors and co-activating receptors such as CD3zeta and 4-1BB, respectively. Thus, CAR expressing T cells are able to detect cancer cells through tumor antigens and can become activated to unleash their cytotoxic potentials in a non-MHC restricted manner. Therapeutic side-effects can occur when T-cell receptor targeting is misdirected to the incorrect tissue causing potentially serious on-target off-tumor cytotoxicity. Factors that influence CAR targeting include expression levels of tumor-associated antigen in normal tissue and the binding affinities of scFvs.Our first step in developing an in vivo, on target, off-tumor, CAR T cell toxicity model was to generate mice with tunable expression of a human tumor antigen in normal tissue. NSG mice were IV injected with recombinant adeno-associated virus serotype 8 (rAAV8) to deliver a truncated human ErbB2 (Her2/neu or CD340) gene and a Katushka fluorescent reporter that were driven by the liver-specific promoter, thyroxine binding globulin (TBG). AAV8 genomic copies (GCs) were injected at varying dilutions of 1.5 x 1012 GC/mouse, 7.25 x 1011 GC/mouseand 1.5x1010 GC/mouse to induce a range of expression of ErbB2 in the liver. Katushka expression was visualized in vivo using the IVIS small animal imager. ErbB2 gene expression was detected using reverse transcription polymerase chain reaction (qRT-PCR) and the ErbB2 protein was detected using western blots and immunohistochemistry (IHC). Our data has shown that expression levels of ErbB2 and the Katushka reporter positively correlated with the number of AAV8 GCs that were injected. This enabled us to obtain ErbB2 expression levels in the liver comparable to the levels seen in either ErbB2High tumors (eg. SK-OV3) or ErbB2Low tumors (eg. PC3 and HEK293T).To determine if affinity tuning of scFvs will allow CAR T cells to discriminate between high and low ErbB2 expression in the liver, T cells were engineered to co-express the click beetle red (CBR) reporter and either a high-affinity scFv, anti-ErbB2 CAR (4D5) or a low-affinity scFv, anti-ErbB2 CAR (4D5-5). These T cells were then IV injected into NSG mice that had either high or low ErbB2-expressing livers. Although these experiments were ongoing at the time of abstract submission, we will show our results on T cell trafficking in the liver, which will be visualized by IHC and by in vivo imaging using the IVIS small animal imager. Liver toxicity will be assessed by histological examination and by measuring liver function via standard enzymatic testing of blood.Furthermore, we aim to show whether affinity tuning of scFvs will allow CAR T cells to selectively recognize and target ErbB2High tumors while sparing ErbB2Low normal tissue. This will be performed by inoculating ErbB2high SK-OV3 tumor cells into mice with ErbB2Low livers followed by IV injection with either 4D5 or 4D5-5 CAR T cells. We expect that the low-affinity anti-ErbB2 CAR (4D5-5) T cells will target the ErbB2High SK-OV3 tumor cells and cause tumor regression while preserving function in the ErbB2Low liver. If so, then we will have shown that our pre-clinical mouse model can be used to identify on-target off-tumor CAR T cell toxicity, which will aid in improving the safety profile and clinical outcomes of future CAR T cell therapies. DisclosuresScholler:Novartis: Patents & Royalties. Zhao:Novartis: Patents & Royalties, Research Funding. June:Novartis: Patents & Royalties, Research Funding.

Surface plasmon resonance assay of inhibition by pharmaceuticals for thyroxine hormone binging to transport proteins

We developed a surface plasmon resonance (SPR) assay to estimate the competitive inhibition by pharmaceuticals for thyroxine (T4) binding to thyroid hormone transport proteins, transthyretin (TTR) and thyroxine binding globulin (TBG). In this SPR assay, the competitive inhibition of pharmaceuticals for introducing T4 into immobilized TTR or TBG on the sensor chip can be estimated using a running buffer containing pharmaceuticals. The SPR assay showed reproducible immobilization of TTR and TBG, and the kinetic binding parameters of T4 to TTR or TBG were estimated. The equilibrium dissociation constants of TTR or TBG measured by SPR did not clearly differ from data reported for other binding assays. To estimate the competitive inhibition of tetraiodothyroacetic acid, diclofenac, genistein, ibuprofen, carbamazepine, and furosemide, reported to be competitive or noncompetitive pharmaceuticals for T4 binding to TTR or TBG, their 50% inhibition concentrations (IC50) (or 80% inhibition concentration, IC80) were calculated from the change of T4 responses in sensorgrams obtained with various concentrations of the pharmaceuticals. Our SPR method should be a useful tool for predicting the potential of thyroid toxicity of pharmaceuticals by evaluating the competitive inhibition of T4 binding to thyroid hormone binding proteins, TTR and TBG.

Early Life Exposure To Phthalate Diesters: Associations With Thyroid Function And Cognitive Function

Background: Epidemiological studies concerning the relations of exposure to phthalates, thyroid function and cognitive function among children could be limited. Objectives: We conducted the longitudinal study to examine the associations of prenatal and postnatal exposure to phthalates, thyroid function and cognitive function in children 2-9 years old. Methods: We recruited 430 pregnant women in their trimester in Taichung, Taiwan from 2001-2002. A total of 110, 79, and 76 children were followed up at ages 2, 5, and 8, respectively. The serum levels of thyroxine (T4), unbound T4 (FT4), triiodothyronine (T3), thyroid-stimulating hormone (TSH), and thyroxine-binding globulin (TBG) in children were measured at three different time points using radioimmunoassay. We also evaluated the children's cognitive function at three followed-up visits using the Bayley and Wechsler tests for assessing neurocognitive function and intelligence (IQ). Urine samples from mothers during pregnancy and from children at each follow-ep visit were analyzed for seven metabolite concentrations of widely used phthalate esters (such as MMP, MEP, MBP, MBzP, MEHP, MEHHP, and MEOHP). We constructed a linear mixed model to examine these associations after adjusted for covariates. Results: We found significant inverse associations between the children's levels of urinary MEHHP, MEOHP, and the sum of the three metabolites of di(2-ethylhexyl) and their serum levels of FT4 (i.e. Beta= -0.04, 95% CI: -0.07, -0.01 for MEOHP). Urinary MMP, MEP, MBP, MBzP, MEHP, and MEOHP levels in children were significantly negatively related to IQ scores (i.e. Beta= -1.85, 95% CI: -3.40, -0.30 for MEOHP). We found a marginally significant positive relationship between the children's serum levels of FT4 and their IQ scores (Beta=5.81, 95% CI: -2.74, 14.36 for MEOHP). Conclusions: Early life exposure to phthalate diesters could be associated with decreasing thyroid function and cognitive development in the young children.

A Study of Thyroid Function in Partial Thyroxine-Binding Globulin Deficiency

Objective: It is generally thought that thyroxine-binding globulin (TBG)-deficient individuals are euthyroid and do not require treatment. However, there have been case reports of TBG deficiency combined with hypothyroidism. The purpose of this study was to investigate the relationship between TBG deficiency and thyroid function. Methods: We reviewed the medical records of 32 patients diagnosed with TBG deficiency between 1997 and 2008 in Soonchunhyang University Seoul Hospital. All were partial TBG deficiency. Eighteen patients had combined hypothyroidism, and 14 patients had normal thyroid function. We compared the TBG, thyroid-stimulating hormone, free thyroxine, and total triiodothyronine levels between these 2 groups. Eighteen patients with TBG deficiency with hypothyroidism started thyroxine medication and continued for 2-3 years. After, they were followed up with thyroid function tests after discontinuing medication for 4 weeks at 2-3 years of age. Results: The TBG level in TBG deficiency with hypothyroidism patients was significantly lower than that in TBG deficiency with normal thyroid function (4.43± 2.22 mg/L vs. 6.23± 1.81 mg/L; P= 0.02). The percent TBG compared with normal mean TBG level according to age in the hypothyroidism patients was also significantly lower than that of patients with normal thyroid function (13.42%± 6.92% vs. 19.08%± 4.87%; P= 0.014). Sixteen of 18 patients diagnosed with TBG deficiency with hypothyroidism showed persistent hypothyroidism at 2-3 years of age. Conclusion: We conclude that TBG-deficient patients should be observed closely and undergo thyroid function testing in order not to miss hypothyroidism. More investigations of TBG deficiency and thyroid function are needed in the future.

Strategies to rescue the consequences of inducible arginase-1 deficiency in mice.

Arginase-1 catalyzes the conversion of arginine to ornithine and urea, which is the final step of the urea cycle used to remove excess ammonia from the body. Arginase-1 deficiency leads to hyperargininemia in mice and man with severe lethal consequences in the former and progressive neurological impairment to varying degrees in the latter. In a tamoxifen-induced arginase-1 deficient mouse model, mice succumb to the enzyme deficiency within 2 weeks after inducing the knockout and retain <2 % enzyme in the liver. Standard clinical care regimens for arginase-1 deficiency (low-protein diet, the nitrogen-scavenging drug sodium phenylbutyrate, ornithine supplementation) either failed to extend lifespan (ornithine) or only minimally prolonged lifespan (maximum 8 days with low-protein diet and drug). A conditional, tamoxifen-inducible arginase-1 transgenic mouse strain expressing the enzyme from the Rosa26 locus modestly extended lifespan of neonatal mice, but not that of 4-week old mice, when crossed to the inducible arginase-1 knockout mouse strain. Delivery of an arginase-1/enhanced green fluorescent fusion construct by adeno-associated viral delivery (rh10 serotype with a strong cytomegalovirus-chicken β-actin hybrid promoter) rescued about 30% of male mice with lifespan prolongation to at least 6 months, extensive hepatic expression and restoration of significant enzyme activity in liver. In contrast, a vector of the AAV8 serotype driven by the thyroxine-binding globulin promoter led to weaker liver expression and did not rescue arginase-1 deficient mice to any great extent. Since the induced arginase-1 deficient mouse model displays a much more severe phenotype when compared to human arginase-1 deficiency, these studies reveal that it may be feasible with gene therapy strategies to correct the various manifestations of the disorder and they provide optimism for future clinical studies.

457. Both Regulatory T and B Cells May Play Roles in Systemic Immune Tolerance Induced by rAAV-Mediated Gene Transfer to Liver

The intramuscular delivery of vectored antibody by recombinant adeno-associated virus (rAAV) holds promise for preventing and treating emerging infectious diseases. Recent studies in nonhuman primates suggested that a single intramuscular injection of rAAV1 expressing anti-SIV neutralizing antibody provided long-term protection from SIV infection. However, some of NHP recipients generated anti-antibody responses that eliminate neutralizing activity of vectored antibodies. We exploit different strategies to engineer AAV vectors that can surmount such anti-antibody responses, one of which is to induce systemic tolerance to vectored antibody. It is well established that the hepatic gene transfer can induce systemic immune tolerance to transgene products. Here, we attempted to use hepatotropic AAV serotypes and hepatocyte-specific promoter for liver-specific gene expression to induce systemic immune tolerance to muscle-expressed transgene products including intracellular β-Galactosidase (β-gal) or secreted Ovalbumin (OVA). First, we tested if the transgene specific CD8+ T cells could be reduced by using liver-specific promoter. C57BL/6 mice were intravenously delivered with rAAV9 vectors expressing β-gal from either ubiquitous chicken β-actin (CB) promoter or liver-specific human thyroxine binding globulin (TBG) promoter. When compared to CB promoter, TBG can achieve significantly higher β-gal expression with reduced β-gal specific CD8+ T cells. To compare the humoral immune responses against the secrete transgene products, AAV8 vectors expressing OVA from CB or TBG were intravenously injected to C57BL/6 mice. AAV8.TBG.OVA injected mice showed significant higher OVA expression than AAV8.CB.OVA injected mice did. Interestingly, while the mice received rAAV1CB.OVA intramuscularly triggered robust anti-OVA IgG1 response with low and transient OVA expression, such responses in the mice treated with intravenously delivered both AAV8 vectors were negligible accompanied with high levels of sustained OVA expression. In addition, the high frequency of regulatory T cells and CD19+CD5+CD1d+ regulatory B cells are detected in the spleens from the mice intravenously delivered both AAV8OVA vectors. Finally, we tested whether hepatic restricted OVA gene transfer by AAV8.TBG.OVA can indeed induce immune tolerance to subsequently and intramuscularly delivered AAV1.CB.OVA in C57BL/6 mice. Again, very low levels of transient OVA expression and high levels of anti-OVA IgG1 were detected in the animals treated with PBS followed by intramuscular AAV1.CB.OVA, whereas the intravenously delivered AAV8.TBG.OVA vectors facilitated the subsequently muscle-directed AAV1-encoded OVA expression without antibody production. Our data suggest that both regulatory T and B cells may play roles in systemic immune tolerance induced by liver-derived transgene expression from liver tropic AAV vector.

Noninvasive 3-dimensional imaging of liver regeneration in a mouse model of hereditary tyrosinemia type 1 using the sodium iodide symporter gene.

Cell transplantation is a potential treatment for the many liver disorders that are currently only curable by organ transplantation. However, one of the major limitations of hepatocyte (HC) transplantation is an inability to monitor cells longitudinally after injection. We hypothesized that the thyroidal sodium iodide symporter (NIS) gene could be used to visualize transplanted HCs in a rodent model of inherited liver disease: hereditary tyrosinemia type 1. Wild-type C57Bl/6J mouse HCs were transduced ex vivo with a lentiviral vector containing the mouse Slc5a5 (NIS) gene controlled by the thyroxine-binding globulin promoter. NIS-transduced cells could robustly concentrate radiolabeled iodine in vitro, with lentiviral transduction efficiencies greater than 80% achieved in the presence of dexamethasone. Next, NIS-transduced HCs were transplanted into congenic fumarylacetoacetate hydrolase knockout mice, and this resulted in the prevention of liver failure. NIS-transduced HCs were readily imaged in vivo by single-photon emission computed tomography, and this demonstrated for the first time noninvasive 3-dimensional imaging of regenerating tissue in individual animals over time. We also tested the efficacy of primary HC spheroids engrafted in the liver. With the NIS reporter, robust spheroid engraftment and survival could be detected longitudinally after direct parenchymal injection, and this thereby demonstrated a novel strategy for HC transplantation. This work is the first to demonstrate the efficacy of NIS imaging in the field of HC transplantation. We anticipate that NIS labeling will allow noninvasive and longitudinal identification of HCs and stem cells in future studies related to liver regeneration in small and large preclinical animal models.

Examine of Thyroid Function in Pediatric Nephrotic Syndrome; Tehran-Iran

Introduction In children with nephrotic syndrome, it is probable to determine a hypothyroid state because of thyroxine (T4), tri-iodothyronine (T3) and thyroid-binding globulin loss in presence of proteinuria. Objectives: To examine thyroid function in pediatric cases of nephrotic syndrome. Methods: In a cross-sectional study, from march 2010 to march 2012, thyroid function tests were performed in 104 patients referred to the nephrology department of children’s medical center, because of nephrotic syndrome. Collected data analyzed with SPSS Statistics 17 and pResults: Sixty one cases identified as hypothyroid patients and were treated with supplementary levothyroxine. There were 41 (67.2%) males and 20 (32.8%) females with the mean age of 3.72±3.35 years. Our patients showed lowered T3 (68.3%) and T4 (64.4%) in comparison with normal values. Median TSH (Thyroid-stimulating hormone) was 11.65±6.71 Micu/ml and 2.82±0.82 in the hypothyroid and euthyroid patients respectively. In all, TSH was negatively correlated with the total urinary protein content . Conclusions: According to this study, the occurrence of hypothyroidism in any child with nephrotic syndrome needs to be mentioned. It is proposed to systematically search hypothyroidism by measuring TSH and free T4 in these patients particularly when proteinuria is prolonged.

Effect of Grand Multiparity on Certain Thyroid Function Tests

Background: The physiology of the thyroid gland changes during pregnancy as a result of the effects of increased TBG and hCG levels and enhanced iodine metabolism. These normal hormonal changes can sometimes make thyroid function tests during pregnancy difficult to interpret. Objective: To compare the levels of thyroxine [T4], triiodothyronine [T3], thyrotropin [TSH] and Thyroxine Binding Globulin [TBG] in grand multiparas, nulliparas [control] and primiparas. Materials: A cross-sectional study was performed in 50 non-pregnant ladies as control group, 50 primiparity pregnant women, and 50 grand multiparity pregnant women. All pregnant women were between 10th -14th weeks gestation. Methods: Serum for T4, T3, TSH and TBG were measured by Enzyme-Linked Immunosorbent Assay [ELISA] . Results: When compared to control group, serum levels of T4, T3 and TBG were increased significantly in primiparity and grand multiparity groups, while serum level of TSH was decreased significantly in both groups of pregnant women. Serum level of T4 increased significantly in grand multiparity group comparing to primiparity group. Conclusion: The results suggest that grand multiparity increased the risk of pregnancy-related complication secondary to thyroiddysfunction.

Selected genetic aspects in the pathogenesis of the thyroid diseases

According to genetic ethiopathogenesis, thyroid diseases may be divided into monogenic and polygenic (multifactorial) thyroid diseases. Monogenic thyroid diseases are the following: 1. congenital defects of thyroid hormones biosynthesis as a result of dyshormonogenetic (majority goitrous) primary congenital hypothyroidism; 2. genetic familial defects of thyroid underdevelopment, including thyroid agenesis, thyroid hypoplasia and ectopia; 3. congenital protein-binding defects, including thyroxine-binding globulin (TBG) defects, albumin and prealbumin defects; 4. congenital resistance to thyroid hormone syndrome; 5. genetic non-autoimmune hyperthyroidism; 6. medullary thyroid carcinoma (MTC) (familial type of the MTC, and multiple endocrine neoplasia MEN 2 A and B), caused by RET gene mutations and inherited as the autosomal dominant mode. About 10-15% of all cases of primary congenital hypothyroidism (CH) are associated with either a goitre or a normal thyroid gland. This type of CH has been linked to a number of defects in thyroid hormonogenesis and is caused by mutations in the following thyroid-specific genes: hNIS, Tg, TPO, PDS, THOX2, DEHAL. It is inherited by the autosomal recessive mode. Only about 2% of primary congenital hypothyroidism cases (CH) due to the defects of the thyroid underdevelopment are familial with genetic background. This type of CH is associated with mutations in genes responsible for the growth or development of thyroid follicle cells such as TSHR, TTF1, TTF2, PAX 8, NKX2, or Hoxa3. Except for defect caused by a mutation of the TSHR gene, such inborn thyroid dysgenesis is associated with an increased incidence of birth defects (such as: respiratory distress, ataxia, muscle hypotomy, choreoathetosis, cleft palate, bilateral choanal atresia, hypoplastic epiglottis, spiky hair). In addition, mutations in the GNAS 1 gene may give congenital hypothyroidism associated with hypogonadisms and Albright’s osteodystrophy, which is the part of pseudohypoparathyroidism type IA and II (pseudopseudohypoparathyroidism). The next group of monogenetic thyroid diseases with less or more evident thyroid dysfunction form the following: 1. TBG partial or complete deficiency and TBG excess due to TBG gene defects with an X-linked inheritance pattern; 2. Generalized, peripheral and pituitary resistance to thyroid hormones mainly caused by TRbeta gene mutations, inherited by the autosomal recessive. The second group of thyroid diseases are the multifactorial (polygenic) ones. Among them the most frequent are: 1. Graves’ hyperthyroidism; 2. Autoimmune thyroiditis; 3. Thyroid carcinoma derived from thyroid follicle cells such as papillary and follicular thyroid carcinoma. Although autoimmune thyroid diseases (AITD), including autoimmune thyroiditis and Graves’ hyperthyroidism with thyroid ophthalmopathy (TAO), are still unclear, they are defined as polygenic diseases resulting from genetic and environmental factors. The environmental factors which play a role in the development of AITD include iodine excess (with amiodarone treatment), selenium deficiency, stress, interferon alpha, bacterial and viral infections and, in the case of Graves’ hyperthyroidism, and tobacco smoking. There are some genes whose polymorphisms have been confirmed in the development of and susceptibility to AITD. These are the following: 1. thyroid-specific genes such as the Tg gene and 2. genes modulating the immune system, such as HLA antigens, CTLA4, PTPN22, genes encoding proinflammatory cytokines, such as: IFN, TGF beta, IL 6, IL 4, IL1 beta, IL10, and others. On the other hand, among the many genes involved in the development of differentiated thyroid carcinoma derived from thyroid follicle thyroid cells (papillary and follicular one), BRAF and RET-PTC seem to be the most important.

Thyroid and growth hormone concentrations in 8-year-old children exposed in utero to dioxins and polychlorinated biphenyls.

The objective of this study was to examine the effects of in utero exposure to polychlorinated biphenyls (PCBs) and dioxins (polychlorinated dibenzo-p-dioxins, dibenzofurans (PCDD/F) on thyroid and growth hormone concentrations and growth in 8-year-old children. A total of 56 children (23 boys, 33 girls) were included in the study. All were stratified into high and low PCDD/F + PCB exposure groups based on maternal median indicator PCB and PCDD/F + PCB concentrations during pregnancy. Height, weight, body mass index, and thyroid and growth hormone concentrations were assessed and compared among the different exposure groups. There were no significant effects of indicator PCB or PCDD/F + PCB exposure levels on growth (height, weight, and bone age) among 8-year-old boys or girls. Boys exposed to high PCDD/F + PCB levels had significantly higher thyroxine-binding globulin (TBG) concentrations than boys exposed to low levels (P = 0.027). Girls exposed to high PCB levels had significantly lower IGF-binding protein-3 (IGFBP-3) concentrations than girls exposed to low levels (P = 0.038). Low levels of in utero exposure to PCDD/F+PCB and high indicator PCB levels were significantly associated with reduced serum concentrations of IGFBP-3. High levels of in utero exposure to PCDD/F+PCB plus either high or low indicator PCB levels were significantly associated with increased serum concentrations of growth hormone, T3, T4, and TBG. These findings suggest that the level of in utero exposure to PCBs and dioxins may affect serum concentrations of growth hormone, thyroid hormones, TBG, and IGFBP-3 in 8-year-old children.

Zonulin, Iron Status, and Anemia in Kidney Transplant Recipients: Are They Related?

BackgroundIn patients after kidney transplantation, anemia is relatively common and is associated with impaired kidney function, subclinical inflammatory state, and immunosuppressive treatment. Zonulin-prehaptoglobin-2, a newly discovered protein, is necessary for integrity of intracellular tight junctions in the gut. Taking into consideration iron metabolism, including its absorption in the gut, we designed a cross-sectional study to look for the possible interactions among zonulin, iron status, and anemia in kidney transplant recipients. MethodsThe study was performed on 72 stable kidney transplant recipients and 22 healthy volunteers. Zonulin, iron status, and inflammatory markers were assessed with the use of commercially available kits. ResultsZonulin was significantly lower in kidney allograft recipients than in healthy volunteers (P < .001). Zonulin correlated with systolic blood pressure (r = −0.33; P < .05), thyroid-binding globulin (r = 0.24; P < .05), hematocrit (r = 0.28; P < .005), hemoglobin (r = 0.32; P < .01), total protein (r = −0.33; P < .01), erythrocyte count (r = 0.26; P < .05), and fasting glucose (r = −0.25; P < .05). Zonulin was not affected by sex, type of immunosuppressive therapy, presence of diabetes, coronary artery disease, heart failure, hypertension, or cause of end-stage renal disease. Zonulin was not related to any of the iron parameters studied. In multiple regression analysis, predictors of zonulin were total protein and thyroglobulin-binding protein, explaining 46% of variation. ConclusionsZonulin, with its poorly defined function, does not seem to play a role in the anemia in kidney allograft recipients; however, it seems to be related to the absorption process in the gut.

Graves’ Disease with Non-functioning Parathyroid Adenoma: An Uncommon Association of Common Diseases

Data on coexisting Graves’ disease (GD), hypoparathyroidism, and autoimmune haemolytic anaemia are limited. Here we report an uncommon case of autoimmune disorder causing Graves’ disease with autoimmune haemolytic anaemia and along with mineralisation of basal ganglia. The patient had a parathyroid nodule along with normal serum calcium and parathyroid hormone levels. The probable cause of this nodule is a compensatory response to autoimmune hypoparathyroidism. Patient has increased levels of T3, T4, free T4, thyroid binding globulin and antithyroglobulin antibody. The ANA and anti dsDNA antibody were within normal limit. The relative deficiency of CD4+FOXP3+Treg cells in peripheral blood also confirms the autoimmune pathogenesis of the disease process. The patient responded to the steroid therapy and later on maintained with low dose carbimazole.

Impact of Controlled Ovarian Hyperstimulation on Thyroid Function

OBJECTIVE: To compare the effects of different protocols of controlled ovarian hyperstimulation on thyroid function with those of the natural menstrual cycle. STUDY DESIGN: Prospective controlled study. SETTING: University Medical Center. PATIENTS: A total of 97 women without a history of endocrine disease undergoing intrauterine insemination either in a natural cycle, or with mild ovarian hyperstimulation, or in vitro fertilization (IVF). MAIN OUTCOME MEASURES: estradiol (E2), thyroxine binding globulin (TBG), free thyroxine (FT4), total thyroxine (TT4) and thyroid stimulating hormone (TSH) during the midluteal phase. RESULTS: In the IVF group midluteal E₂, TBG, and TT₄ were significantly higher; midluteal FT₄ was significantly lower (mean difference: -1.46 pmol/L; P < 0.001) and midluteal TSH was significantly higher (mean difference: 0.52 mU/L; P = 0.015). CONCLUSIONS: Ovarian hyperstimulation in IVF is associated with lower midluteal FT₄ and higher midluteal TSH levels compared to the natural cycle.

Thyroxine-binding globulin, thyroxine level adjusts according to the temperature of the body

Thyroxine-binding globulin, thyroxine level adjusts according to the temperature of the body

6.7 Neonatal thyroid function and the use of povidone-iodine and iodinated contrast media during labour and the postnatal period: a pilot study

ContextThe developing thyroid is sensitive to iodine overload with exposure potentially resulting in goitre and/or hypothyroidism. The British National Formulary (BNF) lists neonates <32 weeks gestation and infants under 1.5...

Temperature-responsive release of thyroxine and its environmental adaptation in Australians

The hormone thyroxine that regulates mammalian metabolism is carried and stored in the blood by thyroxine-binding globulin (TBG). We demonstrate here that the release of thyroxine from TBG occurs by a temperature-sensitive mechanism and show how this will provide a homoeostatic adjustment of the concentration of thyroxine to match metabolic needs, as with the hypothermia and torpor of small animals. In humans, a rise in temperature, as in infections, will trigger an accelerated release of thyroxine, resulting in a predictable 23% increase in the concentration of free thyroxine at 39°C. The in vivo relevance of this fever-response is affirmed in an environmental adaptation in aboriginal Australians. We show how two mutations incorporated in their TBG interact in a way that will halve the surge in thyroxine release, and hence the boost in metabolic rate that would otherwise occur as body temperatures exceed 37°C. The overall findings open insights into physiological changes that accompany variations in body temperature, as notably in fevers.

Response to androgen therapy in patients with dyskeratosis congenita

Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome and telomere biology disorder characterized by dysplastic nails, reticular skin pigmentation and oral leucoplakia. Androgens are a standard therapeutic option for bone marrow failure in those patients with DC who are unable to undergo haematopoietic stem cell transplantation, but there are no systematic data on its use in those patients. We evaluated haematological response and side effects of androgen therapy in 16 patients with DC in our observational cohort study. Untreated DC patients served as controls. Seventy percent of treated DC patients had a haematological response with red blood cell and/or platelet transfusion independence. The expected age-related decline in telomere length was noted in androgen-treated patients. All treated DC patients had at least one significant lipid abnormality. Additional treatment-related findings included a significant decrease in thyroid binding globulin, accelerated growth in pre-pubertal children and splenic peliosis in two patients. Liver enzymes were elevated in both androgen-treated and untreated patients, suggesting underlying liver involvement in DC. This study suggests that androgen therapy can be effectively used to treat bone marrow failure in DC, but that side effects need to be closely monitored.