Thyroid Function Markers Research Articles

Meta-analysis of two genome-wide association studies identifies four genetic loci associated with thyroid function

Thyroid hormones play key roles in cellular growth, development and metabolism. Although there is a strong genetic influence on thyroid hormone levels, the genes involved are widely unknown. The levels of circulating thyroid hormones are tightly regulated by thyrotropin (TSH), which also represents the most important diagnostic marker for thyroid function. Therefore, in order to identify genetic loci associated with TSH levels, we performed a discovery meta-analysis of two genome-wide association studies including two cohorts from Germany, KORA (n = 1287) and SHIP (n = 2449), resulting in a total sample size of 3736. Four genetic loci at 5q13.3, 1p36, 16q23 and 4q31 were associated with serum TSH levels. The lead single-nucleotide polymorphisms of these four loci were located within PDE8B encoding phosphodiesterase 8B, upstream of CAPZB that encodes the β-subunit of the barbed-end F-actin-binding protein, in a former 'gene desert' that was recently demonstrated to encode a functional gene (LOC440389) associated with thyroid volume, and upstream of NR3C2 encoding the mineralocorticoid receptor. The latter association for the first time suggests the modulation of thyroid function by mineral corticoids. All four loci were replicated in three additional cohorts: the HUNT study from Norway (n = 1487) and the two German studies CARLA (CARLA, n = 1357) and SHIP-TREND (n = 883). Together, these four quantitative trait loci accounted for ∼3.3% of the variance in TSH serum levels. These results contribute to our understanding of genetic factors and physiological mechanisms mediating thyroid function.

THYROID FUNCTION, PFOA AND PFOS IN CHILDREN LIVING NEAR A CHEMICAL PLANT

Background and Aims: Altered thyroid hormone levels following exposure to perfluorocarbons (PFCs) have been found in some animal studies. Published epidemiological findings are not consistent and most prior studies have focused on adults. We investigated if concentrations of two PFCs, perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS), were associated with thyroid function among 10,725 children (aged 1-18 years) living near a Teflon manufacturing facility in the Mid-Ohio Valley, USA. Methods: Serum levels of thyroid-stimulating hormone (TSH), total thyroxine (TT4), and T3 uptake were measured and free thyroxine index (FTI) was calculated as biomarkers of thyroid function during 2005-2006, at the same time as serum levels of PFCs were measured. We estimated modeled in utero PFOA concentrations. Child-mother pairing allowed maternal serum concentrations of PFOA estimated at pregnancy to be used as a proxy for in utero exposure to PFOA for 52% of children. We performed multivariate regression analyses between thyroid disease status or thyroid hormone levels and PFOA/PFOS concentrations. Results: At survey, median serum PFOA and PFOS concentrations were 29.3 and 20 ng/mL, respectively, and modeled in utero PFOA concentration was 17.1 ng/mL. The prevalence of reported thyroid disease was 0.5%, and the prevalence of subclinical hypothyroidism and hyperthyroidism based on thyroid hormone levels was 2.6 and 1.0%, respectively. We found a positive association between serum TT4 or FTI and LnPFOS in children (TT4: β=0.19, 95% CI=0.12, 0.26; FTI: β=0.04, 95% CI=0.02, 0.06). Findings for PFOA will also be presented in the conference but must first be shown to the local community. Conclusions: Our results demonstrate a possible association between altered thyroid hormone levels and PFOS concentrations. This study comprises by far the largest population to date of children studied with such levels of PFOA, in relation to markers of thyroid function.

Hypothalamus–pituitary–thyroid axis disruption in rats with breast cancer is related to an altered endogenous oxytocin/insulin-regulated aminopeptidase (IRAP) system

Associations of breast cancer with diseases of the thyroid have been repeatedly reported, but the mechanism underlying this association remains to be elucidated. It has been reported that oxytocin (OXT) attenuates the thyroid-stimulating hormone (TSH) release in response to thyrotrophin-releasing hormone (TRH) and decreased plasma levels of TSH as well as the thyroid hormones by an effect mediated by the central nervous system. Oxytocinase (IRAP) is the regulatory proteolytic enzyme reported to hydrolyze OXT. Changes in IRAP activity have been reported in both human breast cancer and N-methyl-nitrosourea (NMU)-induced rat mammary tumours. Here, we measure IRAP activity fluorometrically using cystyl-β-naphthylamide as the substrate, in the hypothalamus-pituitary-thyroid axis together with the circulating levels of OXT, and its relationship with circulating levels of TSH and free thyroxine (fT4), as markers of thyroid function in control rats and rats with breast cancer induced by NMU. We found decreased thyroid function in rats with breast cancer induced by NMU, supported by the existence of lower serum circulating levels of both TSH and fT4 than their corresponding controls. Concomitantly, we found a decrease of hypothalamic IRAP activity and an increase in circulating levels of OXT. We propose that breast cancer increases OXT pituitary release by decreasing its hypothalamic catabolism through IRAP activity, probably due to the alteration of the estrogenic endocrine status. Thus, high circulating levels of OXT decreased TSH release from the pituitary, and therefore, of thyroid hormones from the thyroid, supporting the association between breast cancer and thyroid function disruption.

Valoración de la función tiroidea durante la gestación: intervalos de referencia de tirotropina y tiroxina no unida a proteína durante el primer trimestre

Background and objectives The physiological changes that occur during pregnancy affect the physiology of the thyroid gland. Consequently, interpretation of thyroid function markers during pregnancy requires trimester-specific reference intervals. The aims of our study were to: 1) establish first-trimester reference intervals for biochemical markers of thyroid function [thyroid-stimulating hormone (TSH) and free thyroxine (T4)] and 2) to establish the prevalence of autoimmune thyroid disease in pregnant women resident in Cartagena (Murcia, Spain). Patients and method A total of 441 women between weeks 11 and 13 of pregnancy were included in this study. A blood sample was extracted from all women to measure TSH, free T4 and antithyroid antibodies. Reference intervals for TSH and free T4 were determined in 400 pregnant women without autoimmune thyroid disease or known thyroid disease. Results Autoimmune thyroid disease was detected in 23 pregnant women (5.2%) who showed TSH levels higher than those in pregnant women without thyroid autoimmunity. First-trimester reference intervals were as follows: TSH: 0.130–3.710 mUI/L; free T4: 0.89–1.50 ng/dL. These reference intervals differed from the non-pregnant reference intervals used in our laboratory. Conclusions The reference intervals established are useful to evaluate thyroid function in women between 11 and 13 weeks of pregnancy. Interpretation of thyroid function requires intervals established in a reference population without autoimmune thyroid disease and with the methodology usually used to analyze these markers.

Weight-of-evidence analysis of human exposures to dioxins and dioxin-like compounds and associations with thyroid hormone levels during early development

Thyroid hormones play a critical role in the proper development of brain function and cell growth. Several epidemiological studies have been conducted to assess potential associations between pre- and post-natal exposure to dioxins or dioxin-like compounds (DLCs) and the levels of circulating thyroid hormones during early development. Dioxins and DLCs include chlorinated dibenzo- p-dioxins, chlorinated dibenzofurans, and mono- and non- ortho polychlorinated biphenyls (PCBs). We identified a total of 23 relevant epidemiological studies (21 cohort studies and 1 case–control study) that measured exposures to various types of dioxins and DLCs as well as markers of thyroid function, such as thyroid stimulating hormone (TSH), total thyroxine (T4), free T4, total triiodothyroxine (T3), free T3, and thyroid-binding globulin concentrations in cord blood or circulation. While some of the studies reported associations between concentrations of dioxins and/or DLCs and some biomarkers of thyroid function, the majority of the observed associations were not statistically significant. Moreover, there were no clear and consistent effects across studies for any of the hormone levels examined, and while a number of studies showed a statistically significant association with exposure for a given marker of thyroid function, other studies showed either no change or changes in the opposite direction for the same thyroid function marker. Similarly, when the results were analyzed considering developmental stage, there generally were no clear and consistent effects at any age from birth through 12 years of age. The absence of a clear correlation between background exposures to dioxins and DLCs and thyroid function biomarkers during development is not consistent with the hypothesis that background exposures to these chemicals cause effects on thyroid function during development.

Reduced nutritional status among multiple myeloma patients during treatment with high-dose chemotherapy and autologous stem cell support

Multiple myeloma (MM) ranks among the most frequent blood cancers in adults. Optimal treatment consists of high-dose chemotherapy and autologous stem cell transplantation. Health-related quality of life (HRQoL) is reduced before, during, and after therapy. Several HRQoL items are associated with nutritional health, e.g., nausea/vomiting, appetite loss and fatigue. It is unknown whether nutritional status in MM is affected by treatment. Hence we assessed nutritional status before, during and (1/2) year after treatment-start. We applied anthropometry (height, weight, hand-grip strength, triceps skinfold) and plasma concentrations of biomarkers to assess nutritional status. HRQoL was determined with the EORTC QLQ-C30 questionnaire. The anthropometrical parameters all decreased (p<0.05) during treatment, but were restored at the end of the observation period. Albumin and the fat-soluble vitamins D and E followed a similar pattern, whereas transferrin and vitamin A were unchanged (p>0.05). Interestingly, markers of thyroid function declined and remained low (p<0.05) even 6 months after start of therapy. Nutrition-associated symptoms used as markers of HRQoL worsened during therapy, but returned to pre-therapy levels. Intensive therapy in MM is associated with a decline in both nutritional status and health-related quality of life.

Effects of Either LT4 Monotherapy or LT4/LT3 Combined Therapy in Patients Totally Thyroidectomized for Thyroid Cancer

After total thyroidectomy all thyroid cancer patients require lifelong treatment with thyroid hormones; the treatment of choice is synthetic levothyroxine (LT4). The question of whether these patients might benefit from the combined LT4 and liothyronine (LT3) treatment has been addressed with conflicting conclusions. The aim of the present study was to compare the effects of combined low LT4/LT3 molar ratio therapy versus LT4 monotherapy on various target organs and tissues in patients thyroidectomized for thyroid cancer. Urine collection (24 hour), a fasting blood sample for laboratory examinations, thyroid function clinical score, and cardiovascular, neurological, and neuropsychological evaluations were obtained. Clinical parameters and peripheral markers of thyroid function were measured during the two different treatment regimens in 20 patients. Mean serum aspartate aminotransferase, alanine aminotransferase, sex hormone binding globulin, and osteocalcin values were significantly higher during the combined treatment. No significant differences in the clinical score, the systolic and diastolic performance, and the neurological and neuropsychological evaluations were observed between the two treatment regimens. Moreover, no alteration due to subclinical hyperthyroidism or to the fluctuations in serum T3 concentrations during the combined therapy was observed. In conclusion, we found no evidence that combined therapy with a low LT4/LT3 molar ratio resulted in improved well-being and cognitive function or in increased thyroid hormone action on peripheral tissues in respect to LT4 monotherapy. Until future large, blind, randomized, and controlled trials prove otherwise, LT4 should remain the standard treatment for thyroid cancer patients.

Supraphysiological doses of levothyroxine alter regional cerebral metabolism and improve mood in bipolar depression

Supplementation of standard treatment with high-dose levothyroxine (L-T(4)) is a novel approach for treatment-refractory bipolar disorders. This study tested for effects on brain function associated with mood alterations in bipolar depressed patients receiving high-dose L-T(4) treatment adjunctive to ongoing medication (antidepressants and mood stabilizers). Regional activity and whole-brain analyses were assessed with positron emission tomography and [(18)F]fluorodeoxyglucose in 10 euthyroid depressed women with bipolar disorder, before and after 7 weeks of open-label adjunctive treatment with supraphysiological doses of L-T(4) (mean dose 320 microg/day). Corresponding measurements were acquired in an age-matched comparison group of 10 healthy women without L-T(4) treatment. The primary biological measures were relative regional activity (with relative brain radioactivity taken as a surrogate index of glucose metabolism) in preselected brain regions and neuroendocrine markers of thyroid function. Treatment-associated changes in regional activity (relative to global activity) were tested against clinical response. Before L-T(4) treatment, the patients exhibited significantly higher activity in the right subgenual cingulate cortex, left thalamus, medial temporal lobe (right amygdala, right hippocampus), right ventral striatum, and cerebellar vermis; and had lower relative activity in the middle frontal gyri bilaterally. Significant behavioral and cerebral metabolic effects accompanied changes in thyroid hormone status. L-T(4) improved mood (remission in seven patients; partial response in three); and decreased relative activity in the right subgenual cingulate cortex, left thalamus, right amygdala, right hippocampus, right dorsal and ventral striatum, and cerebellar vermis. The decrease in relative activity of the left thalamus, left amygdala, left hippocampus, and left ventral striatum was significantly correlated with reduction in depression scores. Results of the whole-brain analyses were generally consistent with the volume of interest results. We conclude that bipolar depressed patients have abnormal function in prefrontal and limbic brain areas. L-T(4) may improve mood by affecting circuits involving these areas, which have been previously implicated in affective disorders.

Simple, rapid, and sensitive thyroid-stimulating hormone immunoassay using europium(III) nanoparticle label

Thyroid-stimulating hormone (TSH) is widely used as a marker of thyroid function. A rapid TSH assay enables diagnosis during the first visit at the doctor’s office aiding to faster and cost-effective medical treatment. To accomplish such an assay method europium(III) chelate nanoparticles were coated with anti-TSH monoclonal antibody. Captured anti-TSH monoclonal antibody was immobilized onto single wells by streptavidin–biotin chemistry and the assay was carried out in dry chemistry format using 5 μl of sample in a 30 μl assay volume in the commercial AiO immunoassay system. The developed TSH nanoparticle assay was performed in a kinetic mode using a 10-min incubation time. The analytical sensitivity of the developed assay was 0.0012 mIU l −1 corresponding to the fourth generation TSH assay and less than 0.02 mIU l −1 when serum-based matrix was used for calibrators. The dynamic range of the assay was more than three orders of magnitude and no high-dose hook effect was observed at 100 mIU l −1 of TSH. Correlation with an automated commercial assay was good ( y = 0.96 ± 0.02, intercept = 0.12 ± 0.09, S y | x = 0.49, R = 0.988). Intra- and inter-assay variations were 4–14 and 6–17%, respectively. The developed quantitative one-step all-in-one dry reagent time-resolved fluorometric immunoassay has great potential for rapid analysis of serum thyroid-stimulating hormone in a point-of-care environment when antibody-coated high specific activity Eu(III) nanoparticles were used as labels.

Steroids, sex hormone-binding globulin, homocysteine, selected hormones and markers of lipid and carbohydrate metabolism in patients with severe hypothyroidism and their changes following thyroid hormone supplementation.

Laboratory markers of thyroid function, selected steroid hormones, sex hormone-binding globulin (SHBG), homocysteine, prolactin, major markers of lipid- and glucose metabolism and of insular-growth hormone axes were investigated in fasting sera from 16 female patients with severe hypothyroidism after thyroidectomy because of thyroid cancer. The results obtained in severe hypothyroidism within 5-6 weeks after withdrawal of thyroid substitution therapy before control scintigraphy were compared with those obtained after correction of thyroid function. Elevated levels of homocysteine and prolactin in hypothyroidism significantly decreased after correction, while SHBG concentration increased. Correction of thyroid function led to significant changes of growth hormone and immunoglobulin F1 (decrease and increase, respectively), while insulin and proinsulin increased only insignificantly. Elevated levels of total cholesterol and triglycerides in hypothyroidism were normalized, along with a significant increase in high density lipoprotein (HDL)-cholesterol. As revealed by correlation and factor analyses, different relationships characterizing both states were found in hypothyroidism and after correction of thyroid function. A strong inverse relationship between homocysteine and free thyroid hormones confirms the effect of thyroid hormones on homocysteine metabolism. No such inverse relation was found in euthyroid state, however. Similarly, in hypothyroidism only, dehydroepiandrosterone sulfate correlated positively with immunoglobulin F1 and homocysteine and negatively with thyroid hormones and SHBG.

Comparison of thyroid function in pregnant and non-pregnant Asian and western Caucasian women

Background: Gestational thyrotoxicosis may be more prevalent in Asian women. Methods: We have measured thyroid function, ferritin and bone specific alkaline phosphatase (BALP) as peripheral markers of thyroid function and hCG in Asian and western Caucasian women in non-pregnant and early pregnancy. Results: TSH was lower in Asian women in non-pregnancy but not during normal pregnancy and this may reflect increased sensitivity of the thyroid gland to thyroid stimulation in the Asian population. No ethnic difference was found in FT3, FT4 or hCG but ferritin was lower and BALP higher in Asian women whether pregnant or not and this may be a reflection of iron balance and vitamin D status. Conclusions: We found during normal pregnancy that dynamic patterns of change for thyroid hormones and hCG are not different in Asian and western Caucasian women. We have developed gestation related reference intervals, which are a pre-requisite to the study of ethnic differences in gestation thyrotoxicosis in pregnancy.

Disfunción tiroidea subclínica

Recent biochemical advances have led to the development of highly sensitive and less expensive assays of serum thyrotrophin (TSH) and both triyodothyronine (T 3 ) and free thyroxin (fT 4 ) for the biochemical assessment of thyroid function. Since TSH is the most sensitive marker of thyroid function, its determination with these new tools makes it possible to detect both subclinical hypo- and hyperthyroidism. Hence, small variations of circulating TSH levels could accurately reflect minor degrees of thyroid disfunction, but clinicians ought to exclude other factors such as acute illnes, drugs or inappropiate thyroid hormone therapy. Bearing this in mind, the clinician should make a individual assesment of every case of thyroid disfunction, and decide hormone therapy accordingly, taking into account the potential risks of iskemic heart disease, osteoporosis, etc., Thus implementing an adecuated long term follows up plan. The management of these patients ouhgt to be allways personalised, considering the risk-benefit ratio, and the general physician should always refer to the specialist endocrinologist any case where thyroid dysfunction could lead to other systemic alterations.

Changes in circulating thyroid hormone levels and systolic time intervals in acute hypothyroidism

We have previously reported that, in thyrotoxic patients treated with carbimazole, serum T4 and T3 levels are the first parameters to return to normal, followed by the systolic time interval (STI, a marker of thyroid function at tissue level) and then the serum TSH. The aim of this study was to compare the rate of change of thyroid hormones, TSH and STI in treated hypothyroid patients after the sudden withdrawal of thyroxine. Serum T4, T3 (free and total) and TSH were measured in 12 patients taking thyroxine for primary hypothyroidism; seven were biochemically euthyroid and five were over-replaced, as defined by an elevated free T4 and a sub-normal TSH. Thyroxine was withdrawn and the measurements repeated three times a week until the STI rose above the euthyroid range (0.26-0.32). After stopping thyroxine, the serum TSH and STI left the normal range, in advance of the free T4 and T3, after 9.5 +/- 0.95 and 12.2 +/- 1.5 days respectively (mean +/- SEM). The TSH was the first parameter to leave the euthyroid range in all subjects except one in whom the serum TSH was fully suppressed (less than 0.05 mU/l) initially. In the euthyroid group the TSH and STI increased rapidly after stopping thyroxine (time to leave euthyroid range 7.4 +/- 0.8 and 9.4 +/- 0.7 days respectively). In contrast, in the over-replaced group serum TSH and STI became elevated after 12.4 +/- 1.0 days (P less than 0.005 vs euthyroid group) and 16.0 +/- 2.7 days (P less than 0.05 vs euthyroid group) respectively. There was no delay in the fall in serum T4 or T3 in the over-replaced group when compared with the euthyroid group. In the evolution of primary hypothyroidism, markers of thyroid function at a tissue level (TSH and STI) become abnormal in advance of thyroid hormones. After stopping thyroxine therapy in treated hypothyroid patients, there is a delayed rise in STI and serum TSH levels in subjects with a subnormal TSH level, as compared with those with a normal TSH on treatment. This suggests mild tissue thyrotoxicosis in these individuals.

Thyrotropin-independent mutant clones from FRTL5 rat thyroid cells: hormonal control mechanisms in differentiated cells.

Mutant cells varying in the pathways of their responses to hormonal stimulation are useful in defining the subcellular steps in the mechanisms of hormone action. FRTL5, a strain of normal and differentiated cells originally derived from adult rat thyroids, which depends on TSH for growth in vitro, was used to produce five TSH-independent mutants, after chemical mutagenesis and selection in medium lacking TSH. Their characterization and comparison with wild type cells demonstrated full retention of differentiated thyroid function markers such as thyroglobulin production and active iodide transport, and a slower growth rate. Characterization of cAMP metabolism in mutants revealed levels of basal cAMP and adenylate cyclase and phosphodiesterase activities similar to those of wild type cells kept in a nonproliferative state in medium lacking TSH. Adenylate cyclase responsiveness to very low doses of TSH (10(-12) M) was fully retained in all mutant clones, but the TSH-dependent cAMP elevation, although comparable to that reported in wild type cells, was not followed by significant growth stimulation in mutants. These findings demonstrate that the persistence of functional TSH receptors in these cells and that of growth regulation in them is independent of cAMP elevation.

Effect of administration of triiodothyronine on aspartate aminotransferase in pyridoxine-deficient rats.

The state of thyroid function and the effect of triiodothyronine (T3) administration on aspartate aminotransferase isozymes in the livers of rats fed on a diet with or without pyridoxine were examined. Decreased thyroid function in pyridoxine-deficient rats was demonstrated using malic enzyme as a marker of thyroid function in the liver. Administration of T3 increased cytosolic aspartate aminotransferase in the liver of pyridoxine-deficient rats, but not of control rats.